tbuckley/cabot-search huggingface dataset:
Elevated Remnant-Like Particle Cholesterol and Triglyceride Levels in Diabetic Men and Women in the Framingham Offspring Study
Authors: Ernst J. Schaefer, Judith R. McNamara, Paulesh K. Shah, Katsuyuki Nakajima, L. Adrienne Cupples, Jose M. Ordovas, Peter W.F. Wilson
Journal: Diabetes Care (2002)

OBJECTIVE—Remnants of triglyceride-rich lipoproteins are thought to be atherogenic. A new antibody-based assay allows for the isolation of remnant-like particles (RLPs) from plasma or serum, and the subsequent measurement of RLP cholesterol (RLPC) and triglycerides (RLPTGs). We hypothesized that diabetic patients would have higher remnant levels than nondiabetic patients. DESIGN AND METHODS—We compared RLPC and RLPTG levels of diabetic subjects (68 women, 121 men) participating in the Framingham Heart Study with those of nondiabetic subjects (1,499 women, 1,357 men). RESULTS—Mean RLPC values for diabetic women were 106% higher than those for nondiabetic women (0.367 ± 0.546 mmol/l [14.2 ± 21.1 mg/dl] vs. 0.179 ± 0.109 mmol/l [6.9 ± 4.2 mg/dl]; P &amp;lt; 0.0001), and RLPTG values for diabetic women were 385% higher than those for nondiabetic women (1.089 ± 2.775 mmol/l [93.1 ± 245.6 mg/dl] vs. 0.217 ± 0.235 mmol/l [19.2 ± 20.8 mg/dl]; P &amp;lt; 0.0001). Similar but less striking differences were observed in diabetic men, who had mean RLPC values 28% higher than those seen in nondiabetic men (0.285 ± 0.261 mmol/l [11.0 ± 10.1 mg/dl] vs. 0.223 ± 0.163 mmol/l [8.6 ± 6.3 mg/dl]; P &amp;lt; 0.001) and mean RLPTG values 70% higher than those seen in nondiabetic men (0.606 ± 1.019 mmol/l [53.6 ± 90.2 mg/dl] vs. 0.357 ± 0.546 mmol/l [31.6 ± 48.3 mg/dl]; P &amp;lt; 0.001). Moreover, diabetic men and women had significantly higher total triglycerides and lower HDL cholesterol levels than nondiabetic subjects. CONCLUSIONS—The data indicate that RLP particles are elevated in diabetic subjects. To achieve optimal reduction of risk for cardiovascular disease, treatment of elevated RLP values, along with the control of LDL cholesterol levels, should be considered.
Protumorigenic Activity of Plasminogen Activator Inhibitor-1 Through an Antiapoptotic Function
Authors: Hua Fang, Veronica R. Placencio, Yves A. DeClerck
Journal: JNCI Journal of the National Cancer Institute (2012)

Plasminogen activator inhibitor-1 (PAI-1) is a protease inhibitor but is paradoxically associated with poor outcomes in cancer patients. However, the mechanisms of its effects on tumor cells have not been explored.
Fungal infections in transplant recipients
Authors: L.P. Nicod, J‐C. Pache, N. Howarth
Journal: European Respiratory Journal (2001)

Fungi are ubiquitous and the respiratory tract is exposed to aerosolized spores of both fungi that are “pathogenic” even in the normal host, such as Cryptococus neoformans , and those that are “opportunistic”, such as Candida and Aspergillus species, among others. Although these latter species may occasionally form fungal balls or induce allergic phenomena in the normal host, they produce more invasive diseases in immunosuppressed patients. Among these diseases, pseudomembranous aspergillosis has recently been described. The diagnostic approach to these entities, and, in particular, the thin dividing line between colonization and infection are addressed, along with the diagnostic value of the various procedures. New prophylactic regimens are reviewed such as the possibility of using amphotericin aerosols in combination with systemic azole administration. The authors would emphasize the importance of restoring lung defences by not only decreasing immunosuppressive regimens but also considering the use of newly available recombinant cytokines such as growth factors, to reduce neutropenia, for instance, in addition to antifungal drugs when infection is diagnosed. However, immunomodulation procedures are far from being well established.
Targeting Apoptosis Pathways in Cancer Therapy
Authors: I. M. Ghobrial, T. E. Witzig, A. A. Adjei
Journal: CA A Cancer Journal for Clinicians (2005)

Apoptosis, or programmed cell death, is a mechanism by which cells undergo death to control cell proliferation or in response to DNA damage. The understanding of apoptosis has provided the basis for novel targeted therapies that can induce death in cancer cells or sensitize them to established cytotoxic agents and radiation therapy. These novel agents include those targeting the extrinsic pathway such as tumor necrosis factor-related apoptosis-inducing ligand receptor 1, and those targeting the intrinsic Bcl-2 family pathway such as antisense bcl-2 oligonucleotides. Many pathways and proteins control the apoptosis machinery. Examples include p53, the nuclear factor kappa B, the phosphatidylinositol 3 kinase pathway, and the ubiquitin/proteosome pathway. These can be targeted by specific modulators such as bortezomib, and mammalian target of rapamycin inhibitors such as CCI-779 and RAD 001. Because these pathways may be preferentially altered in tumor cells, there is potential for a selective effect in tumors sparing normal tissue. This article reviews the current understanding of the apoptotic pathways, including the extrinsic (cytoplasmic) and intrinsic (mitochondrial) pathways, and the agents being developed to target these pathways.
Conformation dependent monoclonal antibodies distinguish different replicating strains or conformers of prefibrillar Aβ oligomers
Authors: Rakez Kayed, Isabel Canto, Leonid Breydo, Suhail Rasool, Tamas Lukacsovich, Jessica Wu, Ricardo Albay, Anna Pensalfini, Stephen Yeung, Elizabeth Head, J Lawrence Marsh, Charles Glabe
Journal: Molecular Neurodegeneration (2010)

Age-related neurodegenerative diseases share a number of important pathological features, such as accumulation of misfolded proteins as amyloid oligomers and fibrils. Recent evidence suggests that soluble amyloid oligomers and not the insoluble amyloid fibrils may represent the primary pathological species of protein aggregates.We have produced several monoclonal antibodies that specifically recognize prefibrillar oligomers and do not recognize amyloid fibrils, monomer or natively folded proteins. Like the polyclonal antisera, the individual monoclonals recognize generic epitopes that do not depend on a specific linear amino acid sequence, but they display distinct preferences for different subsets of prefibrillar oligomers. Immunological analysis of a number of different prefibrillar Aβ oligomer preparations show that structural polymorphisms exist in Aβ prefibrillar oligomers that can be distinguished on the basis of their reactivity with monoclonal antibodies. Western blot analysis demonstrates that the conformers defined by the monoclonal antibodies have distinct size distributions, indicating that oligomer structure varies with size. The different conformational types of Aβ prefibrillar oligomers can serve as they serve as templates for monomer addition, indicating that they seed the conversion of Aβ monomer into more prefibrillar oligomers of the same type.These results indicate that distinct structural variants or conformers of prefibrillar Aβ oligomers exist that are capable of seeding their own replication. These conformers may be analogous to different strains of prions.
Intrapulmonary drug administration in neonatal and paediatric critical care: a comprehensive review
Authors: D. De Luca, P. Cogo, E. Zecca, M. Piastra, D. Pietrini, A. Tridente, G. Conti, V. P. Carnielli
Journal: European Respiratory Journal (2011)

Administration of drugs directly into the respiratory tree first was proposed a long time ago. Surfactant is the paradigmatic example of such therapies. Many other drugs have been used in the same way and further compounds are under investigation for this aim. In the last two decades, despite the wide number of drugs available for direct lung administration in critical care patients, few controlled data exist regarding their use in neonates and infants. This review will focus on drugs clinically available in a critical care setting for neonates and infants, including bronchodilators, pulmonary vasodilators, anti-inflammatory agents, mucolytics, resuscitative anti-infective agents, surfactants and other drugs. We provide an evidence-based comprehensive review of drugs available for intratracheal administration in paediatric and neonatal critical care and we examine possible advantages and risks for each proposed indication.
The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma
Authors: Konstanze Pechloff, Julian Holch, Uta Ferch, Marc Schweneker, Kristina Brunner, Markus Kremer, Tim Sparwasser, Leticia Quintanilla-Martinez, Ursula Zimber-Strobl, Berthold Streubel, Andreas Gewies, Christian Peschel, Jürgen Ruland
Journal: The Journal of Experimental Medicine (2010)

Peripheral T cell lymphomas (PTCLs) are highly aggressive malignancies with poor prognosis. Their molecular pathogenesis is not well understood and small animal models for the disease are lacking. Recently, the chromosomal translocation t(5;9)(q33;q22) generating the interleukin-2 (IL-2)–inducible T cell kinase (ITK)–spleen tyrosine kinase (SYK) fusion tyrosine kinase was identified as a recurrent event in PTCL. We show that ITK-SYK associates constitutively with lipid rafts in T cells and triggers antigen-independent phosphorylation of T cell receptor (TCR)–proximal proteins. These events lead to activation of downstream pathways and acute cellular outcomes that correspond to regular TCR ligation, including up-regulation of CD69 or production of IL-2 in vitro or deletion of thymocytes and activation of peripheral T cells in vivo. Ultimately, conditional expression of patient-derived ITK-SYK in mice induces highly malignant PTCLs with 100% penetrance that resemble the human disease. Our work demonstrates that constitutively enforced antigen receptor signaling can, in principle, act as a powerful oncogenic driver. Moreover, we establish a robust clinically relevant and genetically tractable model of human PTCL.
The cholinesterase-like domain of thyroglobulin functions as an intramolecular chaperone
Authors: Jaemin Lee, Bruno Di Jeso, Peter Arvan
Journal: Journal of Clinical Investigation (2008)

Thyroid hormonogenesis requires secretion of thyroglobulin, a protein comprising Cys-rich regions I, II, and III (referred to collectively as region I-II-III) followed by a cholinesterase-like (ChEL) domain. Secretion of mature thyroglobulin requires extensive folding and glycosylation in the ER. Multiple reports have linked mutations in the ChEL domain to congenital hypothyroidism in humans and rodents; these mutations block thyroglobulin from exiting the ER and induce ER stress. We report that, in a cell-based system, mutations in the ChEL domain impaired folding of thyroglobulin region I-II-III. Truncated thyroglobulin devoid of the ChEL domain was incompetent for cellular export; however, a recombinant ChEL protein (“secretory ChEL”) was secreted efficiently. Coexpression of secretory ChEL with truncated thyroglobulin increased intracellular folding, promoted oxidative maturation, and facilitated secretion of region I-II-III, indicating that the ChEL domain may function as an intramolecular chaperone. Additionally, we found that the I-II-III peptide was cosecreted and physically associated with secretory ChEL. A functional ChEL domain engineered to be retained intracellularly triggered oxidative maturation of I-II-III but coretained I-II-III, indicating that the ChEL domain may also function as a molecular escort. These insights into the role of the ChEL domain may represent potential therapeutic targets in the treatment of congenital hypothyroidism.
Improved Hepatic Toxicity Profile of Portal Vein Adjuvant Hepatic Infusional Chemotherapy
Authors: Moshe Faynsod, Lawrence D. Wagman, Jeff Longmate, Mary Carroll, Lucille A. Leong
Journal: Journal of Clinical Oncology (2005)

To determine whether floxuridine (FUDR) can be delivered with low hepatic toxicity through the portal vein (PV) as an adjuvant to surgically treated colorectal metastases.Fifty-one patients undergoing complete resection and/or ablation for colorectal hepatic metastases were prospectively enrolled at a National Cancer Institute-designated comprehensive cancer center. Two sequential phase II trials were performed. Each trial included complete surgical treatment followed by sequential, alternating (22 patients) or concurrent (29 patients) regional PV FUDR and systemic fluorouracil (FU) with leucovorin chemotherapy.Fifty percent of patients were male. The mean age at diagnosis was 57 years. The mean number of lesions resected was three (range, one to 11 lesions). The stage at diagnosis was II, III, and IV in 16.9%, 52.8%, and 28.3% of patients, respectively. One- and 3-year overall survival rates were 92.7% and 41.8%, respectively. The 1- and 3-year disease-free survival rates were 64.5% and 19%, respectively. The site of first recurrence was hepatic in 35.9% of patients. Treatment was terminated early in 24 patients (17 patients progressed, two refused treatment, and five had nonhepatic toxicities). Fifty-five percent of patients received 75% to 100% of the planned FUDR courses, and 72% received greater than 50% of the planned FUDR dose. Only four patients required dose reductions of FUDR because of grade 3 hepatic toxicity. No patient required biliary stenting or had discontinuation of PV infusion because of hepatic toxicity.The delivery of PV FUDR and FU with leucovorin can be performed with a high percentage of expected drug delivery and a low drug-induced hepatic toxicity rate, while achieving acceptable overall and disease-free survival.
Dysfunctional Epstein-Barr virus (EBV)–specific CD8+T lymphocytes and increased EBV load in HIV-1 infected individuals progressing to AIDS-related non-Hodgkin lymphoma
Authors: Debbie van Baarle, Egbert Hovenkamp, Margareth F. C. Callan, Katja C. Wolthers, Stefan Kostense, Linda C. Tan, Hubert G. M. Niesters, Albert D. M. E. Osterhaus, Andrew J. McMichael, Marinus H. J. van Oers, Frank Miedema
Journal: Blood (2001)
A Phase I Study of<i>In vitro</i>Expanded Natural Killer T Cells in Patients with Advanced and Recurrent Non–Small Cell Lung Cancer
Authors: Shinichiro Motohashi, Aki Ishikawa, Eiichi Ishikawa, Mizuto Otsuji, Toshihiko Iizasa, Hideki Hanaoka, Naomi Shimizu, Shigetoshi Horiguchi, Yoshitaka Okamoto, Shin-ichiro Fujii, Masaru Taniguchi, Takehiko Fujisawa, Toshinori Nakayama
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Human Vα24 natural killer T (Vα24 NKT) cells bearing an invariant Vα24JαQ antigen receptor are activated by a glicolipid ligand α-galactosylceramide (αGalCer; KRN7000) in a CD1d-dependent manner. The human Vα24 NKT cells activated with αGalCer and interleukin-2 have been shown to produce large amounts of cytokines, such as IFN-γ, and also exerting a potent killing activity against various tumor cell lines. We did a phase I study with autologous activated Vα24 NKT cell therapy. Experimental Design: Patients with advanced or recurrent non–small cell lung cancer received i.v. injections of activated Vα24 NKT cells (level 1: 1 × 107/m2 and level 2: 5 × 107/m2) to test the safety, feasibility, and clinical response of this therapeutic strategy. Immunomonitoring was also done in all cases. Results: Six patients were enrolled in this study. No severe adverse events were observed during this study in any patients. After the first and second injection of activated Vα24 NKT cells, an increased number of peripheral blood Vα24 NKT cells was observed in two of three cases receiving a level 2 dose of activated Vα24 NKT cells. The number of IFN-γ-producing cells in peripheral blood mononuclear cells increased after the administration of activated Vα24 NKT cells in all three cases receiving the level 2 dose. No patient was found to meet the criteria for either a partial or a complete response. Conclusions: The clinical trial with activated Vα24 NKT cell administration was well tolerated and carried out safely with minor adverse events even in patients with advanced diseases.
Evaluation of IFNγ release assays for detection of cellular immunity towards M. tuberculosis and CMV in samples from deceased donors
Authors: Tina Schmidt, David Schub, Michaela Wolf, Jan Dirks, Marion Ritter, Sarah Kirsch, Urban Sester, Anne-Bärbel Blaes-Eise, Undine Samuel, Martina Sester
Journal: European Respiratory Journal (2013)

IGRAs may be valuable for risk assessment of organ donors, but no data exist on their feasibility in deceased donors. Therefore, we evaluated the performance of an ELISA, an ELISPOT and a flow-cytometric assay (FACS) to determine T-cell immunity towards M. tuberculosis and CMV in deceased donors.  100 donors (52±17 yrs) were screened at the time of organ procurement. A CMV-IgG ELISA was used as a gold standard for CMV infection. Specific stimulation was performed using PPD, ESAT-6/CFP-10, and a CMV lysate in combination with commercial assay formats (QFT-TB/CMV as ELISA, T-SPOT.TB as ELISPOT).  Indeterminate results were observed in 49.0% of ELISA, 13.3% of FACS and 0% of ELISPOT assays. CMV-specific immunity was detected in 26.0%, 46.9%, and 54.1% of QFT-CMV, FACS, and ELISPOT-samples, respectively. Agreement with serology was highest for FACS (93%, K=0.85), followed by ELISPOT (81%, K=0.61), and ELISA (81%, K=0.62). The percentage of PPD-positive results differed between assays (27.3% for ELISA, 27.6% for FACS, and 48.9% for ELISPOT). Among PPD-positive samples, 8.3% were QFT-TB positive, 16.7% were positive in an ESAT-6/CFP-10-specific FACS-assay, and 25.6% were positive in the T-SPOT.TB test. In the setting of this study, 85.4% of donors had received steroids and 56.3% of ELISAs, 92.9% of ELISPOTs, and 97.0% of FACS samples could be processed within the respective recommended time frame. Nevertheless, neither delayed processing nor steroids had a significant effect on indeterminate results.  In conclusion, cellular immunity may be analysed from samples of deceased donors, although indeterminate results are more frequent than in healthy individuals.
Effects of Dasatinib on Src Kinase Activity and Downstream Intracellular Signaling in Primitive Chronic Myelogenous Leukemia Hematopoietic Cells
Authors: Heiko Konig, Mhairi Copland, Su Chu, Richard Jove, Tessa L. Holyoake, Ravi Bhatia
Journal: Cancer Research (2008)

Abstract Bcr-Abl tyrosine kinase inhibitors (TKI) are effective in inducing remissions in chronic myelogenous leukemia (CML) patients but do not eliminate primitive CML hematopoietic cells. There is a need to identify mechanisms that contribute to retention of CML progenitors. Src family tyrosine kinases have been identified as potential mediators of Bcr-Abl–induced leukemogenesis. Dasatinib (BMS-354825) is a potent dual Abl/Src kinase inhibitor approved for clinical use in CML patients. We evaluated Src activity in primitive human CML progenitors from different stages of disease and investigated effects of Dasatinib on Src activity and downstream signaling pathways. P-Src expression was increased in CD34+ cells and CD34+CD38− cells in all phases of CML. Dasatinib showed potent Src inhibitory activity in CML progenitors, inhibiting both Bcr-Abl–dependent and –independent Src activity. In contrast, Imatinib inhibited only Bcr-Abl–dependent Src activity. Dasatinib inhibited P–mitogen-activated protein kinase (MAPK), P-Akt, and P-STAT5 levels in CML progenitors in the absence of growth factors but not in the presence of growth factors. A marked increase in P-MAPK levels seen in the presence of growth factors with Imatinib was much less prominent with Dasatinib. Dasatinib significantly suppressed CML colony-forming cells and long-term culture-initiating cells but did not significantly alter the level of apoptosis-regulating proteins in CML CD34+ cells. Our results indicate that Dasatinib, in addition to potent anti–Bcr-Abl kinase activity, effectively inhibits Src kinase activity and downstream signaling pathways in CML progenitors but does not induce a strong proapoptotic response. These observations argue against a prominent role for Src kinases in persistence of primitive CML cells in TKI-treated patients. [Cancer Res 2008;68(23):9624–33]
Comparative Sensitivity of Cells From Human Tumors and Derivative Tumor Xenografts to Radiation and Heat Treatments
Authors: E. K. Rofstad
Journal: JNCI Journal of the National Cancer Institute (1992)

Background: Human tumor xenografts in athymic mice are often used to study the efficacy of cancer treatments, but it is not known whether the xenografts accurately reflect the treatment responsiveness of the original tumors. Purpose: To assess the validity of tumor xenografts as specific models of neoplastic disease, a softagar colony assay was used to compare the sensitivity of cells from surgical tumor specimens and derivative xenograft lines to various radiation and heat treatments in vitro. Methods: Xenograft lines were established from melanomas and from carcinomas of the bladder, breast, cervix, and colon. Single-cell suspensions from the original tumors and the corresponding tumor xenografts were subjected to treatments that measured inherent radiation sensitivity, split-dose radiation repair capacity, low-dose-rate radiation sensitivity, inherent heat sensitivity, capacity for development of thermotolerance, and sensitivity to step-down heating (treatment at 43.5 °C followed by treatment at 41.5 °C). Cell survival curves were plotted for each treatment, and a two-tailed Student's t test was used to search for statistically significant correlations between the curves. Results: Although cells from different surgical tumor specimens varied widely in their sensitivity to radiation and heat treatments, there was always a statistically significant correlation ( P <.O5) between the sensitivity of cells from the surgical specimens and the corresponding tumor xenografts. Conclusions: These observations strongly suggest that intrinsic properties of human tumor cells generally are retained during serial heterotransplantation. Thus, human tumor xenograft lines may be valuable tools in studies aimed at identifying cellular properties of importance for the clinical treatment sensitivity of human cancer. This does not necessarily mean, however, that the treatment responsiveness of the xenografts in vivo mirrors the clinical treatment responsiveness of the tumors in patients. [J Natl Cancer Inst 84:1517–1524, 1992]
Nuclear expression of the ubiquitin ligase seven in absentia homolog (SIAH)-1 induces proliferation and migration of liver cancer cells
Authors: Antje Brauckhoff, Mona Malz, Darjus Tschaharganeh, Nisar Malek, Achim Weber, Marc-Oliver Riener, Christopher Soll, Jana Samarin, Michaela Bissinger, Jan Schmidt, Thomas Longerich, Volker Ehemann, Peter Schirmacher, Kai Breuhahn
Journal: Journal of Hepatology (2011)