tbuckley/cabot-search huggingface dataset:
The role of tau protein in HIV-associated neurocognitive disorders
Authors: Lecia AM Brown, James Scarola, Adam J Smith, Paul R Sanberg, Jun Tan, Brian Giunta
Journal: Molecular Neurodegeneration (2014)

Given the increased life expectancy of human immunodeficiency virus (HIV) infected individuals treated with combination antiretroviral therapy (cART) and the ongoing inflammation observed in the brains of these patients, it is likely that premature neurodegeneration as measured by phospho-tau (p-tau) or increased total tau (t-tau) protein may become an increasing problem. This review examines the seven human studies that have occurred over the past 14 years measuring p-tau and/or t-tau in cerebrospinal fluid (CSF) or via post-mortem brain immunohistochemistry. Although not all studies are in agreement as to the changes in p-and t-tau in HIV infected patients, HIV persists in the brain despite cART. Thus is it is suggested that those maintained on long-term cART may develop tau pathology beyond the extent seen in the studies reviewed herein and overtime may then reach the threshold for clinical manifestation.
ANTIGENIC MODULATION IN VITRO
Authors: Christopher W. Stackpole, Janet B. Jacobson, Michael P. Lardis
Journal: The Journal of Experimental Medicine (1974)

The modulation or loss of thymus-leukemia (TL) antigenicity from the surfaces of mouse RADA1 leukemia cells and normal thymocytes during incubation with TL antibody in vitro at 37 degrees C was investigated by cytotoxicity, immunofluorescence, and immunoelectron microscopy. The fate of bivalent and monovalent antibody during modulation was visualized by fluorescence microscopy. Considerable antibody remained bound to the cell surface after modulation, bivalent antibody being displaced topographically into "patches" and "caps" while monovalent antibody was only slightly aggregated on the cell surface. Some antibody was internalized, presumably by pinocytosis, and was sequestered into the Golgi region of the cell. Capping usually occurred over the pole of the cell opposite from the Golgi region, which may explain the lack of extensive pinocytosis of modulating bivalent antibody. Since modulation with monovalent antibody occurs without patch or cap formation, gross topographical redistribution of TL antigen-antibody complexes is not required for modulation, although more subtle displacement of these complexes may be involved. Modulation was demonstrable by cytotoxicity with guinea pig C' but not with absorbed rabbit C', indicating that modulated TL antigens remain bound to the cell surface. A heat-labile factor in TL antiserum and in mouse serum in general is responsible for "blocking" the cytolytic interaction of guinea pig C' with modulated TL antigen-antibody complexes.
Mitochondrial DNA polymorphism in three Antillean island populations of the fruit bat, Artibeus jamaicensis.
Authors: D E Pumo, E Z Goldin, B Elliot, C J Phillips, H H Genoways
Journal: Molecular Biology and Evolution (1988)

The Neotropical fruit bat, Artibeus jamaicensis, occurs throughout Latin America and on many islands in the Caribbean. Populations from Jamaica (in the Greater Antilles) to Barbados (in the Lesser Antilles) have been classified as a subspecies (A.j. jamaicensis) separate from that on the Lesser Antillean island of St. Vincent (A.j. schwartzi). Mitochondrial DNA (mtDNA) was isolated from 54 individuals collected on these islands, analyzed by digestion with restriction endonucleases, and the restriction sites were mapped. Three different mtDNA genotypes (16,000 +/- 200 bp) were identified: J-1 (16 animals from Jamaica, one from St. Vincent, 15 from Barbados), J-2 (two animals from Jamaica), and SV-1 (18 animals from St. Vincent, two from Barbados). The J-1 and J-2 genotypes were estimated to differ from each other by only 0.4%, but the SV-1 genotype differed from J-1 and J-2 by 8.1%-10.5%. The estimated sequence divergence between SV-1 and J-1 is unusually large for mammals that are regarded as conspecific. Restriction mapping showed that the differences among the genotypes (presence or absence of particular restriction sites) were located throughout the genome. The presence of the J-1 mtDNA genotype on Jamaica and on St. Vincent and Barbados (1,400 km away) demonstrates that maternal lineages in these bats are not necessarily confined to single islands or limited geographic regions. The presence of the J-1 mtDNA genotype within the A. j. schwartzi population on St. Vincent and the presence of the SV-1 genotype in two specimens of A. j. jamaicensis from Barbados document genetic exchange between subspecific populations on these islands, which are separated by 180 km of open water.
T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on <i>IFNG</i> gene acetylation and transcription
Authors: Takashi Usui, Jan C. Preiss, Yuka Kanno, Zheng Ju Yao, Jay H. Bream, John J. O'Shea, Warren Strober
Journal: The Journal of Experimental Medicine (2006)

T helper type 1 (Th1) development is facilitated by interrelated changes in key intracellular factors, particularly signal transducer and activator of transcription (STAT)4, T-bet, and GATA-3. Here we show that CD4+ cells from T-bet−/− mice are skewed toward Th2 differentiation by high endogenous GATA-3 levels but exhibit virtually normal Th1 differentiation provided that GATA-3 levels are regulated at an early stage by anti–interleukin (IL)-4 blockade of IL-4 receptor (R) signaling. In addition, under these conditions, Th1 cells from T-bet−/− mice manifest IFNG promotor accessibility as detected by histone acetylation and deoxyribonuclease I hypersensitivity. In related studies, we show that the negative effect of GATA-3 on Th1 differentiation in T-bet−/− cells arises from its ability to suppress STAT4 levels, because if this is prevented by a STAT4-expressing retrovirus, normal Th1 differentiation is observed. Finally, we show that retroviral T-bet expression in developing and established Th2 cells leads to down-regulation of GATA-3 levels. These findings lead to a model of T cell differentiation that holds that naive T cells tend toward Th2 differentiation through induction of GATA-3 and subsequent down-regulation of STAT4/IL-12Rβ2 chain unless GATA-3 levels or function is regulated by T-bet. Thus, the principal function of T-bet in developing Th1 cells is to negatively regulate GATA-3 rather than to positively regulate the IFNG gene.
1,3-β-D-Glucan in Patients Receiving Intravenous Amoxicillin–Clavulanic Acid
Authors: Monique A.S.H. Mennink-Kersten, Adilia Warris, Paul E. Verweij
Journal: New England Journal of Medicine (2006)

To the Editor: The fungal component 1,3-β-D-glucan is increasingly used to diagnose opportunistic invasive mycoses in immunocompromised patients.1–3 The 1,3-β-D-glucan assay (Fungitell, Associates of Cape Cod) was recently approved by the Food and Drug Administration. We found that the serum samples from two patients with hematologic conditions were positive for 1,3-β-D-glucan during treatment with intravenous amoxicillin–clavulanic acid. Serum samples were negative after treatment was discontinued. Neither patient had evidence of invasive fungal disease. Furthermore, 1,3-β-D-glucan was detected in the amoxicillin–clavulanic acid used to treat these patients. We then tested 10 serum samples from six patients treated with intravenous amoxicillin–clavulanic . . .
Lung function, smoking and mortality in a 26-year follow-up of healthy middle-aged males
Authors: K. Stavem, E. Aaser, L. Sandvik, J. V. Bjørnholt, G. Erikssen, E. Thaulow, J. Erikssen
Journal: European Respiratory Journal (2005)

Lung function has been associated with mortality after adjusting for other risk factors; however, few studies have adjusted for physical fitness and reported separate analyses according to smoking status. In 1972–1975, spirometry, clinical and physiological parameters were recorded in 1,623 apparently healthy males aged 40–59 yrs. After 26 yrs of follow-up, the current authors investigated the association between baseline lung function and mortality, adjusting for smoking, physical fitness and other potential factors. By 2000, 615 individuals (38%) had died, with 308 (50%) of these deaths from cardiovascular (CV) causes. Forced expiratory volume in one second was a predictor of all-cause mortality (risk ratio (RR) 1.10 per reduction of 10%) after adjusting for smoking, physical fitness, age, systolic blood pressure, body mass index and serum cholesterol. The corresponding multivariate RR was 1.07 for CV causes and 1.34 for respiratory death. In conclusion, in stratified analyses among current and former smokers, forced expiratory volume in one second % predicted was a strong independent predictor of all-cause mortality and respiratory death among current smokers. Forced expiratory volume in one second % predicted was not associated with mortality among never-smokers.
CXCR4 gene transfer contributes to in vivo reendothelialization capacity of endothelial progenitor cells
Authors: L. Chen, F. Wu, W.-h. Xia, Y.-y. Zhang, S.-y. Xu, F. Cheng, X. Liu, X.-y. Zhang, S.-m. Wang, J. Tao
Journal: Cardiovascular Research (2010)

AimsEndothelial progenitor cells (EPCs) play a pivotal role in endothelial repair after artery injury. The chemokine receptor CXCR4 is a key modulator of the homing of EPCs to impaired artery and reendothelialization. In this study, we addressed the hypothesis that CXCR4 gene transfer could enhance the reendothelialization capacity of EPCs.
ON THE RELATION OF THE OPTIC THALAMUS TO RESPIRATION, CIRCULATION, TEMPERATURE, AND THE SPLEEN
Authors: Ernest Sachs
Journal: The Journal of Experimental Medicine (1911)

From what has already been said, it is apparent that changes in respiration and blood pressure may be produced by stimulation of a very large portion of the optic thalamus; that no one region controls these phenomena; that the spleen shows variations in volume only when marked blood pressure changes occur, and that such a change has been observed on stimulation of many places in the thalamus. Furthermore, the regions in the thalamus from which such effects are obtained are those in which the large afferent paths end; namely, the fillet and superior cerebellar peduncle, and a region directly connected with the vagus nucleus. The portions of the thalamus which proved inert to stimulation were those which in our previous investigation also were inactive; namely, the median nucleus, and the upper anterior end of the lateral—the region through which the fibers of the median nucleus pass. These phenomena are similar in every respect to those observed when an afferent nerve is stimulated. In what has gone before, it has been shown that the respiratory and circulatory changes occurred when one of the sensory paths, or a path running directly to the medullary nuclei governing these functions was stimulated. In explaining these phenomena, therefore, there is no necessity for invoking the existence of special centers.
Indanes—Properties, Preparation, and Presence in Ligands for G Protein Coupled Receptors
Authors: Maris Vilums, Jules Heuberger, Laura H. Heitman, Adriaan P. IJzerman
Journal: Medicinal Research Reviews (2015)

Abstract The indane (2,3‐dihydro‐1 H ‐indene) ring system is an attractive scaffold for biologically active compounds due to the combination of aromatic and aliphatic properties fused together in one rigid system. This bicyclic structure provides a wide range of possibilities to incorporate specific substituents in different directionalities, thus being an attractive scaffold for medicinal chemists. Notably, many indane‐based compounds are being used in the clinic to treat various diseases, such as indinavir, an HIV‐1 protease inhibitor; indantadol, a potent Monoamine Oxidase (MAO)‐inhibitor; the amine uptake inhibitor indatraline; and the ultra‐long‐acting β‐adrenoceptor agonist indacaterol. Given the diversity of targets these drugs act on, one could argue that the indane ring system is a privileged substructure. In the present review, the synthetic and medicinal chemistry of the indane ring system is described. In more detail, it contains a comprehensive overview of compounds bearing the indane substructure with G protein coupled receptor (GPCR) activity, with particular emphasis on their structure–activity relationships (SAR).
NUTRITIONAL PROPERTIES AND SIGNIFICANCE OF VITAMIN GLYCOSIDES
Authors: Jesse F. Gregory III
Journal: Annual Review of Nutrition (1998)

▪ Abstract Glycosylated forms of pyridoxine, vitamin D, niacin, pantothenate, and riboflavin exist in nature, whereas glycosides of retinol and ascorbic acid are products of in vitro transglycosidation. β-Glucosides of pyridoxine (a) are prevalent in plant-derived foods, (b) contribute to human nutrition as partially available sources of vitamin B 6 , (c) undergo partial hydrolysis by a novel mammalian cytosolic β-glucosidase, and (d) exert a weak antagonistic effect on the utilization of free pyridoxine. Niacin exists in grains as complexed forms with low bioavailability, whereas vitamin D glycosides are toxic components of certain calcinogenic plants of importance in animal health. Glycosides of pantothenate and riboflavin appear to be minor products of mammalian metabolism. Glycosylation of retinol or other hydrophobic alcohols may facilitate glycolipid turnover, whereas a stable ascorbyl glucoside may have nutritional applications. Glycosylation of vitamins exerts widely ranging chemical and biological effects, with great nutritional and metabolic significance.
Morphologic Instability and Cancer Invasion
Authors: Vittorio Cristini, Hermann B. Frieboes, Robert Gatenby, Sergio Caserta, Mauro Ferrari, John Sinek
Journal: Clinical Cancer Research (2005)

A solid tumor embedded in host tissue is a three-dimensional arrangement of cells and extracellular matrix that acts as a sink of oxygen and cell nutrients, thus establishing diffusional gradients. This and variations in vascular density and blood flow typically produce intratumoral regions of hypoxia and acidosis, and may result in spatially heterogeneous cell proliferation and migration. Here, we formulate the hypothesis that through these mechanisms, microenvironmental substrate gradients may drive morphologic instability with separation of cell clusters from the tumor edge and infiltration into surrounding normal tissue.We used computer simulations and in vitro experiments.We provide evidence that morphologic instability could be suppressed in vivo by spatially homogeneous oxygen and nutrient supply because normoxic conditions act both by decreasing gradients and increasing cell adhesion and, therefore, the mechanical forces that maintain a well-defined tumor boundary. A properly working tumor microvasculature can help maintain compact noninfiltrating tumor morphologies by minimizing oxygen and nutrient gradients. In contrast, antiangiogenic therapy, by increasing microenvironmental heterogeneity, may promote morphologic instability, leading to invasive patterns even under conditions in which the overall tumor mass shrinks.We conclude that therapeutic strategies focused solely on reduction of vascular density may paradoxically increase invasive behavior. This theoretical model accounts for the highly variable outcome of antiangiogenic therapy in multiple clinical trials. We propose that antiangiogenic strategies will be more consistently successful when aimed at "normalizing" the vasculature and when combined with therapies that increase cell adhesion so that morphologic instability is suppressed and compact, noninvasive tumor morphologies are enforced.
15d-PGJ2 Induces Apoptosis by Reactive Oxygen Species–mediated Inactivation of Akt in Leukemia and Colorectal Cancer Cells and Shows <i>In vivo</i> Antitumor Activity
Authors: Sung-Won Shin, Chi-Yeon Seo, Hoon Han, Jin-Yeong Han, Jin-Sook Jeong, Jong-Young Kwak, Joo-In Park
Journal: Clinical Cancer Research (2009)

Recent studies have shown that 15-deoxy-Delta(12, 14)-prostaglandin J(2) (15d-PGJ(2)), a natural ligand for peroxisome proliferator-activated receptor-gamma (PPARgamma), inhibits cell proliferation and induces apoptosis. The specific molecular mechanisms underlying this effect remain to be elucidated. We examined whether 15d-PGJ(2) has antitumor activity in vitro and in vivo, and investigated the underlying mechanism.We examined 15d-PGJ(2)-induced apoptosis in human leukemia cells in the context of mitochondrial injury, oxidative damage, and signaling pathway disturbances. In addition, we investigated the antitumor effect of 15d-PGJ(2) in a mouse CT-26 s.c. tumor model and HL-60 leukemia xenograft model.15d-PGJ(2) induced apoptosis in leukemia and colorectal cancer cells in a dose-dependent manner and led to generation of reactive oxygen species (ROS) through mitochondria and NADPH oxidase activation, activation of JNK, and inactivation of Akt, a serine/threonine-specific protein kinase. Constitutive activation of Akt for an engineered myristoylated protein prevented 15d-PGJ(2)-mediated apoptosis but not ROS generation. Collectively, these findings suggest a hierarchical model of apoptosis induced by 15d-PGJ(2) in human leukemia cells: oxidative injury represents a primary event resulting in Akt inactivation, which in turn leads to mitochondrial injury and apoptosis. Moreover, 15d-PGJ(2) markedly reduced growth of mouse CT-26 s.c. tumors and HL-60 xenograft tumors and down-regulated p-Akt and Akt expression in vivo.These results suggest that Akt inactivation through ROS production may contribute to 15d-PGJ(2)-induced apoptosis in leukemia and colorectal cancer cell lines and that 15d-PGJ(2) may have therapeutic relevance in the treatment of human leukemia and colorectal cancer.
Targeting of miR34a–NOTCH1 Axis Reduced Breast Cancer Stemness and Chemoresistance
Authors: Eun Young Park, EunSun Chang, Eun Ji Lee, Hyun-Woo Lee, Hyeok-Gu Kang, Kyung-Hee Chun, Yu Mi Woo, Hyun Kyung Kong, Je Yeong Ko, Hiromu Suzuki, Erwei Song, Jong Hoon Park
Journal: Cancer Research (2014)

Human breast cancers include cancer stem cell populations as well as nontumorigenic cancer cells. Breast cancer stem cells have self-renewal capability and are resistant to conventional chemotherapy. miRNAs regulate the expression of many target genes; therefore, dysregulation of miRNAs has been associated with the pathogenesis of human diseases, including cancer. However, a role for miRNA dysregulation in stemness and drug resistance has yet to be identified. Members of the miR34 family are reportedly tumor-suppressor miRNAs and are associated with various human cancers. Our results confirm that miR34a expression was downregulated in MCF7/ADR cells compared with MCF7 cells. We hypothesized that this reduction was due to the p53 (TP53) mutation in MCF7/ADR cells. In this study, we found that primary and mature miR34a were suppressed by treatment with p53 RNAi or the dominant-negative p53 mutant in MCF7 cells. Ectopic miR34a expression reduced cancer stem cell properties and increased sensitivity to doxorubicin treatment by directly targeting NOTCH1. Furthermore, tumors from nude mice treated with miR34a were significantly smaller compared with those of mice treated with control lentivirus. Our research suggests that the ectopic expression of miR34a represents a novel therapeutic approach in chemoresistant breast cancer treatment.
Both Microtubule-Stabilizing and Microtubule-Destabilizing Drugs Inhibit Hypoxia-Inducible Factor-1α Accumulation and Activity by Disrupting Microtubule Function
Authors: Daniel Escuin, Erik R. Kline, Paraskevi Giannakakou
Journal: Cancer Research (2005)

We have recently identified a mechanistic link between disruption of the microtubule cytoskeleton and inhibition of tumor angiogenesis via the hypoxia-inducible factor-1 (HIF-1) pathway. Based on this model, we hypothesized that other microtubule-targeting drugs may have a similar effect on HIF-1alpha. To test that hypothesis, we studied the effects of different clinically relevant microtubule-disrupting agents, including taxotere, epothilone B, discodermolide, vincristine, 2-methoxyestradiol, and colchicine. In all cases, HIF-1alpha protein, but not mRNA, was down-regulated in a drug dose-dependent manner. In addition, HIF-1alpha transcriptional activity was also inhibited by all drugs tested. To further examine whether these effects were dependent on microtubule network disruption, we tested the ability of epothilone B to inhibit HIF-1alpha protein in the human ovarian cancer cell line 1A9 and its beta-tubulin mutant epothilone-resistant subclone 1A9/A8. Our data showed that epothilone B treatment down-regulated HIF-1alpha protein in the parental 1A9 cells but had no effect in the resistant 1A9/A8 cells. These observations were confirmed by confocal microscopy, which showed impaired nuclear accumulation of HIF-1alpha in parental 1A9 cells at epothilone B concentrations that induced extensive microtubule stabilization. In contrast, epothilone B treatment had no effect on either microtubules or HIF-1alpha nuclear accumulation in the resistant 1A9/A8 cells. Furthermore, epothilone B inhibited HIF-1 transcriptional activity in 1A9 cells, as evidenced by a hypoxia response element-luciferase reporter assay, but had no effect on HIF-1 activity in the resistant 1A9/A8 cells. These data directly link beta-tubulin drug binding with HIF-1alpha protein inhibition. Our results further provide a strong rationale for testing taxanes and epothilones in clinical trials targeting HIF-1 in cancer patients.
Autophagy Inhibition Improves Chemosensitivity in BRAFV600E Brain Tumors
Authors: Jean M. Mulcahy Levy, Joshua C. Thompson, Andrea M. Griesinger, Vladimir Amani, Andrew M. Donson, Diane K. Birks, Michael J. Morgan, David M. Mirsky, Michael H. Handler, Nicholas K. Foreman, Andrew Thorburn
Journal: Cancer Discovery (2014)

Abstract Autophagy inhibition is a potential therapeutic strategy in cancer, but it is unknown which tumors will benefit. The BRAFV600E mutation has been identified as important in pediatric central nervous system (CNS) tumors and is known to affect autophagy in other tumor types. We evaluated CNS tumor cells with BRAFV600E and found that mutant (but not wild-type) cells display high rates of induced autophagy, are sensitive to pharmacologic and genetic autophagy inhibition, and display synergy when the clinically used autophagy inhibitor chloroquine was combined with the RAF inhibitor vemurafenib or standard chemotherapeutics. Importantly, we also demonstrate that chloroquine can improve vemurafenib sensitivity in a resistant ex vivo primary culture and provide the first demonstration in a patient harboring the V600E mutation treated with vemurafenib that the addition of chloroquine can improve clinical outcomes. These findings suggest that CNS tumors with BRAFV600E are autophagy-dependent and should be targeted with autophagy inhibition in combination with other therapeutic strategies. Significance: Autophagy inhibition may improve cancer therapy, but it is unclear which tumors will benefit. We found that BRAF mutations cause brain tumor cells to depend on autophagy and display selective chemosensitization with autophagy inhibition. We present a pediatric case in which deliberate autophagy inhibition halted tumor growth and overcame acquired BRAF-inhibition resistance. Cancer Discov; 4(7); 773–80. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 745
No Universally Applicable Thermal Dose Descriptor
Authors: Jacoba van der Zee, Gerard C. van Rhoon, Paul J.M. Rietveld
Journal: Clinical Cancer Research (2006)

To the Editor: We would like to congratulate Thrall et al. for their study on combining radiotherapy with hyperthermia at a prospectively prescribed thermal dose, showing that a high dose results in a higher complete response rate than a low dose and, after correction for other prognostic factors,