tbuckley/cabot-search huggingface dataset:
The small molecule curcumin analog FLLL32 induces apoptosis in melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with anti-tumor activity
Authors: Matthew A Bill, James R Fuchs, Chenglong Li, Jennifer Yui, Courtney Bakan, Don M Benson, Eric B Schwartz, Dalia Abdelhamid, Jiayuh Lin, Dale G Hoyt, Stacey L Fossey, Gregory S Young, William E Carson, Pui-Kai Li, Gregory B Lesinski
Journal: Molecular Cancer (2010)

Abstract Background We characterized the biologic effects of a novel small molecule STAT3 pathway inhibitor that is derived from the natural product curcumin. We hypothesized this lead compound would specifically inhibit the STAT3 signaling pathway to induce apoptosis in melanoma cells. Results FLLL32 specifically reduced STAT3 phosphorylation at Tyr705 (pSTAT3) and induced apoptosis at micromolar amounts in human melanoma cell lines and primary melanoma cultures as determined by annexin V/propidium iodide staining and immunoblot analysis. FLLL32 treatment reduced expression of STAT3-target genes, induced caspase-dependent apoptosis, and reduced mitochondrial membrane potential. FLLL32 displayed specificity for STAT3 over other homologous STAT proteins. In contrast to other STAT3 pathway inhibitors (WP1066, JSI-124, Stattic), FLLL32 did not abrogate IFN-γ-induced pSTAT1 or downstream STAT1-mediated gene expression as determined by Real Time PCR. In addition, FLLL32 did not adversely affect the function or viability of immune cells from normal donors. In peripheral blood mononuclear cells (PBMCs), FLLL32 inhibited IL-6-induced pSTAT3 but did not reduce signaling in response to immunostimulatory cytokines (IFN-γ, IL 2). Treatment of PBMCs or natural killer (NK) cells with FLLL32 also did not decrease viability or granzyme b and IFN-γ production when cultured with K562 targets as compared to vehicle (DMSO). Conclusions These data suggest that FLLL32 represents a lead compound that could serve as a platform for further optimization to develop improved STAT3 specific inhibitors for melanoma therapy.
IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma.
Authors: D G Maloney, A J Grillo-López, D J Bodkin, C A White, T M Liles, I Royston, C Varns, J Rosenberg, R Levy
Journal: Journal of Clinical Oncology (1997)

PURPOSE To evaluate the safety, pharmacokinetics, and biologic effect of multiple doses of the chimeric anti-CD20 monoclonal antibody (mAb) IDEC-C2B8 in patients with relapsed B-cell lymphoma. PATIENTS AND METHODS Twenty patients with relapsed low-grade (n = 15) or intermediate-/high-grade (n = 5) lymphoma received weekly infusions times four of 125 mg/m2 (n = 3), 250 mg/m2 (n = 7), or 375 mg/m2 (n = 10) of IDEC-C2B8. RESULTS Infusional side effects during the initial infusion were mainly grade I/II fever, asthenia, chills, nausea, rash, and urticaria. More serious events were rare. Peripheral-blood B cells were rapidly depleted and slowly recovered over 3 to 6 months. There was no change in mean immunoglobulin (Ig) levels. Antibody serum half-life (and maximum concentration [Cmax]) generally increased between the first and fourth infusions (33.2 hours v 76.6 hours, respectively) following the 375-mg/m2 doses. Six of 18 assessable patients had a partial remission (PR), with a median time to disease progression of 6.4 months (range, 3 to 21.7). Minor responses (MRs) were observed in five patients and progressive disease (PD) in seven. Tumor responses occurred in peripheral blood, bone marrow (BM), spleen, bulky lymph nodes, and extranodal sites, and in patients who had relapsed following high-dose myeloablative chemotherapy. Six of 14 patients (40%) with a low-grade histology responded. Four of six with bulky disease had a PR. CONCLUSION IDEC-C2B8 chimeric anti-CD20 mAb therapy is well tolerated and has clinical activity in patients with relapsed B-cell lymphoma. The 375-mg/m2 dose has been selected for a phase II trial in patients with relapsed low-grade or follicular B-cell lymphoma.
Immunology of Tuberculosis
Authors: JoAnne L. Flynn, John Chan
Journal: Annual Review of Immunology (2001)

The resurgence of tuberculosis worldwide has intensified research efforts directed at examining the host defense and pathogenic mechanisms operative in Mycobacterium tuberculosis infection. This review summarizes our current understanding of the host immune response, with emphasis on the roles of macrophages, T cells, and the cytokine/chemokine network in engendering protective immunity. Specifically, we summarize studies addressing the ability of the organism to survive within macrophages by controlling phagolysosome fusion. The recent studies on Toll-like receptors and the impact on the innate response to M. tuberculosis are discussed. We also focus on the induction, specificity, and effector functions of CD4 + and CD8 + T cells, and the roles of cytokines and chemokines in the induction and effector functions of the immune response. Presentation of mycobacterial antigens by MHC class I, class II, and CD1 as well as the implications of these molecules sampling various compartments of the cell for presentation to T cells are discussed. Increased attention to this disease and the integration of animal models and human studies have afforded us a greater understanding of tuberculosis and the steps necessary to combat this infection. The pace of this research must be maintained if we are to realize an effective vaccine in the next decades.
Molecular Evolution of GYPC: Evidence for Recent Structural Innovation and Positive Selection in Humans
Authors: Jason A. Wilder, Elizabeth K. Hewett, Meredith E. Gansner
Journal: Molecular Biology and Evolution (2009)

GYPC encodes two erythrocyte surface sialoglycoproteins in humans, glycophorin C and glycophorin D (GPC and GPD), via initiation of translation at two start codons on a single transcript. The malaria-causing parasite Plasmodium falciparum uses GPC as a means of invasion into the human red blood cell. Here, we examine the molecular evolution of GYPC among the Hominoidea (Greater and Lesser Apes) and also the pattern of polymorphism at the locus in a global human sample. We find an excess of nonsynonymous divergence among species that appears to be caused solely by accelerated evolution of GYPC in the human lineage. Moreover, we find that the ability of GYPC to encode both GPC and GPD is a uniquely human trait, caused by the evolution of the GPC start codon in the human lineage. The pattern of polymorphism among humans is consistent with a hitchhiking event at the locus, suggesting that positive natural selection affected GYPC in the relatively recent past. Because GPC is exploited by P. falciparum for invasion of the red blood cell, we hypothesize that selection for evasion of P. falciparum has caused accelerated evolution of GYPC in humans (relative to other primates) and that this positive selection has continued to act in the recent evolution of our species. These data suggest that malaria has played a powerful role in shaping molecules on the surface of the human red blood cell. In addition, our examination of GYPC reveals a novel mechanism of protein evolution: co-option of untranslated region (UTR) sequence following the formation of a new start codon. In the case of human GYPC, the ancestral protein (GPD) continues to be produced through leaky translation. Because leaky translation is a widespread phenomenon among genes and organisms, we suggest that co-option of UTR sequence may be an important source of protein innovation.
Disruption and pseudoautosomal localization of the major histocompatibility complex in monotremes
Authors: Juliane C Dohm, Enkhjargal Tsend-Ayush, Richard Reinhardt, Frank Grützner, Heinz Himmelbauer
Journal: Genome biology (2007)

The monotremes, represented by the duck-billed platypus and the echidnas, are the most divergent species within mammals, featuring a flamboyant mix of reptilian, mammalian and specialized characteristics. To understand the evolution of the mammalian major histocompatibility complex (MHC), the analysis of the monotreme genome is vital. We characterized several MHC containing bacterial artificial chromosome clones from platypus (Ornithorhynchus anatinus) and the short-beaked echidna (Tachyglossus aculeatus) and mapped them onto chromosomes. We discovered that the MHC of monotremes is not contiguous and locates within pseudoautosomal regions of two pairs of their sex chromosomes. The analysis revealed an MHC core region with class I and class II genes on platypus and echidna X3/Y3. Echidna X4/Y4 and platypus Y4/X5 showed synteny to the human distal class III region and beyond. We discovered an intron-containing class I pseudogene on platypus Y4/X5 at a genomic location equivalent to the human HLA-B,C region, suggesting ancestral synteny of the monotreme MHC. Analysis of male meioses from platypus and echidna showed that MHC chromosomes occupy different positions in the meiotic chains of either species. Molecular and cytogenetic analyses reveal new insights into the evolution of the mammalian MHC and the multiple sex chromosome system of monotremes. In addition, our data establish the first homology link between chicken microchromosomes and the smallest chromosomes in the monotreme karyotype. Our results further suggest that segments of the monotreme MHC that now reside on separate chromosomes must once have been syntenic and that the complex sex chromosome system of monotremes is dynamic and still evolving.
Bacterial Quorum Sensing: Signals, Circuits, and Implications for Biofilms and Disease
Authors: Arul Jayaraman, Thomas K. Wood
Journal: Annual Review of Biomedical Engineering (2008)

Communication between bacteria, belonging to the same species or to different species, is mediated through different chemical signals that are synthesized and secreted by bacteria. These signals can either be cell-density related (autoinducers) or be produced by bacteria at different stages of growth, and they allow bacteria to monitor their environment and alter gene expression to derive a competitive advantage. The properties of these signals and the response elicited by them are important in ensuring bacterial survival and propagation in natural environments (e.g., human oral cavity) where hundreds of bacterial species coexist. First, the interaction between a signal and its receptor is very specific, which underlies intraspecies communication and quorum sensing. Second, when multiple signals are synthesized by the same bacterium, the signaling circuits utilized by the different signals are coordinately regulated with distinct overall circuit architecture so as to maximize the overall response. Third, the recognition of a universal communication signal synthesized by different bacterial species (interspecies communication), as well that of signals produced by eukaryotic cells (interkingdom communication), is also integral to the formation of multispecies biofilm communities that are important in infection and disease. The focus of this review is on the principles underlying signal-mediated bacterial communication, with specific emphasis on the potential for using them in two applications-development of synthetic biology modules and circuits, and the control of biofilm formation and infection.
Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy. Interaction between hemodynamic and thyroid hormone-induced signals.
Authors: S Izumo, A M Lompré, R Matsuoka, G Koren, K Schwartz, B Nadal-Ginard, V Mahdavi
Journal: Journal of Clinical Investigation (1987)

Expression of the cardiac myosin isozymes is regulated during development, by hormonal stimuli and hemodynamic load. In this study, the levels of expression of the two isoforms (alpha and beta) of myosin heavy chain (MHC) during cardiac hypertrophy were investigated at the messenger RNA (mRNA) and protein levels. In normal control and sham-operated rats, the alpha-MHC mRNA predominated in the ventricular myocardium. In response to aortic coarctation, there was a rapid induction of the beta-MHC mRNA followed by the appearance of comparable levels of the beta-MHC protein in parallel to an increase in the left ventricular weight. Administration of thyroxine to coarctated animals caused a rapid deinduction of beta-MHC and induction of alpha-MHC, both at the mRNA and protein levels, despite progression of left ventricular hypertrophy. These results suggest that the MHC isozyme transition during hemodynamic overload is mainly regulated by pretranslational mechanisms, and that a complex interplay exists between hemodynamic and hormonal stimuli in MHC gene expression.
Assessment of hepatic encephalopathy with visual evoked potentials compared with conventional methods
Authors: Neville L. Sandford, Ronald E. Saul
Journal: Hepatology (1988)

Thirty-six patients with advanced chronic liver disease of predominantly alcoholic etiology and with a documented history or current physical evidence of hepatic encephalopathy were studied and compared to 30 healthy controls. Assessment was made of their mental state, number connection test, venous blood ammonia, electroencephalography and visual evoked potentials with both pattern reversal and flash stimuli. Because of considerable inter- and intraindividual variation in waveform, visual evoked potentials from flash stimuli were considered unreliable. In pattern reversal visual evoked potentials, the latency of the N1 and P1 waves was significantly longer (p less than 0.05) in patients than in controls; however, the wave latencies did not correlate with the mental state score. The mental state score correlated with the number connection test (r = 0.69, p less than 0.001), asterixis (r = 0.36, p less than 0.05), electroencephalography mean dominant frequency (r = 0.44, p less than 0.01) and blood ammonia (r = 0.60, p less than 0.01). In 14 patients studied sequentially, change in the mental state score correlated with change in the number connection test (r = 0.80, p less than 0.01) and asterixis (r = 0.75, p less than 0.01) but not with change in the electroencephalography, blood ammonia or visual evoked potential wave latencies. Although visual evoked potentials are abnormal in patients with alcoholic cirrhosis and encephalopathy, they are less accurate in assessing the level of consciousness than simple bedside evaluation with a number connection test.
Vimentin Filaments Support Extension of Tubulin-Based Microtentacles in Detached Breast Tumor Cells
Authors: Rebecca A. Whipple, Eric M. Balzer, Edward H. Cho, Michael A. Matrone, Jennifer R. Yoon, Stuart S. Martin
Journal: Cancer Research (2008)

Abstract Solid tumor metastasis often involves detachment of epithelial carcinoma cells into the vasculature or lymphatics. However, most studies of cytoskeletal rearrangement in solid tumors focus on attached cells. In this study, we report for the first time that human breast tumor cells produce unique tubulin-based protrusions when detached from extracellular matrix. Tumor cell lines of high metastatic potential show significantly increased extension and frequency of microtubule protrusions, which we have termed tubulin microtentacles. Our previous studies in nontumorigenic mammary epithelial cells showed that such detachment-induced microtentacles are enriched in detyrosinated α-tubulin. However, amounts of detyrosinated tubulin were similar in breast tumor cell lines despite varying microtentacle levels. Because detyrosinated α-tubulin associates strongly with intermediate filament proteins, we examined the contribution of cytokeratin and vimentin filaments to tumor cell microtentacles. Increased microtentacle frequency and extension correlated strongly with loss of cytokeratin expression and up-regulation of vimentin, as is often observed during tumor progression. Moreover, vimentin filaments coaligned with microtentacles, whereas cytokeratin did not. Disruption of vimentin with PP1/PP2A-specific inhibitors significantly reduced microtentacles and inhibited cell reattachment to extracellular matrix. Furthermore, expression of a dominant-negative vimentin mutant disrupted endogenous vimentin filaments and significantly reduced microtentacles, providing specific genetic evidence that vimentin supports microtentacles. Our results define a novel model in which coordination of vimentin and detyrosinated microtubules provides structural support for the extensive microtentacles observed in detached tumor cells and a possible mechanism to promote successful metastatic spread. [Cancer Res 2008;68(14):5678–88]
Women’s Ischemic Syndrome Evaluation
Authors: Carl J. Pepine, Robert S. Balaban, Robert O. Bonow, George A. Diamond, B. Delia Johnson, Paula A. Johnson, Lori Mosca, Steven E. Nissen, Gerald M. Pohost
Journal: Circulation (2004)

T he WISE workshop was convened to review results from the Women's Ischemic Syndrome Evaluation (WISE) study and other studies of ischemic heart disease to examine the nature and scope of gender differences in both chronic and acute cardiac ischemia, in terms of clinical manifestations, detection, and treatment.This section addresses research needs in improved diagnosis of myocardial ischemia in women.
Soluble TNF-α receptor and IL-1 receptor antagonist elevation in BAL in active pulmonary TB
Authors: T.C.y. Tsao, L. Li, M. Hsieh, S. Liao, K.S.s. Chang
Journal: European Respiratory Journal (1999)

Accumulating evidence suggests that patients with active pulmonary tuberculosis (TB) have an alveolar inflammation resulting in the release of tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta in bronchoalveolar epithelial fluid. It was proposed that the levels of these cytokines would correlate with clinical status parameters (extent of pulmonary involvement, fever, and body weight loss) and that their naturally occurring inhibitors would be concomitantly released in the local inflammatory sites. To test this hypothesis lung epithelial lining fluid (ELF) obtained by bronchoalveolar lavage and serum were collected from 29 patients with active pulmonary TB and 15 healthy subjects to determine the levels of these variables using a sandwich enzyme-linked immunosorbent assay (ELISA). ELF levels of TNF-alpha, soluble (s)TNF receptor I (RI), sTNF-receptor II (RII) and interleukin-1 receptor antagonist (IL-1RA) but not IL-1beta, and their serum levels except for sTNF-RII and IL-1beta were significantly higher in TB patients. Nevertheless, only ELF levels of TNF-alpha and IL-1beta were significantly correlated with disease status. No correlation was found between TNF-alpha levels and those of sTNF-RI and sTNF-RII, nor between IL-1beta and IL-1RA in ELF and serum of TB patients, although there was a significant correlation between sTNF-RI and sTNF-RII levels both in ELF and serum. These findings suggest local release of tumour necrosis factor-alpha and interleukin-1beta and a correlation with disease status. Soluble tumour necrosis factor-alpha receptors and interleukin-1beta receptor antagonist, although increased in lung epithelial lining fluid and serum in tuberculosis patients, were not correlated with tumour necrosis factor-alpha and interleukin-1beta or with disease status.
&lt;italic&gt;β&lt;/italic&gt;-Cyclodextrin: Promoting Effect on the Development of Renal Tubular Cell Tumors in Rats Treated With &lt;italic&gt;N&lt;/italic&gt;-Ethyl-&lt;italic&gt;N&lt;/italic&gt;-hydroxyethylnitrosamine
Authors: Yoshio Hiasa, Masato Ohshima, Yoshiteru Kitahori, Noboru Konishi, Toyohisa Fujita, Takashi Yuasa
Journal: JNCI Journal of the National Cancer Institute (1982)

Injection (sc) of beta-cyclodextrin (beta-C) increased the number and size of renal tubular cell tumors in inbred Wistar (W) rats treated with 1,000 ppm of N-ethyl-N-hydroxyethylnitrosamine (EHEN). The incidence of renal tumors at the end of the 32-week experiment was 50% in rats treated with 1,000 ppm EHEN for 2 weeks and 100% in rats treated with 1,000 ppm EHEN for 2 weeks and then given daily sc injections of beta-C for 1 week. The incidence of renal tumors more than 3 mm in diameter was 70% in rats treated with 1,000 ppm EHEN before beta-C but 0% in rats treated with EHEN alone. In addition, beta-C promoted the development of renal tumors in rats treated with 500 ppm EHEN, which is a subthreshold dose for renal tubular cell tumorigenesis. These results show that beta-C promotes EHEN-induced renal tubular cell tumorigenesis.
The Relationship Between the Thrombotic and Infectious Complications of Central Venous Catheters
Authors: Issam I. Raad
Journal: JAMA (1994)

To assess the frequency of thrombotic and infectious complications of long-term use of vascular catheters in cancer patients and to determine whether the two types of complication are related.Case series.A 500-bed tertiary cancer center.Seventy-two cancer patients.During a 16-month period, postmortem examinations of catheterized veins and contralateral uncatheterized veins were done on all patients with indwelling central venous catheters who met study criteria.Catheter-related septicemia determined by clinical and microbiological data as well as postmortem pathology; venous pathological changes such as mural hemorrhage, thrombosis, calcification, ulceration, and inflammation.Premortem clinical and microbiological data were obtained retrospectively on all patients. Pathological changes were noted in 35 catheterized veins (49%) compared with five contralateral control veins (9.2%) (P < .001). Mural thrombi were noted in 27 catheterized veins (38%) compared with only one contralateral control vein (1.4%) (P < .001). Other pathological changes consisted of four central venous catheter-related mural thrombi (5.6%) in the right atrium and four instances (5.6%) of nonbacterial thrombotic endocarditis, three involving the tricuspid and one the mitral valves. Seven patients had catheter-related septicemia. Of the 31 patients with mural thrombosis of the catheterized vein or right atrium, seven developed catheter-related septicemia, whereas none of the 41 patients with normal catheterized veins and atria developed catheter-related septicemia (P < .01).Thrombotic complications are common in catheterized veins and are often associated with catheter sepsis.
Actinic keratosis in the<i>en-face</i>and slice imaging mode of high-definition optical coherence tomography and comparison with histology
Authors: T. Maier, M. Braun-Falco, R.P. Laubender, T. Ruzicka, C. Berking
Journal: British Journal of Dermatology (2012)

Optical coherence tomography (OCT) allows real-time, in vivo examination of nonmelanoma skin cancer. An innovative high-definition (HD)-OCT with a horizontal (en-face) and vertical (slice) imaging mode offers additional information in the diagnosis of actinic keratosis (AK) and may potentially replace invasive diagnostic biopsies. To define the characteristic morphological features of AK by using HD-OCT in the two imaging modes compared with histopathology as gold standard. In total, 20 AKs were examined by HD-OCT in the en-face and slice imaging modes and characteristic features were described and evaluated in comparison with the histopathological findings. Furthermore, the HD-OCT images of a subgroup of AKs were compared with those of the clinically normal adjacent skin. The preoperative in vivo diagnostics showed the following features in the en-face imaging mode of HD-OCT: disruption of stratum corneum, architectural disarray, cellular/nuclear polymorphism in the stratum granulosum/stratum spinosum, and bright irregular bundles in the superficial dermis. In the vertical slice imaging mode the following characteristics were found: irregular entrance signal, destruction of layering, white streaks and dots, and grey areas. In contrast, the clinically healthy adjacent skin showed mainly a regular epidermal 'honeycomb' pattern in the en-face mode and distinct layering of the skin in the slice mode. HD-OCT with both the en-face and slice imaging modes offers additional information in the diagnosis of AK compared with conventional OCT and might enhance the possibility of the noninvasive diagnosis of AK prior to treatment procedures and possibly in the monitoring of noninvasive treatment strategies.