tbuckley/cabot-search huggingface dataset:
Tissue Iron and the Reticulo-Endothelial System in Rheumatoid Arthritis
Authors: D. L. Gardner, L. M. H. Roy
Journal: Annals of the Rheumatic Diseases (1961)

The cause of the normocytic hypochromic anaemia characteristic of rheumatoid arthritis remains unknown.Iron is absorbed normally from the gut (Roy, Alexander, and Duthie, 1955), but in an investigation of the iron content of the bone marrow (Richmond, Gardner, Roy, and Duthie, 1956) it was shown that stainable marrow iron was absent in nineteen of 61 cases and that there was no correlation between the presence or absence of iron in the marrow and the degree of anaemia.It appeared likely that an unknown factor was interfering with the utilization of iron for the synthesis of haemoglobin.An increased tissue avidity for iron comparable to that postulated by Cartwright and Wintrobe (1952) as a cause of the anaemia of infection seemed a possible explanation.Earlier studies (Roy and others, 1955) had shown that saccharated oxide of iron injected intra- venously was rapidly removed from the plasma of patients with rheumatoid arthritis.This observa- tion supported the suggestion of the existence of a state of overactivity or of hyperplasia of the reticulo-endothelial system (Freireich, Ross, Bayles, Emerson, and Finch, 1957).Some evidence for such a hyperplasia was available from morphological studies (Sinclair and Cruickshank, 1956).Overactivity of the reticulo-endothelial system appeared to be a possible explanation for the paradox that iron found histologically in the bone marrow was not utilized in the synthesis of haemoglobin (Richmond and others, 1956).On the basis of this hypothesis, it was postulated that in rheumatoid arthritis the organs comprising the reticulo-endothelial system might contain more iron than those of comparable subjects not suffering from this disease.The present investigation was planned to examine the validity of this hypothesis.
Entry and Intracellular Growth of <i>Legionella dumoffii</i> in Alveolar Epithelial Cells
Authors: KOJI MARUTA, HIROSHI MIYAMOTO, TETSUO HAMADA, MIDORI OGAWA, HATSUMI TANIGUCHI, SHIN-ICHI YOSHIDA
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

We have found that Legionella dumoffii strain Tex-KL (ATCC 33343) invades into and proliferates in the human lung alveolar epithelial-cell line A549 in vitro. The organism associated with the A549 cells at a 10-fold greater magnitude than L. pneumophila Philadelphia-1 during in vitro coculture for 1 h. Thereafter, L. dumoffii Tex-KL invaded the cells at a significantly higher rate (100- to 1,000-fold) than did L. pneumophila Philadelphia-1. After internalization, however, both bacteria proliferated at the same rate. This in vitro finding led us to examine the bacterial localization in lungs in a fatal case of L. dumoffii pneumonia. Double immunostaining revealed the bacteria in surfactant apoprotein A-positive cells (i.e., type II alveolar epithelial cells). Next, we infected guinea pigs intratracheally with L. dumoffii Tex-KL. The animals became sick with a fever from 24 h to 48 h after infection with 104 to 109 cfu of L. dumoffii Tex-KL. The lung tissues were examined through electron microscopy at definite intervals. Many bacteria were found not only inside phagocytic cells in the alveolar space, but also in type I and type II alveolar epithelial cells. These findings strongly suggest that L. dumoffii has an ability to invade into and proliferate in human alveolar epithelial cells, which may explain the rapid and fulminant progress of pneumonia caused by L. dumoffii.
Analysis of gene expression in operons of Streptomyces coelicolor.
Authors: Emma Laing, Vassilis Mersinias, Colin P Smith, Simon J Hubbard
Journal: Genome biology (2006)

Recent studies have shown that microarray-derived gene-expression data are useful for operon prediction. However, it is apparent that genes within an operon do not conform to the simple notion that they have equal levels of expression.To investigate the relative transcript levels of intra-operonic genes, we have used a Z-score approach to normalize the expression levels of all genes within an operon to expression of the first gene of that operon. Here we demonstrate that there is a general downward trend in expression from the first to the last gene in Streptomyces coelicolor operons, in contrast to what we observe in Escherichia coli. Combining transcription-factor binding-site prediction with the identification of operonic genes that exhibited higher transcript levels than the first gene of the same operon enabled the discovery of putative internal promoters. The presence of transcription terminators and abundance of putative transcriptional control sequences in S. coelicolor operons are also described.Here we have demonstrated a polarity of expression in operons of S. coelicolor not seen in E. coli, bringing caution to those that apply operon prediction strategies based on E. coli 'equal-expression' to divergent species. We speculate that this general difference in transcription behavior could reflect the contrasting lifestyles of the two organisms and, in the case of Streptomyces, might also be influenced by its high G+C content genome. Identification of putative internal promoters, previously thought to cause problems in operon prediction strategies, has also been enabled.
Reveromycin A Inhibits Osteolytic Bone Metastasis of Small-Cell Lung Cancer Cells, SBC-5, through an Antiosteoclastic Activity
Authors: Hiroaki Muguruma, Seiji Yano, Soji Kakiuchi, Hisanori Uehara, Makoto Kawatani, Hiroyuki Osada, Saburo Sone
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The purpose of this study was to determine therapeutic effect of a novel antibiotic, reveromycin A, against osteolytic bone metastasis of human small cell lung cancer (SBC-5) cells. Results: Reveromycin A induced apoptosis specifically in osteoclasts in vitro. Although reveromycin A did not inhibit SBC-5 cell proliferation, it suppressed the expression of parathyroid hormone–related peptide. Intravenous inoculation of SBC-5 cells in natural killer cell–depleted severe combined immunodeficient mice produced experimental metastases in multiple organs, including the bone. Daily administration of reveromycin A inhibited the bone metastasis, but not visceral metastasis, in a dose-dependent manner. Histologic analyses revealed that although treatment with reveromycin A did not affect the number of proliferating tumor cells, it decreased the number of osteoclasts and increased apoptotic cells in bone lesions. Conclusions: These findings suggest that reveromycin A may inhibit osteolytic bone metastasis through suppression of osteoclast activity by directly inducing apoptosis and indirectly inhibiting tumor cell–derived parathyroid hormone–related peptide production. Therefore, reveromycin A may be a novel, potent therapeutic agent against osteolytic bone metastasis of lung cancer in humans.
THE USE OF MODIFIED GLOBIN AS A PROTEIN SUPPLEMENT IN NORMAL INDIVIDUALS 1
Authors: Christine Waterhouse, E. Henry Keutmann, Leonard D. Fenninger
Journal: Journal of Clinical Investigation (1953)

tain fundamental differences between the meta- bolism of globin and albumin were apparent. PATIENTS AND PROCEDURESThe clinical background of the four patients con- cerned in this study was as follows:H. B., male, age 35, was admitted to the hospital for hysterical symptoms.He had lost about 20 lbs. in the year prior to this study.There was no evidence of or- ganic disease.G. V., male, age 25, had rheumatic heart disease with mitral stenosis and insufficiency, and aortic stenosis and insufficiency.This patient had been a subject on the metabolism ward twice before and had on one occasion received intravenous serum albumin.It was felt that comparative effects of albumin and globin in this patient would be of considerable interest.E. C. was a 51 year old white male with probable peripheral neuritis.His admission to the hospital was precipitated by difficulty in walking.Although it is probable that alcoholism was responsible for his neuro- logical difficulty, no evidence of liver disease was found.P. B., female, age 26, had a severe psychoneurosis.The patient was poorly nourished, but had no organic disease.Each patient was given a two-day rotating basic diet
Carboplatin, ifosfamide, and mesna (CIM) for the treatment of gynecological carcinosarcoma
Authors: N. Walji, A. Zachariah, C. Yap, S. A. Hussain, C. J. Poole, A. El-Modir, R. Ganesan, I. N. Fernando
Journal: Journal of Clinical Oncology (2009)

e16539 Background: A GOG trial comparing cisplatin/ifosfamide/mesna chemotherapy versus whole abdominal irradiation for FIGO stages I-IV carcinosarcoma (CS) showed an estimated median survival (MS) of 50 months for chemotherapy but high toxicity. This study investigates the efficacy and tolerability of a novel regimen using carboplatin AUC 5, ifosfamide 3 g/m 2 and mesna 1 g/m 2 (CIM) in both the adjuvant and metastatic setting. Methods: Retrospective analysis of women with CS treated from May 1997-May 2007 with CIM (group 1) versus other chemotherapy regimens (group 2). Toxicity was graded according to the Common Toxicity Criteria and MS estimated using the Kaplan-Meier method. Results: Of 51 eligible women (median age 71 years) 35 (69%) had stage 3 or 4 disease. 35/51 (69%) received chemotherapy; 2 with stage 1c disease received pelvic radiotherapy (pRT) alone whilst the remaining 14 were unfit for any treatment. Median follow-up for the treated patients is 45 months. 11/35 patients (31%) received CIM as first-line chemotherapy. Other regimens included: carboplatin (n = 14); carboplatin/paclitaxel (n = 3); carboplatin/epirubicin (n = 3); carboplatin/doxorubicin (n = 2); doxorubicin/ifosfamide (n = 1); cisplatin/ifosfamide (n = 1). 20/35 (57%) received adjuvant chemotherapy (AC) of which 8 received CIM; 11/20 patients also received adjuvant pRT. MS in the CIM AC group is 54.7 months compared to 37.4 months for other regimens. 3/8 patients (37.5%) in the CIM arm developed recurrent disease compared to 9/12 (75%) for other regimens. 4/16 patients received CIM as first- or second-line palliative chemotherapy. All patients responded of whom 2 achieved clinical and radiological complete response (CR). One woman subsequently relapsed and achieved a second CR with CIM. MS for all chemotherapy-treated patients is 54.7 months (group 1) versus 20.6 months (group 2) (p = 0.07). No patients in group 1 experienced any grade 3/4 toxicity and all patients completed the prescribed treatment. There were 2 unexpected treatment-related deaths in group 2, one of whom received carboplatin/paclitaxel and the other carboplatin/epirubicin. Conclusions: CIM appears to be efficacious and well tolerated in the treatment of CS and merits further investigation in clinical trials. No significant financial relationships to disclose.
Effects of induced mast cell activation on prostaglandin E and metalloproteinase production by rheumatoid synovial tissue in vitro
Authors: L C Tetlow, N Harper, T Dunningham, M A Morris, H Bertfield, D E Woolley
Journal: Annals of the Rheumatic Diseases (1998)

<h3>OBJECTIVE</h3> To determine whether induced mast cell activation/degranulation in rheumatoid synovial explants modulates the production of prostaglandin E (PGE<sub>2</sub>), and the matrix metalloproteinases (MMPs) collagenase 1, gelatinase A, and stromelysin 1. <h3>METHODS</h3> Synovial explant cultures were treated either with rabbit IgG anti-human IgE as a mast cell (MC) secretagogue or with non-immune rabbit IgG as controls. After 20 hours conditioned medium was assayed for the release of MC tryptase, PGE<sub>2</sub>, collagenase 1, gelatinase A, and stromelysin 1 using radioimmunoassay, enzyme linked immunosorbent assay, western blot, and zymogram techniques; tissue explants were examined immunohistologically for the relative distributions of MC tryptase, collagenase 1, and stromelysin 1. <h3>RESULTS</h3> Over a 20 hour incubation period the MC secretagogue treated explants showed a significant increase in the quantities of released tryptase and PGE<sub>2</sub> compared with controls. By contrast, the three MMPs showed variable values between experiments in response to MC activation; no reproducible trend of either an increased or decreased production of each MMP over control values was evident. Each MMP initially appeared as an inactive precursor form; collagenase 1 and stromelysin 1 were more effectively processed to active forms in the MC activated cultures. Immunolocalisation studies of MC activated explants showed that areas of extracellular tryptase were commonly associated with the local production of both collagenase 1 and stromelysin 1. <h3>CONCLUSION</h3> MC degranulation induced artificially in rheumatoid synovial explant cultures consistently resulted in an increased production of PGE<sub>2</sub> but had variable effects on the quantification of released collagenase 1, gelatinase A, and stromelysin 1. Such observations support the concept that activated synovial MCs within their native environment stimulate the production of non-MC derived PGE<sub>2</sub> and may contribute to the regulation and processing of specific MMPs; both aspects represent important components of the inflammatory and degradative processes of the rheumatoid lesion.
Safety and antitumor activity of recombinant soluble Apo2 ligand
Authors: Avi Ashkenazi, Roger C. Pai, Sharon Fong, Susan Leung, David A. Lawrence, Scot A. Marsters, Christine Blackie, Ling Chang, Amy E. McMurtrey, Andrea Hebert, Laura DeForge, Iphigenia L. Koumenis, Derf Lewis, Louise Harris, Jeanine Bussiere, Hartmut Koeppen, Zahra Shahrokh, Ralph H. Schwall
Journal: Journal of Clinical Investigation (1999)

TNF and Fas ligand induce apoptosis in tumor cells; however, their severe toxicity toward normal tissues hampers their application to cancer therapy. Apo2 ligand (Apo2L, or TRAIL) is a related molecule that triggers tumor cell apoptosis. Apo2L mRNA is expressed in many tissues, suggesting that the ligand may be nontoxic to normal cells. To investigate Apo2L's therapeutic potential, we generated in bacteria a potently active soluble version of the native human protein. Several normal cell types were resistant in vitro to apoptosis induction by Apo2L. Repeated intravenous injections of Apo2L in nonhuman primates did not cause detectable toxicity to tissues and organs examined. Apo2L exerted cytostatic or cytotoxic effects in vitro on 32 of 39 cell lines from colon, lung, breast, kidney, brain, and skin cancer. Treatment of athymic mice with Apo2L shortly after tumor xenograft injection markedly reduced tumor incidence. Apo2L treatment of mice bearing solid tumors induced tumor cell apoptosis, suppressed tumor progression, and improved survival. Apo2L cooperated synergistically with the chemotherapeutic drugs 5-fluorouracil or CPT-11, causing substantial tumor regression or complete tumor ablation. Thus, Apo2L may have potent anticancer activity without significant toxicity toward normal tissues.
Combating Resistance to Anti-IGFR Antibody by Targeting the Integrin β 3-Src Pathway
Authors: Dong Hoon Shin, Hyo-Jong Lee, Hye-Young Min, Sun Phil Choi, Mi-Sook Lee, Jung Weon Lee, Faye M. Johnson, Kapil Mehta, Scott M. Lippman, Bonnie S. Glisson, Ho-Young Lee
Journal: JNCI Journal of the National Cancer Institute (2013)

BackgroundSeveral phase II/III trials of anti–insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibodies (mAbs) have shown limited efficacy. The mechanisms of resistance to IGF-1R mAb-based therapies and clinically applicable strategies for overcoming drug resistance are still undefined.
Adenovirus-mediated E2F-1 gene transfer in nonsmall-cell lung cancer induces cell growth arrest and apoptosis
Authors: H. Kuhn, U. Liebers, C. Gessner, A. Schumacher, C. Witt, J. Schauer, I. Kovesdi, G. Wolff
Journal: European Respiratory Journal (2002)

Since overexpression of E2F-1 has been shown to induce apoptosis, the ability of adenovirus-mediated transfer of E2F-1 to inhibit tumour growth in nonsmall-cell lung cancer cell lines was investigated. Three cell lines with various genomic status were infected with AdE2F. Cell proliferation and viability were determined by trypan blue exclusion. Apoptosis induction was assessed by flow cytometry and poly-adenosine diphosphate-ribose-polymerase cleavage assay. In vivo , the effect of E2F-1 on tumour growth was determined in severe combined immunodeficiency (SCID) mice. The current experiments showed that overexpression of E2F-1 suppressed tumour cell growth. The population of apoptotic cells was dramatically increased 96 h after infection with AdE2F. Inhibition of cell growth and induction of apoptosis was not dependent on genomic status. Moreover, treatment of implanted tumours in SCID mice with AdE2F inhibited tumour growth. These data suggest that adenovirus-mediated E2F-1 gene therapy may be effective in the treatment of nonsmall-cell lung cancer.
External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study
Authors: Michel Bolla, Geertjan Van Tienhoven, Padraig Warde, Jean Bernard Dubois, René-Olivier Mirimanoff, Guy Storme, Jacques Bernier, Abraham Kuten, Cora Sternberg, Ignace Billiet, José Lopez Torecilla, Raphael Pfeffer, Carmel Lino Cutajar, Theodore Van der Kwast, Laurence Collette
Journal: The Lancet Oncology (2010)
Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study
Authors: J. A. Driver, A. Beiser, R. Au, B. E. Kreger, G. L. Splansky, T. Kurth, D. P. Kiel, K. P. Lu, S. Seshadri, P. A. Wolf
Journal: BMJ (2012)

<b>Objectives</b> To relate cancer since entry into the Framingham Heart Study with the risk of incident Alzheimer’s disease and to estimate the risk of incident cancer among participants with and without Alzheimer’s disease. <b>Design</b> Community based prospective cohort study; nested age and sex matched case-control study. <b>Setting</b> Framingham Heart Study, USA. <b>Participants</b> 1278 participants with and without a history of cancer who were aged 65 or more and free of dementia at baseline (1986-90). <b>Main outcome measures</b> Hazard ratios and 95% confidence intervals for the risks of Alzheimer’s disease and cancer. <b>Results</b> Over a mean follow-up of 10 years, 221 cases of probable Alzheimer’s disease were diagnosed. Cancer survivors had a lower risk of probable Alzheimer’s disease (hazard ratio 0.67, 95% confidence interval 0.47 to 0.97), adjusted for age, sex, and smoking. The risk was lower among survivors of smoking related cancers (0.26, 0.08 to 0.82) than among survivors of non-smoking related cancers (0.82, 0.57 to 1.19). In contrast with their decreased risk of Alzheimer’s disease, survivors of smoking related cancer had a substantially increased risk of stroke (2.18, 1.29 to 3.68). In the nested case-control analysis, participants with probable Alzheimer’s disease had a lower risk of subsequent cancer (0.39, 0.26 to 0.58) than reference participants, as did participants with any Alzheimer’s disease (0.38) and any dementia (0.44). <b>Conclusions</b> Cancer survivors had a lower risk of Alzheimer’s disease than those without cancer, and patients with Alzheimer’s disease had a lower risk of incident cancer. The risk of Alzheimer’s disease was lowest in survivors of smoking related cancers, and was not primarily explained by survival bias. This pattern for cancer is similar to that seen in Parkinson’s disease and suggests an inverse association between cancer and neurodegeneration.
Metformin Accelerates the Growth of BRAFV600E-Driven Melanoma by Upregulating VEGF-A
Authors: Matthew J. Martin, Robert Hayward, Amaya Viros, Richard Marais
Journal: Cancer Discovery (2012)

Abstract The antidiabetic drug metformin has antitumor activity in a variety of cancers because it blocks cell growth by inhibiting TORC1. Here, we show that melanoma cells that are driven by oncogenic BRAF are resistant to the growth-inhibitory effects of metformin because RSK sustains TORC1 activity even when AMP-activated protein kinase (AMPK) is activated. We further show that AMPK targets the dual-specificity protein phosphatase DUSP6 for degradation and this increases ERK activity, which then upregulates the VEGF-A protein. Critically, this drives angiogenesis and accelerates the growth of BRAF-driven tumors in mice. Unexpectedly, however, when VEGF signaling is inhibited, instead of accelerating tumor growth, metformin inhibits tumor growth. Thus, we show that BRAF-driven melanoma cells are resistant to the antigrowth effects of AMPK and that AMPK mediates cell-autonomous and cell-nonautonomous effects that accelerate the growth of these cells in vivo. Significance: Metformin inhibits the growth of most tumor cells, but BRAF-mutant melanoma cells are resistant to metformin in vitro, and metformin accelerates their growth in vivo. Unexpectedly, VEGF inhibitors and metformin synergize to suppress the growth of BRAF-mutant tumors, revealing a combination of drugs that may be effective in these patients. Cancer Discov; 2(4); 344–55. ©2012 AACR. This article is highlighted in the In This Issue feature, 288
Predominant Distribution of Nifedipine-Insensitive, High Voltage–Activated Ca <sup>2+</sup> Channels in the Terminal Mesenteric Artery of Guinea Pig
Authors: Hiromitsu Morita, Helen Cousins, Hitoshi Onoue, Yushi Ito, Ryuji Inoue
Journal: Circulation Research (1999)

Abstract —We have found nifedipine-insensitive (NI), rapidly inactivating, voltage-dependent Ca 2+ channels (current, NI- I Ca ) with unique biophysical and pharmacological properties in the terminal branches of guinea pig mesenteric artery, by using a whole-cell mode of the patch-clamp technique. The fraction of NI- I Ca appeared to increase dramatically along the lower branches of mesenteric artery, amounting to almost 100% of global I Ca in its periphery. With 5 mmol/L Ba 2+ as the charge carrier, NI- I Ca was activated with a threshold of −50 mV, peaked at −10 mV, and was half-activated and inactivated at −11 and −52 mV, respectively, generating a potential range of constant activation near the resting membrane potential. The NI- I Ca was rundown resistant, was not subject to Ca 2+ -dependent inactivation, and exhibited the pore properties typical for high voltage–activated Ca 2+ channels; Ba 2+ is ≈2-fold more permeable than Ca 2+ , and Cd 2+ is a better blocker than Ni 2+ (IC 50 , 6 and 68 μmol/L, respectively). Relatively specific blockers for N- and P/Q-type Ca 2+ channels such as ω-conotoxins GVIA and MVIIC (each 1 μmol/L) and ω-agatoxin IVA (1 μmol/L) were ineffective at inhibiting NI- I Ca , whereas nimodipine partially (10 μmol/L; ≈40%) and amiloride potently (≈75% with 1 mmol/L; IC 50 ; 107 μmol/L) blocked the current. Although these properties are reminiscent of R-type Ca 2+ channels, expression of the α 1E mRNA was not detected using reverse transcriptase–polymerase chain reaction. These results strongly suggest the predominant presence of NI, high voltage–activated Ca 2+ channels with novel properties, which may be abundantly expressed in peripheral small arterioles and contribute to their tone regulation.