tbuckley/cabot-search huggingface dataset:
Phase I and Pharmacokinetic Study of the Ribonucleotide Reductase Inhibitor, 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone, Administered by 96-Hour Intravenous Continuous Infusion
Authors: Scott Wadler, Della Makower, Caroline Clairmont, Paula Lambert, Karen Fehn, Mario Sznol
Journal: Journal of Clinical Oncology (2004)

3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP; Triapine; Vion Pharmaceuticals Inc, New Haven, CT) is a potent inhibitor of ribonucleotide reductase, with activity in preclinical tumor model systems. A phase I trial was initiated to determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of a 96-hour intravenous (IV) continuous infusion in patients with advanced cancer.Initially, courses were administered every 3 weeks, using an accelerated titration design. Subsequently, courses were administered every 2 weeks, and the dose was escalated in cohorts of three to six patients.Twenty-one patients were enrolled, seven on the every-3-week schedule and 14 on the every-other-week schedule. Three of six patients at 160 mg/m(2)/d developed dose-limiting toxicities including neutropenia, hyperbilirubinemia, and nausea or vomiting. Based on these initial results, the dose for 3-AP was re-escalated beginning at 80 mg/m(2)/d but administered every 2 weeks. At 120 mg/m(2)/d, three of seven patients had dose-limiting but reversible asthenia, hyperbilirubinemia, and azotemia or acidosis; however, in the case of renal and hepatic adverse events, the events were related to pre-existing borderline abnormal organ function. Therefore, the recommended phase II dose for 3-AP administered by 96-hour IV infusion is 120 mg/m(2)/d every 2 weeks. Detailed pharmacokinetic studies demonstrated linear kinetics up to 160 mg/m(2), with substantial inter-patient variability. There was no correlation between dose and clearance (R(2) = 0.0137). There were no objective responses, but there was prolonged stabilization of disease or decreases in serum tumor markers associated with stable disease in four patients.The 96-hour infusion of 3-AP is safe and well tolerated at the recommended phase II doses. Phase II trials of Triapine are ongoing.
Microbes and the proteoglycan connection.
Authors: A O Fuller
Journal: Journal of Clinical Investigation (1994)

Microbes and the Proteoglycan Connection Editorial How do microbes (viruses, bacteria, and protozoa) attach to cells for adhesion, colonization, or entry?How does this associ- ation influence infection and pathogenesis?Studies of the mechanism of attachment and the molecules involved are be- ginning to provide new insights into the critical early steps in microbial infection.Cell surface glycosaminoglycans (GAGs) such as heparan sulfate (HS), dermatan sulfate (DS), and chondroitin sulfate (CS) are long repeating sulfated glycoconjugates that are found on many cells and tissues ofanimal hosts ( 1 ).They are usually linked to a core protein to form proteoglycans and have been shown to be important for cell association of several microbes (2, 3).These include initial binding of herpes simplex virus (HSV), pseudorabies virus (PRV), human cytomegalovirus (HCMV), varicella zoster virus, bovine herpesvirus types 1 and 4, and possibly human immunodeficiency virus; adhesion of protozoa such as trypanosomes; and colonization by several bacteria (Chlamydia trachomatis and Bordetella pertussis).Now the Lyme disease spirochete, Borrelia burgdorferi, also seems to bind proteoglycans, as described in this issue of The Journal by Issacs (2).Association with cell surface GAGs offers notable advan- tages for microbes.GAGs provide many binding options since they are easily accessible, ubiquitous, and abundant on eucary- otic cells (1).Versatility in fine structure of GAGs provides specificity to the microbe for cell association.Initial interaction
Knowledge Is Not Enough
Authors: Robert H. Moser
Journal: New England Journal of Medicine (1977)

MY colleague was steaming. "I really cannot take much more of this. This is third go-around with Ms. Brown, and she still refuses a liver biopsy. I've given her a crash course in hepatic anatomy and pathophysiology and still she is not satisfied." He indicated our waiting room, where 20 patients sat. "I am already running an hour late, and I just cannot make rounds and get home three or four hours late, again! What do people want these days? Does she really think that I would want to do a biopsy if I did not think it was in . . .
Tumors Initiated by Constitutive Cdk2 Activation Exhibit Transforming Growth Factor β Resistance and Acquire Paracrine Mitogenic Stimulation during Progression
Authors: Patrick Corsino, Bradley Davis, Mary Law, Anna Chytil, Elizabeth Forrester, Peter Nørgaard, Nicole Teoh, Brian Law
Journal: Cancer Research (2007)

Abstract Cyclin D1/cyclin-dependent kinase 2 (Cdk2) complexes are present at high frequency in human breast cancer cell lines, but the significance of this observation is unknown. This report shows that expression of a cyclin D1–Cdk2 fusion protein under the control of the mouse mammary tumor virus (MMTV) promoter results in mammary gland hyperplasia and fibrosis, and mammary tumors. Cell lines isolated from MMTV–cyclin D1–Cdk2 (MMTV-D1K2) tumors exhibit Rb and p130 hyperphosphorylation and up-regulation of the protein products of E2F-dependent genes. These results suggest that cyclin D1/Cdk2 complexes may mediate some of the transforming effects that result from cyclin D1 overexpression in human breast cancers. MMTV-D1K2 cancer cells express the hepatocyte growth factor (HGF) receptor, c-Met. MMTV-D1K2 cancer cells also secrete transforming growth factor β (TGFβ), but are relatively resistant to TGFβ antiproliferative effects. Fibroblasts derived from MMTV-D1K2 tumors secrete factors that stimulate the proliferation of MMTV-D1K2 cancer cells, stimulate c-Met tyrosine phosphorylation, and stimulate the phosphorylation of the downstream signaling intermediates p70s6k and Akt on activating sites. Together, these results suggest that deregulation of the Cdk/Rb/E2F axis reprograms mammary epithelial cells to initiate a paracrine loop with tumor-associated fibroblasts involving TGFβ and HGF, resulting in desmoplasia. The MMTV-D1K2 mice should provide a useful model system for the development of therapeutic approaches to block the stromal desmoplastic reaction that likely plays an important role in the progression of multiple types of human tumors. [Cancer Res 2007;67(7):3135–44]
BULLOUS IODIDE ERUPTION IN ASSOCIATION WITH MALIGNANT ENDOCARDITIS AND NEPHRITIS
Authors: H. G. ADAMSON
Journal: British Journal of Dermatology (1938)

Journal Article BULLOUS IODIDE ERUPTION IN ASSOCIATION WITH MALIGNANT ENDOCARDITIS AND NEPHRITIS Get access H. G. ADAMSON H. G. ADAMSON Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology and Syphilis, Volume 50, Issue 4, 1 April 1938, Pages 167–173, https://doi.org/10.1111/j.1365-2133.1938.tb10528.x Published: 01 April 1938
Mortality in COPD: role of comorbidities
Authors: D. D. Sin, N. R. Anthonisen, J. B. Soriano, A. G. Agusti
Journal: European Respiratory Journal (2006)

Chronic obstructive pulmonary disease (COPD) represents an increasing burden throughout the world. COPD-related mortality is probably underestimated because of the difficulties associated with identifying the precise cause of death. Respiratory failure is considered the major cause of death in advanced COPD. Comorbidities such as cardiovascular disease and lung cancer are also major causes and, in mild-to-moderate COPD, are the leading causes of mortality. The links between COPD and these conditions are not fully understood. However, a link through the inflammation pathway has been suggested, as persistent low-grade pulmonary and systemic inflammation, both known risk factors for cardiovascular disease and cancer, are present in COPD independent of cigarette smoking. Lung-specific measurements, such as forced expiratory volume in one second (FEV<sub>1</sub>), predict mortality in COPD and in the general population. However, composite tools, such as health-status measurements (<i>e.g.</i> St George9s Respiratory Questionnaire) and the BODE index, which incorporates Body mass index, lung function (airflow Obstruction), Dyspnoea and Exercise capacity, predict mortality better than FEV<sub>1</sub> alone. These multidimensional tools may be more valuable because, unlike predictive approaches based on single parameters, they can reflect the range of comorbidities and the complexity of underlying mechanisms associated with COPD. The current paper reviews the role of comorbidities in chronic obstructive pulmonary disease mortality, the putative underlying pathogenic link between chronic obstructive pulmonary disease and comorbid conditions (<i>i.e.</i> inflammation), and the tools used to predict chronic obstructive pulmonary disease mortality.
Updates to Policies and Procedures Related to Potential Scientific and Academic Misconduct in the Journals of the American Diabetes Association
Authors: Christian S. Kohler
Journal: Diabetes Care (2011)

On behalf of the American Diabetes Association (ADA), we are indebted to the departing editorial teams of Diabetes and Diabetes Care , led by Peter C. Butler, MD, and Vivian A. Fonseca, MD, respectively. Over the last five years, both editorial teams have not only taken great efforts to cement the status of Diabetes and Diabetes Care as the premier journals devoted to diabetes research, but they have also diligently worked to ensure that research published in ADA journals adheres to international standards and requirements for biomedical publications.

Based on the input of Drs. Butler and Fonseca and their editorial teams, as well as the recommendations of various publications policy advisory groups (most notably the International Committee of Medical Journal Editors and the World Association of Medical Editors), the Association's Publications Policy Committee (PPC) has recently completed a comprehensive review of the publication policies and procedures for Diabetes and Diabetes Care . As part of the review process, ADA has made important updates to its policies and procedures related to potential academic and scientific misconduct in manuscripts submitted to its journals. We highly encourage all authors to review both the publication policies (1,2) and the instructions for authors (3,4) for Diabetes and Diabetes Care . The following are three important updates that authors should be aware of before submitting their work to the journals.

First, to help protect against the publication of plagiarized and previously published work, Diabetes and Diabetes Care adopted a widely used plagiarism detection system (5) in 2009. The system scans the text of submitted papers and compares it to a comprehensive and growing database of full-text scholarly and …
PAR-1 and Thrombin: The Ties That Bind the Microenvironment to Melanoma Metastasis
Authors: Maya Zigler, Takafumi Kamiya, Emily C. Brantley, Gabriel J. Villares, Menashe Bar-Eli
Journal: Cancer Research (2011)

Progression of melanoma is dependent on cross-talk between tumor cells and the adjacent microenvironment. The thrombin receptor, protease-activated receptor-1 (PAR-1), plays a key role in exerting this function during melanoma progression. PAR-1 and its activating factors, which are expressed on tumor cells and the surrounding stroma, induce not only coagulation but also cell signaling, which promotes the metastatic phenotype. Several adhesion molecules, cytokines, growth factors, and proteases have recently been identified as downstream targets of PAR-1 and have been shown to modulate interactions between tumor cells and the microenvironment in the process of melanoma growth and metastasis. Inhibiting such interactions by targeting PAR-1 could potentially be a useful therapeutic modality for melanoma patients.
DIFFERENTIAL DIAGNOSIS OF SCHIZOPHRENIA IN THE LIGHT OF THE CONCEPT OF PERSONALITY-STRATIFICATION
Authors: OTTO KANT
Journal: American Journal of Psychiatry (1940)

In this paper the differential diagnostic difficulties in schizophrenia have been considered in the light of the concept of personality- stratification. As a working hypothesis three different strata are distinguished. In addition to the essentially somatic basic stratum, two higher strata are considered, the vital and the psychological strata. It is assumed that the schizophrenic psychosis always reaches beyond the level of the psychological stratum, involving the vital stratum also. Similar appearing symptoms can therefore be discriminated by pointing out their different setting, i. e., the different depth of personality structure in which they occur. A set of criteria are described on the basis of which it is possible to decide whether a given symptom belongs to one or another stratum. By way of illustration, these criteria have been applied to the four most important differential-diagnostic questions, namely differentiation between schizophrenia on the one hand, and psychopathic states, neurosis, manic-depressive psychosis as well as certain exogenous schizophrenia-like pictures on the other.
Hormonal palliation of chemoresistant ovarian cancer: three consecutive phase II trials of the Mid-Atlantic Oncology Program.
Authors: J D Ahlgren, N M Ellison, R J Gottlieb, F Laluna, J J Lokich, P R Sinclair, W Ueno, G L Wampler, K Y Yeung, D Alt
Journal: Journal of Clinical Oncology (1993)

PURPOSE To evaluate the efficacy of three hormonal manipulations in the palliation of chemoresistant ovarian cancer, and to analyze the results in the light of other clinical trials. PATIENTS AND METHODS Three sequential phase II trials were performed in patients with refractory epithelial ovarian carcinoma, using high-dose megestrol acetate (800 mg/d for 30 days, then 400 mg/d), high-dose tamoxifen (80 mg/d for 30 days, then 40 mg/d), and aminoglutethimide (1 g/d plus tapering doses of hydrocortisone). Results were compared with those described in the world literature from trials of the same or similar agents. RESULTS No responses were seen among 30 assessable patients treated with megestrol acetate, and most (but not all) similar trials have reported low response rates. Five responses (17%) were seen among 29 patients treated with tamoxifen. Two responses exceeded 5 years in duration. No responses were seen among 15 patients treated with aminoglutethimide. CONCLUSION Antiestrogen therapy may offer the possibility of useful and, occasionally, long-term palliation of refractory epithelial ovarian carcinoma, with little toxicity. There may be a trend toward a dose-response effect, which represents a suitable topic for a future prospective trial.
Proteasomal degradation of O-GlcNAc transferase elevates hypoxia-induced vascular endothelial inflammatory response†
Authors: Hongtao Liu, Zhongxiao Wang, Shujie Yu, Jian Xu
Journal: Cardiovascular Research (2014)

Hypoxia induces vascular inflammation by a mechanism not fully understood. Emerging evidence implicates O-GlcNAc transferase (OGT) in inflammation. This study explored the role of OGT in hypoxia-induced vascular endothelial inflammatory response. Hypoxia was either induced (1% O2 chamber) or mimicked by exposure to hypoxia-mimetic agents in cultured endothelial cells. Hypoxia increased hypoxia-inducible factor (HIF-1α) and inflammatory response (gene and protein expression of interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1, and E-selectin) but, surprisingly, reduced OGT protein (not mRNA) levels. Hypoxia-mimetic CoCl2 failed to reduce OGT when proteasome inhibitors were present, suggesting proteasome involvement. Indeed, CoCl2 enhanced 26S proteasome functionality evidenced by diminished reporter (UbG76V-GFP) proteins in proteasome reporter cells, likely due to increased chymotrypsin-like activities. Mechanistically, β-TrCP1 mediated OGT degradation, since siRNA ablation of this E3 ubiquitin ligase stabilized OGT. Administration of the oxidative stress inhibitors reversed both proteasome activation and OGT degradation. Furthermore, up-regulation of OGT by stabilization, overexpression, or activation mitigated CoCl2-elicited inflammatory response. These observations were recapitulated in a mouse (C57BL/6J) model mimicking hypoxia, in which lung tissues presented higher levels of HIF-1α, proteasome activity, and inflammatory response, but lower levels of OGT (n = 5/group, hypoxia vs. normoxia, P < 0.05). However, administration of an activator of OGT (glucosamine: 1 mg/g/day, vehicle: saline, ip, 5 days) abolished the up-regulation of proteasome activity and inflammatory response (n = 5/group, the treated vs. untreated hypoxia groups, P < 0.05). 26S proteasome-mediated OGT reduction contributed to hypoxia-induced vascular endothelial inflammatory response. Modulation of OGT may represent a new approach to treat diseases characterized by hypoxic inflammation.
DC-SIGN Induction in Alveolar Macrophages Defines Privileged Target Host Cells for Mycobacteria in Patients with Tuberculosis
Authors: Ludovic Tailleux, Nhan Pham-Thi, Anne Bergeron-Lafaurie, Jean-Louis Herrmann, Patricia Charles, Olivier Schwartz, Pierre Scheinmann, Philippe H Lagrange, Jacques de Blic, Abdellatif Tazi, Brigitte Gicquel, Olivier Neyrolles
Journal: PLoS Medicine (2005)

Background Interplays between Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB) in human and host professional phagocytes, namely macrophages (Mϕs) and dendritic cells (DCs), are central to immune protection against TB and to TB pathogenesis. We and others have recently shown that the C-type lectin dendritic cell–specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN; CD209) mediates important interactions between mycobacteria and human monocyte-derived DCs (MoDCs) in vitro. Methods and Findings In order to explore the possible role of DC-SIGN in M. tuberculosis infection in vivo, we have analysed DC-SIGN expression in broncho-alveolar lavage (BAL) cells from patients with TB (n = 40) or with other non-mycobacterial lung pathologies, namely asthma (n = 14) and sarcoidosis (n = 11), as well as from control individuals (n = 9). We show that in patients with TB, up to 70% of alveolar Mϕs express DC-SIGN. By contrast, the lectin is barely detected in alveolar Mϕs from all other individuals. Flow cytometry, RT-PCR, and enzyme-linked immunosorbent assay analyses of BAL-derived fluids and cells indicated that M. tuberculosis infection induces DC-SIGN expression in alveolar Mϕs by a mechanism that is independent of Toll-like receptor-4, interleukin (IL)-4, and IL-13. This mechanism most likely relies on the secretion of soluble host and/or mycobacterial factors that have yet to be identified, as both infected and uninfected bystander Mϕs were found to express DC-SIGN in the presence of M. tuberculosis. Immunohistochemical examination of lung biopsy samples from patients with TB showed that the bacilli concentrate in pulmonary regions enriched in DC-SIGN-expressing alveolar Mϕs in vivo. Ex vivo binding and inhibition of binding experiments further revealed that DC-SIGN–expressing alveolar Mϕs constitute preferential target cells for M. tuberculosis, as compared to their DC-SIGN− counterparts. In contrast with what has been reported previously in MoDCs in vitro, ex vivo DC-SIGN ligation by mycobacterial products failed to induce IL-10 secretion by alveolar Mϕs, and IL-10 was not detected in BALs from patients with TB. Conclusion Altogether, our results provide further evidence for an important role of DC-SIGN during TB in humans. DC-SIGN induction in alveolar Mϕs may have important consequences on lung colonization by the tubercle bacillus, and on pulmonary inflammatory and immune responses in the infected host.
Bioartificial Kidney Ameliorates Gram-Negative Bacteria-Induced Septic Shock in Uremic Animals
Authors: William H. Fissell, Liandi Lou, Simin Abrishami, Deborah A. Buffington, H. David Humes
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. The bioartificial kidney (BAK) consists of a conventional hemofiltration cartridge in series with a renal tubule assist device (RAD) containing 109 porcine renal proximal tubule cells. BAK replaces filtration, transport, and metabolic and endocrinologic activities of a kidney. Previous work in an acutely uremic dog model demonstrated that BAK ameliorated endotoxin (lipopolysaccharide [LPS])-induced hypotension and altered plasma cytokine levels. To further assess the role of BAK in sepsis in acute renal failure, dogs were nephrectomized and 48 h later administered intraperitoneally with 30 × 1010 bacteria/kg of E. coli. One hour after bacterial administration, animals were placed in a continuous venovenous hemofiltration circuit with either a sham RAD without cells (n = 6) or a RAD with cells (n = 6). BP, cardiac output, heart rate, pulmonary capillary wedge pressure, and systemic vascular resistance were measured throughout the study. All animals tested were in renal failure, with blood urea nitrogen and serum creatinine concentrations greater than 60 and 6 mg/dl, respectively. RAD treatment maintained significantly better cardiovascular performance, as determined by arterial BP (P < 0.05) and cardiac output (P < 0.02), for longer periods than sham RAD therapy. Consistently, all sham RAD-treated animals, except one, expired within 2 to 9 h after bacterial administration, whereas all RAD-treated animals survived more than 10 h. Plasma levels of TNF-α, IL-10, and C-reactive protein (CRP) were measured during cell RAD and sham RAD treatment. IL-10 levels were significantly higher (P < 0.01) during the entire treatment interval in the RAD animals compared with sham controls. These data demonstrated in a pilot large animal experiment that the BAK with RAD altered plasma cytokine levels in acutely uremic animals with septic shock. This change was associated with improved cardiovascular performance and increased survival time. These results demonstrate that the addition of cell therapy to hemofiltration in an acutely uremic animal model with septic shock ameliorates cardiovascular dysfunction, alters systemic cytokine balance, and improves survival time. E-mail: [email protected]