tbuckley/cabot-search huggingface dataset:
Wyeth suppresses research on pill, programme claims
Authors: G. van Heteren
Journal: BMJ (2001)

A Dutch radio broadcast has reopened the debate on the venous thromboembolic risks of the third generation of oral contraceptive pills. The broadcast, by an investigative team from the radio station VPRO, looked into the industrial tactics to keep these drugs in the market.

The team, known as Argos, claimed that the pill manufacturer Wyeth had shelved a 1997 study said to indicate clear increases in the risks of developing deep venous thrombosis in several third generation pills. The Argos team recently came into possession of the summary, key findings, and conclusions of the Wyeth study.

When the team sought further comment, the company refused to disclose the full report on the grounds that it “did not add anything” to existing knowledge of the subject.

On further inquiry, it emerged that Wyeth had in fact submitted the study results to the European Medicines Evaluation Agency in 1999, after a legal suit was mounted in Germany concerning third generation contraceptives. The results, however, …
AR42, a novel histone deacetylase inhibitor, as a potential therapy for vestibular schwannomas and meningiomas
Authors: M. L. Bush, J. Oblinger, V. Brendel, G. Santarelli, J. Huang, E. M. Akhmametyeva, S. S. Burns, J. Wheeler, J. Davis, C. W. Yates, A. R. Chaudhury, S. Kulp, C.-S. Chen, L.-S. Chang, D. B. Welling, A. Jacob
Journal: Neuro-Oncology (2011)

Neurofibromatosis type 2 (NF2) is an autosomal-dominant disease that results in the formation of bilateral vestibular schwannomas (VSs) and multiple meningiomas. Treatment options for NF2-associated tumors are limited, and to date, no medical therapies are FDA approved. The ideal chemotherapeutic agent would inhibit both VS and meningiomas simultaneously. The objectives of this study are (1) to test the efficacy of AR42, a novel histone deacetylase inhibitor, to inhibit VS and meningioma growth and (2) to investigate this drug's mechanisms of action. Primary cultures of human VS and meningioma cells were established. Nf2-deficient mouse schwannoma and benign human meningioma Ben-Men-1 cells were also cultured. Cells were treated with AR42, and the drug's effects on proliferation and the cell cycle were analyzed using a methanethiosulfonate assay and flow cytometry, respectively. Human phospho-kinase arrays and Western blots were used to evaluate the effects of AR42 on intracellular signaling. The in vivo efficacy of AR42 was investigated using schwannoma xenografts. Tumor volumes were quantified using high-field, volumetric MRI, and molecular target analysis was performed using immunohistochemistry. AR42 inhibited the growth of primary human VS and Nf2-deficient mouse schwannoma cells with a half maximal inhibitory concentration (IC50) of 500 nM and 250–350 nM, respectively. AR42 also inhibited primary meningioma cells and the benign meningioma cell line, Ben-Men-1, with IC50 values of 1.5 µM and 1.0 µM, respectively. AR42 treatment induced cell-cycle arrest at G2 and apoptosis in both VS and meningioma cells. Also, AR42 exposure decreased phosphorylated Akt in schwannoma and meningioma cells. In vivo treatment with AR42 inhibited the growth of schwannoma xenografts, induced apoptosis, and decreased Akt activation. The potent growth inhibitory activity of AR42 in schwannoma and meningioma cells suggests that AR42 should be further evaluated as a potential treatment for NF2-associated tumors.
In situ cellular analysis of α-fetoprotein gene expression in regenerating rat liver after partial hepatectomy
Authors: Dominique Bernuau, Anne Poliard, Gérard Feldmann
Journal: Hepatology (1988)

Cellular analysis of hepatic α-fetoprotein gene expression in normal adult rat and during regeneration induced by partial hepatectomy was performed at the cellular level by in situ hybridization using 35 S-labeled complementary DNA probes and immunoperoxidase techniques. In normal adult rat liver sections, a few α-fetoprotein mRNA-cDNA hybrids are detected over all hepatocytes. No protein is detected with routine immunoperoxidase methods. However, after in vivo colchicine blockade of α-fetoprotein secretion, 10 to 20% α-fetoprotein-positive hepatocytes are observed. In regenerating livers, at 2, 6 and 24 hr (before and at the time of the peak of DNA synthesis in the periportal zones), a rise of the nuclear signal level is observed selectively in periportal hepatocytes, without modification of the cytoplasmic signal. At 48 hr (when most hepatocytes have completed at least one replicative cycle), almost all hepatocytes throughout the liver lobule display a rise of the nuclear (2- to 3-fold) and cytoplasmic (1.5- to 2-fold) signal level compared to nonoperated rats. These data show that all hepatocytes in the adult liver express a small number of α-fetoprotein mRNA sequences; they appear to be translated in protein whose secretion can be blocked by colchicine. The moderate increase in α-fetoprotein gene expression induced by liver regeneration takes place in all hepatocytes, in apparently two distinct steps: a very early nuclear accumulation of α-fetoprotein mRNA sequences and a late cytoplasmic accumulation of α-fetoprotein mRNA molecules.
Temporal Dissociation Between Lithium-Induced Changes in Frontal Lobe <i>myo</i>-Inositol and Clinical Response in Manic-Depressive Illness
Authors: Gregory J. Moore, Joseph M. Bebchuk, Julieclaire K. Parrish, Michael W. Faulk, Cynthia L. Arfken, Joan Strahl-Bevacqua, Husseini K. Manji
Journal: American Journal of Psychiatry (1999)

OBJECTIVE: The most widely accepted hypothesis regarding the mechanism underlying lithium's therapeutic efficacy in manic-depressive illness (bipolar affective disorder) is the inositol depletion hypothesis, which posits that lithium produces a lowering of myo-inositol in critical areas of the brain and the effect is therapeutic. Lithium's effects on in vivo brain myo-inositol levels were investigated longitudinally in 12 adult depressed patients with manic-depressive illness. METHOD: Medication washout (minimum 2 weeks) and lithium administration were conducted in a blinded manner. Regional brain myo-inositol levels were measured by means of quantitative proton magnetic resonance spectroscopy at three time points: at baseline and after acute (5–7 days) and chronic (3–4 weeks) lithium administration. RESULTS: Significant decreases (approximately 30%) in myo-inositol levels were observed in the right frontal lobe after short-term administration, and these decreases persisted with chronic treatment. The severity of depression measured by the Hamilton Depression Rating Scale also decreased significantly over the study. CONCLUSIONS: This study demonstrates that lithium administration does reduce myo-inositol levels in the right frontal lobe of patients with manic-depressive illness. However, the acute myo-inositol reduction occurs at a time when the patient's clinical state is clearly unchanged. Thus, the short-term reduction of myo-inositol per se is not associated with therapeutic response and does not support the inositol depletion hypothesis as originally posited. The hypothesis that a short-term lowering of myo-inositol results in a cascade of secondary signaling and gene expression changes in the CNS that are ultimately associated with lithium's therapeutic efficacy is under investigation.
Immunohistological Changes in Dilated Cardiomyopathy Induced by Immunoadsorption Therapy and Subsequent Immunoglobulin Substitution
Authors: Alexander Staudt, Frank Schäper, Verena Stangl, Andreas Plagemann, Marco Böhm, Kurt Merkel, Gerd Wallukat, Klaus D. Wernecke, Karl Stangl, Gert Baumann, Stephan B. Felix
Journal: Circulation (2001)

Background —Immunoadsorption (IA) and subsequent immunoglobulin (Ig) G substitution represent an additional therapeutic approach in dilated cardiomyopathy (DCM). It remains to be elucidated whether this treatment modulates myocardial inflammation, which is possibly a causal factor of ventricular dysfunction. Methods and Results —From 25 DCM patients (EF &lt;30%), 12 patients were randomized for IA therapy and subsequent IgG substitution at 1-month intervals until month 3. Before (&lt;7 days) and after IA therapy, right ventricular biopsies were obtained from all patients. Biopsies were also obtained at intervals of 3 months from 13 patients without IA/IgG treatment (controls). IA/IgG treatment induced improvement in left ventricular ejection fraction from 21.3±1.7% (±SEM) to 27.0±1.3% ( P &lt;0.01 versus baseline/controls) and reduction of the β-receptor autoantibody serum levels ( P &lt;0.01 versus baseline/controls). The number of CD3 cells decreased from 5.7±0.8 to 2.9±0.5 cells/mm 2 ( P &lt;0.01 versus baseline/controls). This decline was paralleled by a decrease in CD4 ( P &lt;0.01 versus baseline/controls) and CD8 ( P &lt;0.05 versus baseline/controls) lymphocytes. The number of leukocyte common antigen–positive cells (leukocytes) was reduced from 20.0±3.2 to 9.9±2.8 cells/mm 2 ( P &lt;0.01 versus baseline/ P &lt;0.05 versus controls). HLA class II expression decreased from 2.1±0.7% to 1.1±0.4% ( P &lt;0.05 versus controls/baseline). The number of immunopositive cells and the expression of HLA class II in controls remained stable. In both groups, the degree of fibrosis remained unchanged. Conclusions —IA and subsequent IgG substitution mitigate myocardial inflammation in DCM.
THE CASE OF WIGHT VERSUS FIELD.
Authors: George Padley, CharlesA. Aikin, A. Billing, WalterJ. Bryant, W.H. Broadbent, JohnH. Bryant, Frederick Cock, Alfred Collinson, James Copland, J. Brendon Curgenven, Frederick Danford, JohnGregory Forbes, GeoG. Gascoyen, George Gaskoin, WilliamHenry Gardner, R. Dawson Harling, Ernest Hart, Thos. Harvey Hill, Henry Bence Jones, C. Handfield Jones, Cundell Juler, SamuelA. Lane, JamesR. Lane, J.C. Langmore, Charles Malton, W.O. Markham, Charles Miles, John Morgan, WilliamB. Owen, Richard Quain, Charles Royston, Joseph Rushforth, Francis Sibson, E.H. Sieveking, William Smith, Richard Tamplin, John Taylor, Haynes Walton, Thos. Watson, Erasmus Wilson
Journal: The Lancet (1866)
A Cluster of Transfusion-Associated Babesiosis Cases Traced to a Single Asymptomatic Donor
Authors: Joanna Dobroszycki, Barbara L. Herwaldt, Fouad Boctor, James R. Miller, Jeanne Linden, Mark L. Eberhard, Jing Ja Yoon, Nahed M. Ali, Herbert B. Tanowitz, Fitzroy Graham, Louis M. Weiss, Murray Wittner
Journal: JAMA (1999)

The risk of acquiring babesiosis by blood transfusion is largely unknown since in areas where it is endemic it is often an asymptomatic infection.To investigate and treat a cluster of blood transfusion-associated babesiosis cases.Case series and epidemiologic investigation.Urban inner-city hospital.Six persons who received Babesia microti-infected blood components from a donor.Diagnosis and successful therapy of babesiosis following transfusion.Six individuals (1 adult, 1 child, and 4 neonates) were exposed to products from a single blood donation by an asymptomatic Babesia-infected donor. Three of the 6 exposed patients became parasitemic. Polymerase chain reaction testing, animal inoculation studies, and indirect immunofluorescent antibody testing were used to confirm the presence of Babesia microti in the donor's blood and to establish the presence of infection in 3 of the 6 recipients. The 3 infected recipients and 1 additional recipient were treated without incident.Physicians should consider babesiosis in the differential diagnosis of a febrile hemolytic disorder after blood transfusion. Prompt diagnosis is important since babesiosis is responsive to antibiotic therapy and, untreated, can be a fatal disease in certain risk groups.
The Mechanism of 5-Methyltetrahydrofolate Transport by Human Erythrocytes
Authors: Richard F. Branda, Bruce K. Anthony, Harry S. Jacob
Journal: Journal of Clinical Investigation (1978)

The mechanism involved in 5-methyltetrahydrofolate uptake by human cells is poorly understood. To more clearly elucidate this physiologically important process, transport of the vitamin was studied in human erythrocytes. 5-methyltetrahydrofolate uptake was found to increase with reticulocytosis, but measurable incorporation occurred in erythrocyte suspensions depleted of reticulocytes, leukocytes, and platelets, indicating uptake by mature erythrocytes. Incubation of erythrocytes with increasing concentrations of [(14)C]5-methyltetrahydrofolate resulted in increasing uptake but decreasing percentage incorporation, consistent with saturation of a carrier system. Both influx and efflux phases of uptake were temperature dependent, with almost no transport at 4 degrees C. Uptake of [(14)C]5-methytetrahydrofolate was effectively inhibited by unlabeled 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, and methotrexate, but not by pteroylglutamic acid. Prior incubation with 5-formyltetrahydrofolate increased uptake of [(14)C]5-methyltetrahydrofolate, and extracellular 5-formyltetrahydrofolate enhanced efflux of [(14)C]5-methyltetrahydrofolate. Nearly total depletion of ATP increased uptake of [(14)C]5-methyltetrahydrofolate, but efflux was unchanged. Column chromatography of membrane-free hemolysate after incubation with [(14)C]5-methyltetrahydrofolate showed 95% of radioactivity corresponded to marker radioisotope, and no other peak was noted. Thus peripheral erythrocytes incorporate 5-methyltetrahydrofolate by a saturable, temperature-dependent, substrate-specific process which is influenced by counter-transport. This mechanism is qualitatively similar to the carrier-mediated transport of folate compounds previously described in other cell types. Therefore, human erythrocytes should be useful for detailed characterization of this membrane carrier system.
Diagnostic utility of cerebrospinal fluid flow cytometry in patients with and without prior hematologic malignancy
Authors: Alexandra E. Kovach, Michelle E. DeLelys, Abigail S. Kelliher, Laura J. Dillon, Robert P. Hasserjian, Judith A. Ferry, Frederic I. Preffer, Aliyah R. Sohani
Journal: American Journal of Hematology (2014)

Flow cytometry (FCM) is an adjunct study to routine analysis of cerebrospinal fluid (CSF) to investigate for involvement by a hematologic malignancy. However, in our experience, FCM only infrequently detects abnormalities in CSF. To help optimize resources without forfeiting clinically important data, we sought to determine evidence-based indications and criteria for performing FCM on CSF. FCM results of 316 consecutive CSF specimens were retrospectively reviewed and correlated with clinical history, total nucleated cell (TNC) counts, and results of concurrent cytologic review. Of 255 samples adequate for analysis, 54% were from patients with a prior history of hematologic malignancy, of which 12% (17 cases) were abnormal by FCM. Corresponding TNC counts among samples with abnormal FCM ranged from 0-1050 cells/µL, and only 44% showed abnormal morphology on concurrent cytology. Of the remaining 46% of samples from patients with no known history of hematologic malignancy who had CSF sampling for neurological indications, only one (1%) was abnormal by FCM. This specimen had an elevated TNC count (39 cells/µL) but lacked clearly abnormal findings on concurrent cytology. These results support the use of CSF FCM only in patients with a history of hematologic malignancy or, in the absence of such a history, in samples showing pleocytosis. If these criteria were applied to the current cohort using a TNC count cut-off of >5 cells/µL, 23% of samples would have been deferred from testing, resulting in decreased cost, improved efficiency, and reduction in the need for unnecessary testing without a negative impact on clinical care.
Randomized, Controlled Trial of Topical Exit-Site Application of Honey (Medihoney) versus Mupirocin for the Prevention of Catheter-Associated Infections in Hemodialysis Patients
Authors: David Wayne Johnson, Carolyn van Eps, David William Mudge, Kathryn Joan Wiggins, Kirsty Armstrong, Carmel Mary Hawley, Scott Bryan Campbell, Nicole Maree Isbel, Graeme Robert Nimmo, Harry Gibbs
Journal: Journal of the American Society of Nephrology (2005)

The clinical usefulness of hemodialysis catheters is limited by increased infectious morbidity and mortality. Topical antiseptic agents, such as mupirocin, are effective at reducing this risk but have been reported to select for antibiotic-resistant strains. The aim of the present study was to determine the efficacy and the safety of exit-site application of a standardized antibacterial honey versus mupirocin in preventing catheter-associated infections. A randomized, controlled trial was performed comparing the effect of thrice-weekly exit-site application of Medihoney versus mupirocin on infection rates in patients who were receiving hemodialysis via tunneled, cuffed central venous catheters. A total of 101 patients were enrolled. The incidences of catheter-associated bacteremias in honey-treated (n = 51) and mupirocin-treated (n = 50) patients were comparable (0.97 versus 0.85 episodes per 1000 catheter-days, respectively; NS). On Cox proportional hazards model analysis, the use of honey was not significantly associated with bacteremia-free survival (unadjusted hazard ratio, 0.94; 95% confidence interval, 0.27 to 3.24; P = 0.92). No exit-site infections occurred. During the study period, 2% of staphylococcal isolates within the hospital were mupirocin resistant. Thrice-weekly application of standardized antibacterial honey to hemodialysis catheter exit sites was safe, cheap, and effective and resulted in a comparable rate of catheter-associated infection to that obtained with mupirocin (although the study was not adequately powered to assess therapeutic equivalence). The effectiveness of honey against antibiotic-resistant microorganisms and its low likelihood of selecting for further resistant strains suggest that this agent may represent a satisfactory alternative means of chemoprophylaxis in patients with central venous catheters.
A mutation in the <i>Icsbp1</i> gene causes susceptibility to infection and a chronic myeloid leukemia–like syndrome in BXH-2 mice
Authors: Karine Turcotte, Susan Gauthier, Ashleigh Tuite, Alaka Mullick, Danielle Malo, Philippe Gros
Journal: The Journal of Experimental Medicine (2005)

BXH-2 mice develop a fatal myeloid leukemia by a two-step mutagenic process. First, a BXH-2–specific recessive mutation causes a myeloproliferative syndrome. Second, retroviral insertions alter oncogenes or tumor suppressors, resulting in clonal expansion of leukemic cells. We have identified a recessive locus on chromosome 8 (Myls) that is responsible for myeloproliferation in BXH-2. This Myls interval has been narrowed down to 2 Mb and found to contain several positional candidates, including the interferon consensus sequence–binding protein 1 gene (Icsbp, also known as interferon regulatory factor 8 [IRF8]). We show that BXH-2 mice carry a mutation (915 C to T) resulting in an arginine-to-cysteine substitution at position 294 within the predicted IRF association domain of the protein. Although expression of Icsbp1 mRNA transcripts is normal in BXH-2 splenocytes, these cells are unable to produce interleukin 12 and interferon-γ in response to activating stimuli, confirming that R294C behaves as a loss-of-function mutation. Myeloproliferation in BXH-2 mice is concomitant to increased susceptibility to Mycobacterium bovis (BCG) despite the presence of resistance alleles at the Nramp1 locus. These results suggest a two-step model for chronic myeloid leukemia in BXH-2, in which inactivation of Icsbp1 predisposes to myeloproliferation and immunodeficiency. This event is required for retroviral replication, and subsequent insertional mutagenesis that causes leukemia in BXH-2 mice.
Double-Blind Randomized Phase II Study of the Combination of Sorafenib and Dacarbazine in Patients With Advanced Melanoma: A Report From the 11715 Study Group
Authors: David F. McDermott, Jeffrey A. Sosman, Rene Gonzalez, F. Stephen Hodi, Gerald P. Linette, Jon Richards, James W. Jakub, Muralidhar Beeram, Stefano Tarantolo, Sanjiv Agarwala, Gary Frenette, Igor Puzanov, Lee Cranmer, Karl Lewis, John Kirkwood, J. Michael White, Chenghua Xia, Kiran Patel, Evan Hersh
Journal: Journal of Clinical Oncology (2008)

This phase II study evaluated the efficacy and safety of sorafenib plus dacarbazine in patients with advanced melanoma.This randomized, double-blind, placebo-controlled, multicenter study enrolled chemotherapy-naive patients with stage III (unresectable) or IV melanoma. A total of 101 patients received placebo plus dacarbazine (n = 50) or sorafenib plus dacarbazine (n = 51). On day 1 of a 21-day cycle, patients received intravenous dacarbazine 1,000 mg/m(2) for a maximum of 16 cycles. Oral sorafenib 400 mg or placebo was administered twice a day continuously. The primary end point was progression-free survival (PFS) by independent assessment. Secondary and tertiary end points included time to progression (TTP), response rate, and overall survival (OS).Median PFS in the sorafenib plus dacarbazine arm was 21.1 weeks versus 11.7 weeks in the placebo plus dacarbazine arm (hazard ratio [HR], 0.665; P = .068). There were statistically significant improvements in PFS rates at 6 and 9 months, and in TTP (median, 21.1 v 11.7 weeks; HR, 0.619) in favor of the sorafenib plus dacarbazine arm. No difference in OS was observed (median, 51.3 v 45.6 weeks in the placebo plus dacarbazine and sorafenib plus dacarbazine arms, respectively; HR, 1.022). The regimen was well tolerated and had a manageable toxicity profile.Sorafenib plus dacarbazine was well tolerated in patients with advanced melanoma and yielded an encouraging improvement in PFS. Based on these findings, additional studies with the combination are warranted in this patient population.
ATR-Dependent Phosphorylation of FANCM at Serine 1045 Is Essential for FANCM Functions
Authors: Thiyam Ramsing Singh, Abdullah Mahmood Ali, Manikandan Paramasivam, Arun Pradhan, Kebola Wahengbam, Michael M. Seidman, Amom Ruhikanta Meetei
Journal: Cancer Research (2013)

Abstract Fanconi anemia (FA) is a genome instability syndrome that has been associated with both cancer predisposition and bone marrow failure. FA proteins are involved in cellular response to replication stress in which they coordinate DNA repair with DNA replication and cell-cycle progression. One regulator of the replication stress response is the ATP-dependent DNA translocase FANCM, which we have shown to be hyperphosphorylated in response to various genotoxic agents. However, the significance of this phosphorylation remained unclear. Here, we show that genotoxic stress–induced FANCM phosphorylation is ATR-dependent and that this modification is highly significant for the cellular response to replication stress. We identified serine (S1045) residue of FANCM that is phosphorylated in response to genotoxic stress and this effect is ATR-dependent. We show that S1045 is required for FANCM functions including its role in FA pathway integrity, recruiting FANCM to the site of interstrand cross links, preventing the cells from entering mitosis prematurely, and efficient activation of the CHK1 and G2–M checkpoints. Overall, our data suggest that an ATR-FANCM feedback loop is present in the FA and replication stress response pathways and that it is required for both efficient ATR/CHK1 checkpoint activation and FANCM function. Cancer Res; 73(14); 4300–10. ©2013 AACR.