tbuckley/cabot-search huggingface dataset:
Prophylactic Platelet Transfusion
Authors: Sherrill J Slichter
Journal: New England Journal of Medicine (2013)

To the Editor: We recently reported on a trial1 that was similar to the Trial of Prophylactic Platelets (TOPPS) by Stanworth et al. (May 9 issue).2 TOPPS showed that a strategy of prophylactic platelet transfusion, as compared with a strategy of no prophylaxis, was marginally superior in preventing bleeding of World Health Organization (WHO) grade 2 or higher in patients with hematologic cancers. This superiority was observed primarily in patients with leukemia. In patients undergoing autologous transplantation, the two strategies were equally effective. Many bleeding episodes of WHO grade 2 are not a relevant clinical problem. Among patients undergoing autologous transplantation, we observed virtually no severe bleeding with the noprophylaxis strategy. In accordance with TOPPS, we observed severe bleeding primarily in patients with leukemia. Post hoc analysis of 443 induction and consolidation cycles showed significantly more bleeding during induction. We think that the transfusion strategy should be adjusted to different hematologic cancers and treatments. In our experience, there is no strategy that fits all. In conclusion, in 453 autologous transplantations, a no-prophylaxis strategy was safe.1-3 The number of platelet transfusions was reduced significantly when prophylactic transfusion was omitted.1,2 Transfusions are not benign.4 We therefore do not agree with the conclusion of Slichter’s editorial regarding TOPPS.5 In adult patients with low bleeding risk (e.g., those undergoing autologous transplantation), it is now time to rethink prophylactic platelet transfusion.
Decitabine-induced apoptosis is p53-independent and mediated through reactive oxygen species (ROS) production and caspase activation
Authors: Tamer Fandy, Anchalee Jiemjit, Hetty Carraway, Stephen Baylin, James Herman, Steven Gore
Journal: Cancer Research (2007)

693  Despite their clinical activity in the treatment of myelodysplastic syndrome and acute myeloid leukemia, the precise mechanism behind the clinical efficacy of DNA methyltransferase (DNMT) inhibitors is not clear. Mechanisms beyond DNMT inhibition and gene re-expression may be required for clinical response. In this study, we evaluated the possible genotoxic effects of the DNMT inhibitor decitabine in leukemia cell lines. Decitabine induced DNA damage in ML-1, BV-173, KG-1a (p53 mutated) and HL-60 (p53 null) leukemia cells as indicated by the double strand break (DSB) marker γ-H2AX. Decitabine induced G2/M cell cycle arrest for 24 or 48 h followed by apoptosis in the four cell lines, regardless of their p53 status. To further investigate the role of p53 in decitabine-induced apoptosis, pretreatment of p53-wild type cells (ML-1 and BV-173) with pifithrin-α (p53 transactivation inhibitor) did not significantly decrease decitabine-induced apoptosis but did inhibit apoptosis in response to cytarabine. Moreover, nutlin-3a (MDM2 inhibitor) did not enhance decitabine-induced apoptosis but did enhance cytarabine-induced apoptosis, further confirming the dispensable role of p53 in decitabine-induced apoptosis. ROS are known inducers of DNA damage. Decitabine treatment generated ROS in the 4 cell lines; however, γ-H2AX induction was insensitive to the ROS scavenger N-acetyl-L-cysteine (NAC), indicating that DNA damage by decitabine is ROS-independent. ROS generation can induce apoptosis in caspase-dependent or -independent manner. NAC treatment partially inhibited decitabine-induced apoptosis, indicating that ROS generation is not the only apoptosis initiator. Inhibition of caspases activity by the pan-caspase inhibitor Z-VAD-FMK also partially inhibited decitabine-induced apoptosis, suggesting the involvement of other factors in addition to caspases in decitabine-induced apoptosis. The role of ROS generation in caspase activation requires further investigation. Our data demonstrate that decitabine can induce DNA damage in a ROS-independent manner and apoptosis in a p53-independent manner through both ROS production and caspase activation.
Abstract 2871: Allele-specific modulation of cancer metabolism by a long noncoding RNA
Authors: Roxana S. Redis, Cristina Ivan, Luz Vela, Weiqin Lu, Cristian Rodriguez-Aguayo, Andre LB Ambrosio, Sandra M. Gomes Dias, Ioana Berindan-Neagoe, George A. Calin
Journal: Cancer Research (2015)

Abstract Altered energy metabolism is a cancer hallmark as malignant cells tailor their metabolic pathways to meet their energy requirements. Glucose and glutamine are the two major nutrients that fuel cellular metabolism and the pathways utilizing these nutrients are often altered in cancer. In this study we show that the long non-codingRNA CCAT2, located at 8q24 amplicon on cancer risk associated rs6983267 SNP, regulates cancer metabolism in vitro and in vivo, in an allele-specific manner by binding the cleavage factor I (CFIm) complex with distinct affinities, complementary to the risk for colon cancer. The newly formed RNA:protein complex, CCAT2:CFIm, regulates the alternative splicing of glutaminase 1 (GLS1) by selecting the poly(A) site in intron 14 of the precursor mRNA. This results in the preferential expression of the GAC, the more catalytically active GLS1 isoform. Our findings, supported by data in human colorectal cancer samples from multiple cohorts, including TCGA dataset, and multiple animal models, uncover complex mechanisms of cancer metabolism regulation controlled by a long non-codingRNA. Citation Format: Roxana S. Redis, Cristina Ivan, Luz Vela, Weiqin Lu, Cristian Rodriguez-Aguayo, Andre LB Ambrosio, Sandra M. Gomes Dias, Ioana Berindan-Neagoe, George A. Calin. Allele-specific modulation of cancer metabolism by a long noncoding RNA. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2871. doi:10.1158/1538-7445.AM2015-2871
Aerosol therapy with liposome-encapsulated cisplatin for lung cancer in orthotopically implanted SCID mice
Authors: Kazuya Kondo, Haruhiko Fujino, Junji Kimura, Hiromitsu Takizawa, Naruhiko Sawada, Takanori Miyoshi, Shoji Sakiyama, Yasumasa Monden
Journal: Cancer Research (2004)

641  Background: Most of patients with lung cancer die of progressive metastatic disease despite of multitherapeutic modalities, although recently there is great hope offered by several new anticancer drugs and new therapy targeted to biologic abnormalities. Direct drug delivery of chemotherapy to the lung can increase both the drug concentration and exposure in the tumor of the lung. To determine whether this approach has utility against lung cancer, the efficacy of aerosol therapy with liposome-encapsulated cisplatin was determined using orthotopically implanted SCID mouse model of the lung cancer cell line Ma44-3. Materials: liposome-encapsulated cisplatin, TRX-20:PEG5000-DSPE: Rhodamine DHPE=50:42:8:0.5:0.2, cisplatin (0.5mg/ml), average diameter of article 120nm. Method and results: 1) Adhesion test between tumor cell line and liposome- cisplatin: 3 lung caner cell lines (Ma44-3, Ma25, FT821) were incubated with 100ug/mL rhodamine-labeled liposome in the incubation medium for 4 h. Fluorescence image were obtained using fluorescence microscope. Adhesion potential of liposome to cells: Ma44-3>> Ma25> FT821. 2) Antitumor effect of liposome-cisplatin to cancer cell line in vitro: We measured IC50 of liposome-cisplatin and only cisplatin in Ma44-3 cell line for 48 and 96 h incubation. using modified MTT (PreMix WST-1) assay. The IC50 of only cisplatin and liposome- cisplatin was 40 and 10 ug/mL at 48 h, 40 and 1.5 ug/mL at 96 h, respectively. The antitumor effect of liposome-cisplatin was very higher than that of only cisplatin. 3) Accumulation of liposome-cisplatin of the lung and tumor in SCID mice: The mice (n=6) were exposed to aerosol (3 mL volume of rhodamine-labeled liposome-cisplatin (500ug/mL)) for 15 min. The mice were sacrificed on day 1 and 4 after administration. The left lung including tumor was removed, and embedded by OCT compound. The frozen sections were examined using fluorescence microscope. The liposome-cisplatin was accumulated in lung tissues and tumor cells. 4) Efficacy of aerosol therapy of liposome-cisplatin in vivo: The aerosol treatment was performed on day 5 after implantation. The mice (n=5) were sacrificed on 12 day after inplantation. The volume of implanted tumors was measured. The volume of tumor with aerosol treatment was smaller than that without treatment (mean volume: 3775 versus 7269 mm3). Conclusion: These data suggest that aerosol treatment with liposome-encapsulated cisplatin may be useful for therapy of lung cancer.
Synergistic interactions of the Hsp90 inhibitor 17AAG and the PI3K inhibitor LY294002 in non-small cell lung cancer (NSCLC) cell lines involve disruption of Akt and c-raf signalling
Authors: Sofia Angelaki, Savita Lnu, Erika Brown, Gregory Ayers, Vassiliki A. Papadimitrakopoulou
Journal: Cancer Research (2005)

4200   Background: 17-allylamino-demethoxygeldanamycin (17AAG) inhibits the chape-roning action of heat-shock protein 90 (Hsp90) and promotes the proteasomal degradation of multiple oncogenic signalling molecules such as EGFR and Akt. 17AAG has shown promising growth inhibition in a variety of cancer cell lines and xenografts and is currently in clinical development. Non-small cell lung cancer (NSCLC) cells rely on multiple genetic abnormalities for their survival. Thus, on the basis of combinatorial attack of multiple targets by Hsp90 inhibitors the effects of 17AAG on human NSCLC cell lines were investigated. Methods and Results: Exposure of H1792, H292, H596, H1299, A549, H460 and H157 cells to 17AAG resulted in dose and time dependent inhibition of proliferation exhibiting IC50 (inhibitory concentration) values for cell viability at 72 h that ranged from 1.07 ± 0.28 to 7.87 ± 1.27 uM (Mean ± SE) as measured by MTT assays. In A549 and H157 cells flowcytometry revealed 17AAG-induced G1 cell cycle arrest and subsequent apoptosis and immunoblot analysis showed a decline in c-raf and Akt expression levels. Since Akt is a central effector of NSCLC cell proliferation and survival we reasoned that dual targeting of Akt signalling by exposure of A549 and H157 cells to 17AAG plus LY294002, a PI3K inhibitor, would enhance the 17AAG-induced effects. Indeed, isobologram analysis and calculation of the combination indices (CI) at the IC50 level demonstrated highly synergistic interactions. The combination enhanced 17AAG-induced cell cycle and proapoptotic effects as evidenced by both flowcytometry and immunoblot analysis of relevant proteins and led to a further decline in Akt and c-raf signalling. Inducible expression of a constitutively active gag-Akt construct introduced in H1299 cells attenuated but did not completely abolish the observed synergism. Moreover, dowregulation of c-raf signalling by combined treatment with 17AAG plus U0126, a MEK inhibitor produced synergistic antiproliferative effects in A549 and H157 cell lines. Enhancement of 17AAG-induced cell cycle effects was shown in both cell lines, whereas potentiation of proapoptotic effects was only evident in A549 cells that exhibited a decline in Akt activation along with the downregulation in c-raf signalling. Conclusions: Taken together the above findings demonstrate that the efficacy of 17AAG against lung cancer cell lines can be potentiated by the combination with either a PI3K or a MEK inhibitor and that the synergism between 17AAG and LY294002 is mediated through concurrent interference with at least Akt and c-raf signalling. The information obtained from the present study could have direct applications in the management of NSCLC (supported by NCI P50 CA97007).
Rheumatic Fever
Authors: F. Bach, A. Freedman, L. Bernstock
Journal: BMJ (1952)

bf events ?Why does the cardiac patient pass into a dying state with a resting minute volume of circulation the same as that of an upright soldier ?The realization of ignorance brings its gleam of hope that continued research will add to our therapeutic power: cardiac surgery and new technical developments in investi- gation are adding daily to our knowledge and extending our experience in depth.In time some of the pictures crudely sketched in these lectures will be more clearly perceived, and be submitted once again to a much more rational and complete interpretation than we can give to-day.(Figs. 5, 6, and 7 are reproduced from Acta Medica Scandi-
hCGβ overexpression leads to enhanced wnt/β-catenin signaling in the mouse mammary gland and redundancy of epithelial ERα in mammary tumorigenesis
Authors: Aino Kuorelahti, Anni Wärri, Susana Rulli, Ilpo Huhtaniemi, Matti Poutanen
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4840 

Purpose of this study was to investigate endocrine induction of mammary tumorigenesis by using transgenic (TG) mice which express human chorionic gonadotropin β-subunit (hCGβ) under the ubiquitin C promoter. These mice have multiple endocrine abnormalities secondary to the transgene expression, including precocious puberty, increased level of circulating estradiol at peripuberty, followed by increasing circulating levels of progesterone and prolactin. Precocious puberty stimulates abnormal branching of the mammary ducts, and lobuloalveolar differentiation of the mammary gland is evident in 3-month-old virgin mice. The formation of estrogen (ER) and progesterone receptor (PR) negative, aggressive malignant tumors is observed at the age of 9 months. Tumorigenesis is initially hormonally driven, since ovariectomy abolishes the pathological changes. Mammary gland gross morphology (whole mounts) and histology were studied, and immunohistochemical staining for ER, PR, keratins 5 and 6, and β-catenin was performed. The findings indicate that the mammary glands have a similar histopathology to that observed in TG mice with activated Wnt/β-catenin pathway. This was demonstrated with focally increased expression of β-catenin and signs of aberrant epidermal differentiation, as shown by abnormal staining for keratins 5 and 6. Furthermore, the tumors did not express detectable levels of ERα. Quantitative RT-PCR of the Wnt genes was used to study the mechanism of the activated Wnt-pathway in the mammary gland. Especially, the expression of Wnt5b was increased already at the age of 3 months, and up-regulation of Wnt5b and 7b expression was observed in the subsequently appearing tumors. To further clarify the contribution of the transiently increased estrogen level at peripuberty, to the phenotype of the TG mammary gland, we transplanted ERα knock-out (αERKO) mammary epithelium to the cleared mammary fat pads of the hCGβ TG females at pre-pubertal age. Suprisingly, the lack of ERα had no effect on mammary gland hyperplasia or on the expression of Wnt genes measured at the age of 5 months. Furthermore, pre-cancerous lesions were identical with and without ERα expression in the mammary epithelium, indicating reduncancy of the epithelial ERα in the mammary tumorigenesis observed in the hCGβ mice. Thus, the hCGβ TG mammary gland tumorigenesis serves as a model for hormonally induced but epithelial ERα -independent, β-catenin stabilizing breast carcinogenesis.
Abstract 1184: Changes In Total Cholesterol Levels In The Icelandic Population Is Not Attributable To Lipid Lowering Medication Use
Authors: Vilmundur Gudnason, Bolli Thorsson, Karl Andersen, Gunnar Sigurdsson
Journal: Circulation (2008)

Background: Total cholesterol (TC) levels have decreased in Western populations over the last decades. This has largely been attributed to changes in dietary intake, mainly reduced intake of saturated fat. The drop in population TC has been very great from the early 1990s in Iceland and many other countries, coinciding with the introduction of lipid lowering medication. A number of studies have examined the changes in TC and frequently attribute the drop to statin use. However, few studies have been able to address this directly due to lack of information on statin use in the same individuals as TC has been measured in at the population level. Methods &amp; results: We address this in the population based studies of the Icelandic Heart Association, the Reykjavik study and related studies carried out over the last 40 years. TC was measured in fasting blood in 8 different cross sectional samples between 1967 and 2007 of close to 30.000 men and women of age 45– 65 with information on lipid medication. Statin use has been increasing mainly after 1990 and today statin use is about 12% among men and about 5% in women. The changes in population TC in men with and without the use of lipid lowering medication is shown in the Figure . The decline in population level of TC has the same characteristic for the 88% not taking lipid lowering drugs as for those 12% on medication. The same picture is seen for women. Conclusion: It can be stated that the rapid decline in TC of the Icelandic population over the last 15 years or so is not explained by the introduction of lipid lowering medication. It is likely that the same applies to other populations where similar picture is seen and lipid lowering medication is at a similar or even less level.
Regulatory mutations in TBX3 disrupt asymmetric hair pigmentation that underlies Dun camouflage color in horses
Authors: Freyja Imsland, Kelly McGowan, Carl-Johan Rubin, Corneliu Henegar, Elisabeth Sundström, Jonas Berglund, Doreen Schwochow, Ulla Gustafson, Páll Imsland, Kerstin Lindblad-Toh, Gabriella Lindgren, Sofia Mikko, Lee Millon, Claire Wade, Mikkel Schubert, Ludovic Orlando, Maria Cecilia T Penedo, Gregory S Barsh, Leif Andersson
Journal: Nature Genetics (2015)
Abstract A08: Activation of Wnt/β-catenin in acinar cells accelerates Kras-induced PDAC, while activation of Wnt signaling pathways in stroma induces mucinous cystic neoplasm
Authors: Makoto Sano, David R. Driscoll, Wilfredo E. DeJesus-Monge, David S. Klimstra, Brian C. Lewis
Journal: Cancer Research (2015)

Abstract Pancreatic ductal adenocarcinoma (PDAC) commonly develops following activating mutations in the KRAS oncogene. Activation of the Wnt signaling pathway is also commonly observed in PDAC, yet whether Wnt ligand induced signaling promotes pancreatic tumorigenesis in vivo remains unclear. To ascertain the impact of postnatal activation of the Wnt signaling pathways in PDAC development, we combined the elastase-tva-based RCAS-TVA pancreatic cancer model with the established LSL-KrasG12D, Ptf1a-cre model. Delivery of RCAS viruses encoding β-cateninS37A and Wnt1 stimulated the progression of premalignant PanIN and PDAC development. Mice injected with RCAS-β-cateninS37A and Wnt1 had reduced survival relative to RCAS-GFP controls (log-rank test; p &amp;lt; 0.05). Immunohistochemical analysis demonstrated cytoplasmic and nuclear staining of β-catenin in Wnt1-induced PDAC, and enhanced staining for the Wnt target gene Axin2 in the tumor epithelium, but not the reactive stroma. Interestingly, we also found that female mice injected with RCAS-Wnt1, but neither RCAS-β-cateninS37A nor RCAS-GFP, developed mucinous cystic neoplasm (MCN). These lesions displayed stereotypical ovarian-like stroma that was positive for estrogen receptor (ER) and progesterone receptor (PR), but they lacked the typical mucinous epithelium observed in human MCN. Analysis of tissue specimens confirmed of activation of both the Wnt/β-catenin and PCP signaling pathways in the stroma, but not the epithelium of MCN lesions. Analysis of human MCN cases identified activation of these Wnt signaling pathways in the ovarian-like stroma, but not the cyst epithelium. Together, these data suggest that the Wnt/β-catenin signaling pathway in acinar cells stimulates Kras-induced PDAC development, while activation of Wnt signaling pathways in the stroma stimulates the development of the ovarian-like stroma and contributes to MCN formation in vivo. Citation Format: Makoto Sano, David R. Driscoll, Wilfredo E. DeJesus-Monge, David S. Klimstra, Brian C. Lewis. Activation of Wnt/β-catenin in acinar cells accelerates Kras-induced PDAC, while activation of Wnt signaling pathways in stroma induces mucinous cystic neoplasm. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A08.
Abstract A77: Investigating the role of ADAM10 in pancreatic tumor differentiation
Authors: Louise V. Peverley, Christopher J. Halbrook, Jason C. Hall, Christine M. Ardito, Howard C. Crawford
Journal: Cancer Research (2015)

Abstract Pancreatic adenocarcinoma (PDAC) is the 4th most common cause of cancer related deaths in the United States and has a dismal 5-year survival rate of 6%. This prognosis is attributed the disease’s fast and asymptomatic progression to metastasis, leading to late diagnosis upon which time there are few treatment options available. The A Disintegrin and Metalloproteinase (ADAM) family are sheddase proteins known to regulate cell adhesion and function. This regulation can allow ADAMs to influence the ability of tumor cells to disseminate from the primary tumor and metastasize to distant organs. ADAM10, which is seen to be up-regulated in both chronic pancreatitis and PDAC, cleaves a variety of substrates including several cell adhesion molecules such as L1-CAM, N-Cadherin, and E-Cadherin. Using a conditional knockout for ADAM10 in the Kras+/G12D;Ptf1a+/Cre (KC) mouse model of pancreatic cancer, we have observed an absence of metastasis when ADAM10 is genetically ablated. To investigate the potential role that ADAM10 plays in this, we used a shRNA approach to knock-down ADAM10 expression in various human pancreatic cancer cells lines. Analysis of these cell lines suggests a partial restoration of a less aggressive, differentiated phenotype, consistent with the increased longevity of the ADAM10 knockout KC mice. Citation Format: Louise V. Peverley, Christopher J. Halbrook, Jason C. Hall, Christine M. Ardito, Howard C. Crawford. Investigating the role of ADAM10 in pancreatic tumor differentiation. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A77.
Neither dabigatran nor rivaroxaban were linked to increased GI bleeding compared with warfarin
Authors: Ronald L. Koretz
Journal: Annals of Internal Medicine (2015)

Source Citation Abraham NS, Singh S, Alexander GC, et al. Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study. BMJ. 2015;350:h1857. 25910928