tbuckley/cabot-search huggingface dataset:
Azacitidine in untreated acute myeloid leukemia: A report on 149 patients
Authors: Sylvain Thépot, Raphael Itzykson, Valerie Seegers, Christian Recher, Emmanuel Raffoux, Bruno Quesnel, Jacques Delaunay, Thomas Cluzeau, Anne Marfaing Koka, Aspasia Stamatoullas, Marie‐Pierre Chaury, Caroline Dartigeas, Stéphane Cheze, Anne Banos, Pierre Morel, Isabelle Plantier, Anne‐Laure Taksin, Jean Pierre Marolleau, Cecile Pautas, Xavier Thomas, Francoise Isnard, Blandine Beve, Yasmine Chait, Agnes Guerci, Norbert Vey, Francois Dreyfus, Lionel Ades, Norbert Ifrah, Herve Dombret, Pierre Fenaux, Claude Gardin
Journal: American Journal of Hematology (2013)

Limited data are available on azacitidine (AZA) treatment and its prognostic factors in acute myeloid leukemia (AML). One hundred and forty‐nine previously untreated AML patients considered ineligible for intensive chemotherapy received AZA in a compassionate patient‐named program. AML diagnosis was de novo, post‐myelodysplastic syndromes (MDS), post‐MPN, and therapy‐related AML in 51, 55, 13, and 30 patients, respectively. Median age was 74 years, median white blood cell count (WBC) was 3.2 × 10 9 /L and 58% of the patients had ≥30% marrow blasts. Cytogenetics was adverse in 60 patients. Patients received AZA for a median of five cycles (range 1–31). Response rate (including complete remission/CR with incomplete recovery/partial remission) was 27.5% after a median of three cycles (initial response), and 33% at any time (best response). Only adverse cytogenetics predicted poorer response. Median overall survival (OS) was 9.4 months. Two‐year OS was 51% in responders and 10% in non‐responders ( P &lt;0.0001). Adverse cytogenetics, WBC &gt;15 × 10 9 /L and ECOG‐PS ≥2 predicted poorer OS, while age and marrow blast percentage had no impact. Using MDS IWG 2006 response criteria, among patients with stable disease, those with hematological improvement had no significant survival benefit in a 7 months landmark analysis. Outcomes observed in this high‐risk AML population treated with AZA deserve comparison with those of patients treated intensively in prospective studies. Am. J. Hematol. 89:410–416, 2014. © 2013 Wiley Periodicals, Inc.
<i>Garden</i>
Authors: Jeanette M. Smith
Journal: JAMA (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Quarfloxin (CX-3543) disrupts the Nucleolin/ rDNA quadruplex complexes, inhibits the elongation by RNA Polymerase I and exhibits potent antitumor activity in models of cancer
Authors: Denis Drygin, Jeffrey Whitten, William Rice, Sean O'Brien, Michael Schwaebe, Amy Lin, Caroline Ho, Katy Trent
Journal: Cancer Research (2008)

3301  RNA Polymerase I (Pol I) is a critical component of the Ribosome Biogenesis pathway and can be regulated with small molecules at the initiation step, elongation step or at its catalytic site. The initiation step of Pol I dependents on proteins such as SL1 and UBF. Another nucleolar protein, Nucleolin, binds to the rDNA gene and modulates Pol I transcription elongation. rDNA contains multiple GC-rich sequences which can form quadruplex secondary structures. Such structures were shown to possess sub-nanomolar affinities for Nucleolin. Small molecule drug Quarfloxin (CX-3543) disrupts the Nucleolin/ rDNA quadruplex complexes in biochemical assays as well as in cells and consistent with Pol I elongation inhibition has been found to suppress rRNA synthesis. The compound also showed strong antitumor effect in multiple cell lines and demonstrates good efficacy in xenograft models of cancer.  Using a novel search algorithm we identified 14 potential quadruplex sites in the non-template strand of each human rRNA gene. The DNA oligonucleotides corresponding to those sites were synthesized and their quadruplex nature was confirmed by CD spectrophotometry. Eleven of these quadruplexes bound to Nucleolin with Kd’s of under 10 nM. These Nucleolin/ quadruplex complexes were disrupted by Quarfloxin, a compound designed to bind G-quadruplexes, with Ki’s in the range of 0.15 to 1.0 uM as measured by electrophoretic mobility shift assay. Treatment with Quarfloxin resulted in dissociation of Nucleolin from rDNA quadruplexes as well as redistribution of Nucleolin from nucleoli into nucleoplasm as monitored by ChIP and immunofluorescence microscopy. Nuclear run-on experiment demonstrated that Quarfloxin inhibited the elongation by RNA Polymerase I in isolated nuclei with IC50 = 3.3 uM. This translated in the inhibition of rRNA synthesis in HCT-116 cells with IC50 = 4.3 uM as measured by qRT-PCR. This inhibition was specific for RNA Polymerase I as Quarfloxin failed to affect the synthesis of c-myc mRNA by RNA Polymerase II at these concentrations. Quarfloxin triggered apoptosis and inhibited multiple tumor cell lines in Alamar Blue cell viability assay typically with an average IC50 of approximately 1.0 uM. The molecule also demonstrated antitumor activity in multiple Xenograft models of human cancer when given IV, for instance in the Mia PaCa-2 model of pancreatic cancer with a T/C of 42%.  Compounds that bind rDNA Quadruplexes can inhibit rRNA synthesis. Quarfloxin disrupts Nucleolin/ rDNA quadruplex complexes, selectively inhibits rRNA synthesis, and possesses broad spectrum cell proliferation inhibition potency and antitumor activity in Xenograft models of cancer.
Abstract MP03: All-Cause Mortality and Cardiorespiratory Fitness Among Patients with a Family History of CHD - The FIT Project
Authors: Jaideep Patel, Mahmoud Al Rifai, Rupert K Hung, Khurram Nasir, Steve J Keteyian, Clinton A Brawner, Mouaz H Al-Mallah, Michael J Blaha
Journal: Circulation (2015)

BACKGROUND: The extent to which cardiorespiratory fitness (CRF) provides meaningful risk stratification among those with a family history (FH) of coronary heart disease (CHD) is yet to be defined. We compare all-cause mortality in individuals with a FH of CHD to those without. METHODS: We retrospectively studied 68,947 patients without history of CHD (n=7,980) or heart failure (n=1,564) who underwent physician-referred treadmill stress testing between 1991 and 2009. FH of CHD was defined as a self-reported compatible history of CHD in a first-degree relative. CRF was based on peak estimated metabolic equivalents (METS) and categorized into 4 groups: &lt;6, 6 to 10, 10 to 12, and ≥12 METS. Multivariable-adjusted Cox proportional hazards models were used to study the association between increasing METS categories and risk of mortality using the lowest METS category as the reference. Adjusted mortality rates were calculated using direct standardization. Multiplicative interaction testing was performed for FH and METS categories. RESULTS: Overall, 50% (n=34,532) of patients (mean age 53.5±12 years, 49% males) reported a FH of CHD. Compared to those without a FH, those with a FH were more likely to abuse tobacco (43% vs 40%) and have hyperlipidemia (47% vs 42%), but less likely to be diabetic (18% vs 22%). FH was significantly associated with mortality after adjusting for traditional risk factors, however an association was not observed with the addition of METS [HR(95%CI)]: 0.92(0.88-0.97) and 0.96(0.91-1.01), respectively. Adjusted mortality rates were lower with increasing METS categories (43%,19%,10% and 7% in those without a FH vs 34%,15%,8% and 5%, respectively, in those with a FH). In fully adjusted models, increasing METS categories were associated with a lower risk of mortality (figure), without effect modification by FH of CHD (P=0.37). CONCLUSION: CRF limited an independent mortality association with FH. Higher levels of CRF were associated with similar reductions in mortality risk in those with and without a FH of CHD.
Abstract 708A: Suppression of glycolysis by retinoic acid sensitizes hepatocellular carcinoma cells to apoptosis induced by sorafenib via AMPK activation
Authors: Goshi Shiota, Hiroki Shimizu, Keita Kanki
Journal: Cancer Research (2015)

Abstract Aims: Hepatocellular carcinoma (HCC) is the fifth cause of cancer death all over the world and its prognosis is very poor. To improve the prognosis of HCC patients, a novel therapy including chemotherapy against HCC should be developed. The strategies to enhance the efficacy of anticancer drugs are required. Sorafenib is the only drug to prolong overall survival of the patients with HCC, however, the outcome is not still satisfactory. In this study, we investigated the effects of combination treatment of anticancer drugs and retinoids,which has been known to show antitumor activity, in HCC cells. Methods: Cytotoxicity of combination treatment of retinoids (all-trans retinoic acid (ATRA), NIK-333 and Am80) and anticancer drugs (sorafenib, adriamycin, cisplatin, mitomycin C and 5-FU) was examined by cell viability assay. The effect on energy metabolic pathway, such as AMPK activation, intracellular ATP level, and the expression of glycolytic and TCA cycle genes were examined in HepG2 cells treated with sorafenib alone or in combination with retinoids. Induction of apoptosis was evaluated in the cells treated with the combination treatment of sorafenib and ATRA. Results: ATRA enhanced the cytotoxic effects of all 5 anticancer drugs tested, being much more effective than NIK-333 andAm80.AMPK activation, reduction of ATP content, and downregulation of glycolytic genes GLUT-1 and LDHA were observed in the cells treated with ATRA alone or in combination with sorafenib. In the combination treatment, increased apoptosis which was followed by activation of p38MAPK and JNK, upregulation and translocation of Bax to mitochondria, and activation of caspase-3 was observed. Conclusion: ATRA is useful for enhancing the cytotoxicity of antitumor drugs for HCC by regulating energy metabolism in HCC cells. Citation Format: Goshi Shiota, Hiroki Shimizu, Keita Kanki. Suppression of glycolysis by retinoic acid sensitizes hepatocellular carcinoma cells to apoptosis induced by sorafenib via AMPK activation. [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 708A. doi:10.1158/1538-7445.AM2015-708A
Similar Incidence Of Febrile Neutropenia With Same-Day Versus Subsequent Day G-CSF Administration In Non-Hodgkin Lymphoma Patients Receiving R-CHOP Chemotherapy
Authors: James Karol, Lisa Rybicki, John Sweetenham, Mitchell R Smith, Brian T. Hill, Brad Pohlman, Deepa Jagadeesh, Elizabeth Gazdick, Katie Fenner, Amanda L. Maggiotto, Robert M Dean
Journal: Blood (2013)
Substitution of another opioid for morphine
Authors: M. T Fallon, B. O'Neill, M K Makin, J E Ellershaw
Journal: BMJ (1998)

Editor—We would like to clarify some important points arising from Murray’s letter about the substitution of another opioid for morphine being of use in pain control.1 The first is the description of pain being “relatively resistant to morphine.” It is more useful to think of responsiveness to opioids as a continuum; the factors that generally decide the position on the continuum are the side effects of opioids, particularly sedation.2 Some pains, especially neuropathic pain, require larger doses of opioids, which consequently give rise to more troublesome side effects and thus limit an escalation of the dose and the achievement of adequate analgesia. Opioid toxicity results from an unfavourable balance between analgesia and the side effects of opioids. 

While alternative opioids may produce a better outcome,3 the safest and most efficient management of opioid toxicity is to reduce the opioid dose in the first instance rather than switch to an alternative opioid. This approach commonly achieves the desired balance between analgesia and side effects.4

Murray’s comment about ketamine (an N-methyl D-aspartate (NMDA) antagonist) in neuropathic pain is interesting. The NMDA antagonists are promising drugs for the treatment of pain syndromes with the clinical phenomena of central “wind-up” (allodynia, hyperalgesia, hyperpathia). The opioid mechanism does, however, seem to be crucial here also; NMDA antagonists seem to renew the opioid responsiveness in vitro and in the clinical situation.5

While alternative opioids to morphine, and the NMDA antagonists, are important as analgesics, we would reinforce a simple, systematic approach to pain control as outlined in the first paper in the ABC series on palliative care. In particular, opioid toxicity should be managed initially by decreasing the opioid dose rather than automatically switching to an alternative opioid.
Abstract 1463: Engraftment of patient derived xenografts on mice with a humanized immune system
Authors: Annika Wulf-Goldenberg, Maria Stecklum, Klaus Eckert, Diana Behrens, Iduna Fichtner, Jens Hoffmann
Journal: Cancer Research (2015)

Abstract The stimulation of the endogenous antitumor immunity has the potential to achieve clinically significant tumor regression. The recent clinical success with antibodies interfering with immune checkpoints on T-cells (PD1 and CTLA-4) has motivated oncology research world wide to focuses on new immunotherapy approaches. Further immune regulatory molecules are currently in target validation and together with cancer vaccines, therapeutic antibodies, immunoconjugates, and tumor reactive T-cells (CARTs) they all might contribute to an improved cancer therapy in the next years. The identification and validation of new targets for antitumor immune therapy is still a challenge for the preclinical research as the classical syngeneic tumor models are of limited translational value and the patient-derived human tumor xenograft models (PDX) are growing on immunodeficient animals. In first studies using human mononuclear cells (MNC) we demonstrated the engraftment of human T cells on immunodeficient mice. The transplanted human mononuclear cells (MNC) differentiated in T cell as measured by CD3, CD4 and CD8 expression. The inoculation and tumor growth of SW480 colon cancer cells on humanized mice was possible concurrent with accumulation of human T cells in the tumor. Our aim was the further improvement of this test system and the demonstration of a functional reconstitution of a human immune system by engrafting human hematopoietic stem cells in immunodeficient mice. Humanized mice were transplanted with patient derived melanoma fragments without evidence for rejection correlated with an increase of human T cells in the peripheral blood. Drug sensitivity testing with various immunoconjugates will follow. Our humanized mouse models will enable a more appropriate preclinical assessment of immune-based therapeutic antitumor strategies especially when combining the humanized mouse with patient-derived tumor xenografts. Citation Format: Annika Wulf-Goldenberg, Maria Stecklum, Klaus Eckert, Diana Behrens, Iduna Fichtner, Jens Hoffmann. Engraftment of patient derived xenografts on mice with a humanized immune system. [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 1463. doi:10.1158/1538-7445.AM2015-1463
The role of language in the dual process theory of thinking
Authors: Jonathan St. B. T. Evans, David E. Over
Journal: Behavioral and Brain Sciences (2002)

Carruthers’proposals would seem to implicate language in what is known as System 2 thinking (explicit) rather than System 1 thinking (implicit) in contemporary dual process theories of thinking and reasoning. We provide outline description of these theories and show that while Carruthers’characterization of non-verbal processes as domain-specific identifies one critical feature of System 1 thinking, he appears to overlook the fact that much cognition of this type results from domain-general learning processes. We also review cognitive psychological evidence that shows that language and the explicit representations it supports are heavily involved in supporting System 1 thinking, but falls short of supporting his claim that it is the medium in which domain-general thinking occurs.
Comparison of the effects on bronchial hyperresponsiveness of antiallergic agents and beclomethasone dipropionate in long‐term bronchial asthma
Authors: K. Hoshino, A. Kawasaki, Y. Mizushima, R. Oosaki, S. Yano, M. Kobayashi
Journal: Allergy (1993)

The effect of antiallergic agents (DSCG) (disodium cromoglycate, ketotifen, and ibudilast) and beclomethasone dipropionate inhaler (BDI) on bronchial hyperresponsiveness to histamine inhalation was retrospectively assessed in 72 asthmatic patients with more than a year's duration of the disease. Decrease in bronchial hyperresponsiveness to histamine was observed in 10 out of the 33 (30%) antiallergic-agents-treated patients (group A, mean duration = 7.8 months), in 12 of 19 (63.2%) BDI-treated patients (group B, 6.2 months), but only 2 of the 20 (10%) control patients (group C, 7.8 months). Improvement of histamine PC20 was from 310 to 597 micrograms/ml (P < 0.01) in group A, from 308 to 1622 micrograms/ml (P < 0.0005) in group B, and from 575 to 525 micrograms/ml (NS) in group C. A significant decrease in the peripheral eosinophil count was observed only in group B. The improvement in bronchial hyperresponsiveness was parallel with that of asthmatic symptoms; the percentage of patients becoming symptom-free rose from 12 to 42%, 5 to 89%, and 5 to 20% in groups A, B, and C, respectively. Out of 11 unimproved patients in group A, 7 showed a significant improvement in their histamine PC20 by BDI treatment (mean PC20: 311-->1828 micrograms/ml). These results suggest that BDI might be more effective than antiallergic agents in the treatment of patients with long-standing bronchial asthma.
SREC-1 expression in dendritic cells requires TLR signaling and mediates the immune functions of Hsp70
Authors: Jianlin Gong, Bangmin Zhu, stuart calderwood
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

260 

Heat shock proteins play an unusual role in immunosurveiIlance in capturing intracellular antigens, ferrying them to antigen presenting cells (APC) and mediating cross priming of T lymphocytes. However the salient mechanisms are still obscure. We show that Hsp70 mediated cross priming involves binding to scavenger receptor SREC-1 on the surface of dendritic cells (DC). Exposure of DC to Hsp70-peptide complexes leads to Hsp70 uptake as well as induction of SREC-1 mRNA and cell surface protein expression. SREC-1 expression was dependent on toll-like receptor/MyD88 signaling and ablation of this pathway inhibited SREC-1 expression, Hsp70 binding and cross priming of T lymphocytes. Furthermore, the expression of SREC-1 was correlated with the induction of tumor antigen-specific T cells. Killing of murine breast carcinoma cells by immunization with Hsp70-based vaccines was dependent on SREC-1 expression in host dendritic cells.
Abstract P055: Changes in Red Meat Consumption and Subsequent Risk of Type 2 Diabetes: Three Cohorts of US Men and Women
Authors: An Pan, Qi Sun, JoAnn E Manson, Walter C Willett, Frank B Hu
Journal: Circulation (2013)

Introduction: Red meat consumption has been consistently associated with an increased risk of type 2 diabetes (T2D). However, it remains largely unknown whether changes in red meat intake are related to subsequent T2D risk. Methods: We followed 26,358 men in the Health Professionals Follow-up Study (HPFS, 1986-2006), 48,710 women in the Nurses’ Health Study (NHS, 1986-2006) and 74,077 women in NHS II (1991-2007). Diet was assessed by validated food frequency questionnaires and updated every 4 years. Incident T2D was confirmed by a validated supplementary questionnaire. Time-dependent Cox proportional hazard models were used to calculate relative risks (RRs) for changes in red meat consumption during a 4-year interval in relation to risk of T2D in the subsequent 4 years, with adjustment for age, family history, race, marital status, initial red meat consumption, initial and changes in other lifestyle factors (physical activity, smoking status, alcohol intake, and dietary quality). The results in the three cohorts were pooled by inverse-variance-weighted random-effects meta-analyses. Results: During 1,965,911 person-years of follow-up, we documented 7,521 incident T2D cases. In the multivariate-adjusted models, increasing red meat intake during a 4-year interval was associated with an increased risk of subsequent 4-year T2D risk in each cohort (all P-trend &lt;0.001), and the pooled RR for one serving/d increment of red meat consumption was 1.30 (95% CI: 1.23, 1.38). The RR was attenuated to 1.20 (95% CI: 1.13, 1.27) after adjustment for baseline body mass index and concurrent weight change. We found significant interaction between initial red meat consumption and changes in red meat consumption with the subsequent risk of T2D; among participants with initial low (&lt;2 servings/wk) or moderate (2-6 servings/wk) levels of red meat consumption, an increase of one serving/d during a 4-year interval was related to an elevated risk of incident T2D in the subsequent 4 years, and the pooled RR was 1.99 (95% CI: 1.47, 2.70) and 1.51 (95% CI: 1.25, 1.81), respectively. However, the association was much weaker (pooled RR 1.16; 95% CI: 1.05, 1.27) in individuals with high initial red meat consumption levels (≥1 serving/d), and the association was not linear in the HPFS and NHS II. Conclusions: Increasing red meat consumption over time is associated with an elevated subsequent risk of T2D, and the association is partly mediated by body weight changes. The association also depends on the initial red meat consumption levels. Our results add further evidence that limiting red meat consumption over time can confer benefits on diabetes prevention.