tbuckley/cabot-search huggingface dataset:
Genome-wide screen reveals antitumor Zalypsis® as a strong inducer of DNA double strand breaks
Authors: Ana Herrero, Javier Botet, Carmen Cuevas, Federico Gago, Sergio Moreno
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

5733 

Zalypsis® (PM00104) is a novel synthetic antineoplastic agent currently in Phase I clinical development. Zalypsis is related to the marine natural compounds Jorumycin and Renieramycin. It has strong antitumor activity in a wide variety of tumour lines in vitro and in vivo. Preliminary data suggests that the agent has DNA binding properties, induces cell cycle arrest and inhibits transcription. However, the precise mechanism of action of this agent remains mostly unknown. To provide some insight into the mode of action of Zalypsis in eukaryotic cells we have used the yeast Saccharomyces cerevisiae as a model system. We have screened the complete set of approximately 5,000 viable S. cerevisiae haploid deletion mutants to identify genes that, when deleted, confer sensitivity or resistance to Zalypsis. Using this method we identified approximately 350 mutants hypersensitive to the drug and about 90 mutants resistant to its activity. Mutants showing altered fitness in the presence of Zalypsis have been further analyzed, using concentrations above and below the ones employed in the screening. Therefore, we have generated a sensitivity / resistance profile specific for each mutant. Among the genes deleted in the 40 most sensitive strains we found those encoding components of the MRX complex, involved in sensing double strand breaks (DSB), as well as several members of the homologous recombination proteins of the Rad52 epistasis group, which are recruited to the sites of DNA damage specifically during S-phase and G2. In addition, some deletion mutants of the Swi/Snf complex, a chromatin remodeling complex conserved in humans, were also found to be extremely sensitive to the compound. It has been recently shown that inactivation of the Swi/Snf complexes results in inefficient DSB repair and increased DNA damage sensitivity as well as a large defect in H2AX phosphorylation (Park et al., EMBO J 25, 3986-3997, 2006). Altogether, these results reveal that the DNA damage repair machinery is essential to overcome Zalypsis induced DNA damage and suggest that this damage is mainly due to DSBs. In addition, we have also identified genes whose deletion confers resistance to Zalypsis. Among the 90 resistant mutants we found proteins involved in DNA metabolism and repair. The strain with a deletion of the gene encoding SUMO ligase Siz1 came up as one the most resistant mutants to Zalypsis. A role for this protein in the inhibition of homologous recombination at replication forks has been described recently (Watts, DNA Repair 5, 399-403, 2006), indicating again that the main lesions induced by Zalypsis are DSBs. The role of the genes encoding DNA interacting proteins in confering resistance to Zalypsis requires further investigation. Nevertheless our results indicate that these proteins are mediating the Zalypsis-induced cell death.
Another editor bites the dust
Authors: R. Smith
Journal: BMJ (1999)

News p 273 

Earlier this week the Massachusetts Medical Society, owner of the New England Journal of Medicine , announced that Jerome P Kassirer, the editor, would be leaving. His tenure will end in eight months, but he will start a seven month sabbatical at the beginning of September. The Boston Globe , which broke the story, reported that Kassirer had been fired.1 The society denied this and said his contract was simply not being renewed. His precipitous departure, seven months after the firing of George Lundberg, editor of JAMA ,2 is likely to cause another round of soul searching over balancing editorial independence and accountability.

Kassirer has fallen out with the Massachusetts Medical Society over the use of the powerful brand name of the journal, a battle also fought by his predecessor. The society …
Organic arsenic in patients (pts) with advanced solid tumors: Phase-1 results of zio-101 (s-dimethylarsino-glutathione)
Authors: L. H. Camacho, D. S. Hong, C. Gutierrez, C. A. Parker, M. A. Purdom, N. M. Tannir, S. Moulder, R. P. Gale, B. Schwartz, R. Kurzrock
Journal: Journal of Clinical Oncology (2007)

3554 Background: ZIO-101(S-dimethylarsino-glutathione), a novel organic arsenic, is active against multiple cancers in vitro and in animal models. Anti-cancer activity is multifaceted and is mediated by disrupted mitochondrial function, increased reactive oxygen species (ROS) production, modified signal transduction and anti-angiogenesis. Methods: Phase-1 dose finding study to determine maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), and toxicities of ZIO-101 in patients with advanced solid tumors. Results: 34 pts (18 M/16 F) received 78–588 mg/m 2 /d IV for 5 consecutive days every 4 weeks. Median age was 61 (range, 42–79 y). Median N prior regimens was 3 (1–5). Pts had colorectal (N=17; 12 evaluable), renal (N=4), lung (N=3), melanoma (N=2), pancreas (N=2) and others (N=6). Median N of cycles was 2 (range, 1–12). MTD is 420 mg/m 2 /d and DLT was transient confusion, and ataxia. Fatigue, nausea and emesis were = grade-2. ZIO-101 was otherwise well-tolerated: There are no hematological toxicities and no QTc- prolongation. Five patients had stable-disease 4–12 mo (colorectal [N=3], renal [N=2],). PK studies at 420 mg/m 2 /d: t max = 1 h (SD + 0.9), C max = 1.06 μg/L (SD ± 0.07 μg/mL), t 1/2 = 17.8 h (SD ± 1.4 h) and AUC 0- 8 = 25.9 mg·h/L (SD ± 0.8mg.h/L). 1 pt had complete resolution of a brain metastasis (renal) and 1 patient had a substantial decrease of a liver metastasis (pancreas). Conclusions: ZIO-101 was well tolerated. MTD is 420 mg/m 2 /d and DLT is transient confusion and ataxia. There was observed clinical benefit in five patients. Expansion cohort is ongoing to further test toxicities and antitumor activity. Phase II studies are ongoing. [Table: see text]
Abstract 10133: Targeted Disruption of p50 Subunit of Nuclear Factor kappa B (NF{kappa}B) Leads to Spontaneous Myocarditis in Mice
Authors: Milan Gautam, Atsushi Izawa, Yuji Shiba, Yuichiro Kashima, Jun Koyama, Minoru Hongo, Kenji Sano, Takuma Hayashi, Kazunaga Agematsu, Motoki Ichikawa, Uichi Ikeda
Journal: Circulation (2011)

Background: A key transcription factor NFκB orchestrates pro-inflammatory and autoimmune responses, and thus interference with its activation has been believed to represent new therapeutic approach...
A medical-toxicological view of tattooing
Authors: Peter Laux, Tewes Tralau, Jutta Tentschert, Annegret Blume, Sascha Al Dahouk, Wolfgang Bäumler, Eric Bernstein, Beatrice Bocca, Alessandro Alimonti, Helen Colebrook, Christa de Cuyper, Lars Dähne, Urs Hauri, Paul C Howard, Paul Janssen, Linda Katz, Bruce Klitzman, Nicolas Kluger, Lars Krutak, Thomas Platzek, Victoria Scott-Lang, Jørgen Serup, Wera Teubner, Ines Schreiver, Elena Wilkniß, Andreas Luch
Journal: The Lancet (2015)
Abstract 3304: Effects Of Pioglitazone On Myocardial Blood Flow And Glucose Utilization In Non-diabetic Patients With Familial Combined Hyperlipidemia
Authors: Lucia Leccisotti, Rossi P Naoumova, Heiko Kindler, Marco Mongillo, Muhammad T Khan, Claire Neuwirth, Mary Seed, Paul Holvoet, John Betteridge, Paolo G Camici
Journal: Circulation (2007)
Abstract 16640: Foxo1 Impairs Whereas Statin Protects Endothelial Function in Hyperglycemic Conditions Through Reciprocal Regulation of Kruppel-like Factor 2
Authors: Hae-Young Lee, Seock-Won Youn, Hyun-Jai Cho, Yoo-Wook Kwon, Sae-Won Lee, Young-Bae Park, Byung-Hee Oh, Hyo-Soo Kim
Journal: Circulation (2011)

Endothelial dysfunction is an initial critical factor in the pathogenesis of diabetic vascular complications. Krüppel-like factor 2 ( KLF2) is implicated as a key molecule maintaining endothelial function. We investigated the role of a forkhead transcription factor, FOXO1, and HMG-CoA reductase inhibitor in KLF2 regulation in hyperglycemic conditions. FOXO1 expression was increased by 190% (p&lt;0.05), whereas KLF2 and eNOS expression were decreased by 60% (p&lt;0.05) and by 70% (p&lt;0.05) in human umbilical vein endothelial cells incubated in 30 mM glucose for 24 h, all of which were completely reversed by FOXO1 siRNA. Adenovirus-mediated overexpression of FOXO1 decreased the expression of KLF2 and eNOS by 49% and 69% (p&lt;0.05). Atorvastatin (1 μM) inhibited FOXO1 not only by increasing phosphorylation by 170% (p&lt;0.05) but also by degrading FOXO1 protein by 70% (p&lt;0.05). Atorvastatin also restored KLF2 expression suppressed in high glucose conditions similar to the control level (92.3 ± 3.4%, p=0.1), which was totally blocked by co-incubation with mevalonate. A chromatin immunoprecipitation analysis demonstrated that glucose and atorvastatin reciprocally regulated KLF2 at transcription level by modulating binding of FOXO1 to its promoter regions at -609 and -754bp. In vivo experiment with the OLETF rats, the animal models of type 2 diabetes, FOXO1 in the endothelial lining of the thoracic aorta was mainly located in the nucleus and KLF2 (41.5±3.9%, p&lt;0.05) and eNOS (62.5 ± 1.8%, p&lt;0.05) expressions were significantly decreased compared with the control LETO rats, which were reversed by atorvastatin administered with 5 mg/kg/day for &gt; 4 weeks (KLF2 expression by 157.3 ± 37% and eNOS expression by 112.5 ± 27% of the control values). The endothelium-dependent vasodilation with acetylcholine were significantly decreased in OLETF rats (23.4 ± 22.8% of the LETO rats, p&lt;0.05), which was significantly improved both by atorvastatin (67.3 ± 0.5%, p&lt;0.05) and by adenovirus-mediated overexpression of KLF2 (61.4 ± 15.4%, p&lt;0.05). In conclusion, KLF2 suppression by FOXO1 may be a plausible mechanism of endothelial dysfunction in diabetes. The findings of this study suggest implication of intensive statin treatment in preventing diabetic vasculopathy.
Abstract 2155: One year clinical outcomes associated with the use of a Zotarolimus eluting stent: A Single-Center Canadian Experience
Authors: Luke Drzymala, Andrew Ha, Derek So, Chris Glover
Journal: Circulation (2007)

Background: The use of drug eluting stents (DES) has improved clinical and angiographic outcomes by reducing the need for target vessel revascularization (TVR). Clinical outcomes associated with the use a novel DES, the Zotarolimus-eluting phosphorylcholine-coated (Endeavor®) stent are less well established. A randomized clinical trial examining the benefits of the Endeavor® stent the rates of target vessel revascularization (TVR), target lesion revascularization (TLR) and stent thrombosis (ST) rates at 9 months in a select “study population” were reported as 7.9%, 4.6% and 0.5% respectively. These studies examined the outcomes of the Endeavor® stents in patients with single and non-complex lesions, while excluding patients with Acute Coronary Syndrome (ACS), Left Main (LM) lesions or In-stent restenosis (ISR). The outcomes of the Endeavor® stents in a “real-world” population have not been studied. The objective of this study was to evaluate the safety and efficacy of Endeavor® stents in consecutive patients from a single, high volume Canadian center. Methods &amp; Results: The charts and angiogram reports of consecutive pts between June 2005 and June 2006, who received ≥ 1 Endeavor® stents were reviewed (n=462). In total, 667 Endeavor® stents were deployed in 462 patients. These patients were: 71% male, 65+/−9.1 year-old, 45% DM, 51% smokers, 62% HTN, 73% with dyslipidemia, and 5% with previous bypass surgery. The indications for stenting were: stable CAD 47.7%, ACS 47.1% and STEMI 5.1%. Endeavor® stents were utilized for ISR in 9% of cases. Average stent size was 19.7 +/− 5.8 × 2.9 +/− 0.3mm. At 12 month follow-up, TLR and TVR rates of 6.9% and 8.9% were observed, along with 2 cases of acute ST. There were no cases of late ST (&gt;1 month post stent implantation). Myocardial Infarction occurred in 3.5% patients over 12 months. Discussion: In a Canadian interventional cardiology center, TLR, TVR and ST rates of 6.9%, 8.9% and 0.6% were observed at 12 months post-implantation. Despite including patients with multiple lesions, complex lesions, ACS and ISR, the rates observed at our center were comparable to those observed in a select study population. Most importantly there were no late stent thrombosis.
Abstract 14103: Comprehensive Risk Factor Control Improves Survival: The Bypass Angioplasty Revascularization Investigation 2 Diabetes
Authors: Vera Bittner, Marnie Bertolet, Rafael Barraza, Michael E Farkouh, Suzanne H Goldberg, Kodangudi B Ramanathan, J B Redmon, Laurence Sperling, Martin K Rutter
Journal: Circulation (2011)

Introduction: BARI 2D evaluated the efficacy of prompt coronary revascularization on a background of protocol-guided aggressive medical therapy (AMT) among patients with Type 2 diabetes including f...
Abstract 1429: Defects in Connexin Signaling Underlie Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy in a Novel Mouse Model
Authors: Katherine Banares, Adam Wright, Joyce Chuang, Ciu Li, Kunfu Ouyang, Yusu Gu, Jeff H Omens, Andrew M McCulloch, Sylvia M Evans, Kirk L Peterson, Farah Sheikh
Journal: Circulation (2008)

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a genetic form of cardiomyopathy, which is typically characterized by right but also recently left ventricular dysfunction, fib...
Abstract 17002: Post-Arrest Arterial Hyper-Oxygenation and Cardiac Mitochondrial Function
Authors: Steven Yeh, Mark G Angelos
Journal: Circulation (2011)

Introduction: Post-ischemic re-oxygenation is necessary to minimize ischemic injury, but itself can induce further reperfusion injury through the induction of reactive oxygen species (ROS). Utilization of oxygen within the cell primarily occurs in the mitochondria. The objective of this study was to determine heart mitochondrial function following 1 hour of controlled arterial oxygenation following cardiac arrest and ROSC. We hypothesized that arterial hyper-oxygenation following ROSC would result in greater impairment of heart mitochondrial function. Methods: Two experimental protocols were completed using a rat KCl arrest model. In experiment 1, animals underwent a 6 min cardiac arrest and were resuscitated with standard thumper CPR, ventilation and epinephrine and then ventilated with 100% O2 (hyperoxia group) or 40% O2 (normoxia group) for 60 min. In experiment 2, animals underwent a 25 min cardiac arrest and were resuscitated with cardiopulmonary bypass. Arterial PO2 was titrated to either hyperoxic or normoxic levels for 60 min post ROSC. In both experiments, at the end of 60 min, heart mitochondria were isolated and mitochondrial respiratory function was compared between groups. Results: In experiment 1, post-ROSC arterial PaO2 was 280 ± 40 mm Hg in the hyperoxic group and 105 ± 10 mm Hg in the normoxic group. Mitochondrial respiration, defined as respiration control ratio (state 3/4 respiration), was significantly higher in the normoxic group compared to the hyperoxic group (n=6/group, p &lt;0.05). In experiment 2, during the 60 min post ROSC period, arterial PaO2 was 441 ± 10 mm Hg in the hyperoxic group and 107 ± 9 mm Hg in the normoxic group (n=6/group, p&lt;0.001). Mitochondrial respiration, 60 min after ROSC, was significantly higher in the hyperoxic group compared with the normoxic group (n=6/group, p&lt;0.05). Post-ROSC arterial hyperoxemia (compared with normoxemia) was associated with worse mitochondrial function after a short cardiac arrest but improved mitochondrial function after a prolonged cardiac arrest. We conclude that post-ischemic arterial hyperoxia is an important variable in mitochondrial functional recovery but the severity of the ischemia may attenuate this effect by limiting reperfusion oxygen delivery to the mitochondria.
MP introduces bill to protect children from unlicensed medicines
Authors: Gavin Yamey
Journal: BMJ (2000)

Andrew Love, Labour MP for Edmonton in north London, introduced a bill in the British parliament last week aimed at reducing the risk to children from unlicensed and untested medicines.

The bill aims to strengthen the testing and licensing of medicines for children, giving them the same protection as adults afforded by the 1968 Medicines Act. It has all party support and is backed by the Consumers'Association and the Royal College of Nursing. An early day motion supporting the measure and calling for doctors to give more information to parents on drugs prescribed to their children was signed by over 100 MPs.

In a recent …
Frontline Chemoimmunotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Shows Superior Efficacy in Comparison to Bendamustine (B) and Rituximab (BR) in Previously Untreated and Physically Fit Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Final Analysis of an International, Randomized Study of the German CLL Study Group (GCLLSG) (CLL10 Study)
Authors: Barbara Eichhorst, Anna Maria Fink, Raymonde Busch, Gabor Kovacs, Christian Maurer, Elisabeth Lange, Hubert Köppler, Michael G Kiehl, Martin Soekler, Rudolf Schlag, Ursula Vehling-Kaiser, Georg R.A. Köchling, Christoph Plöger, Michael Gregor, Torben Plesner, Marek Trneny, Kirsten Fischer, Hartmut Döhner, Michael Kneba, Clemens-Martin Wendtner, Wolfram Klapper, Karl Anton Kreuzer, Stephan Stilgenbauer, Sebastian Böttcher, Michael Hallek
Journal: Blood (2014)
Treatment of Hepatocellular Carcinoma with Thalidomide: Assessment with Power Doppler Ultrasound
Authors: Chiun Hsu, Chiung-Nien Chen, Ann-Lii Cheng
Journal: Liver Cancer (2009)

Hepatocellular carcinoma (HCC) is typically a hypervascular tumor and anti-angiogenesis therapy may be effective for the treatment of HCC. Thalidomide has been shown to inhibit angiogenesis induced by various proangiogenic factors and may produce objective tumor response in various cancers. In HCC, thalidomide may produce complete or partial remission in ~ 4–7% of patients and disease stabilization in 10–20% patients with advanced disease. We have performed a prospective study using power Doppler ultrasound to evaluate the vascular response to thalidomide treatment in patients with advanced HCC. Patients who achieved objective tumor response to thalidomide tended to have a higher pretreatment vascularity index, defined as the number of colored (vascular) pixels within a well-demarcated tumor area divided by the number of total pixels in that area, than patients who did not. The pretreatment vascularity index also correlated with levels of circulating angiogenic factors. The value of power Doppler ultrasound in future clinical trials of anti-angiogenesis therapy of HCC is discussed.
Abstract 4386: Single-Center Experience in Large Cohort of Patients with Pulmonary Arterial Hypertension Related to Congenital Heart Disease over 15 years: Effect of New Therapies
Authors: Sotiria C Apostolopoulou, Alexandros Tsoutsinos, Maria Kiaffas, Cleo V Laskari, Spyridon Rammos
Journal: Circulation (2008)

Introduction: The aim of this study was to define the epidemiology, clinical parameters and 15-year follow-up of a large single-center cohort of patients with pulmonary arterial hypertension (PAH) related to congenital heart disease (CHD) and to evaluate the effect of emerging therapeutic strategies in this population. Methods: All patients diagnosed with PAH related to CHD between 1993 and 2008 were studied and clinical, echocardiographic, maximal and submaximal exercise as well as hemodynamic data were recorded. Results: A total of 60 pts aged 21 ± 14 (0.1–51) years at diagnosis were included in the study. Of these, 44 (73%) had unrestrictive mixing lesions and Eisenmenger syndrome and the rest non-mixing lesions, mainly repaired CHD. Of this population, 24 (40%) were &lt;18yrs and the remainder adults at diagnosis at our institution. Seven (12%) pts in WHO Class II received no therapy, 45 (75%) pts in Class II-III monotherapy (34 bosentan with 1 discontinuation after corrective surgery, 6 sildenafil, 5 sitaxsentan) with clinical and exercise improvement. Due to deterioration, 6 (10%) pts received addition of sildenafil after 3±1 years of bosentan monotherapy and 2 (3%) pts addition of epoprostenol after 1 year of the above combination therapy. Over 6±4 (1–15) years of follow-up, 49 (82%) pts remained stable on no or monotherapy, 4 pts (7%) deteriorated after 1–5 years monotherapy but stabilized on combination therapy and 7 (12%) pts died (3 from intractable right heart failure despite escalation of therapy and 4 suddenly while on therapy). The unrestrictive mixing group had 2 (4%) and the non-mixing group 5 (33%) deaths respectively. Conclusions: Long-term improvement and stabilization is possible in pts with PAH related to CHD with either monotherapy or combination therapy in case of deterioration overtime while on treatment. Death in this population may be sudden or due to intractable right heart failure, while survival is significantly better in pts with unrestrictive mixing. Larger long-term registry studies are needed to evaluate survival and clinical condition of these pts in the current treatment era and to improve medical management of this population.
Abstract 8689: Platelet CD40 Receptor Expression Accelerates Platelet Induced Atherogenesis
Authors: Dirk Lievens, Tom Seijkens, Larissa Thevissen, Linda Beckers, Erwin Wijnands, Oliver Soehnlein, Norbert Gerdes, Christian Weber, Esther Lutgens
Journal: Circulation (2011)

Beyond an eminent role in hemostasis and thrombosis, platelets are important mediators of inflammation and protagonists of atherogenesis. Here we investigated the inflammatory propensity of platelet-specific expression of the CD40 receptor, an integral membrane protein of the tumor necrosis factor receptor (TNF-R) family. Besides its presence on immune and other cell types the CD40 receptor is constitutively expressed on platelets where its function remains unknown. Platelets were isolated from Apoe−/− or Cd40−/−Apoe−/− mice, activated with thrombin, and injected (3x107 platelets, i.v.), into 17-week-old Apoe−/− mice every 5 days for 12 weeks. Compared to infusion of activated Apoe−/− (wild type) platelets, injection of activated Cd40−/−Apoe−/− platelets caused a 73% decrease in plaque size (Apoe−/− platelets 18.3x104 + 2.7x104 μm2 vs Cd40−/−Apoe−/− platelets 6.7 x104 + 2.1 x104 μm2, Vehicle 9.8 x104 + 2.8 x104 μm2, p&lt;0.05) in the aortic arch. Absence of CD40 on platelets reduced the absolute number of plaque macrophages (Mac-3) by 39% but did not affect the content of CD45+ cells and CD3+ T lymphocytes. Flow cytometric analysis revealed an elevated number of circulating Ly6G+ neutrophils (+32%) upon injection of activated platelets. However, this increase was absent when CD40-deficient platelets, were injected highlighting the inflammatory potential of platelets and a central role for CD40 in this process. In addition, we detected a 20% decrease in the formation of platelet-leukocyte aggregates in vitro while intravital microscopy in carotid arteries showed a 2-fold decrease of platelet adhesion to the vessel wall of mice, injected with activated Cd40-/- platelets, In sum, this study reveals that platelet CD40 promotes atherosclerosis by interaction with both neutrophils and endothelial cells, thereby amplifying leukocyte recruitment to sites of vascular injury.
Abstract 12612: Exercise Training Reduces Ca2+-Calmodulin-dependent Protein Kinase Type II Dependent Phosphorylation of the Cardiac Ryanodine Receptor and Ca2+ Leak From the Sarcoplasmic Reticulum in Mice With Mutant Cardiac Ryanodine Receptor 2
Authors: Ravinea Manotheepan, Tore K Danielsen, Mani Sadredini, Stephen Lehnart, Ivar Sjaastad, Mathis K Stokke
Journal: Circulation (2013)

Introduction: Catecholaminergic Polymorphic Ventricular Tachycardia caused by RyR2 mutations predisposes to stress-induced arrhythmias due to disrupted Ca2+ handling in ventricular cardiomyocytes. ...