Publications by authors named "B Czako"

22 Publications

  • Page 1 of 1

New Onset of DiabetEs in aSsociation with pancreatic ductal adenocarcinoma (NODES Trial): protocol of a prospective, multicentre observational trial.

BMJ Open 2020 11 19;10(11):e037267. Epub 2020 Nov 19.

First Department of Medicine, University of Szeged, Szeged, Hungary

Introduction: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with an overall 5-year survival of approximately 8%. The success in reducing the mortality rate of PDAC is related to the discovery of new therapeutic agents, and to a significant extent to the development of early detection and prevention programmes. Patients with new-onset diabetes mellitus (DM) represent a high-risk group for PDAC as they have an eightfold higher risk of PDAC than the general population. The proposed screening programme may allow the detection of PDAC in the early, operable stage. Diagnosing more patients in the curable stage might decrease the morbidity and mortality rates of PDAC and additionally reduce the burden of the healthcare.

Methods And Analysis: This is a prospective, multicentre observational cohort study. Patients ≥60 years old diagnosed with new-onset (≤6 months) diabetes will be included. Exclusion criteria are (1) Continuous alcohol abuse; (2) Chronic pancreatitis; (3) Previous pancreas operation/pancreatectomy; (4) Pregnancy; (5) Present malignant disease and (6) Type 1 DM. Follow-up visits are scheduled every 6 months for up to 36 months. Data collection is based on questionnaires. Clinical symptoms, body weight and fasting blood will be collected at each, carbohydrate antigen 19-9 and blood to biobank at every second visit. The blood samples will be processed to plasma and analysed with mass spectrometry (MS)-based metabolomics. The metabolomic data will be used for biomarker validation for early detection of PDAC in the high-risk group patients with new-onset diabetes. Patients with worrisome features will undergo MRI or endoscopic ultrasound investigation, and surgical referral depending on the radiological findings. One of the secondary end points is the incidence of PDAC in patients with newly diagnosed DM.

Ethics And Dissemination: The study has been approved by the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (41085-6/2019). We plan to disseminate the results to several members of the healthcare system includining medical doctors, dietitians, nurses, patients and so on. We plan to publish the results in a peer-reviewed high-quality journal for professionals. In addition, we also plan to publish it for lay readers in order to maximalise the dissemination and benefits of this trial.

Trial Registration Number: ClinicalTrials.gov NCT04164602.
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http://dx.doi.org/10.1136/bmjopen-2020-037267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678370PMC
November 2020

An enolase inhibitor for the targeted treatment of ENO1-deleted cancers.

Nat Metab 2020 12 23;2(12):1413-1426. Epub 2020 Nov 23.

Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We have previously identified a subset of cancers harbouring homozygous deletion of the glycolytic enzyme enolase (ENO1) that have exceptional sensitivity to inhibition of its redundant paralogue, ENO2, through a therapeutic strategy known as collateral lethality. Here, we show that a small-molecule enolase inhibitor, POMHEX, can selectively kill ENO1-deleted glioma cells at low-nanomolar concentrations and eradicate intracranial orthotopic ENO1-deleted tumours in mice at doses well-tolerated in non-human primates. Our data provide an in vivo proof of principle of the power of collateral lethality in precision oncology and demonstrate the utility of POMHEX for glycolysis inhibition with potential use across a range of therapeutic settings.
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http://dx.doi.org/10.1038/s42255-020-00313-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744354PMC
December 2020

Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties.

J Med Chem 2020 11 29;63(21):12957-12977. Epub 2020 Oct 29.

Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.

Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound (IPN60090), which is currently in phase 1 clinical trials. Compound attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit glutaminase in humans.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01398DOI Listing
November 2020

Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib.

Cancer Res 2020 11 14;80(21):4840-4853. Epub 2020 Sep 14.

Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas.

Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors such as the EGFR inhibitor (EGFRi), osimertinib, in non-small cell lung cancer (NSCLC) is limited by acquired resistance. Multiple clinically identified mechanisms underlie resistance to osimertinib, including mutations in EGFR that preclude drug binding as well as EGFR-independent activation of the MAPK pathway through alternate RTK (RTK-bypass). It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism, and the plasticity between multiple resistance mechanisms could restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. Here, we report the discovery of IACS-13909, a specific and potent allosteric inhibitor of SHP2, that suppresses signaling through the MAPK pathway. IACS-13909 potently impeded proliferation of tumors harboring a broad spectrum of activated RTKs as the oncogenic driver. In EGFR-mutant osimertinib-resistant NSCLC models with EGFR-dependent and EGFR-independent resistance mechanisms, IACS-13909, administered as a single agent or in combination with osimertinib, potently suppressed tumor cell proliferation and caused tumor regression . Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFRi-resistant NSCLC. SIGNIFICANCE: These findings highlight the discovery of IACS-13909 as a potent, selective inhibitor of SHP2 with drug-like properties, and targeting SHP2 may serve as a therapeutic strategy to overcome tumor resistance to osimertinib.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1634DOI Listing
November 2020

Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R.

J Med Chem 2020 09 18;63(17):9888-9911. Epub 2020 Aug 18.

IACS (Institute of Applied Cancer Science), University of Texas MD Anderson Cancer Center, 1881 East Road, Houston, Texas 77054, United States.

Tumor-associated macrophages (TAMs) have a significant presence in the tumor stroma across multiple human malignancies and are believed to be beneficial to tumor growth. Targeting CSF1R has been proposed as a potential therapy to reduce TAMs, especially the protumor, immune-suppressive M2 TAMs. Additionally, the high expression of CSF1R on tumor cells has been associated with poor survival in certain cancers, suggesting tumor dependency and therefore a potential therapeutic target. The CSF1-CSF1R signaling pathway modulates the production, differentiation, and function of TAMs; however, the discovery of selective CSF1R inhibitors devoid of type III kinase activity has proven to be challenging. We discovered a potent, highly selective, and orally bioavailable CSF1R inhibitor, IACS-9439 (). Treatment with led to a dose-dependent reduction in macrophages, promoted macrophage polarization toward the M1 phenotype, and led to tumor growth inhibition in MC38 and PANC02 syngeneic tumor models.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00936DOI Listing
September 2020

The 3 Enantiomer Drives Enolase Inhibitory Activity in SF2312 and Its Analogues.

Molecules 2019 Jul 9;24(13). Epub 2019 Jul 9.

Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.

We recently reported that SF2312 ((1,5-dihydroxy-2-oxopyrrolidin-3-yl)phosphonic acid), a phosphonate antibiotic with a previously unknown mode of action, is a potent inhibitor of the glycolytic enzyme, Enolase. SF2312 can only be synthesized as a racemic-diastereomeric mixture. However, co-crystal structures with Enolase 2 (ENO2) have consistently shown that only the (3,5)-enantiomer binds to the active site. The acidity of the alpha proton at C-3, which deprotonates under mildly alkaline conditions, results in racemization; thus while the separation of four enantiomeric intermediates was achieved via chiral High Performance Liquid Chromatography (HPLC) of the fully protected intermediate, deprotection inevitably nullified enantiopurity. To prevent epimerization of the C-3, we designed and synthesized MethylSF2312, ((1,5-dihydroxy-3-methyl-2-oxopyrrolidin-3-yl)phosphonic acid), which contains a fully-substituted C-3 alpha carbon. As a racemic-diastereomeric mixture, MethylSF2312 is equipotent to SF2312 in enzymatic and cellular systems against Enolase. Chiral HPLC separation of a protected MethylSF2312 precursor resulted in the efficient separation of the four enantiomers. After deprotection and inevitable re-equilibration of the anomeric C-5, (3)-MethylSF2312 was up to 2000-fold more potent than (3)-MethylSF2312 in an isolated enzymatic assay. This observation strongly correlates with biological activity in both human cancer cells and bacteria for the 3 enantiomer of SF2312. Novel X-ray structures of human ENO2 with chiral and racemic MethylSF2312 show that only (35-enantiomer occupies the active site. Enolase inhibition is thus a direct result of binding by the (35-enantiomer of MethylSF2312. Concurrent with these results for MethylSF2312, we contend that the (3,5)-SF2312 is the single active enantiomer of inhibitor SF2312.
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http://dx.doi.org/10.3390/molecules24132510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651268PMC
July 2019

Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation.

Cell Rep 2019 01;26(2):469-482.e5

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

The plasticity of a preexisting regulatory circuit compromises the effectiveness of targeted therapies, and leveraging genetic vulnerabilities in cancer cells may overcome such adaptations. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is characterized by oxidative phosphorylation (OXPHOS) deficiency caused by fumarate hydratase (FH) nullizyogosity. To identify metabolic genes that are synthetically lethal with OXPHOS deficiency, we conducted a genetic loss-of-function screen and found that phosphogluconate dehydrogenase (PGD) inhibition robustly blocks the proliferation of FH mutant cancer cells both in vitro and in vivo. Mechanistically, PGD inhibition blocks glycolysis, suppresses reductive carboxylation of glutamine, and increases the NADP/NADPH ratio to disrupt redox homeostasis. Furthermore, in the OXPHOS-proficient context, blocking OXPHOS using the small-molecule inhibitor IACS-010759 enhances sensitivity to PGD inhibition in vitro and in vivo. Together, our study reveals a dependency on PGD in OXPHOS-deficient tumors that might inform therapeutic intervention in specific patient populations.
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http://dx.doi.org/10.1016/j.celrep.2018.12.043DOI Listing
January 2019

Monocyte adhesion with platelet satellitism and phagocytosis in Hodgkin lymphoma.

Am J Hematol 2018 12 23;93(12):1561. Epub 2018 Sep 23.

Department of Haematology, Watford General Hospital, Watford, United Kingdom.

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http://dx.doi.org/10.1002/ajh.25241DOI Listing
December 2018

An inhibitor of oxidative phosphorylation exploits cancer vulnerability.

Nat Med 2018 07 11;24(7):1036-1046. Epub 2018 Jun 11.

Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors.
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http://dx.doi.org/10.1038/s41591-018-0052-4DOI Listing
July 2018

SF2312 is a natural phosphonate inhibitor of enolase.

Nat Chem Biol 2016 Dec 10;12(12):1053-1058. Epub 2016 Oct 10.

Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77054.

Despite being crucial for energy generation in most forms of life, few if any microbial antibiotics specifically inhibit glycolysis. To develop a specific inhibitor of the glycolytic enzyme enolase 2 (ENO2) for the treatment of cancers with deletion of ENO1 (encoding enolase 1), we modeled the synthetic tool compound inhibitor phosphonoacetohydroxamate (PhAH) into the active site of human ENO2. A ring-stabilized analog of PhAH, in which the hydroxamic nitrogen is linked to Cα by an ethylene bridge, was predicted to increase binding affinity by stabilizing the inhibitor in a bound conformation. Unexpectedly, a structure-based search revealed that our hypothesized backbone-stabilized PhAH bears strong similarity to SF2312, a phosphonate antibiotic of unknown mode of action produced by the actinomycete Micromonospora, which is active under anaerobic conditions. Here, we present multiple lines of evidence, including a novel X-ray structure, that SF2312 is a highly potent, low-nanomolar inhibitor of enolase.
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http://dx.doi.org/10.1038/nchembio.2195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110371PMC
December 2016

A rare disease presenting as pyrexia, hepatosplenomegaly and pancytopenia.

Br J Hosp Med (Lond) 2015 Jul;76(7):426-7

Consultant in Haematology in the Department of Haematology, Watford General Hospital, Watford.

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http://dx.doi.org/10.12968/hmed.2015.76.7.426DOI Listing
July 2015

MGN-3 arabinoxylan rice bran modulates innate immunity in multiple myeloma patients.

Cancer Immunol Immunother 2013 Mar 2;62(3):437-45. Epub 2012 Sep 2.

Cancer Research Institute SAS, Vlarska 7, 833 91, Bratislava, Slovakia.

Dendritic cells (DCs) and natural killer (NK) cells are central components of innate immunity for controlling tumor growth. The therapeutic effects of certain anti-myeloma drugs are partially mediated by targeting the innate immune response. In addition, novel types of natural compounds have been developed that efficiently modulate the activity of both the cellular and humoral compartments of immunity. MGN-3 is known as an activator of natural killer cells, inducer of apoptosis and cytokine production, and modulator of dendritic cell maturation and differentiation in vitro. We have performed a randomized, placebo-controlled study to examine the effects of MGN-3 on innate immune system parameters in 48 multiple myeloma patients. We performed immunophenotypic analysis of peripheral blood samples, determined NK cell activity, and assessed the cytokine profiles of plasma before and during 3 months of treatment. The results demonstrate a clear increase in NK activity in MGN-3-treated patients compared to the placebo group, an increased level of myeloid DCs in peripheral blood, and augmented concentrations of T helper cell type 1-related cytokines. The present study suggests that MGN-3 may represent an immunologically relevant product for activating innate immunity in multiple myeloma patients and warrants further testing to demonstrate clinical efficacy.
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http://dx.doi.org/10.1007/s00262-012-1344-zDOI Listing
March 2013

Synthesis and opioid activity of novel 6-substituted-6-demethoxy-ethenomorphinans.

Bioorg Med Chem 2010 May 29;18(10):3535-42. Epub 2010 Mar 29.

Department of Organic Chemistry, University of Debrecen, PO Box 20, H-4010, Debrecen, Hungary.

A set of novel 6-substituted orvinols was synthesized and pharmacologically characterized in order to explore the effect of the polarity and steric effects of these new moieties on the opioid activity. It was revealed that longer 6-O-alkyl chains led to increased agonistic activities, while the lack of C6-etheral oxygen gave rise to an antagonistic profile at the opioid receptors in the mouse ileum.
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http://dx.doi.org/10.1016/j.bmc.2010.03.068DOI Listing
May 2010

Treatment of newly diagnosed patients with acute promyelocytic leukemia with modified spanish treatment protocol.

Neoplasma 2010 ;57(3):270-9

Department of Clinical Oncology, National Cancer Institute (NCI), Bratislava, Slovakia.

The results of treatment of acute promyelocytic leukemia, when combination ATRA + chemotherapy is used in induction and maintainance therapy and risk adapted strategy applied in consolidation, improved at present time. Enhanced supportive therapy also contribute to improved outcome of APL patients. 3 - year relapse free, overall survival and clinical and biological presenting features of APL patients were evaluated. Since January, 2001 till March, 2009, 32 patients treated with modified spanish treatment scheme were assessed. After june 2003 risk adapted strategy in protocol therapy according to spanish treatment group with ATRA and anthracyclines in consolidation therapy in high and intermediate risk patients was used. Cytoreduction therapy in patients with initially high leukocyte count was the modification of spanish treatment scheme. 29 (90.6%) patients achieved complete hematologic remission, 2 (6.3 %) molecular relapses were observed, death was observed in 4 patients (12.5%). The estimated 3-year OS was 90.6%; 95% CI (80.5%-100.0%), and estimated 3-year RFS was 95.5 %; 95 % CI (86.8%-100.0%). Survival results correspond with other published clinical studies. The number of relapses was slightly lower and the incidence of ATRA syndrome (50%) was higher when compare with the results of other study groups. Current recommendations for treatment with risk-adapted strategy for patients with newly diagnosed acute promyelocytic leukemia resulted in our patients group to comparable outcome and good compliance like in other published studies.
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http://dx.doi.org/10.4149/neo_2010_03_270DOI Listing
July 2010

Discovery of potent and practical antiangiogenic agents inspired by cortistatin A.

J Am Chem Soc 2009 Jul;131(25):9014-9

Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.

The discovery that cortistatins A and J show noteworthy antiangiogenic activity prompted an investigation of the possibility that simpler and much more easily made compounds based on a steroid core might have useful bioactivity. These studies have led to the development of several potent, water-soluble compounds that may be suitable for local application to treat ocular wet macular degeneration, an important cause of blindness, as well as for treatment of various other angiogenesis-dependent diseases. One of these substances was tested in a mouse retinal angiogenesis model and found to inhibit angiogenesis at a locally administered dose of 500 pmol. Comparison of cell migration data for this and two other synthetic compounds with published data on cortistatin A indicate that they inhibit vascular endothelial growth factor-induced cell migration of human umbilical vein endothelial cells more strongly than cortistatin A.
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http://dx.doi.org/10.1021/ja902601eDOI Listing
July 2009

A short, scalable synthesis of the carbocyclic core of the anti-angiogenic cortistatins from (+)-estrone by B-ring expansion.

Org Lett 2008 Nov 30;10(22):5247-50. Epub 2008 Oct 30.

Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

A rapid and scalable synthesis of the carbocyclic core of the potent antiangiogenic natural products, the cortistatins, is presented starting from readily available (+)-estrone. Key steps include a regio- and stereoselective benzylic cyanation and a Demjanov rearrangement.
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http://dx.doi.org/10.1021/ol802328nDOI Listing
November 2008

Isolated extra-medullary relapse of acute leukemia following allogeneic bone marrow transplantation.

Bratisl Lek Listy 2008 ;109(8):358-61

Department of Hematology and Transfusion Medicine, Faculty of Medicine, University Hospital, Comenius University, Bratislava, Slovakia.

Isolated extramedullary relapse (IEMR) of acute leukemia (AL) after allogeneic bone marrow transplantation (BMT) is a rare occurrence. It is seen more commonly after BMT than after conventional chemotherapy (CHT) alone. We describe the natural history and response to treatment in four patients with IEMR following allogeneic BMT. The results indicate a stronger graft-versus-leukemia (GVL) effect in the marrow than in the peripheral tissues (Fig. 4, Ref. 13). Full Text (Free, PDF) www.bmj.sk.
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October 2008

Establishing the method of chimerism monitoring after allogeneic stem cell transplantation using multiplex polymerase chain reaction amplification of short tandem repeat markers and Amelogenin.

Neoplasma 2007 ;54(5):424-30

Bone Marrow Transplantation Unit, Department of Pediatrics, Comenius University Medical School, Limbová 1, 833 40 Bratislava, Slovak Republic.

We describe the implementation, optimization, sensitivity determination and first clinical results of polymerase chain reaction (PCR) amplification of polymorphic short tandem repeat (STR) markers and Amelogenin locus coupled with fluorescent detection and capillary electrophoresis in chimerism monitoring of patients transplanted at three different transplant centers using a commercially available multiplex microsatellite assay. The chimerism analysis was performed with genomic DNA extracted from unselected peripheral blood leukocytes of one hundred pediatric and adult patients, who underwent allogeneic stem cell transplantation (SCT) from human leukocyte antigen (HLA) matched or one antigen mismatched related or unrelated donors for malignant (70 patients) and non-malignant (30 patients) diseases. Tested were 79 donor recipient pairs for 15 STR systems and identified an informative marker in all but one of them (98,7%), using 6 selected systems out of these fifteen, that appeared highly informative in our patients population. In 21 sex-mismatched donor recipient pairs we used the Amelogenin locus to distinguish the X and Y chromosome. In sixty-three out of these 100 patients chimerism was regularly analyzed from blood samples taken at various time points after SCT with the median follow up of 17 months. Complete chimerism (CC), maintained over the whole follow-up period, was detected in 24 (38, 1%), stable and decreasing mixed chimerism (MC) in 28 (44, 4%) and increasing MC in 11 patients (17, 5%). Patients with CC, stable and decreasing MC showed a significantly better (p 0,005) overall survival rate (0, 81), compared to those with increasing MC (0, 24). These results demonstrate that STR-based chimerism monitoring with sensitivity above 1% and high informativity (98, 7% of donor recipient pairs) is necessary in establishing the origin of engrafted cells after an allogeneic SCT, in detecting graft rejection and that it may contribute in identifying patients with imminent leukemia relapse.
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October 2007

Construction of bicyclic ring systems via a transannular SmI2-mediated ketone-olefin cyclization strategy.

J Org Chem 2007 Mar 2;72(5):1755-64. Epub 2007 Feb 2.

Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA.

The development of novel methods and strategies for the formation of polycyclic ring structures is of utmost importance in organic synthesis. The present study describes the investigation of a transannular cyclization strategy for constructing bicyclic ring systems. To test the viability of the approach, the SmI2-mediated ketone-olefin coupling reaction, a method previously developed in this laboratory, was examined. Investigation of the transannular cyclization of cyclooctene, cyclodecene, and cycloundecene derivatives revealed that the process proceeds with high yield and diastereoselectivity, and in the case of larger ring-sized compounds, with excellent regioselectivity. The regioselectivity of the annulation process could be rationalized based on examining the low energy conformations of the keto alkene starting materials. These results demonstrate the efficiency and the potential of the transannular cyclization tactic for the creation of bicyclic ring systems.
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http://dx.doi.org/10.1021/jo062292dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515389PMC
March 2007

A general route toward the synthesis of the cladiellin skeleton utilizing a SmI2-mediated cyclization.

J Org Chem 2006 Feb;71(3):1172-80

Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA.

An efficient synthesis of the cladiellin skeleton is reported utilizing methods that were previously developed in this laboratory. The approach is based on a SmI(2)-mediated cyclization reaction for the construction of the oxacyclononane unit. A [4 + 3] annulation strategy was used to create the octahydroisobenzofuran moiety. This route provides the cladiellin skeleton in only 14 steps without the use of protecting groups. The present approach also enabled the synthesis of the 3,7-diastereomer of the natural product polyanthellin A.
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http://dx.doi.org/10.1021/jo052290dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2505338PMC
February 2006

Effect of the Ca2+ chelators EDTA and EGTA on sinoatrial-node activity and heart irritability.

Acta Physiol Acad Sci Hung 1982 ;60(3):155-64

The effect of the Ca-chelators EDTA and EGTA on sinoatrial activity and heart irritability was studied in dog experiments by perfusing the artery supplying the sinoatrial node. Beside the usual ECG recordings left and right atrial and left and right ventricular epicardial electrograms, His-bundle electrogram and the early activity of the sinoatrial node were recorded. In addition action potentials were recorded from the left auricle and right ventricle of the dog hearts. Local application around the sinoatrial and atrio-ventricular nodes of EDTA and EGTA caused sinus bradycardia and later sinus arrest within 1 min after introduction of the drugs. For substitution of the sinus rhythm junctional (seldom lower atrial) escape rhythm developed. One to two minutes later it was followed by atrial premature beats and even later atrial flutter and fibrillation could be recorded. In one third of the cases atrial fibrillation was followed by secondary ventricular fibrillation. Atrio-ventricular impulse conduction was prolonged in the av node by EDTA and EGTA. Atrial action potentials and the slow (Ca dependent) ventricular action potentials were depressed by EDTA and EGTA.
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September 1983