Synthesis, cytotoxic activity, and DNA binding properties of antitumor cis-1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine cinnamoyl esters.

Monocinnamoyl esters at position 2 of (+/-)-cis-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one and their acetyl derivatives at position 1 were prepared as stabilized analogues of the anticancer alkylating agent S23906-1. Monocinnamoyl esters at position 2 were slower DNA alkylators than the reference 2-monoacetate. Mixed esters bearing an acetyl ester group at position 1 and a cinnamoyl ester group at position 2 alkylated DNA slower than S23906-1.

Induction chemoradiotherapy facilitates radical resection of T4 non-small cell lung cancer invading the spine.

Objective: We evaluated the outcome, long-term results, and factors affecting outcome of induction chemoradiotherapy followed by surgical resection for T4 non-small cell lung cancer invading the spine.

Methods: Retrospective analysis of 23 consecutive patients undergoing radical vertebral resection for non-small cell lung cancer invading the spine between 1996 and 2007 was performed. In most cases, induction chemoradiotherapy consisted of cisplatin and etoposide followed by 45 Gy of radiation.

Benzopyridooxathiazepine derivatives as novel potent antimitotic agents.

Herein, we describe the structure-activity relationship study of a new 1-(arylalkyl)-11H-benzo[f]-1,2-dihydropyrido[3,2,c][1,2,5]oxathiazepine 5,5-dioxide series of antimitotic agents. The pharmacological results obtained from previous works allowed us to identify compound 1 as a new cytotoxic agent inhibiting tubulin polymerization. We have undertaken the synthesis of its non-methylated analogue 7 and have extended our investigations to a novel, structurally related benzopyridooxathiazepine dioxide series.

Genetic markers for the diagnosis and prognosis of pheochromocytoma.

The last 5 years have witnessed important advances in understanding the mechanisms of tumorigenesis of chromaffin cells. Large-scale microarray analyses of pheochromocytomas have identified two distinct gene-expression profiles encompassing all hereditary and sporadic tumors. Gene-expression profiling of benign and malignant pheochromocytomas is providing a better understanding of the mechanisms of metastasis.

Synthesis and CHK1 inhibitory potency of Hymenialdisine analogues.

A series of thieno[3,2-b]pyrroloazepinones derivatives related to Hymenialdisine were prepared and tested for CHK1 inhibitory activity. Nanomolar inhibitions were achieved when electron-withdrawing substituents were introduced at position 3 of the thiophene ring.

Technique for prolonged normothermic ex vivo lung perfusion.

Background: The inhibition of cellular metabolism induced by hypothermia obviates the possibility of substantial reparative processes occurring during organ preservation. The aim of this study was to develop a technique of extended (12-hour) ex vivo lung perfusion (EVLP) at normothermia for assessment and protective maintenance of the donor lung.

Methods: Six double-lung blocks from 35-kg pigs and 5 single human lungs were subjected to 12 hours of normothermic EVLP using acellular Steen Solution.

Synthesis, cytotoxic activity, and mechanism of action of furo[2,3-c]acridin-6-one and benzo[b]furo[3,2-h]acridin-6-one analogues of psorospermin and acronycine.

Compounds possessing the epoxyfuran system present in the natural cytotoxic dihydrofuroxanthone psorospermin (4) fused onto the acridone or benzo[b]acridone chromophores present in the antitumor acronycine (1) and S23906-1 (3) were prepared. The basic furoacridone and benzofuroacridone cores bearing an isopropenyl substituent at a convenient position were synthesized by condensation of 1,3-dihydroxyacridone (7) or 1,3-dihydroxybenz[b]acridin-12(5H)-one (9) with (E)-1,4-dibromo-2-methylbut-2-ene. In both series, the (2R*,1'S*) epoxides, with the same relative configuration as psorospermin, were the most active compounds, exhibiting cytotoxic properties with IC50 values in the 10-100 nM range.

Rebeccamycin derivatives as dual DNA-damaging agents and potent checkpoint kinase 1 inhibitors.

Rebeccamycin is an indolocarbazole class inhibitor of topoisomerase I. In the course of structure-activity relationship studies on rebeccamycin derivatives, we have synthesized analogs with the sugar moiety attached to either one or both indole nitrogens. Some analogs, especially those with substitutions at the 6' position of the carbohydrate moiety, exhibit potent inhibitory activity toward checkpoint kinase 1 (Chk1), a kinase that has a major role in the G(2)/M checkpoint in response to DNA damage.

Impact of human donor lung gene expression profiles on survival after lung transplantation: a case-control study.

Primary graft dysfunction (PGD) continues to be a major cause of early death after lung transplantation. Moreover, there remains a lack of accurate pretransplant molecular markers for predicting PGD. To identify distinctive donor lung gene expression signatures associated with PGD, we profiled human donor lungs using microarray technology prior to implantation.

Induction chemoradiation therapy followed by surgical resection for non-small cell lung cancer (NSCLC) invading the thoracic inlet.

Objective: The role of induction therapy for non-small cell lung cancer (NSCLC) invading the thoracic inlet is unclear. We reviewed our experience with induction chemoradiation followed by surgical resection for NSCLC invading the thoracic inlet.

Methods: We performed a retrospective review of 44 consecutive patients with NSCLC invading the thoracic inlet, treated with induction chemoradiation (two cycles of cisplatin and etoposide concurrently with 45Gy of radiation) followed by surgical resection between 1996 and 2007.

Risk factors for major complications after extrapleural pneumonectomy for malignant pleural mesothelioma.

Background: Factors associated with increased risk of major complications after extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma are not well characterized; in particular, the risks of induction chemotherapy and red blood cell (RBC) transfusion have not been well defined.

Methods: We reviewed our experience with 62 consecutive EPP (28 right sided) performed in our institution for malignant pleural mesothelioma between January 1993 and May 2007. A total of 44 patients underwent induction chemotherapy with cisplatin-based therapy.

Novel 5-azaindolocarbazoles as cytotoxic agents and Chk1 inhibitors.

We describe here an efficient synthesis of new 5-azaindolocarbazoles designed for cytotoxic and Chk1 inhibiting properties. The synthesis of 'symmetrical' and 'dissymmetrical' structures is discussed. Concerning the dissymmetrical 5-azaindolocarbazoles derivatives, with both an indole moiety and a 5-azaindole moiety, the synthesis was achieved using two very efficient key steps.

Structure-activity relationships in the acronycine and benzo[b]acronycine series: role of the pyran ring.

In order to explore the structure-activity relationships in the acronycine series, simplified analogues of cis-1,2-diacetoxy-1,2-dihydroacronycine and cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine (S23906-1, under clinical trials) lacking the fused pyran ring, but possessing an acetoxymethyl leaving group at position 4 were prepared. These new analogues only displayed marginal antiproliferative activity compared to the parent compounds. The presence of the angularly fused dimethylpyran ring appears as an indispensable structural requirement to observe significant cytotoxic activity in this series.

[Translational research and Cancer Plan].

The French Cancer Plan 2003-2007 has made translational research central to its research programme, to ensure the care-research continuum and the quickest application possible for the most recent discoveries, for the patients' benefit. This is a new field of research, still little-known or ill-understood. A working group, composed of physicians and researchers from academic research and industrial research, sought to define translational research in cancerology and define the issues at stake in it.

Novel E-ring camptothecin keto analogues (S38809 and S39625) are stable, potent, and selective topoisomerase I inhibitors without being substrates of drug efflux transporters.

Camptothecin (CPT) analogues are powerful anticancer agents but are chemically unstable due to their alpha-hydroxylactone six-membered E-ring structure, which is essential for trapping topoisomerase I (Top1)-DNA cleavage complexes. To stabilize the E-ring, CPT keto analogues with a five-membered E-ring lacking the oxygen of the lactone ring (S38809 and S39625) have been synthesized. S39625 has been selected for advanced preclinical development based on its promising activity in tumor models.

Atypical structure and phylogenomic evolution of the new eutherian oocyte- and embryo-expressed KHDC1/DPPA5/ECAT1/OOEP gene family.

Several recent studies have shown that genes specifically expressed by the oocyte are subject to rapid evolution, in particular via gene duplication mechanisms. In the present work, we have focused our attention on a family of genes, specific to eutherian mammals, that are located in unstable genomic regions. We have identified two genes specifically expressed in the mouse oocyte: Khdc1a (KH homology domain containing 1a, also named Ndg1 for Nur 77 downstream gene 1, a target gene of the Nur77 orphan receptor), and another gene structurally related to Khdc1a that we have renamed Khdc1b.

Identification of potential gene markers and insights into the pathophysiology of pheochromocytoma malignancy.

Context: Pheochromocytomas are catecholamine-producing tumors that are generally benign but that can also present as or develop into malignancy. Occurrence of malignant pheochromocytomas can only be asserted by imaging of metastatic lesions.

Objectives: We conducted a gene expression profiling of benign and malignant tumors to identify a gene signature that would allow us to discriminate benign from malignant pheochromocytomas and to gain a better understanding of tumorigenic pathways associated with malignancy.

Reversed halo sign in lymphomatoid granulomatosis.

Lymphomatoid granulomatosis is a rare lymphoproliferative disorder which affects extranodal sites, most commonly lung. Radiologically, it typically presents with multiple nodular opacities that may wax and wane. The reversed halo sign has previously been reported in cryptogenic organizing pneumonia and more recently in South American blastomycosis.

Hyaluronidase offers an efficacious treatment for inaesthetic hyaluronic acid overcorrection.

Background: Hyaluronic acid is generally accepted today as the "gold standard" filler agent, and its use has subsequently grown enormously. In addition, newer facial volume augmentation indications are constantly evolving. Rare adverse events, such as granulomas, have been described.

Improved results of induction chemoradiation before surgical intervention for selected patients with stage IIIA-N2 non-small cell lung cancer.

Objective: Optimal management of stage IIIA-N2 non-small cell lung cancer remains controversial. The surgical arm of the North American Intergroup 0139 trial was adopted as the standard treatment for patients with resectable N2 disease at the University Health Network. Results after 7 years of experience are reported.

Luminance contrast with clear and yellow-tinted intraocular lenses.

Purpose: To determine whether yellow-tinted intraocular lenses (IOLs) negatively affect luminance contrast in postoperative cataract patients.

Setting: Department of Ophthalmology, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada.

Synthesis and biological activities of isogranulatimide analogues.

The synthesis of new isogranulatimide analogues, their inhibitory activities toward the Checkpoint 1 kinase (Chk1), and their in vitro cytotoxicities toward four tumor cell lines (one murine L1210 leukemia, and three human cell lines: DU145 prostate carcinoma, A549 non-small cell lung carcinoma, and HT29 colon carcinoma) are described. The affinity for DNA of some representative compounds and their ability to induce DNA cleavage mediated by topoisomerase I have been examined. In some of the newly synthesized compounds, the imidazole heterocycle of isogranulatimide is replaced by a pyrrole and/or the indole unit is replaced by a 7-azaindole.

Novel stable camptothecin derivatives replacing the E-ring lactone by a ketone function are potent inhibitors of topoisomerase I and promising antitumor drugs.

The E-ring lactone is the Achilles' heel of camptothecin derivatives: although it is considered necessary for the inhibition of the enzyme topoisomerase I (topo1), the opening of the lactone into a carboxylate abolishes the generation of topo1-mediated DNA breaks. S38809 is a novel camptothecin analog with a stable 5-membered E-ring ketone; therefore, it lacks the lactone function. DNA relaxation and cleavage assays revealed that S38809 functions as a typical topo1 poison by stimulating DNA cleavage at T downward arrow G sites.

Synthesis and cytotoxic activity of dimeric analogs of acronycine in the benzo[b]pyrano[3,2-h]acridin-7-one series.

Coupling of 6-hydroxy-3,3-14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one (6) with alpha,omega-diiodoalkanes of varying length under alkaline conditions gave dimers 7-10. Halogenated ethers 11-14, cyclization products 15-17, and compounds 18-22 were also isolated in small yield from the reaction mixtures. Compounds 7-10 were more potent than acronycine and benzo[b]acronycine in inhibiting L1210 cell proliferation.

Extracorporeal membrane oxygenation for primary graft dysfunction after lung transplantation: analysis of the Extracorporeal Life Support Organization (ELSO) registry.

Background: Some patients with severe primary graft dysfunction (PGD) after lung transplantation (LTx) require gas exchange support using an extracorporeal membrane oxygenator (ECMO) as a life-saving therapy. A few single-center experiences have been reported with relatively few cases of ECMO after LTx.

Methods: We reviewed outcomes of ECMO in lung transplant recipients included in the Extracorporeal Life Support Organization (ELSO) registry, which was established with the intention to improve quality and outcome of extracorporeal life support (ECLS) in patients treated with ECMO applied for all indications.