On magnetic leaf-wise intersections

In this article we introduce the notion of a magnetic leaf-wise intersection point which is a generalization of the leaf-wise intersection point with magnetic effects. We also prove the existence of magnetic leaf-wise intersection points under certain topological assumptions.Comment: 43 page

The Importance of DNA Repair in Tumor Suppression

The transition from a normal to cancerous cell requires a number of highly specific mutations that affect cell cycle regulation, apoptosis, differentiation, and many other cell functions. One hallmark of cancerous genomes is genomic instability, with mutation rates far greater than those of normal cells. In microsatellite instability (MIN tumors), these are often caused by damage to mismatch repair genes, allowing further mutation of the genome and tumor progression. These mutation rates may lie near the error catastrophe found in the quasispecies model of adaptive RNA genomes, suggesting that further increasing mutation rates will destroy cancerous genomes. However, recent results have demonstrated that DNA genomes exhibit an error threshold at mutation rates far lower than their conservative counterparts. Furthermore, while the maximum viable mutation rate in conservative systems increases indefinitely with increasing master sequence fitness, the semiconservative threshold plateaus at a relatively low value. This implies a paradox, wherein inaccessible mutation rates are found in viable tumor cells. In this paper, we address this paradox, demonstrating an isomorphism between the conservatively replicating (RNA) quasispecies model and the semiconservative (DNA) model with post-methylation DNA repair mechanisms impaired. Thus, as DNA repair becomes inactivated, the maximum viable mutation rate increases smoothly to that of a conservatively replicating system on a transformed landscape, with an upper bound that is dependent on replication rates. We postulate that inactivation of post-methylation repair mechanisms are fundamental to the progression of a tumor cell and hence these mechanisms act as a method for prevention and destruction of cancerous genomes.Comment: 7 pages, 5 figures; Approximation replaced with exact calculation; Minor error corrected; Minor changes to model syste

Compactness for Holomorphic Supercurves

We study the compactness problem for moduli spaces of holomorphic supercurves which, being motivated by supergeometry, are perturbed such as to allow for transversality. We give an explicit construction of limiting objects for sequences of holomorphic supercurves and prove that, in important cases, every such sequence has a convergent subsequence provided that a suitable extension of the classical energy is uniformly bounded. This is a version of Gromov compactness. Finally, we introduce a topology on the moduli spaces enlarged by the limiting objects which makes these spaces compact and metrisable.Comment: 38 page

An exact sequence for contact- and symplectic homology

A symplectic manifold $W$ with contact type boundary $M = \partial W$ induces a linearization of the contact homology of $M$ with corresponding linearized contact homology $HC(M)$. We establish a Gysin-type exact sequence in which the symplectic homology $SH(W)$ of $W$ maps to $HC(M)$, which in turn maps to $HC(M)$, by a map of degree -2, which then maps to $SH(W)$. Furthermore, we give a description of the degree -2 map in terms of rational holomorphic curves with constrained asymptotic markers, in the symplectization of $M$.Comment: Final version. Changes for v2: Proof of main theorem supplemented with detailed discussion of continuation maps. Description of degree -2 map rewritten with emphasis on asymptotic markers. Sec. 5.2 rewritten with emphasis on 0-dim. moduli spaces. Transversality discussion reorganized for clarity (now Remark 9). Various other minor modification

Algebraic Torsion in Contact Manifolds

We extract a nonnegative integer-valued invariant, which we call the "order of algebraic torsion", from the Symplectic Field Theory of a closed contact manifold, and show that its finiteness gives obstructions to the existence of symplectic fillings and exact symplectic cobordisms. A contact manifold has algebraic torsion of order zero if and only if it is algebraically overtwisted (i.e. has trivial contact homology), and any contact 3-manifold with positive Giroux torsion has algebraic torsion of order one (though the converse is not true). We also construct examples for each nonnegative k of contact 3-manifolds that have algebraic torsion of order k but not k - 1, and derive consequences for contact surgeries on such manifolds. The appendix by Michael Hutchings gives an alternative proof of our cobordism obstructions in dimension three using a refinement of the contact invariant in Embedded Contact Homology.Comment: 53 pages, 4 figures, with an appendix by Michael Hutchings; v.3 is a final update to agree with the published paper, and also corrects a minor error that appeared in the published version of the appendi

Weak and strong fillability of higher dimensional contact manifolds

For contact manifolds in dimension three, the notions of weak and strong symplectic fillability and tightness are all known to be inequivalent. We extend these facts to higher dimensions: in particular, we define a natural generalization of weak fillings and prove that it is indeed weaker (at least in dimension five),while also being obstructed by all known manifestations of "overtwistedness". We also find the first examples of contact manifolds in all dimensions that are not symplectically fillable but also cannot be called overtwisted in any reasonable sense. These depend on a higher-dimensional analogue of Giroux torsion, which we define via the existence in all dimensions of exact symplectic manifolds with disconnected contact boundary.Comment: 68 pages, 5 figures. v2: Some attributions clarified, and other minor edits. v3: exposition improved using referee's comments. Published by Invent. Mat

Oxaliplatin plus raltitrexed and leucovorin-modulated 5-fluorouracil i.v. bolus: a salvage regimen for colorectal cancer patients

The aim of the present study was to define the activity and tolerability of a triplet regimen including oxaliplatin 130 mg m−2 (2 h i.v. infusion) and raltitrexed 3.0 mg m−2 (15 min i.v. infusion) given on day 1, followed by levo-folinic acid 250 mg m−2 (2 h i.v. infusion) and 5-fluorouracil 1050 mg m−2 i.v. bolus on day 2, every 2 weeks, in pretreated colorectal cancer patients. From April 1999 to December 2000, 50 patients were enrolled: 26 were males and 24 females, their median age was 63 (range, 43–79) years; ECOG performance status was 0 in 26 patients, ⩾1 in 24 patients; 26 patients had received previous adjuvant chemotherapy, 40 patients had been exposed to one or two lines of palliative chemotherapy (including irinotecan in 31 cases); 18 patients were considered chemo-refractory. A total of 288 cycles were administered, with a median number of 6 (range 1–12) courses per patient. A complete response was obtained in three patients, and a partial response in nine patients, giving a major response rate of 24% (95% confidence interval, 13–38%), while 15 further patients showed a stable disease, for an overall control of tumour growth in 60% of patients. Three complete responses and three partial responses were obtained in patients pretreated with irinotecan (response rate, 19%); among refractory patients, three achieved partial responses (response rate, 13%). After a median follow-up of 18 (range, 10–30) months, 40 patients showed a progression of disease: the growth modulation index ranged between 0.2 and 2.5: it was ⩾1.33 (showing a significant delay of tumour growth) in 16 (40%) patients. Actuarial median progression-free survival time was 7.6 months, and median survival time was 13.6 months: estimated probability of survival was 55% at 1 year. Main severe toxicity was neutropenia: World Health Organisation grade 4 affected 32% of patients; non-haematological toxicity was mild: World Health Organisation grade 3 diarrhoea was complained of by 8%, and grade 3 stomatitis by 4% of patients; neurotoxicity (according to Lévi scale) was scored as grade 3 in 8% of patients. In conclusion, this regimen was manageable and active as salvage treatment of advanced colorectal cancer patients; it showed incomplete cross-resistance with irinotecan-based treatments, and proved to delay the progression of disease in a relevant proportion of treated patients

Avoidable mortality across Canada from 1975 to 1999

BACKGROUND: The concept of 'avoidable' mortality (AM) has been proposed as a performance measure of health care systems. In this study we examined mortality in five geographic regions of Canada from 1975 to 1999 for previously defined avoidable disease groups that are amenable to medical care and public health. These trends were compared to mortality from other causes. METHODS: National and regional age-standardized mortality rates for ages less than 65 years were estimated for avoidable and other causes of death for consecutive periods (1975–1979, 1980–1985, 1985–1989, 1990–1994, and 1995–1999). The proportion of all-cause mortality attributable to avoidable causes was also determined. RESULTS: From 1975–1979 to 1995–1999, the AM decrease (46.9%) was more pronounced compared to mortality from other causes (24.9%). There were persistent regional AM differences, with consistently lower AM in Ontario and British Columbia compared to the Atlantic, Quebec, and Prairies regions. This trend was not apparent when mortality from other causes was examined. Injuries, ischaemic heart disease, and lung cancer strongly influenced the overall AM trends. CONCLUSION: The regional differences in mortality for ages less than 65 years was attributable to causes of death amenable to medical care and public health, especially from causes responsive to public health

Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth

Antitumour effects of retinoids are attributed to their influence on cell proliferation, differentiation, apoptosis and angiogenesis. In our effort to develop useful agents for breast cancer therapy, we evaluated the effects of four representative retinoic acid metabolism blocking agents (RAMBAs, VN/14-1, VN/50-1, VN/66-1 and VN/69-1) on growth inhibition of oestrogen receptor positive (ER +ve, MCF-7 and T-47D) and oestrogen receptor negative (ER −ve, MDA-MB-231) human breast cancer cells. Additionally, we investigated the biological effects/molecular mechanism(s) underlying their growth inhibitory properties as well as their antitumour efficacies against MCF-7 and MCF-7Ca tumour xenografts in nude mice. We also assessed the effect of combining VN/14-1 and all-trans-retinoic acid (ATRA) on MCF-7 tumuor xenografts. The ER +ve cell lines were more sensitive (IC50 values between 3.0 and 609 nM) to the RAMBAs than the ER −ve MDA-MB-231 cell line (IC50=5.6–24.0 μM). Retinoic acid metabolism blocking agents induced cell differentiation as determined by increased expression of cytokeratin 8/18 and oestrogen receptor-α (ER-α). Similar to ATRA, they also induced apoptosis via activation of caspase 9. Cell cycle analysis indicated that RAMBAs arrested cells in the G1 and G2/M phases and caused significant downregulation (>80%) of cyclin D1 protein. In vivo, the growth of MCF-7 mammary tumours was dose-dependently and significantly inhibited (92.6%, P<0.0005) by VN/14-1. The combination of VN/14-1 and ATRA also inhibited MCF-7 breast tumour growth in vivo (up to 120%) as compared with single agents (P<0.025). VN/14-1 was also very effective in preventing the formation of MCF-7Ca tumours and it significantly inhibited the growth of established MCF-7Ca tumours, being as effective as the clinically used aromatase inhibitors, anastrozole and letrozole. Decrease in cyclin D1 and upregulation of cytokeratins, Bad and Bax with VN/14-1 may be responsible for the efficacy of this compound in inhibiting breast cancer cell growth in vitro and in vivo. Our results suggest that our RAMBAs, especially VN/14-1 may be useful novel therapy for breast cancer