100 research outputs found
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 with contact type boundary induces
a linearization of the contact homology of with corresponding linearized
contact homology . We establish a Gysin-type exact sequence in which the
symplectic homology of maps to , which in turn maps to
, by a map of degree -2, which then maps to . Furthermore, we
give a description of the degree -2 map in terms of rational holomorphic curves
with constrained asymptotic markers, in the symplectization of .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 130βmgβmβ2 (2βh i.v. infusion) and raltitrexed 3.0βmgβmβ2 (15βmin i.v. infusion) given on day 1, followed by levo-folinic acid 250βmgβmβ2 (2βhβi.v. infusion) and 5-fluorouracil 1050βmgβmβ2βi.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, 43β79) years; ECOG performance status was 0 in 26 patients, β©Ύ1 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 1β12) 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, 13β38%), 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, 10β30) months, 40 patients showed a progression of disease: the growth modulation index ranged between 0.2 and 2.5: it was β©Ύ1.33 (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 LΓ©vi 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 (1975β1979, 1980β1985, 1985β1989, 1990β1994, and 1995β1999). The proportion of all-cause mortality attributable to avoidable causes was also determined. RESULTS: From 1975β1979 to 1995β1999, 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 βve, 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 609βnM) to the RAMBAs than the ER βve MDA-MB-231 cell line (IC50=5.6β24.0βΞΌM). Retinoic acid metabolism blocking agents induced cell differentiation as determined by increased expression of cytokeratin 8/18 and oestrogen receptor-Ξ± (ER-Ξ±). 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
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