A coarse-grained bead spring model of short polymer chains is studied by constant pressure molecular dynamics (MD) simulations. Due to two competing length scales for the length of effective bonds and the energetically preferred distance between nonbonded beads, one observes a glass transition when dense melts are cooled down (as shown in previous work, at a pressure p=1 the mode coupling critical temperature is at Tc≈0.45 and the Vogel–Fulcher temperature is T0≈0.33, in Lennard-Jones units). The present work extends these studies, estimating a cooling-rate-dependent glass transition temperature Tg(Γ) by cooling the model system from T=0.6 down to T=0.3, applying cooling rates from Γ≈10−3 to Γ≈10−6 (in MD time units), and attempting to identify Tg(Γ) from a kink in the volume versus temperature or potential energy versus temperature curves. It is found that Tg(Γ) lies in the range 0.43⩽Tg(Γ)⩽0.47, for the cooling rates quoted, and the variation of Tg(Γ) for Γ is compatible with the expected logarithmic variations. We will show why a detailed distinction between competing theories on these cooling rate effects would need an excessive amount of computer time. To estimate also the melting transition temperature Tm of this model, the sytem was prepared in a crystalline configuration as an initial state and heated up. The onset of diffusion, accompanied by an isotropization of the pressure tensor was observed for Tm≈0.77. This implies that the model is suitable for studying deeply supercooled melts.
Purpose: The aim of the present study was to optimize and simplify photodynamic therapy using a new liposomal formulation of the photosensitizer meta-(tetrahydroxyphenyl)chlorin [m-THPC (Foscan); liposomal m-THPC (Fospeg)] and to reduce systemic reactions to the photosensitizer. Experimental Design:To examine the pharmacokinetics of liposomal m-THPC, we determined tissue and plasma variables in feline patients with spontaneous squamous cell carcinoma. In vivo fluorescence intensity measurements of tumor and skin were done with a fiber spectrophotometer after i.v. injection of m-THPC or liposomal m-THPC in 10 cats. Blood samples, drawn at several time points after photosensitizer administration, were analyzed by high-performance liquid chromatography. The first reports on photodynamic therapy (PDT) date back to the beginning of the last century, when researchers observed that a combination of light with hematoporphyrin induces cell death (1). In 1995, the U.S. Food and Drug Administration approved PDT as a novel form of therapy against cancer, and since then, PDT has been used more frequently.PDT includes two components combined to induce cellular and tissue effects in an oxygen-dependent manner. The first is a ''light-sensitive'' substance called the photosensitizer. The second is light of a specific wavelength (laser light) to maximally activate the tumor-localized photosensitizer. On activation, a photosensitizer undergoes type I (electron or hydrogen transfer) or type II (local generation of cytotoxic singlet oxygen) photochemical reactions.Tumor destruction associated with PDT involves three principal mechanisms (2): (a) direct tumor cell kill (3), (b) destruction of tumor-associated vasculature (4 -6), and (c) activation of an immune response against tumor cells (7,8). A short drug-light interval allows the photosensitizer to accumulate predominantly in the vascular compartment. PDTmediated vascular effects range from transient vascular spasm, vascular stasis, and thrombus formation to total permanent vessel occlusion and can include enhanced vascular leakiness (5). A longer drug-light interval results in maximal concentration of the photosensitizer in the tumor, causing direct tumor cell destruction. This was shown recently for the secondgeneration photosensitizer meta-(tetrahydroxyphenyl)chlorin [m-THPC (Foscan)] and indicates that the in vivo effects occur via an indirect vascular effect as well as a more direct effect at different drug-light intervals (9, 10).To optimize PDT, liposomes are presently being tested as carrier and delivery systems with the aim of improving the tumoritropic behavior of photosensitizers.
Background: Squamous cell carcinomas are common skin tumors in cats. We investigated photodynamic therapy (PDT) using a new liposomal photosensitizer as a minimally invasive, effective treatment that can be easily performed while achieving good cosmetic results.Aim: The goal of this study was to assess and describe possible toxicities using a liposomal formulation of the photosensitizer meta-(Tetrahydroxyphenyl)Chlorin (m-THPC) and investigate if favorable pharmacokinetics translate into favorable tumor response and control.Animals: Eighteen client-owned cats with 20 spontaneous cutaneous squamous cell carcinomas were included in the study. Methods: PDT was performed using a new, liposomal formulation of the photosensitizer. Toxicity, tumor response, and tumor control were evaluated retrospectively.Results: No general adverse effects were observed in cats treated with the new liposomal formulation. Mild local toxicity such as erythema and edema were seen in 15% of the patients. All cats responded to therapy, with a complete response rate of 100%. The overall 1-year control rate was 75%. The tumor recurrence rate was 20% with a median time to recurrence of 172.25 (687.1) days.Conclusions and Clinical Importance: A new liposomal photosensitizer was successfully used for squamous cell carcinoma in cats and was well tolerated. There were no systemic adverse effects observed with the liposomal formulation. The favorable pharmacokinetics of the liposomal drug resulted in a favorable tumor response.
Feline head and neck squamous cell carcinoma (SCC) is a loco-regional disease harbouring a poor prognosis. The complex anatomic location precludes aggressive surgical resection and tumours recur within weeks to few months. Response to chemotherapy and local control after radiation therapy has been disappointing. In this study, a multimodal approach including medical treatment (thalidomide, piroxicam and bleomycin), radiation therapy (accelerated, hypofractionated protocol) and surgery was attempted in six cats. Treatment was well tolerated. Three cats with sublingual SCC were alive and in complete remission at data analysis closure after 759, 458 and 362 days. One cat with laryngeal SCC died of renal lymphoma after 51 days and the other with maxillary SCC died of a primary lung tumour 82 days after diagnosis. In both cats, the SCC was in complete remission. Only one cat developed metastases after 144 days. These encouraging preliminary results merit further evaluation in future trials.
We evaluated the response of 38 dogs treated with a coarsely fractionated, palliative radiation protocol based on CT-based 3D treatment planning. Dogs with histologically confirmed malignant nasal tumors were studied. Treatment prescriptions consisted of 3-4 x 8 Gy, 4-5 x 6 Gy, or 10 x 3 Gy fractions. Selected patient and tumor factors were evaluated for an effect on outcome. Resolution of clinical signs was reported after irradiation in all dogs. Acute toxicities were mild and short lived. Thirty-seven of 38 dogs died or were euthanized due to tumor-related disease. Overall median progression-free interval (PFI) was 10 months. Tumor stage affected response, with modified stage 1 patients having a median PFI 21.3 months vs. a median PFI of 8.5 months for modified stage 2 patients (P = 0.0006). Modified stage was the only factor significantly related to outcome. Based on these findings, a palliative radiation prescription based on computerized treatment planning may be justified in some canine nasal tumor patients.
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