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Since uterine cervical cancer is regarded as a radiosensive tumor, ionizing radiation is the most frequently used treatment modality against the disease. Although the crucial end-point is radiation-induced cell death, the tumors are not equally sensitive to radiation. Determining the criteria that may be used to predict tumor radiosensitivity is of importance; however, little success has been achieved thus far. In radioresistant cases the therapeutic strategy should be changed, thereby avoiding ineffective or unnecessary treatment. Furthermore, identification of the underlying molecular processes leading to radioresistance may lead to novel radiosensitising strategies. Cervical smears were obtained from seven patients with locally advanced cervical cancer following each radiotherapy, and the radiation-induced damage of cancer tissue was examined by routine cytology. Since the formation of DNA double-strand breaks is considered critical for the cytocidal effect of radiation therapy, the molecular changes of the neoplastic cells were also assessed by laser scanning cytometry (LSC). Radiation-induced morphological changes of cancer cells were evident at a dose of 7.2 Gy, whereas increased DNA content (or DNA index) was observed prior to the onset of morphological changes. Molecular change was detected earlier than the morphological change of the irradiated cancer cells, indicating the feasibility of LSC in predicting the radiosensitivity of cervical cancer tissue.

The prognosis of advanced colorectal cancer (aCRC) remains poor, and development of new therapeutic approaches, including immunotherapy, is needed urgently. Herein we report on our phase II study of personalized peptide vaccination (PPV) in 60 previously treated patients with aCRC, who had failed at least one regimen of standard chemotherapy and/or targeted therapy. For PPV, a maximum of four HLA-matched peptides were individually selected from a pool of 31 different peptide candidates based on preexisting host immunity, and administered subcutaneously without severe adverse events. Boosting of IgG and cytotoxic T lymphocyte (CTL) responses specific to the administered peptides was observed in 49% and 63%, respectively, of the patients, who completed the first cycles of six vaccinations. Median overall survival (OS) time was 498 days, with 1- and 2-year survival rates of 53% and 22%, respectively. Multivariate Cox regression analysis of prevaccination factors showed that plasma IL6, IP-10, and BAFF levels were significantly prognostic for OS [hazard ratio (HR), 1.508, P = 0.043; HR, 1.579, P = 0.024; HR, 0.509, P = 0.002, respectively]. In addition, increased peptide-specific CTL responses after vaccination were significantly predictive of favorable OS (HR, 0.231; P = 0.021), suggesting a causal relationship between biologic and clinical efficacy of PPV. On the basis of the safety profile and potential clinical efficacy, we believe that clinical trials of PPV would be warranted for previously treated patients with aCRC., (©2014 American Association for Cancer Research.)

Rearrangements of anaplastic lymphoma kinase (ALK) have been recently identified in non-small cell lung carcinomas. Previous studies have revealed characteristic features, including adenocarcinoma histology and mucin production, in ALK-positive lung carcinoma. The present study evaluated immunohistochemistry (IHC) in ALK-positive lung carcinoma using two different antibodies, clone 5A4 and D5F3, and compared the results. On the basis of the aforementioned characteristic features, out of 359 primary lung carcinomas, the ALK status of 14 adenocarcinomas was screened using the intercalated antibody-enhanced polymer (iAEP) method with antibody 5A4, and this was compared with the ALK status obtained using rabbit monoclonal antibody D5F3 and fluorescence in situ hybridization for ALK. Eight cases were demonstrated to be ALK-positive by IHC. Seven cases exhibited ALK rearrangement, which was demonstrated by fluorescence in situ hybridization. The IHC for ALK obtained using D5F3 was comparable with that of the iAEP and exhibited low heterogeneity. This finding suggests that IHC for ALK could be useful in limited tissue samples, such as biopsy specimens or cytology, for the screening of ALK-positive lung carcinoma. In the present study, it was demonstrated that IHC with ALK monoclonal antibody D5F3 was useful for screening lung adenocarcinoma harboring ALK rearrangement.

A proportion of angiotensin II type 1 receptor blockers (ARBs) improves glucose dyshomeostasis and insulin resistance in a clinical setting. Of these ARBs, telmisartan has the unique property of being a partial agonist for peroxisome proliferator-activated receptor γ (PPARγ). However, the detailed mechanism of how telmisartan acts on PPARγ and exerts its insulin-sensitizing effect is poorly understood. In this context, we investigated the agonistic activity of a variety of clinically available ARBs on PPARγ using isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) system. Based on physicochemical data, we then reevaluated the metabolically beneficial effects of telmisartan in cultured murine adipocytes. ITC and SPR assays demonstrated that telmisartan exhibited the highest affinity of the ARBs tested. Distribution coefficient and parallel artificial membrane permeability assays were used to assess lipophilicity and cell permeability, for which telmisartan exhibited the highest levels of both. We next examined the effect of each ARB on insulin-mediated glucose metabolism in 3T3-L1 preadipocytes. To investigate the impact on adipogenesis, 3T3-L1 preadipocytes were differentiated with each ARB in addition to standard inducers of differentiation for adipogenesis. Telmisartan dose-dependently facilitated adipogenesis and markedly augmented the mRNA expression of adipocyte fatty acid-binding protein (aP2), accompanied by an increase in the uptake of 2-deoxyglucose and protein expression of glucose transporter 4 (GLUT4). In contrast, other ARBs showed only marginal effects in these experiments. In accordance with its highest affinity of binding for PPARγ as well as the highest cell permeability, telmisartan superbly activates PPARγ among the ARBs tested, thereby providing a fresh avenue for treating hypertensive patients with metabolic derangement.

We demonstrate the spontaneous formation of spherical complex M12L24, which is composed of 12 palladium ions and 24 bidentate ligands, by molecular dynamics simulations. In contrast to our previous study on the smaller M6L8 cage, we found that the larger M12L24 self-assembly process involves noticeable kinetic trapping at lower nuclearity complexes, e.g., M6L12, M8L16, and M9L18. We also found that the kinetic trapping behaviors sensitively depend on the bend angle of ligands and the metal-ligand binding strength. Our results show that these kinetic effects, that have generally been neglected, are important factor in self-assembly structure determination of larger complexes as M12L24 in this study.

Hydroxyapatite (HAP) was mineralized in poly(vinyl alcohol) (PVA)/poly(acrylic acid) (PAA) complex hydrogel immersed in a salt solution containing PAA. The transparent HAP/polymer composite swelled in water depending on the HAP content; high HAP content gave small swelling and vice versa. The HAP content reached about 80 wt % at most. Observation of the cross section of the composite by energy-dispersive analysis of X-ray (EDAX) revealed that the composite consisted of two phases, i.e., a hard HAP-rich phase and a soft polymer-rich phase. In the HAP-rich phase, the space inside the hydrogel was occupied by HAP, while HAP was not mineralized in the polymer-rich phase. The nucleation seemed to take place, at first, at the middle depth of the hydrogel where the HAP-rich phase was formed. The HAP-rich phase grew its size toward the surface of the hydrogel at the cost of the polymer-rich phase. The presence of phosphorus, P, in the polymer-rich phase indicated the adsorption of HPO(4)(2-) on the polymer chain of the hydrogel via hydrogen bonding, accompanied with Ca(2+) because of electrostatic constraints. This adsorption of ions in addition to Donnan distribution of ions leads to the formation of a hypercomplex that can be regarded as a precursor of the HAP-rich phase. The change of the hypercomplex into the HAP-rich phase is discontinuous and hence concluded as a phase transition. By comparison of our mineralization system with the biomineralization system of HAP and CaCO(3), the physicochemical mechanism of the mineralization process in the present system was found to be similar to that in biological systems. In this sense, we termed the present system an artificial biomineralization system.

The polarization curve of an acid-base interface in a hydrogel medium has a diode characteristic. Two of each such electrolyte diodes can be combined to give an electrolyte transistor. When a salt is added to the alkaline or to the acidic part of a reverse biased electrolyte diode, the current response is highly nonlinear. If the salt is added to the acidic side, even bistability can be observed. This bistability can generate complex oscillations in a base-acid-base electrolyte transistor. These nonlinear effects are studied experimentally and theoretically. While the nonlinear salt effect can be explained with the Nernst-Planck equations, to understand the bistable behavior further investigations are necessary. (c) 1999 American Institute of Physics.

Experimental and computational studies of the formation and evolution of scroll waves in three-dimensional excitable media are presented. Scroll waves are initiated in the photosensitive Belousov-Zhabotinsky reaction by perturbing traveling waves transverse to their direction of propagation. Scroll rings are generated by perturbing circular waves, which expand or contract depending on the strength of an imposed excitability gradient and its direction relative to the rotational direction of the scroll wave. (c) 1998 American Institute of Physics.