Comparative analysis of immunohistochemical markers with invasiveness and histologic differentiation in squamous cell carcinoma and basal cell carcinoma of the skin

BACKGROUND: This study evaluates several tumor-related markers to examine the expression pattern of markers according to the invasiveness and histopathologic differentiation of squamous cell carcinoma and basal cell carcinoma. METHODS: Ninety-four cases of squamous cell carcinoma and 108 cases of basal cell carcinoma using tissue array in order to determine correlations between the expression of Ki-67, p53, EGFR, CD44v6, MMP-1 and MMP-3, invasiveness and histologic differentiation. In order to determine invasiveness, we measured the depth of invasion in resected tissues. RESULTS: The depth of invasion showed a correlation with CD44v6 expression of tumor cell in both squamous cell carcinoma and basal cell carcinoma (P = 0.009, P = 0.036, respectively) and with the MMP-1 expression of stromal cell in squamous cell carcinoma (P = 0.010). The differentiation of squamous cell carcinoma was correlated with Ki-67 index. The loss of palisading arrangement in basal cell carcinoma was correlated with the MMP-1 expression of stromal cells (P = 0.045). CONCLUSIONS: CD44v6 and MMP-1, expressed in tumor cells and stromal cells respectively, are significant markers associated with the invasiveness of tumors in squamous cell carcinoma and basal cell carcinoma of the skin and that it will be helpful to evaluate the invasiveness by measuring the expression of these markers.     

Synergistic Effects of High-dose Soybean Intake with Iodine Deficiency, but Not Sulfadimethoxine or Phenobarbital, on Rat Thyroid Proliferation

The specificity and dose dependence of the synergistic effects of soybean intake with iodine deficiency on the induction of thyroid proliferation were investigated in female F344 rats. In the first experiment, rats were divided into 6 groups, each consisting of 5 annuals, and fed a basal diet containing 20% gluten, an iodine-deficient basal diet alone or an iodine-deficient diet containing 0.2%, 1.0%, 5.0% or 25% defatted soybean for 5 weeks. Soybean feeding synergistically induced thyroid hyperplasias with iodine deficiency only at the 25% dose. In the second experiment, rats were also divided into 6 groups, each consisting of 5 animals, and fed a basal diet, a diet containing 20% defatted soybean, 0.025% Sulfadimethoxine (SDM), 20% defatted soybean+0.025% SDM, 0.05% phenobarbital (PB) or 20% defatted soybean+0.05% PB for 5 weeks. The SDM treatments significantly (P<0.05-0.01) increased the thyroid weights, but this increase rate was less prominent in the SDM+soybean group than in the SDM alone group. The PB treatment was also associated with a tendency for increase in thyroid weight, but again this was smaller in the PB+soybean group than in the PB alone group. Although the SDM or PB treatments reduced the serum triiodothyronine and thyroxine levels and consequently increased the serum thyroid-stimulating hormone (TSH) levels, the soybean feeding did not affect or rather attenuated these changes. Our results clearly indicate that soybean feeding does not synergistically enhance the effects of SDM or PB on the rat thyroid. Thus it can be concluded that soybean intake specifically interacts with iodine deficiency in induction of thyroid proliferative lesions in rats, only at high doses.     

Inhibition of γ-irradiation induced adhesion molecules and NO production by alginate in human endothelial cells

Inflammation is a frequent radiation-induced reaction following therapeutic irradiation. Treatment of human umbilical endothelial cells (HUVEC) with gamma-irradiation (gammaIR) induces the expression of adhesion proteins such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Since the upregulation of these proteins on endothelial cell surface has been known to be associated with inflammation, interfering with the expression of adhesion molecules is an important therapeutic target. In the present study, we demonstrate that high mannuronic acid-containing alginate (HMA) inhibits gammaIR induced expression of ICAM-1, VCAM-1, and E-selectin on HUVEC in a dose dependent manner. HMA also inhibited gammaIR induced production of Nitric oxide (NO). These data suggest that HMA has therapeutic potential for the treatment of various inflammatory disorder associated with an increase of endothelial leukocyte adhesion molecules.     

Inhibition of 3-phosphoinositide–dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts

Cellular senescence is defined as a stable, persistent arrest of cell proliferation. Here, we examine whether senescent cells can lose senescence hallmarks and reenter a reversible state of cell-cycle arrest (quiescence). We constructed a molecular regulatory network of cellular senescence based on previous experimental evidence. To infer the regulatory logic of the network, we performed phosphoprotein array experiments with normal human dermal fibroblasts and used the data to optimize the regulatory relationships between molecules with an evolutionary algorithm. From ensemble analysis of network models, we identified 3-phosphoinositide–dependent protein kinase 1 (PDK1) as a promising target for inhibitors to convert the senescent state to the quiescent state. We showed that inhibition of PDK1 in senescent human dermal fibroblasts eradicates senescence hallmarks and restores entry into the cell cycle by suppressing both nuclear factor κB and mTOR signaling, resulting in restored skin regeneration capacity. Our findings provide insight into a potential therapeutic strategy to treat age-related diseases associated with the accumulation of senescent cells.

Cellular senescence is defined as a stable, persistent exit from the cell cycle in response to stresses such as telomere shortening, oxidative stress, oncogene activation, and DNA damage (1, 2). A benefit of cellular senescence is prevention of tumorigenesis by blocking proliferation of damaged cells that may undergo malignant transformation (2, 3). However, senescent cells accumulate in tissues during aging and secrete proinflammatory cytokines, which can contribute to aging and age-related diseases, including cancer (2, 3). In studies with animal models, elimination of senescent cells prevents, alleviates, or reverses symptoms of aging (4, 5) and various age-related diseases (6, 7), such as osteoarthritis and atherosclerosis.Cell-cycle arrest alone is not cellular senescence; cellular senescence requires additional signals that convert transient cell-cycle arrest into persistent exit from the cell cycle so that the cells fail to proliferate in response to growth signals, a process called geroconversion (8, 9). Terminally differentiated, nonmitotic cells can also undergo senescence; thus, cell-cycle exit is only one aspect of the senescent phenotype. Cellular senescence is a complex biological mechanism regulated by various signaling pathways (10, 11). Signaling pathways that mediate cellular senescence can be divided into three major categories. The first category includes the pathways that cause cell-cycle arrest in response to DNA damage, such as p53/p21^CIP1 and p16^INK4a/pRb pathways (11–14). The second category consists of the pathways mediating cell growth and energy metabolism, such as PI3K/AKT/mTOR and SIRT1/AMPK pathways (15–18). Activation of mTOR in cells arrested by persistent DNA damage represents a second stimulus that can convert transiently arrested cells into senescent cells that exhibit hypertrophy and an expanded lysosomal compartment (19). The last category consists of the pathways mediating the senescence-associated secretory phenotype (SASP) (3, 10, 20). The SASP is a characteristic feature of senescent cells and reflects their secretion of proinflammatory cytokines and chemokines. These cytokines and chemokines maintain cellular senescence through positive autoregulatory feedbacks, affect nonsenescent nearby cells, and promote aging and age-related diseases, including cancer (3, 21). Nuclear factor κB (NF-κB) activity is important for SASP, and suppression of NF-κB prevents age-related diseases and delays aging in mice (22, 23).Spontaneous reversion from senescence to proliferation is extremely rare, but the reversion through manipulations is not. Some studies reported that senescent cells can reenter the cell cycle (24). The current understanding of senescence is as a dynamic multistep process that is reversible under some conditions (25). About 70 to 90% of cells with low p16^INK4a levels in replicative senescence, which is senescence related to the finite number of divisions a cell can perform before telomeres become too short, resume proliferation following p53 inactivation (26). Inactivation of p53 also enables cells to escape from therapy-induced senescence, caused by the chemotherapeutic agent Adriamycin (27). Cells with oncogene-induced senescence can also escape from the senescent state. For instance, about 50% of mouse embryo fibroblasts with high Ras levels reenter the cell cycle upon inactivation of all three Rb family members (28), and about 70% of the fibroblasts reenter upon activation of H3K9 demethylases (29).Here, we applied a systems biology approach to identify mechanisms underlying cell-cycle arrest, cell growth, and the SASP with the goal of finding inhibitable targets to convert the senescent state to the quiescent state. We studied normal human dermal fibroblasts (NHDFs), which can be experimentally induced into the senescent state (8). We constructed a molecular signaling network of cellular senescence using information in the literature and network databases to identify the relevant molecules, experimental data from time series of phosphorylated proteins in NHDFs to define the input–output relationships that reflect cellular states upon each input condition, and an evolutionary algorithm to determine the regulatory logic of the network (SI Appendix, Fig. S1 A–C). By analyzing the regulatory signaling network, we predicted that PDK1 was an inhibitor target that can convert senescent fibroblasts to quiescent fibroblasts (SI Appendix, Fig. S1D). To validate this prediction, we conducted experiments with NHDFs exposed to PDK1 inhibitors (SI Appendix, Fig. S1E), which eliminated hallmarks of cellular senescence, restored the proliferation of the cells in response to growth factors, and restored skin regeneration capacity in two-dimensional (2D) culture and a three-dimensional (3D) skin equivalent model. Our findings provide insight into a potential therapeutic strategy to treat aging and age-related diseases.     

Catechin glycoside fromUlmus davidiana

Catechin and catechin glycoside named uldavioside A were isolated from the Korean folk medicineUlmus davidiana. Based on chemical and physicochemical evidences, their structure have been determined as (+)-catechin (1) and (+)-catechin-5-O-β-D-apiofuranoside (2).     

Cytomegalovirus antigenemia as a useful marker of symptomatic cytomegalovirus infection after renal transplantation--a report of 130 consecutive patients

In earlier work we demonstrated that CMV immediate early antigens can be detected in peripheral blood leukocytes of patients with active CMV infection. We now report a comparison of the antigenemia assay and an anti-CMV ELISA in a prospective longitudinal study of 130 renal transplant recipients who were monitored for active CMV infection during the first 3 months after transplantation. Active CMV infection developed in 56 patients. The antigenemia assay had a sensitivity of 89% and a specificity of 93% in the diagnosis of active CMV infection; for the ELISA these figures were 95 and 100%, respectively. In 22 of the 56 patients a CMV syndrome occurred. Antigenemia was demonstrated in all 22 patients while an antibody response occurred in 21 of them. The antigenemia assay became positive 8 +/- 7 days before the onset of symptoms while the antibody response was observed 4 +/- 9 days after the onset of symptoms. The pattern of antigenemia was helpful for monitoring the course of the infection. The maximum level of antigenemia was significantly higher and its duration significantly longer in symptomatic than asymptomatic infection. We conclude that CMV antigenemia is a sensitive, specific, and early marker of CMV infection. The antigenemia assay is of great value in monitoring patients with a high risk of CMV infection.     

Randomized clinical trial of mitomycin C as an adjunct to radiotherapy in head and neck cancer

A randomized prospective clinical trial was carried out to assess the usefulness of the addition of mitomycin C to radiation therapy used alone or in combination with surgery for the treatment of squamous cell carcinoma of the head and neck region. One hundred and twenty patients with biopsy proven tumor of the oral cavity, oropharynx, larynx, hypopharynx, and nasopharynx were randomly assigned to receive or not receive mitomycin C; all other aspects were similar in the two treatment groups. One hundred and seventeen patients were evaluable with a median follow-up time of greater than 5 years. Acute and chronic normal tissue radiation reactions were equivalent in the two treatment groups. Hematologic and pulmonary toxicity were observed in the drug treated patients. Actuarial disease-free survival at 5 years was 49% in the radiation therapy group and 75% in the radiation therapy plus mitomycin C group, p less than 0.07. Local recurrence-free survival was 66% in the radiation therapy group and 87% in the radiation therapy plus mitomycin C group, p less than 0.02. The findings demonstrate that mitomycin C can be administered safely as an adjunct to radiation therapy in the treatment of head and neck cancer. The drug improves local tumor control without enhancing normal tissue radiation reactions.     

Objective evaluation for severity of atopic dermatitis by morphologic study of skin surface contours

BACKGROUND/AIMS: Wide variation in outcome methodology can make the interpretation of patient outcomes confusing and the comparison of the results of different studies almost impossible. It is important to objectively measure and record the severity of atopic dermatitis (AD) for routine clinical practice and research. The aim of this study was to evaluate whether morphologic study of skin surface contours might be helpful to objectively quantify the severity of AD. METHODS: Thirty atopic patients (12 females, 18 males) participated in this study. Moisturizer was applied twice daily for 2 weeks. Bioengineering methods such as D-Squame, corneometer, evaporimeter, and spectrophotometer were measured at the start of the study and after 1 week and 2 weeks. In addition, we assessed moisturizer effects after 3 h of moisturizer application.The stereoimage optical topometer (SOT) based on a new concept of stereoimage was applied for this study. We compared SOT, other bioengineering methods, and the severity scoring of atopic dermatitis (SCORAD) index. RESULTS: After 3 h of application with moisturizer, the results measured by SOT, conventional optical profilometer (COP), D-Squame, and corneometer showed significant differences (P<0.05). After 1 and 2 weeks, there were significant changes in the results measured by SOT, COP, D-Squame, corneometer, spectrophotometer, and SCORAD index. We observed a significant correlation between bioengineering methods and the SCORAD index (P<0.05). CONCLUSION: These data indicate that morphologic study of skin surface contours are useful in evaluating of AD severity. If we would combine methods to evaluate the physiologic changes and those such as SOT to measure the morphological changes of skin surface, we could evaluate more objectively and quantitatively the severity of AD.