XPA gene-deficient, SCF-transgenic mice with epidermal melanin are resistant to UV-induced carcinogenesis

Photobiologic investigations have been performed using animals without epidermal melanocytes. We developed xeroderma pigmentosum group A gene-deficient (XPA (-/-)), stem cell factor transgenic (SCF-Tg) mice, which one defective in nucleotide excision repair and have epidermal melanocytes, and investigated protective effects of epidermal melanin against UV-induced injuries. When irradiated to UVB, XPA (-/-) mice developed greatly enhanced responses including acute inflammation, cyclobutane pyrimidine dimer (CPD) formation, keratinocyte apoptosis, depletion of Langerhans cells and immunosuppression of contact hypersensitivity, but XPA (-/-), SCF-Tg mice showed much less responses to the same dose of UVB. XPA (-/-), SCF-Tg mice did not develop skin cancers after repeated exposures to UVB for 30 wk at a total dose of 72 J per cm(2), which induced a significant number of tumors even in wild-type, XPA (+/+) mice, and was lethal dose for XPA (-/-) mice. Dimethylbenz (alpha) anthracence (DMBA) induces DNA damages, which require XPA protein to be repaired. Topical application of DMBA produced a significant inflammation, CPD formation, apoptosis, immunosuppression, and skin cancers in XPA (-/-), SCF-Tg mice as well as XPA (-/-) mice. These findings indicate that epidermal melanin has a high ability to protect DNA damage by UVB radiation, and thereby, prevent UV-induced inflammation, immunosuppression, and carcinogenesis.     

Extent and contraindications for sacral amputation in patients with recurrent rectal cancer: a systematic literature review

Background  

Abdominosacral amputation is a potentially curative surgical approach for patients with recurrent rectal cancer. Previous reports have described differing extents of sacral resection. Most of these reports stated that high sacral involvement of the tumor is a contraindication for surgery; however, the basis for this is unclear.     

Effects of interleukin-1beta and prostaglandin E2 on prostaglandin D synthase production in cultivated rat leptomeningeal cells.

Although the interleukin (IL)-1 receptor is densely distributed in the leptomeninges constituting the blood/cerebrospinal fluid barrier, its physiologic significance has remained unclear. In the present study, we show that in cultured leptomeningeal cells, IL-1beta, tumor necrosis factors, or lipopolysaccharide causes a prominent increase in the synthesis and release of prostaglandin (PG) D synthase, which catalyzes the final step in the biosynthesis of PGD2. Although significant increases in the amount of PGD synthase were also observed with cells exposed to somatostatin, thrombin, or ciliary neurotrophic factor, these were much smaller than were those induced by the proinflammatory cytokines. Other agents tested including IGF-I had no effect upon the enzyme levels in the culture media. Furthermore, we found that the increased secretion of PGD synthase by IL-1beta was completely inhibited by 10(-7) M PGE2. The same dose of PGD2 or 15-deoxy-Delta(12-14)PGJ2 had no effect upon the IL-1beta action. In addition, PGE2 increased the level of fibronectin and eliminated the expression of zonula occludentes-1, a tight junction-associated protein from cultured cells, effects likely reflecting a loss of barrier integrity. These results demonstrate the importance of inflammatory stimuli as a physiologic regulator of the leptomeningeal cell function.     

Signaling pathways involved in DNA synthesis and migration in response to lysophosphatidic acid and low-density lipoprotein in coronary artery smooth muscle cells

Low-density lipoprotein (LDL) and lysophosphatidic acid (LPA), one of the lipid components of lipoprotein, induced the DNA synthesis of coronary artery smooth muscle cells (CASMCs). The LDL- and LPA-induced DNA synthesis was markedly inhibited by the LPA receptor antagonist Ki16425, pertussis toxin, small interfering RNAs targeted for LPA₁ receptors, and a potent calcineurin inhibitor cyclosporine A. It has been reported that LDL and LPA induced a migration response in a manner sensitive to Ki16425, pertussis toxin, and a LPA₁ receptor-specific small interfering RNA. However, cyclosporine A was ineffective in inhibiting the migration response. Instead, an epidermal growth factor (EGF) receptor tyrosine kinase inhibitor markedly suppressed the migration response to LDL and LPA without having any significant effect on DNA synthesis. Thus, the LDL-induced stimulation of DNA synthesis and migration in CASMCs is mediated by its component LPA through LPA₁ receptors and G_i/o-proteins. Ca²⁺/calcineurin pathways and transactivation of EGF receptors mediate LPA₁-receptor-induced DNA synthesis and migration, respectively.     

The effect of pancreatopeptidase E (elastase) on anastomotic intimal thickness in two types of vascular prosthesis

To determine the effects of pancreatopeptidase E (elastase) on anastomotic intimal thickness in vascular prostheses, expanded polytetrafluoroethylene (ePTFE) and Dacron grafts were implanted in the infrarenal aortas of 28 adult mongrel dogs, divided into four groups of seven dogs each according to the type of graft used and whether or not elastase was given. Thus, group E received ePTFE grafts without elastase; group D received Dacron grafts without elastase; group E + Ela received ePTFE grafts with concomitant oral elastase, 8 mg/kg per day; and group D + Ela received Dacron grafts with elastase given at the same dosage as in group E + Ela. Each graft was harvested 4 months following surgery for histologic examination. It was clearly observed that elastase suppressed intimal growth at the proximal and distal anastomoses in the ePTFE grafts (P<0.05), but not in the Dacron grafts. Furthermore, when we measured the smooth muscle cell percent extinction (%E) on microspectrophotometry in the intima within 2 mm of the proximal and distal anastomoses, it was found that elastase reduced intimal smooth muscle proliferation at the anastomosis of the ePTFE grafts, but not the Dacron grafts (P<0.05). These data suggest that elastase suppresses intimal growth by inhibiting smooth muscle cell migration and proliferation in the vascular prostheses of low but not of high porosity.     

Rationale for the use of combination angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker therapy in heart failure.

BACKGROUND: The present multicenter study investigated whether the combination of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) is more beneficial for preventing left ventricular remodeling and suppressing neurohumoral factors than either ACEI or ARB alone. METHODS AND RESULTS: One hundred and six patients with mild-to-moderate congestive heart failure treated in 26 Japanese institutes were randomly assigned to the combination therapy or monotherapy. Changes in physical activity (New York Heart Association functional classes, Specific Activity Scale (SAS)), concentrations of neurohumoral factors (plasma renin activity, angiotensin II, aldosterone, and brain natriuretic peptide (BNP)), and cardiac function for 6 months were compared between the 2 groups. It was found that the combination therapy, which was administered at doses standard in Japan, increased the SAS score (4.5 +/- 1.5 to 4.9 +/- 1.5, p<0.05) and decreased the plasma BNP concentration (183 +/- 163 to 135 +/- 118 pg/ml, p<0.05). In contrast, there were no changes in SAS score (4.5 +/- 1.4 to 4.6 +/- 1.4, NS) or BNP concentration (156 +/- 157 to 151 +/- 185 pg/ml, NS) in the patients receiving monotherapy. CONCLUSIONS: The results of the study demonstrate that the combination therapy, even at the standard doses for Japan, improves physical activity and plasma BNP concentration more than the monotherapy. A larger study is required to assess the effects of the combination therapy on major clinical outcomes.     

The potent peptide antagonist to angiogenesis, C16Y, and cisplatin act synergistically in the down-regulation of the Bcl-2/Bax ratio and the induction of apoptosis in human ovarian cancer cells

Cisplatin is one of the most potent antitumor agents for ovarian cancer, but has also been implicated in normal tissue cytotoxicity. We examined the effect of cisplatin alone and in combination with C16Y, a newly-identified anti-angiogenic peptide from the NH2-terminal domains of the γ-chain of laminin-1, on the modulation of Bcl-2/Bax expression and induction of apoptosis in ovarian cancer cells (OVACAR3). C16Y did not elicit cell death of human umbilical vein endothelial cells (HUVECs). Cisplatin exerted a lethal effect with an EC50 of 10?μM in OVACAR3s. In the presence of 25 or 50?μg/ml of C16Y (a range which has no effect against HUVECs), the EC50 for cisplatin in OVACAR3s decreased to 3.5 and 2.0?μM, respectively. Using fluorescence-activated cell sorting (FACS) analysis of DNA stained OVACAR3s and terminal deoxynucleotide tranferase-mediated dUTP nick end-labeling (TUNEL), we found that even at concentrations of 1 and 3?μM cisplatin, C16Y at 10 and 25?μg/ml increased the incidence of apoptosis in OVACAR3s by 3-5-fold. Each drug had some measurable effect on Bax protein expression. Furthermore, Bcl-2 protein expression levels were markedly reduced by C16Y alone and cisplatin alone in a dose-dependent manner. The combination of C16Y and cisplatin resulted in a further dramatic reduction in Bcl-2, underscoring the pronounced synergy produced by cisplatin and C16Y together. On the other hand, C16Y did not activate any other signal transduction pathways that usually culminate in the activation of apoptosis, such as the p53, p21waf1, p73, ERK1/2 or PI3-AKT pathways. These observations suggest that the suppression of the Bcl-2/Bax ratio may play an important role in mediating the synergistic effect of cisplatin and C16Y on the induction of apoptosis in OVACAR3 cells.     

Drug-induced interstitial lung disease in molecular targeted therapies: high-resolution CT findings

Drug-induced lung injury (DLI) comprises a wide variety of pathologies, each with a unique imaging pattern, so there are no characteristic imaging findings to establish diagnosis. When DLI is suspected, evaluation must exclude progression of underlying disease, infection, and mimicking diseases. Correct diagnosis requires integration of clinical information and radiologic, laboratory, and pathological findings when available. We describe the radiologic findings of DLI, the roles of the findings in the management of patients with DLI, and the limitations of radiologic diagnosis.