A case of carcinoma associated with anal fistula resected after preoperative chemoradiotherapy

A 66-year-old man with a 39-year history of anal fistula was admitted to our hospital for anal pain and bleeding. Fistulectomy was carried out for anal fistula. Histological examination of the specimen revealed carcinoma associated with anal fistula. A computed tomography showed that the tumor had invaded the prostate. Therefore, preoperative chemoradiotherapy(S-1 plus radiation 40 Gy/body)for locally advanced cancer was performed. Magnetic resonance imaging showed that the boundary between the tumor and the prostate was unclear, but we performed an abdominoperineal resection and the prostate was fully preserved. Histopathologically, no cancer cell existed on the surgical margin. The histological effect of chemoradiotherapy was judged as grade 2. This case suggested that surgical treatment combined with preoperative chemoradiotherapy may be effective for locally advanced carcinoma associated with anal fistula, in which preservation of adjacent organs is considered to be difficult.     

Nasal delivery of P-gp substrates to the brain through the nose-brain pathway

The objective of this study was to evaluate in rats the potential utility of the nasal route to enhance central nervous system (CNS) delivery of drugs recognized by P-glycoprotein (P-gp). Well-known P-gp substrates verapamil and talinolol were perfused nasally or infused intravenously, and when plasma concentrations following intravenous infusion and nasal perfusion showed similar profiles. The concentration of verapamil in the brain after nasal perfusion was twice that after intravenous infusion. Although talinolol in the brain and the cerebrospinal fluid after i.v. infusion were below the detection limit, it was detected after nasal perfusion. When rats were treated with cyclosporin A, brain concentrations of verapamil after both administration modes were increased significantly, while those of talinolol were not significantly changed. Since the permeability of talinolol is low, talinolol in the brain which was transported directly from the nasal cavity has little chance of transport by P-gp localized in the apical membrane of cerebral microvessel endothelial cells. The potential for drug delivery utilizing the nose-CNS route was confirmed for P-gp substrates. The advantage of nasal delivery over i.v. delivery of talinolol to the brain was more significant than that of verapamil, suggesting that nasal administration is more useful strategy for the brain delivery of low-permeability P-gp substrates than the use of P-gp inhibitors.     

Myosin light chain kinase/actin interaction in phorbol dibutyrate-stimulated smooth muscle cells

Previous work has suggested that in addition to its kinase activity, myosin light chain kinase (MLCK) exhibits non-kinase properties within its N-terminus that could influence cytoskeletal organization of smooth muscle cells (A. Nakamura et al. Biochem Biophys Res Commun. 2008;369:135-143). Myosin ATPase activity measurements indicate that the 26-41 peptide of MLCK significantly decreases ATPase activity as the concentration of this peptide increases. Sliding velocity of actin-filaments on myosin and stress responses in skinned smooth muscle tissue are also inhibited. Peptide-mediated uptake and the microinjection technique in cells indicate that the peptide was necessary for actin-filament stabilization. Fluorescence resonance energy transfer analysis indicated that in the presence of MLCK, α-actin but not β-actin remodeled during phorbol 12,13-dibutyrate (PDBu)-induced contractions. PDBu also induced podosomes in the cell. When MLCK expression was down-regulated by introduction of RNAi for MLCK by lentivirus vector into the cells, we failed to observe the podosome induction upon PDBu stimulation. Rescue experiments indicate that the non-kinase activity of MLCK plays an important role in maintaining actin stress fibers and in the PDBu-induced reorganization of actin-filaments in smooth muscle cells.     

Gas bioengineering using hemoglobin-vesicles for versatile clinical applications

Blood transfusion systems have greatly benefited human health and welfare. Nevertheless, some problems remain: possibility of infection, blood type mismatching, immunological response, and a short shelf life that is insufficient for stockpiling for emergency situations. Realization of artificial O(2) carriers is anticipated to solve such problems. During the long development of hemoglobin (Hb)-based O(2) carriers, many side effects of cell-free Hb molecules have arisen, and have implied the physiological importance of the cellular structure of red blood cells (RBCs). Therefore, Hb-vesicles (HbVs) have been developed as artificial red cells that encapsulate a concentrated Hb solution in thin lipid bilayer vesicles. This Hb encapsulation can shield various toxic effects of molecular Hbs, especially reactions with endogenous NO and CO as vasorelaxation factors. Physicochemical analyses have clarified that Hb encapsulation retards these gaseous reactions significantly. "Gas Bioengineering" is intended to create systems using bioengineering and chemical engineering techniques to facilitate the transport of or regulate the concentration of endogenous or exogenous gaseous molecules (such as O(2), NO, and CO) that are sometimes vital and sometimes toxic to humans. Gas bioengineering using HbVs underscores the potential of HbVs as a transfusion alternative and promises its use for other clinical applications that remain unattainable using RBC transfusion.     

The cell cycle regulator Cdh1 controls the pool sizes of hematopoietic stem cells and mature lineage progenitors by protecting from genotoxic stress

Various key cell cycle components, especially G0/G1 regulators, have effects not only on cell proliferation but also on cell differentiation. Cdh1, one of the co-activators that maintain anaphase-promoting complex/cyclosome activity, plays a crucial role in the mitotic phase, but has recently been identified as a G0/G1 regulator, suggesting that the role of Cdh1 in cell differentiation. Here, we generated Cdh1 conditional gene-trap mice to examine Cdh1 functions in adult tissues by overcoming the embryonic lethality of Cdh1 homozygous gene-trap mice. We focused on the hematopoietic system and found that Cdh1-deficient mice exhibited a general decrease in mature lineage progenitor cells and a significant increase in short-term hematopoietic stem cells. This phenomenon became conspicuous by irradiation shortly after Cdh1 downregulation, suggesting that Cdh1 regulates the pool sizes of the hematopoietic stem cells and mature lineage progenitor cells by protecting cells from genotoxic stress. We also found that the irradiation-induced G2/M checkpoint was defective in Cdh1-deficient BM cells, causing the loss of stem/progenitor cells. This is the first report revealing Cdh1 function in adult hematopoiesis and showing a role of Cdh1 in a G2/M checkpoint regulation in vivo.     

Significant survival improvement of patients with recurrent breast cancer in the periods 2001-2008 vs. 1992-2000

Background  

It is unclear whether individualized treatments based on biological factors have improved the prognosis of recurrent breast cancer. The purpose of this study is to evaluate the survival improvement of patients with recurrent breast cancer after the introduction of third generation aromatase inhibitors (AIs) and trastuzumab.     

Preloading Coil in Plug Method (p-CIP) with the AVP 2 for large Portosystemic Shunt Embolization

Hepatic encephalopathy caused by a large portosystemic shunt (PSS) can be treated by endovascular embolization of the shunt. The PSS diameter can be >20 mm; it occasionally poses technical difficulties. Here, a 72-year-old woman with liver cirrhosis, hyperammonemia, and large spleno-renal shunt underwent shunt embolization using an Amplatzer vascular plug 2 (AVP2) and metallic coils. The preloading coil in plug method (p-CIP), which facilitated embolization inside the AVP2 without cannulation from outside, was employed to overcome technical difficulties. We propose the use of p-CIP with an AVP2 as a tool for treatment of hepatic encephalopathy with PSS.     

Safety and effectiveness of a new enzyme-targeting radiosensitization treatment (KORTUC II) for intratumoral injection for low-LET radioresistant tumors

Linear accelerator-based radiotherapy has little effect on tumors such as malignant melanoma, various types of sarcoma, and most locally-advanced neoplasms that have grown to several centimeters or more. These tumors contain many hypoxic cancer cells or large amounts of anti-oxidative enzymes, and are therefore resistant to low linear energy transfer radiation. Therefore, it was necessary to develop a new radiosensitizer to overcome these situations. We previously developed a new enzyme-targeting radiosensitization treatment named KORTUC I, which uses 3% w/v hydrogen peroxide solution-soaked gauze. We developed a new radiosensitizer for intratumoral injection (KORTUC II), comprising a combination of hydrogen peroxide and sodium hyaluronate. After providing a fully informed written consent, 52 patients with unresectable or recurrent neoplasms (53 lesions) were enrolled in the KORTUC II trial. The present study of 52 patients with unresectable or recurrent neoplasms showed that KORTUC II is safe when injected intratumorally, well tolerated, and can efficiently exert a radiation sensitizing effect. Because this radiosensitizer is safe and less expensive than other methods, and can be applied for almost every type of low-LET radio-resistant neoplasm, it has potential for worldwide and immediate use.     

Anti-adult T-cell leukemia effects of Bidens pilosa

We evaluated the effects of Bidens pilosa, a plant found in tropical and subtropical regions, and investigated the molecular pathways responsible for the anti-adult T-cell leukemia (ATL) effect. Water extracts of B. pilosa had growth suppressive effects on human T-cell leukemia virus type 1 (HTLV-1)-infected T-cell lines and ATL cells. B.?pilosa extracts arrested cells in G1 cell cycle and induced apoptosis of HTLV-1-infected T-cell lines. B. pilosa extracts inhibited also the phosphorylation of IκB kinase β and IκBα, and NF-κB-DNA binding, in conjunction with reduction of expression of proteins involved in G1/S cell cycle transition and suppression of apoptosis. Reactive oxygen species played a role in B.?pilosa-mediated suppression of NF-κB activity. B.?pilosa extracts also inhibited the expression of JunB and JunD, resulting in suppression of AP-1-DNA binding. In animals harboring tumors of HTLV-1-infected T-cell origin, treatment with B. pilosa extracts suppressed tumor growth. Our results suggest that B. pilosa is a potentially useful medicinal plant for treatment of ATL.