FK317, a novel substituted dihydrobenzoxazine, exhibits potent antitumor activity against human tumor xenografts in nude mice.

The antitumor effects of FK317, a novel substituted dihydrobenzoxazine, were evaluated using human tumor xenografts (small cell lung cancer, non-small cell lung cancer, stomach cancer, colon cancer, pancreatic cancer, breast cancer, cervical cancer and ovarian cancer). Tumor growth-inhibitory effects and the effective dose-range of FK317 were much stronger and broader, respectively, than those of reference drugs such as mitomycin C, adriamycin, cisplatin, taxol and irinotecan. Furthermore, the body weight decrease and myelosuppression in FK317-treated mice were less than in the animals given any of the reference drugs. To explain this tumor selectivity, the distribution of FK317 was investigated after dosing tumor-bearing mice with the 14C-labelled compound. The concentration of FK317 in tumor tissues was relatively low, and long tumor retention was not observed. However, thin-layer chromatographic separation revealed that the radioactivity in the tumor resided mainly in strongly cytotoxic metabolites, while that in other tissues resided mainly in non-cytotoxic metabolites. These results suggest that FK317 shows strong antitumor activity without side effects, and one reason for this is its specific metabolite pattern. FK317 is now undergoing phase I clinical trials.     

Anatomy of the iliolumbar ligament

Information is lacking in the literature on the precise anatomy of the iliolumbar ligament and its individual differences. The morphologic pattern, length, and width of the iliolumbar ligament were determined in 56 embalmed lumbosacral spines from human cadavers. It was possible to classify the iliolumbar ligament into two groups: Type A (74 ligaments), in which anterior and posterior ligaments had separate courses; and Type B (32 ligaments), in which anterior and posterior ligaments moved together as one band. The angle of the posterior iliolumbar ligament in Type A was oriented significantly more posteriorly than that in Type B. The posterior iliolumbar ligament was significantly shorter and oriented more posteriorly in male anatomic specimens than in female ones.     

Immune cells contribute to systemic cross-talk between the embryo and mother during early pregnancy in cooperation with the endocrine system

In early pregnancy, human chorionic gonadotropin (HCG) stimulates the corpus luteum to produce progesterone that in turn maintains human embryo implantation in the uterus. This inevitable communication through blood circulation can be called 'systemic cross-talk between the embryo and mother'. Despite considerable evidence suggesting that the human corpus luteum cannot be maintained by HCG alone, no other responsible soluble factors have been proposed. We found that peripheral blood mononuclear cells (PBMC) derived from pregnant women promoted progesterone production by human luteal cells and propose that both hormones and immune cells participate in this systemic cross-talk. This systemic cross-talk by immune cells is believed to operate in embryo implantation. Splenocytes derived from pregnant mice promoted endometrial differentiation and embryo implantation in vivo . Human PBMC derived from women early in pregnancy promoted invasion of murine embryos in vitro. In addition, recombinant HCG increased the effects of human PBMC on murine embryo invasion. Human chorionic gonadotropin also increased chemokine production by human PBMC through a lectin–glycan interaction, which is a primitive pathway in the immune system. Furthermore, chemokines were shown to induce human trophoblast invasion. These findings suggest that the immune system positively contributes to systemic cross-talk between the embryo and mother in cooperation with the endocrine system. (Reprod Med Biol 2006; 5 : 19–29)     

Surgery for pulmonary metastases from colorectal carcinoma

BACKGROUND: This study aims to clarify which patients would benefit by surgery for pulmonary metastases from colorectal carcinoma. METHODS: A retrospective study was undertaken in 25 patients who had undergone complete resection. In all cases, prethoracotomy carcinoembryonic antigen (CEA) level was measured and mediastinal or hilar lymph nodes were histologically examined. RESULTS: Overall 5-year survival was 39.2%. The 5-year survival rate for patients with a normal CEA level was 61.1%, as compared with 19.0% for patients with an elevated CEA level (p = 0.0423). The 5-year survival rate for patients without a lymph node metastasis was 49.5%, as compared with 14.3% for patients with a lymph node metastasis (p = 0.0032). No lymph node metastasis was a predictor of longer survival by univariate and multivariate analyses. The primary site, disease-free interval, and number and size of the metastasis were not significant prognostic factors. CONCLUSIONS: A resection for pulmonary metastasis from colorectal carcinoma is effective in patients with a normal CEA level and without a lymph node metastasis.     

Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers.

PURPOSE: LATS1 and LATS2 are tumor suppressor genes implicated in the regulation of cell cycle. Methylation status of the promoter regions of these genes as well as its correlation with their mRNA levels were studied in human breast cancers. Correlation of LATS1 and LATS2 mRNA levels with clinicopathologic characteristics of breast tumors were also studied. EXPERIMENTAL DESIGN: Methylation status of promoter regions of LATS1 and LATS2 was studied by a methylation-specific PCR and mRNA expression levels of LATS1 and LATS2 were determined by a real-time PCR assay in 30 breast cancers. In addition, correlation of LATS1 and LATS2 mRNA levels with clinicopathologic characteristics was studied in 117 breast cancers. RESULTS: Methylation-specific PCR showed that of 30 tumors, LATS1 promoter region was hypermethylated in 17 tumors (56.7%) and LATS2 promoter region was hypermethylated in 15 (50.0%) tumors. LATS1 mRNA levels in breast tumors with hypermethylation (2.15 +/- 0.37, mean +/- SE) were significantly (P < 0.01) lower than those without hypermethylation (6.09 +/- 1.38), and LATS2 mRNA levels in breast tumors with hypermethylation (1.42 +/- 0.66) were also significantly (P < 0.01) lower than those without hypermethylation (3.10 +/- 1.00). The decreased expression of LATS1 or LATS2 mRNA was significantly associated with a large tumor size, high lymph node metastasis, and estrogen receptor and progesterone receptor negativity. Furthermore, the decreased expression of LATS1 mRNA, but not LATS2 mRNA, was significantly (P < 0.05) associated with a poor prognosis. CONCLUSIONS: Hypermethylation of the promoter regions of LATS1 and LATS2 likely plays an important role in the down-regulation of their mRNA levels in breast cancers, and breast cancers with a decreased expression of LATS1 or LATS2 mRNA levels have a biologically aggressive phenotype.     

Phenotype and function of a CD56+ peripheral blood monocyte.

G-CSF primed CD34 cells cultured for 2-3 weeks in IL-2 and stem cell factor generate CD56(high) cells with phenotypic and morphologic features of NK cells, and a novel adherent CD56(low) CD16- population expressing myeloid markers (CD33 and HLA-DR). We hypothesized that similar cells might also occur in peripheral blood. In 13/13 normal individuals, we found a circulating population of CD56(low), CD33+, FcgammaRI+, FcgammaRII+, HLA-DR+, CD11b(high), CD14+ monocytes closely resembling the cultured CD56(low)CD33+ cells. They may represent a normal counterpart of the CD56+ CD33+ hybrid myeloid/natural killer cell leukemia. Their mean frequency was 1.3+/-1% (standard deviation), range 0.16-3.5%, of total mononuclear cells. CD56(low)CD33+ cells, primed with cytomegalovirus antigen, induced autologous T-lymphocyte proliferation comparably to CD56-, CD14+ peripheral blood monocytes (PBM). Conversely, CD56(low) cells induced greater T-cell proliferation than CD56- PBM when lymphocyte responders were HLA mismatched. Unstimulated CD56(low)CD33+ cells showed a low antiproliferative effect on K562, which was increased upon LPS stimulation. The pattern of cytokine production by CD56(low)CD33+ cells and PBM largely overlapped; however, they produced detectable levels of IL-6 and IL-1beta. These results define a minor monocyte population with distinct phenotypic and functional features.     

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Naja melanoleuca cobra venom contains two forms of complement-depleting factor (CVF)

Two forms of complement-depleting cobra venom factor (CVFm1 and CVFm2), possessing molecular masses of 142.6 kDa (CVFm1) and 143.1 kDa (CVFm2), according to MALDI mass-spectrometry, were isolated from the Naja melanoleuca cobra venom. As shown by polyacrylamide gel electrophoresis in the presence of SDS, both forms similarly to factor from the Naja kaouthia cobra venom (CVFk) consist of three polypeptide chains with molecular masses of about 70, 50, and 30 kDa, the two large subunits being glycosylated. As determined by MALDI mass-spectrometry, 30 kDa subunits of CVFm1 and CVFm2 have considerably different finger-prints of tryptic digests that suggests differences in their amino acid sequences. A study of activity in vivo has shown no significant differences in C3 consumption by CVFm1, CVFm2 and CVFk in mouse blood. However, as shown by an immunoassay method, they differ in their ability to activate the complement system via C3 conversion, the ratio of these activities for CVFm1:CVFm2:CVFk being 2.5:1.6:1. Kinetic studies using a hemolytic test showed that complement depletion by CVFm1 is faster than that by CVFm2. Thus, for the first time the presence in a single venom of two forms of CVF differing by both amino acid sequence and biological activity has been shown.     

Anesthetic management for placement of tracheobronchial stents in patients with airway stenosis

We report the anesthetic management for stents placement in patients with tracheobronchial stenosis. The subjects were 6 patients with lung cancer and one patient with tracheal invasion of esophageal cancer. Anesthesia was induced with propofol, fentanyl and vecuronium, and maintained with propofol and vecuronium. After intubation, tracheostomy was performed. The patients were kept apnic during insertion of stents. Three patients had dynamic stents inserted from tracheostomy site and one orally. Three patients had Dumon stents inserted orally, but the procedure in one patient was cancelled because her stent could not be placed at appropriate position. We recommend the anesthetic management through the tracheostomy site for the placement of Dumon tubes or dynamic stents.     

Three approaches to surgical treatment of traumatic disruption of the thoracic aorta

Traumatic disruption of the thoracic aorta is said to occur most often near the aortic isthmus because of the mechanisms of aortic injury. Between November 1990 and August 1999, we encountered eight cases of surgical treatment for traumatic injury of the thoracic aorta combined with multi-system injury. In some cases, the injury was located near the aortic isthmus; in such cases, we selected surgical options that made use of three different approaches, namely, media sternotomy, posterolateral left thoracotomy, and anteroaxillal thoracotomy. Each approach has advantages and disadvantages. In selecting an appropriate approach, it is not only necessary to consider the various features of the approach itself, but it is also necessary to consider other factors, such as the assisting apparatus in use, the effects of other injuries sustained by perioperative positioning, safety measures against accidental bleeding during surgery, deployment of the operative field, and potential complications after surgery.