Trans-selective cyclizations of alpha-bromocarboxamides and E/Z-mixed internal olefins catalyzed by a Fe salt.

There are several reports of lactam cyclizations, but most yield less-substituted lactam rings. Therefore, diastereoselective cyclization to yield highly substituted lactams is one of the challenges in this field. We therefore propose a strategy involving the reactions of α-halocarboxamides with E/Z-mixed internal olefins here. An Fe/triphos catalyst system is effective in reactions between α-bromocarboxamides and internal olefins to form trans lactams with quaternary carbons. Control experiments reveal that the reaction involves a radical process. This reaction may be useful in the field of pharmaceuticals, as γ-lactam moieties constitute the core structures of numerous drugs and natural alkaloids.

[A case of advanced gastric cancer treated with curative resection after preoperative combined chemotherapy with docetaxel, cisplatin, and S-1].

A 67-year-old woman with epigastralgia was admitted to our hospital and was diagnosed with type 3 advanced gastric cancer with lymph node metastases.The clinical diagnosis was Stage III A(cT3, N2, M0).Since curative surgery was not feasible, we administered preoperative combination chemotherapy with docetaxel, cisplatin(CDDP), and S-1.After 3 courses of chemotherapy, the lymph nodes became undetectable on computed tomography(CT).Distal gastrectomy was performed with curative intent, and the final diagnosis was Stage IIA(ypT3, N0, M0).There has been no recurrence for 1 year and 4 months after the operation.

The rs6983267 SNP is associated with MYC transcription efficiency, which promotes progression and worsens prognosis of colorectal cancer.

BACKGROUND: The oncogenic single nucleotide polymorphism rs6983267, located on 8q24.21, may affect copy number aberrations and/or expression profiles in colorectal cancer (CRC). We investigated the role of this single nucleotide polymorphism in the clinical outcome of CRC. METHODS: Array comparative genomic hybridization (aCGH) and oligomicroarrays were performed on cancer cells from 157 primary CRC tissues. Expression profiles were analyzed by means of extraction expression module (EEM) analyses. Mutations in TP53, KRAS, and BRAF and microsatellite instability were also examined in 107 of the 157 cases. RESULTS: aCGH analysis revealed two clusters; more frequent genomic copy number alteration (CNA) was observed in the 89 cases in cluster B than in the 18 cases in cluster A. The average CNA was higher in samples containing the major allele (GT/TT) of rs6983267 than in those containing the minor allele (GG). Additionally, MYC expression was the highest in samples containing the GG allele (n = 18), followed by the GT and TT alleles (n = 41 and 48, respectively). EEM analysis revealed dominant up-regulation of MYC in samples containing the minor allele. Moreover, the presence of the minor allele in a MYC-positive, CNA-negative context predicted a poorer prognosis than the presence of the major allele in a MYC-negative, CNA-positive context in CRC. CONCLUSIONS: The presence of the minor allele of rs6983267 at 8q24.21 worsened the prognosis of CRC through up-regulation of MYC transcription. Furthermore, progression of CRC may require global CNA in the presence of the major allele and with lack of MYC transcription.

[A case of pathologically complete response of local recurrence in the mesorectum after multidisciplinary therapy].

The patient was a 68-year-old man who had undergone sigmoidectomy 1 year previously. Adjuvant therapy with tegafur- uraci(l UFT) and Leucovorin( UZEL) was administered. Seven months later, the carcinoembryonic antigen( CEA) level increased to 7.5 ng/mL. Enhanced computed tomography (CT) revealed a 4-cm mass in the mesorectum, and the patient was diagnosed as having local recurrence. Chemotherapy with oxaliplatin, 5-fluorouracil, and Leucovorin( mFOLFOX6) and radiation therapy( 60 Gy) were administered. As the tumor could not be detected after chemoradiotherapy, abdominoperineal resection was performed. Pathological examination showed no cancer and indicated a complete response. The patients CEA level has not increased and no recurrence has been detected on enhanced CT for 3.5 years. The tumor could be decreased in size by chemoradiotherapy and the operation could be safely performed without resecting other organs. Although surgery is generally performed for local recurrence, multidisciplinary therapy could be useful in performing such surgery safely.

Increased risk for CRC in diabetic patients with the nonrisk allele of SNPs at 8q24.

BACKGROUND: Colorectal cancer (CRC) oncogenesis was considered to be determined by interactions between genetic and environmental factors. Specific interacting factors that influence CRC morbidity have yet to be fully investigated. METHODS: A multi-institutional collaborative study with 1511 CRC patients and 2098 control subjects was used to compare the odds ratios for the occurrence of polymorphisms at 11 known single nucleotide polymorphisms (SNPs). TaqMan PCR and questionnaires were used to evaluate the effects of environmental exposures. RESULTS: Variants of rs6983267 on 8q24 were the most significant markers of risk for CRC (odds ratio 1.16, 95% confidence interval 1.06-1.27, P = 0.0015). Non-insulin-dependent diabetes mellitus (DM), a higher body mass index at age 20, and meat consumption were environmental risk factors, whereas a tuna-rich diet and vitamin intake were protective factors. The cohort of rs6983267 SNP major (T) allele at 8q24 and DM had a 1.66-fold higher risk ratio than the cohort of major allele patients without DM. CONCLUSIONS: We confirmed that interactions between the genetic background and environmental factors are associated with increased risk for CRC. There is a robust risk of the minor G allele at the 8q24 rs6983267 SNP; however, a major T allele SNP could more clearly reveal a correlation with CRC specifically when DM is present.

Kinesin 18A expression: clinical relevance to colorectal cancer progression.

Kif18A, a member of the kinesin superfamily of molecular motor proteins, is a microtubule depolymerase and a key regulator of chromosome congregation. Kif18A's role in cancer progression has not been well defined. Our hypothesis is that Kif18A has a role in the progression of colorectal cancer (CRC). To investigate this expression of Kif18A, mRNA was assessed by quantitative real-time PCR in 113 operative specimens of primary CRC. Kif18A was overexpressed and significantly (p < 0.0001) higher in CRC than in normal colon tissue. Kif18A overexpression in CRC significantly correlated with clinicopathologic factors such as tumor stage (p < 0.0001), lymphatic invasion (p = 0.001), lymph node metastasis (p = 0.01), venous invasion (p = 0.002) and peritoneal dissemination (p = 0.02), suggesting that it has a key role in CRC progression. In multivariate analysis, high Kif18A expression had independent significance for poorer overall survival after resection of CRC (p = 0.037). To demonstrate Kif18A's role in CRC progression, we performed translational and in situ studies. Using in vitro studies on CRC cell lines, we evaluated Kif18A's role in proliferation, migration and invasion. CRC cells transfected with Kif18A cDNA demonstrated significant enhanced migration (p < 0.01) and invasion (p = 0.018) compared to mock-transfected cells. When Kif18A was targeted with specific small interfering RNA, CRC cells had significantly reduced proliferation (p < 0.01), migration (p < 0.01) and invasion (p < 0.05). The in vitro and translational studies demonstrated that Kif18A expression is related to events of metastasis and is a significant factor for CRC progression.

Comprehensive analysis of the clinical significance of inducing pluripotent stemness-related gene expression in colorectal cancer cells.

BACKGROUND: We previously determined that cancer stem-like cells may influence the susceptibility of colorectal cancer (CRC) cells to chemotherapeutic agents. Although Takahashi and Park identified a set of induced pluripotent stem cell (iPS)-related genes required for normal stem cell maintenance, the precise role of iPS-related gene expression in CRC pathogenesis remains to be determined. The purpose of this study was to clarify the clinical relevance of "stemness"-regulating gene expression in CRC cases. MATERIALS AND METHODS: Cancer cells were excised from tissues of 79 CRC cases by laser microdissection (LMD), and quantitative RT-PCR was used to evaluate expression levels of the iPS-related genes c-MYC, SOX2, OCT3/4, LIN28, KLF4, and NANOG, and to identify any associations between their expression and clinicopathological CRC progression. RESULTS: We found that LIN28 expression is significantly associated with lymph node metastasis (p = 0.018) and Dukes stage (p = 0.0319). SOX2expression is also correlated with lymph node metastasis. Furthermore, the ten cases with Dukes D disease expressed significantly higher levels of SOX2transcript than the other 69 cases (p = 0.0136). In contrast, KLF4 expression was inversely related to Dukes stage. Expression of c-MYC, OCT3/4, and NANOG did not appear to have clinical relevance in CRC cases. CONCLUSION: The present analysis strongly suggests that altered expression of several iPS-related genes plays a role in CRC pathogenesis.

Salusins: newly identified bioactive peptides with hemodynamic and mitogenic activities.

The discovery of endogenous bioactive peptides has typically required a lengthy identification process. Computer-assisted analysis of cDNA and genomic DNA sequence information can markedly shorten the process. A bioinformatic analysis of full-length, enriched human cDNA libraries searching for previously unidentified bioactive peptides resulted in the identification and characterization of two related peptides of 28 and 20 amino acids, which we designated salusin-alpha and salusin-beta. Salusins are translated from an alternatively spliced mRNA of TOR2A, a gene encoding a protein of the torsion dystonia family. Intravenous administration of salusin-alpha or salusin-beta to rats causes rapid, profound hypotension and bradycardia. Salusins increase intracellular Ca2+, upregulate a variety of genes and induce cell mitogenesis. Salusin-beta stimulates the release of arginine-vasopressin from rat pituitary. Expression of TOR2A mRNA and its splicing into preprosalusin are ubiquitous, and immunoreactive salusin-alpha and salusin-beta are detected in many human tissues, plasma and urine, suggesting that salusins are endocrine and/or paracrine factors.

Effects of endothelin receptor antagonists on endothelin-1 and inducible nitric oxide synthase genes in a rat endotoxic shock model.

Levels of the endothelium-derived vasoconstrictor endothelin (ET)-1 and the vasodilator nitric oxide (NO) are markedly increased in endotoxic shock, although the pathophysiological role of ET-1 and its relation to NO under septic conditions remains obscure. To delineate the roles of ET-1 and the ET receptors, and the NO/inducible NO synthase (iNOS) system in endotoxic shock, we examined the gene expression of ET-1, ET receptors A and B (ETA and ETB) and iNOS in the heart and the liver of a rat endotoxic shock model, and we studied the effects of ET receptor antagonists on haemodynamics, survival rate and expression of ET-1, ET receptors and iNOS. Administration of bacterial lipopolysaccharide (LPS) into rats caused a profound hypotension with resultant death. However, these effects were blocked by a non-selective ETA/ETB receptor antagonist (TAK044), but not by an ETA-selective antagonist (BQ123). Injection of LPS caused a marked elevation in the plasma levels of both ET-1 and NO, which were not affected by treatment with either ET receptor antagonist. Administration of LPS caused increases in levels of ET-1, ETB and iNOS mRNA in the heart and the liver, whereas ETA mRNA expression was markedly downregulated in these organs. These results suggest that ET receptor subtype genes are differentially regulated in major organs from endotoxic shock rats, and that non-selective ET receptor antagonists ameliorate endotoxin-induced hypotension and death irrespective of iNOS-derived NO.

Cytokine-activated Jak-2 is involved in inducible nitric oxide synthase expression independent from NF-kappaB activation in vascular smooth muscle cells.

Inflammatory cytokines, such as interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, activate nuclear factor-kappa B (NF-kappaB) which transactivates inducible nitric oxide synthase (iNOS) gene in vascular smooth muscle cells (VSMCs). However, it remains obscure whether cytokine-mediated iNOS expression in VSMCs requires signaling pathway(s) other than NF-kappaB activation. The present study was designed to elucidate whether protein tyrosine kinases (PTKs) are involved in the cytokine-induced NF-kappaB activation and iNOS expression in cultured rat VSMCs. Both IL-1beta and TNF-alpha stimulated NF-kappaB activity, iNOS mRNA and protein expression with massive nitrite/nitrate (NOx) production in rat VSMCs. PTK inhibitors (genistein, herbimycin A) dose-dependently inhibited the cytokine-stimulated NOx production and iNOS mRNA expression. However, neither genistein nor herbimycin A affected the cytokine-stimulated phosphorylation and degradation of IkappaB-alpha, or NF-kappaB activation, whereas they completely blocked the cytokine-stimulated iNOS transcriptional activity. Tyrphostin B42 (AG490), a Jak-2 tyrosine kinase inhibitor, similarly blocked the cytokine-induced NOx production, iNOS expression and its promoter activity without affecting NF-kappaB-dependent transcription. Transfection of a dominant-negative Jak-2 mutant antagonized the cytokine-induced NOx production and iNOS expression, while wild-type Jak-2 expressing construct was without effect. These data indicate that the cytokine-induced iNOS expression involves activation of Jak-2 signaling pathway independent from NF-kappaB activation in rat VSMCs.