Sakyomicins A, B, C and D: new quinone-type antibiotics produced by a strain of Nocardia. Taxonomy, production, isolation and biological properties

Actinomycete strain M-53, a new soil isolate, was found to produce four quinone-type antibiotics. Antibiotic sakyomicin components, A, B, C and D were isolated from the fermentation broth of strain M-53 by XAD-2 column chromatography, silica gel column chromatography and Sephadex LH-20 column chromatography. The components are active against Gram-positive bacteria. Strain M-53 was identified as a strain of genus Nocardia.     

The role of intraoperative radiation therapy in the treatment of bile duct cancer

Since October, 1976, we have treated a total of 81 patients with bile duct cancer. Fifty of these patients had cancer that originated at and/or infiltrated into the main hepatic ducts. Five patients had cancer on the upper to middle portion, 19 on the middle to intrapancreatic bile duct, and the remaining 7 had diffusely involved tumors. Fifty of the 81 patients underwent resections. Of the 50 patients, 33 received curative or noncurative resection alone, 14 were treated by resection plus intraoperative radiotherapy (IORT), and the remaining 3 received postoperative external irradiation. Thirty-one of the 81 patients did not undergo tumor resection. Of these, 6 had IORT and 4 underwent external radiotherapy after bile drainage. The remaining 21 underwent bile drainage alone. Curative resection achieved the best cumulative 5-year survival rate of 59.3%. IORT plus noncurative resection showed a superior 2-year survival rate of 17,1% compared to 9.0% after noncurative resection alone. Only 1 patient treated by IORT plus bile drainage survived more than 2 years and subsequently died at 34 months. In the earlier stage of the development of the combination therapy with resection and IORT, severe complications were experienced in 9 patients (so treated), including remarkable obstructive changes of the hepatic arteries. In the later stage, resection plus IORT with a reduced single dose (20 Gy), using a smaller field size (3.7±1.4 cm) and beam energy (7.3±3.0 MeV), did not result in complication and produced 2 long-term survivors among 5 patients. Fractionated external irradiation (30–40 Gy/4–5 weeks) has been added to the IORT recently. These results indicate that noncurative resection plus IORT in combination with external radiation would improve the prognosis of the patient with advanced bile duct cancer.

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Resumen A partir de octubre de 1976, hemos tratado 81 pacientes con cáncer de la vía biliar. Cincuenta de estos pacientes presentaban cáncer que se originaba y/o infiltraba los canales hepáticos principales. Cinco tenían cáncer de la región superior a media, 19 de la región media a la intrahepática, y los restantes 7 presentaban tumores de extensión difusa. Cincuenta de los 81 pacientes fueron sometidos a resección. De los 50, 33 fueron tratados mediante resecciones curativas o no curativas solamente, 14 mediante resección más radioterapia intraoperatoria (RTIO), y los 3 restantes recibieron radioterapia externa postoperatoria. Treinta y uno de 81 pacientes no fueron sometidos a resección. De estos, seis tuvieron RTIO y 4 radioterapia externa después de drenaje biliar. Los 21 restantes tuvieron drenaje biliar solamente. La resección curativa logró la mejor tasa de supervivencia acumulada a 5 años, 59.3%. La RTIO más resección no curativa exhibió una tasa de supervivencia a 2 años de 17.1%, superior a la de 9.0% de los pacientes sometidos a resección solamente. Con la RTIO combinada con drenaje biliar, sólo un paciente sobrevivió más de 2 años y murió a los 34 meses.En la etapa inicial de desarrollo de la terapia combinada de resección y RTIO, se presentaron complicaciones severas en 9 pacientes así tratados, incluyendo alteraciones severas de las arterias hepáticas. En la etapa siguiente, la resección combinada con RTIO de dosis única (20 Gy) utilizando un campo de menor extensión (3.7±1.4 cm) y menor energía (7.3±3.0 MeV) no resultó en complicaciones y produjo 2 supervivencias a largo plazo entre 5 pacientes. Recientemente se ha añadido la irradiación externa fraccionada (30–40 Gy/4–5 semanas) a la RTIO. Los resultados indican que la resección no curativa más RTIO en combinación con irradiación externa podrían mejorar el pronóstico del paciente con cáncer avanzado de la vía biliar.

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Résumé Depuis octobre 1976, les auteurs ont traité 81 malades porteurs d'un cancer biliaire. Cinquante d'entre eux présentaient un cancer qui prenait son origine et/ou infiltrait les canaux biliaires principaux dont 5 cancers de la partie haute ou de la partie moyenne de l'arbre biliaire, 19 de la partie moyenne et de la partie intra-pancréatique, 7 diffus. Cinquante des 81 lésions furent réséqués. Des 50 opérés: 33 furent traités par exérèse isolée à titre curatif ou palliatif, 14 par exérèse et irradiation per-opératoire, 3 par irradiation externe post-opératoire. Trente et un des 81 malades ne subirent pas d'exérèse: 6 furent traités par irradiation intra-opératoire, 4 par irradiation externe après mise en place d'un drainage biliaire, 21 par simple drainage. La survie à 5 ans fut de 59.3% après exérèse curative. La survie à plus de 2 ans fut de 17.1% après exérèse palliative complétée par irradiation et de 9% après simple exérèse. Un seul malade survécut 34 mois après irradiation opératoire et drainage biliaire.Au début de cette expérience thérapeutique combinant l'exérèse et l'irradiation opératoire, 9 malades dévelopèrent des complications sévères dues en particulier à l'obstruction des artères hépatiques. Ultérieurement en employant une seule dose de 20 grays, un champ d'irradiation plus petit (3.7±1.4 cm) et une source plus forte d'energie (7.3±3.0 MeV). Ces complications furent évitées et 2 malades sur 5 bénéficièrent d'un longue survie. Récemment à l'irradiation peropératoire a été ajoutée une irradiation externe fractionnée (30–40 grays/4–5 semaines). Ces résultats démontrent que l'exérèse palliative de la tumeur associée à l'irradiation interne peropératoire et à l'irradiation externe postopératoire est susceptible d'améliorer le pronostic du cancer biliaire parvenu à un stade évolutif avancé.

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Supported in part by Grant-in-Aid for Cancer Research, No. 60-13, Ministry of Health and Welfare, Japan.     

Smoking, alcohol drinking, green tea consumption and the risk of esophageal cancer in Japanese men

BACKGROUND: Although smoking and alcohol drinking are established risk factors of esophageal cancer, their public health impact is unclear. Furthermore, the effect of green tea is controversial. METHODS: The present study was based on a pooled analysis of two prospective cohort studies. A self-administered questionnaire about health habits was distributed to 9,008 men in Cohort 1 and 17,715 men in Cohort 2, aged 40 years or older, with no previous history of cancer. We identified 38 and 40 patient cases with esophageal cancer among the subjects in Cohort 1 (9.0 years of follow-up) and Cohort 2 (7.6 years of follow-up), respectively. Cox proportional hazards regression was used to estimate hazard ratios (HRs) of the risk of esophageal cancer incidence. RESULTS: Cigarette smoking, alcohol drinking and green tea consumption were significantly associated with an increased risk of esophageal cancer. Compared with men who had never smoked, never drunk alcohol or green tea, the pooled multivariate HRs (95% confidence intervals) were 5.09 (1.80-14.40) (p for trend <0.0001), 2.73 (1.55-4.81) (p for trend=0.0002), or 1.67 (0.89-3.16) (P for trend=0.04) for men who were currently smoking > or =20 cigarettes/day, drinking alcohol daily, or drinking > or =5 cups green tea/day, respectively. The population attributable fractions of esophageal cancer incidence that was attributable to smoking, alcohol drinking and green tea consumption were 72.0%, 48.6%, and 22.1%, respectively. CONCLUSIONS: Among the variables studied, smoking has the largest public health impact on esophageal cancer incidence in Japanese men, followed by alcohol drinking and green tea drinking.     

Reciprocal changes in endothelium-derived hyperpolarizing factor- and nitric oxide-system in the mesenteric artery of adult female rats following ovariectomy

1. To explore the effects of estrogen on arterial functions, we examined endothelium-derived hyperpolarizing factor (EDHF)- and NO-mediated responses in isolated mesenteric arteries of female rats, 4 weeks after sham-operation (CON), ovariectomy (OVX) and OVX plus chronic estrogen treatment (OVX+E(2)). Tissue levels of connexins-40, 43 (major components of gap junction), inducible NOS (iNOS), endothelial NOS (eNOS) and eNOS regulator proteins such as calmodulin, heat shock protein 90 (hsp90) and caveolin-1 were also examined using Western blot. 2. In OVX, acetylcholine (ACh)-induced EDHF-mediated relaxation and membrane hyperpolarization of arterial smooth muscles were reduced, whereas ACh-induced NO-mediated relaxation was enhanced, leading to no change in ACh-induced relaxation. 3. In OVX, connexin-40 and 43 were decreased. Tissue levels of eNOS and its positive regulators (calmodulin and hsp90) were unchanged, but that of its negative regulator, caveolin-1, was decreased. The levels of iNOS in mesenteric artery and aorta and plasma levels of NO metabolites and cholesterol were elevated. 4. In OVX, contraction of the artery by phenylephrine was reduced, but augmented by nonspecific inhibitor of NOS to the comparable level as that in CON group. The contraction in OVX group unlike that in CON group was augmented by specific iNOS inhibitor, and the difference between contractions in the presence of nonspecific and specific inhibitor as an index of eNOS activity was increased. 5. In OVX+E(2), all these changes were recovered. 6. In all groups, EDHF-mediated relaxation was suppressed by 18beta-glycyrrhetinic acid, an inhibitor of gap junction. 7. These results indicate that estrogen deficiency does not change the diameter of mesenteric artery: it reduces EDHF-mediated relaxation by decreasing gap junction, whereas it augments NO-mediated relaxation via an increase in NO release. Increased NO result from increased activity of eNOS subsequent to a decrease in caveolin-1 and from induction of iNOS. However, excessive NO generation with elevated plasma cholesterol would raise a risk for atherosclerosis.     

Age-Related Changes of Transforming Growth Factor β1 in Japanese Children

BackgroundTransforming growth factor β1 (TGFβ1) is an important factor in immunomodulation. The expression of TGFβ1 has been shown to be influenced by the C-509 T polymorphism in the TGFβ1 gene. We investigated age-related changes of plasma TGFβ1 levels in a birth-cohort study. In addition, the genotypes of the C-509 T polymorphism were investigated in allergic and non-allergic subjects.MethodsSixty-four neonates who met the following criteria were enrolled in this cohort study: 1) full-term vaginally delivery; 2) underwent DNA polymorphism analysis; and 3) questionnaire forms were filled out by parents at 0, 6 and 14 months of age. The umbilical cord blood at 0 months and peripheral blood at 6, and 14 months were collected. Plasma TGFβ1 levels were measured at 0, 6 and 14 months of age. Genomic DNA was extracted from their umbilical cord blood. The genotype of the subjects was examined for the presence of C- 509 T.ResultsThe plasma TGFβ1 level at 6 months was the highest of the 3 measurements (at 0, 6, and 14 months of age). The TGFβ1 levels at 14 months in allergic subjects were significantly higher than those in non-allergic subjects (p = 0.03). All subjects with bronchial asthma (n = 3) had the TT genotype of the C-509 T polymorphism.ConclusionsThe plasma TGFβ1 levels change with age. In addition, TGFβ1 may play a role in the pathogenesis of bronchial asthma.     

CSN5/Jab1 inhibits cardiac L-type Ca2+ channel activity through protein-protein interactions

L-type Ca(2+) channels have a wide tissue distribution and play essential roles in physiological responses. Recent studies have indicated that regulation of L-type Ca(2+) channels involves the assembly of macromolecular signaling complexes such as the beta(2)-adrenergic receptor signaling complex, the small G-protein kir/Gem and the BK channel. Here, we report the previously unidentified role of another protein in binding to the II-III linker of the alpha(1C) subunit of the L-type Ca(2+) channel. This protein is COP9 signalosome subunit 5 (CSN5)/Jun activation domain-binding protein 1 (Jab1). We have demonstrated that CSN5 interacts specifically with the II-III linker of the alpha(1C) subunit in a yeast two-hybrid system. The alpha(1C) subunit and CSN5 were coimmunoprecipitated in rat heart and both proteins were colocalized in sarcolemmal membranes and transverse tubules of cardiac myocytes. Silencing of CSN5 mRNA using siRNA decreased the endogenous protein level of CSN5 and activated L-type Ca(2+) channels expressed in COS7 cells. These data indicate that CSN5 is a protein that plays a newly defined functional role in association with the cardiac L-type Ca(2+) channel.