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Purpose: This investigation evaluated the inhibitory effect of S-2- (3-aminopropylamino)-ethylphosphorothioic acid (WR-2721) against the initiation of mammary tumourigenesis by irradiation, and the antipromotion activity of tamoxifen in the development of radiation-initiated mammary tumours. Materials and methods: Lactating rats were injected with WR-2721 and then irradiated with γ-rays (1.5 Gy) at day 21 of lactation. The rats were divided into three groups 1 month after irradiation and were implanted with a pellet either of cholesterol as an inert control, diethylstilbestrol (DES) as a tumour-promoting agent, or DES combined with tamoxifen. For the control experiments, non-irradiated and irradiated rats receiving saline instead of WR-2721 were treated with a pellet by the same procedures. Results: The highest incidence (85%) for tumourigenesis of mammary glands was observed in the irradiated rats that had been previously injected with saline following treatment with DES Administration of WR-2721 prior to the irradiation significantly decreased the incidence of mammary tumours to 52.2%. The treatment with DES pellets combined with tamoxifen in the irradiated rats previously injected with saline also markedly suppressed the incidence of mammary tumours even further to 4.4%. Also, the development of mammary tumours was completely prevented in the rats treated with WR-2721 prior to irradiation and then implanted with DES pellets combined with tamoxifen. Conclusions: These results suggest that the administration of WR2721 prior to irradiation has an inhibitory effect on the initiation phase, resulting in a partial reduction of mammary tumour development, and that the combination of WR-2721 at the initiation phase with tamoxifen at the promotion phase is quite effective in preventing mammary tumourigenesis induced by radiation. [ABSTRACT FROM AUTHOR]

The localization of 3 β-hydroxysteroid dehydrogenase/isomerase (3 β-HSD) was studied in bovine adrenal glands by light as well as electron microscopic immunocytochemistry, using anti-bovine adrenal 3 β-HSD antibody. With light microscopy the cytoplasm of the glomerulosa cells was weakly immunostained, while that of the fasciculata-reticularis cells was intensely immunostained though both the capsular connective tissue cells and the medullary cells were entirely negative for this reaction. Electron microscopic immunocytochemistry revealed that the positive reaction products for 3 β-HSD were present on the membrane of smooth endoplasmic reticulum of the cortical cells, especially that of the fasciculata and reticularis cells. Other cell organelles such as mitochondria and Golgi apparatus were entirely negative. The present results indicate that 3 β-HSD is present in the membrane of smooth endoplasmic reticulum of bovine adrenal cortical cells. [ABSTRACT FROM AUTHOR]

Arsenopyrite is the most common arsenic-bearing sulfide mineral in nature. It is readily oxidized and releases toxic arsenic (As) into the environment when exposed to atmospheric conditions via anthropogenic activities like mining, mineral processing, extractive metallurgy, and underground space developments. Carrier-microencapsulation (CME) is a technique that uses metal(loid)-organic complexes to selectively form protective coatings on the surfaces of sulfide minerals. In this study, CME using Al-catecholate complexes (i.e., Al-based CME) was investigated to suppress the oxidation of arsenopyrite. Aluminum(III) and catechol form three complex species depending on the pH and among them, [Al(cat)]+ was the most effective in suppressing arsenopyrite oxidation. Its suppressive effect was improved as [Al(cat)]+ concentration increased due most likely to the formation of a more extensive surface protective coating at higher concentrations. Surface characterization of leaching residues using SEM-EDX and XPS indicates that CME-treated arsenopyrite was covered with bayerite (γ-Al(OH)3). The results of electrochemical studies showed that the surface protective coatings suppressed both anodic and cathodic half-cell reactions of arsenopyrite oxidation.

Introduction: Kitasato University Hospital offers a training course for community pharmacists that focus on advanced pharmacy management care in outpatient cancer chemotherapy. The objective of this training program is to facilitate the transition from general to oncology certification for community pharmacists with limited experience in outpatient oncology to support the acquisition of an oncology specialty., Aim: To evaluate the relationship between the changes in awareness, knowledge, and self-assessment that advanced pharmacy management care traineeship in an outpatient oncology unit for community pharmacists brings to trainees and the duration of training., Methods: A quantitative text analysis was conducted of the daily training reports of six community pharmacists who had participated previously in the training course and had received in-service training in oncology for at least 30 days. The pre- and post-training results of the knowledge tests and self-assessments of confidence, understanding, and performance were compared. This study was approved by the Research Ethics Committee of Kitasato Institute Hospital in October 2019 (Study No. 19044)., Results: The terms Prescription , Recommendation were extracted from the daily report after the 21st day of oncology in-service training. Furthermore, factors such as knowledge of cancer pharmacotherapy, confidence in patient education regarding the side effects of chemotherapy, and understanding of the work of pharmacists in outpatient cancer chemotherapy significantly increased at the end of the training., Conclusions: Community pharmacists with limited experience in outpatient oncology could improve their knowledge, understanding, and awareness of outpatient oncology patient care through 30 days of in-service oncology training in a hospital setting. The issues that emerged included training pharmacists to send follow-up documents on the patients' side effects and medication status as well as developing the literature search environment in community pharmacies., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Takahiro Fukawa, Koichiro Atsuda and Katsuya Otori received research funds for an endowed chair from the Medical System Network Co. Ltd. Medical System Network Co. Ltd was not involved in this study in any way except for funding of an endowed chair. However, the community pharmacies where the trainees were employed include affiliates of Medical Systems Network Co. Ltd.

Existing antiemetic therapy against emetic-risk agents across malignancies 24 h post-dose in the acute period in cisplatin (CDDP)-based regimens yields a satisfactory complete response (CR) rate of ≥90%. However, the control rate after 24 h in the delayed period is unsatisfactory. This study compared the efficacy of fosnetupitant (F-NTP), a neurokinin 1 receptor antagonist, with that of fosaprepitant (F-APR) and aprepitant (APR) in the treatment of patients with cancer at high emetic risk due to chemotherapy. In this retrospective case-control study involving patients receiving cisplatin-containing regimens and neurokinin 1 receptor antagonists, patients were divided into three groups based on prophylactic antiemetic therapy: F-NTP, F-APR, and APR. The CR rate was evaluated for each period up to 168 h and further subdivided into acute (0-24 h), delayed (24-120 h), overall (0-120 h), and beyond-delayed (120-168 h) periods. Eighty-eight patients were included in the F-NTP group, 66 in the F-APR group, and 268 in the APR group. The CR rates at 0-168 and 120-168 h after cisplatin administration were significantly higher in the F-NTP group than in the F-APR and APR groups. After adjusting for confounding factors, F-NTP use was an independent factor in the multivariate analysis. Prophylactic antiemetic therapy, including F-NTP, was effective and well-tolerated during the delayed period. The efficacy of F-NTP in managing chemotherapy-induced nausea and vomiting was superior to those of F-APR and APR during the study period.

Background: Exclusive breastfeeding, a longer breastfeeding duration, and interaction with the baby during lactation improve mothers' mental health. However, few studies have targeted women around 2.5 years after childbirth, when women are still considered to have been in a period of mental and physical health vulnerability. This study examined this aspect in a large cohort of mother-child pairs., Methods: Data were obtained from 85,735 mothers in an ongoing nationwide birth cohort study in Japan. Exposures were exclusive breastfeeding (yes/no), continued breastfeeding up to 2 years (yes/no), and interaction with the baby during feeding (yes/no). Outcomes were mothers' mental and physical health 2.5 years after childbirth measured using Mental and Physical Component Summary scores (MCS and PCS scores, respectively) from the 8-item Short-Form Health Survey. Generalized additive mixed model analysis was used to derive each estimate for the three exposures and their interactions, with each "no" answer as reference., Results: Exclusive breastfeeding and interaction with the baby during feeding were associated with MCS score increases of 0.28 (95%CI: 0.10-0.47) and 0.41 (95%CI: 0.29-0.54), respectively. However, no associations were found for continued breastfeeding up to 2 years and no interactions were identified. No significant differences were observed for PCS scores., Limitations: All variables were measured using a self-administered questionnaire., Conclusions: Continued exclusive breastfeeding until 6 months and interaction with the baby during feeding may help to promote mother's mental health 2.5 years after childbirth. These findings further strengthen the rationale for the World Health Organization's recommended lactation practices., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

This research aimed to examine the efficacy of the early initiation of breastfeeding within 1 h of birth, early skin-to-skin contact, and rooming-in for the continuation of exclusive breastfeeding until 6 months postpartum. The research used data from the Japan Environment and Children's Study (JECS), a nationwide government-funded birth cohort study. A total of 80,491 mothers in Japan between January 2011 and March 2014 who succeeded or failed to exclusively breastfeed to 6 months were surveyed in JECS. Multiple logistic regression model was used to analyse the data. The percentage of mothers who succeeded in exclusively breastfeeding to 6 months is 37.4%. Adjusted odds ratios were analysed for all 35 variables. Early initiation of breastfeeding (adjusted odds ratio [AOR]: 1.455 [1.401-1.512]), early skin-to-skin contact (AOR: 1.233 [1.165-1.304]), and rooming-in (AOR: 1.567 [1.454-1.690]) affected continuation of exclusive breastfeeding. Regional social capital (AOR: 1.133 [1.061-1.210]) was also discovered to support the continuation of breastfeeding. In contrast, the most influential inhibiting factors were starting childcare (AOR: 0.126 [0.113-0.141]), smoking during pregnancy (AOR: 0.557 [0.496-0.627]), and obese body type during early pregnancy (AOR: 0.667 [0.627-0.710]).

Mining activities often generate large amounts of sulfide-rich wastes containing arsenopyrite (FeAsS), which when dissolved releases toxic arsenic (As) and generates acid mine drainage (AMD) that are both disastrous to the environment. To suppress arsenopyrite dissolution, a technique that selectively coats sulfide minerals with a protective layer of Al-oxyhydroxide called Al-based carrier-microencapsulation (CME) was developed. Although a previous study of the authors showed that Al-based CME could significantly limit arsenopyrite dissolution, nature of the coating formed on arsenopyrite, including its electrochemical properties, is still not well understood. Moreover, stability of the coating once exposed to weathering conditions remains unclear. Better understanding of these important issues would greatly improve Al-based CME especially in its application to real mine wastes. In this study, nature of the coating formed by Al-based CME was investigated using SEM-EDX, DRIFTS and XPS while the electrochemical properties of the coating were evaluated by cyclic voltammetry and chronoamperometry. Meanwhile, stability of the coating was elucidated using consecutive batch leaching experiments and weathering cell tests. SEM-EDX, DRIFTS and XPS results indicate that the protective coating formed on arsenopyrite by Al-based CME was mainly composed of bayerite (α-Al(OH) 3 ), gibbsite (γ-Al(OH) 3 ), and boehmite (γ-AlO(OH)). These Al-based coatings, which have insulating properties, made arsenopyrite less electrochemically active. The coatings also limited the extent of both the anodic and cathodic half-cell reactions of arsenopyrite oxidation that suppressed As release and acid generation. Weathering cell tests indicated that the oxidation of CME-treated arsenopyrite was effectively limited until about 15 days but after this, it started to gradually progress with time due to the increasing acidity of the system where Al-based coatings became unstable. Nonetheless, CME-treated arsenopyrite was less oxidized based on the released amounts of Fe, As and S suppressed by 80, 60 and 70%, respectively, compared with the one treated with control., (© 2020 Published by Elsevier Ltd.)

Background: Few studies have reported the dosage of cefmetazole (CMZ) for intraoperative antimicrobial prophylaxis in patients underwent surgery for colorectal cancer. We therefore examined the optimal intraoperative dosage of CMZ according to pharmacokinetic/pharmacodynamic (PK/PD) theory in patients who undergoing surgery for colorectal cancer., Methods: The study group comprised 23 patients with colorectal cancer who underwent surgery, using CMZ as antimicrobial treatment to prevent postoperative infection. CMZ was administered intravenously within 60 min before surgery. PK/PD analysis was performed by population pharmacokinetic analysis and Monte-Carlo simulation., Results: The final population pharmacokinetic parameters of CMZ were as follows: CL CMZ  = 0.0704 × creatinine clearance (Ccr) and Vd CMZ  = 0.163 × body weight (Bw). In patients with a Ccr of ≥90 to <130 mL/min, the probability of achieving concentrations exceeding MIC was 52.9 to 82.2% at 2 h after the initial dose and less than 20% at 3 h after the initial dose., Conclusions: Additional doses of CMZ should be given every 2 h in patients with a Ccr of ≥90 to <130 mL/min, every 3 h in those with a Ccr of ≥50 to <90 mL/min, and every 4 to 5 h in those with a Ccr of ≥10 to <50 mL/min.

Background/aims: This study was designed to clarify the pharmacokinetics of prophylactically administered cefmetazole in serum, intestinal tissue, and subcutaneous adipose tissue in patients who underwent surgery for colorectal cancer., Methodology: Cefmetazole sodium (1 g) was given intravenously during the induction of anesthesia, followed by a 1-g dose after 3 hours. Blood samples were taken at the start of surgery, immediately before administration of the additional dose of cefmetazole, at the time of lesion resection, and at the time of wound closure. Tissue samples were obtained immediately after lesion resection and at the time of wound closure. Concentrations of cefmetazole in serum and tissue were measured by high performance liquid chromatography using an internal standard for calibration. Minimum inhibitory concentrations (MIC80) of cefmetazole for Escherichia coli, Klebsiella pneumoniae, and Bacteroides fragilis were measured, and pharmacokinetics were evaluated., Results: In subcutaneous adipose tissue, cefmetazole concentrations were maintained higher than the MIC80's for E. coli and K. pneumoniae, but were low in all patients regardless of the time of measurement., Conclusions: The low transition rate of cefmetazole into subcutaneous adipose tissue indicates the need for additional measures, such as high-pressure washing of the subcutaneous wound tissue.

The effects of TMG [2-(alpha-d-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol], a water-soluble vitamin E derivative, administered after irradiation on the mortality of X-irradiated mice and on the development of tumors in the mammary and pituitary glands in rats were investigated. When TMG (650 mg/kg) was administered intraperitoneally (i.p.) to C3H mice immediately after whole-body exposure to 7 Gy radiation, the 30-day survival was significantly higher than that of the control mice. The i.p. administration of TMG at 4 h after irradiation significantly improved survival compared to that of the controls, but administration 8 h after irradiation did not have a significant effect. Subcutaneous administration of TMG immediately after irradiation also decreased mortality significantly. When dams of lactating Wister rats were exposed to 1.5 Gy of X rays at day 21 after parturition and were then treated with diethylstilbestrol as a tumor promoter, the incidence of mammary tumors and pituitary tumors was increased compared to that in the nonirradiated control group. The administration of TMG (600 mg/kg, i.p.) after irradiation significantly reduced the incidence of mammary tumors and pituitary tumors. The number of rats that were free of both mammary and pituitary gland tumors was enhanced fourfold by TMG. These results suggest that TMG is effective in preventing radiation-induced bone marrow death in mice and in reducing mammary and pituitary tumors in rats even when it is administered after irradiation.

This study evaluated whether nitric oxide (NO) derived from nitric oxide synthase (NOS) induced by radiation is associated with tumorigenesis in the mammary glands. When rats were exposed to whole-body irradiation with gamma-rays (1.5 Gy) immediately after weaning and then treated with diethylstilbestrol, as an irradiated control, the tumor incidence (85%) was increased 7.6-fold in comparison with that (11.1%) of the non-irradiated control. The tumor incidence declined to 28.6% in the rats injected intraperitoneally with phenyl-N-tert-butylnitrone (PBN, 160 mg/kg), an inhibitor of inducible NOS (iNOS) expression and also a spin trapping agent, 30 min before irradiation. Also, the tumor incidence (25%) in rats orally administered with N-(3-(aminomethyl)-benzyl)-acetamide (1400W, 2.3+/-0.1 mg/day), a highly selective inhibitor of iNOS, dissolved in drinking water for 3 days after the irradiation was less than one-third of that in the irradiated control. On treatment with PBN or 1400W, no adenocarcinoma developed. Many of the mammary tumors that developed in the irradiated rats were positive for the estrogen receptor (ER). In contrast, ER was not detected in the tumors yielded from irradiated rats administered with PBN or 1400W. These results indicate that iNOS-derived NO may participate in the formation of estrogen-dependent mammary adenocarcinomas following radiation.

Nitric oxide (NO) and its reaction products have been shown to cause DNA damage and to be mutagenic. To elucidate whether NO produced by irradiation participates in the initiation of mammary tumorigenesis, we performed experiments using the nitric oxide-specific scavenger Fe(2+)-diethyldithiocarbamate complex (Fe(DETC)(2)) or a selective inhibitor for inducible nitric oxide synthase (iNOS), S,S(')-(4-phenylene-bis(1,2-ethanedinyl))bis-isothiourea (1,4-PB-ITU). Mother rats at day 21 of lactation were injected simultaneously with diethyldithiocarbamate intraperitoneally and Fe(2+)-citrate subcutaneously to form Fe(DETC)(2), in vivo, and then irradiated with 1.5Gy gamma-rays immediately after the injection. An additional injection of chemicals followed twice at 8 and 24h after the irradiation in the same manner. Both control and treated rats were then implanted with diethylstilbestrol pellets as a tumor promoter. The mammary tumor incidence in the experimental group was significantly reduced to one-fourth of that in the irradiated-alone group as the control. On the other hand, when mother rats took drinking water containing 0.005% 1,4-PB-ITU for 6 days from 3 days prior to irradiation at day 21 of lactation, a low tumor incidence in the iNOS inhibitor-treated groups was observed in the 1-year period. This report is the first to show that the NO derived from iNOS is an important radical for radiation-induced initiation of tumorigenesis of mammary glands in rats.

Purpose: We evaluated the radioprotective action of curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] extracted from Curcuma longa LINN against the acute and chronic effects and the mortality induced by exposure to radiation using female rats., Methods and Materials: For the assay of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urine, a marker for acute effects, Wistar-MS virgin rats were fed the basal diet with exposure at 0 or 3 Gy to gamma-rays from a 60Co source as the control. Rats in the experimental groups received whole-body irradiation with 3 Gy and were fed a diet containing 1% (wt/wt) curcumin for 3 days before and/or 2 days after irradiation. The urine was collected for a 24-h period between 1 and 2 days after irradiation. Urine samples were used to determine the 8-OHdG level using an enzyme-linked immunosorbent assay and the creatinine level by a modified Jaffé reaction. For long-term effects, rats at Day 17 of pregnancy were fed a diet containing curcumin for 3 days before and/or 3 days after irradiation with 1.5 Gy, and received a pellet of diethylstilbestrol as the promoter. The rats were examined for mammary and pituitary tumors for 1 year. To determine survival, virgin rats received whole-body irradiation with 9.6 Gy and were fed a diet containing curcumin for 3 days before and/or 3 days after irradiation. After irradiation, all rats were assessed daily for survival for 30 days., Results: Acutely in virgin rats irradiated with 3 Gy, the creatinine-corrected concentration and total amount of 8-OHdG in the 24-h urine samples were higher (approximately 1.3-fold) than the corresponding values in the nonirradiated controls. Adding curcumin to the diet for 3 days before and/or 2 days after irradiation reduced the elevated 8-OHdG levels by 50-70%. The evaluation of the protective action of curcumin against the long-term effects revealed that curcumin significantly decreased the incidence of mammary and pituitary tumors. However, the experiments on survival revealed that curcumin was not effective when administered for 3 days before and/or 3 days after irradiation (9.6 Gy)., Conclusion: These findings demonstrate that curcumin can be used as an effective radioprotective agent to inhibit acute and chronic effects, but not mortality, after irradiation.

We have hypothesized that one aspect of the antitumor activity of curcumin (diferuloylmethane) during the promotion stage of mammary gland tumorigenesis may be linked to reduction of free radicals (Inano et al., Carcinogenesis, 20: 1011-1018, 1999). Nitric oxide (NO) has been found to inflict damage on important biomolecules, and the overproduction of NO in diseases may be implicated in carcinogenesis and tumor progression. We have reported that the presence of three isoforms of nitric oxide synthases (NOS) and NO generation in the mammary gland correlate with the mammary gland development and mammary carcinogenesis. We, therefore, investigated the inhibitory activity of curcumin for the production of NO in rat mammary glands by using an organ culture system to validate the effectiveness and usefulness of curcumin in the pathophysiology of the mammary gland. A diced mammary gland (approximately 3 mm cubes) from the inguinal part of a female Wistar-MS rat treated with estradiol and progesterone was cultured with 2 ml of 5% FCS/DMEM in the presence or absence of LPS (0.5 microg/ml) for 2-3 days. Curcumin ( approximately 100 microM) was added at the same time to the LPS-treated cultures. In some experiments, curcumin was added to the culture after the LPS had been washed out. The NO production was significantly increased (by almost 20-fold compared to the control) by the addition of LPS to the culture system. This enhancement of NO production by LPS was reduced to 76 and to 56% by addition of 30 and 100 microM curcumin, respectively, to the culture. When LPS was eliminated from the culture after prestimulation for 1 day, the production of NO by the mammary gland dropped off, although some NO was still detectable. Curcumin did not further inhibit the production of NO by the prestimulated mammary gland after the elimination of LPS from the culture. The inducible nitric oxide synthase (iNOS, 122 kDa) and endothelial nitric oxide synthase (eNOS, 152 kDa) isoforms were detected in the mammary gland extracts at the end of the organ culture. The quantity of iNOS was apparently increased in the gland treated with LPS, while the eNOS expression was clearly diminished. Curcumin (100 microM) obviously suppressed the iNOS expression in the mammary glands cultured with LPS, and a recovery in the eNOS expression was observed. On the other hand, curcumin exhibited scavenging activity for the NO released from N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethanamine (NOC 12), a NO donor compound, in the coincubation mixture. These results indicate that curcumin has the ability to inhibit iNOS induction by LPS in the mammary gland and to scavenge NO radicals, which might explain, at least partly, its therapeutic properties in inflammation of the mammary gland., (Copyright 2000 Academic Press.)

We evaluated the effect of WR-2721 [S-2-(3-aminopropylamino)-ethylphosphorothioic acid] and cysteamine (2-mercaptoethylamine) on the development of radiation-induced mammary tumors in rats. Pregnant rats were treated with WR-2721 or cysteamine 30 min prior to whole-body irradiation with gamma rays from a (60)Co source at a dose of 1.5 or 2.6 Gy. Additional pregnant rats were given saline and then exposed to gamma rays at a dose of 0, 1.5 or 2.6 Gy as a control. All rats were implanted with pellets of diethylstilbestrol, a tumor promoter, 1 month after termination of nursing and were observed for 1 year to detect palpable mammary tumors. No mammary tumors developed in the saline-injected nonirradiated rats. However, when rats were irradiated with 1.5 or 2. 6 Gy after saline treatment, the incidence of mammary tumors was high (71.4 and 92.3%, respectively). Administration of WR-2721 or cysteamine prior to irradiation with 1.5 Gy significantly decreased the tumor incidence (23.8 and 20.8%, respectively). Tumor prevention by either agent was less effective at the higher dose. The appearance of the first mammary tumor occurred later in rats treated with WR-2721 or cysteamine than in the control rats. An increasing rate of adenocarcinoma in the control group was observed with increasing dose from 1.5 Gy up to 2.6 Gy. However, the development of adenocarcinoma did not increase after pretreatment with WR-2721 or cysteamine in rats irradiated with 2.6 Gy. Many of the mammary tumors that developed in the control rats were of the ER(+)PgR(+) type. Administration of WR-2721 produced no tumors of the ER(+)PgR(+) type. Cysteamine treatment increased the development of ER-negative tumors. The serum concentration of progesterone was significantly higher in rats treated with WR-2721 or cysteamine than in the control rats. On the other hand, the estradiol-17beta concentration was reduced by treatment with WR-2721, but not significantly compared to the control. WR-2721 and cysteamine had no effect on the prolactin concentration of the irradiated rats. The results suggest that administration of WR-2721 or cysteamine prior to the irradiation has a potent preventive effect on theinitiation phase during mammary tumorigenesis.

The purpose of this study was to determine the promotional role of estrogen and progestin in the development of radiation-induced mammary tumors. To eliminate the effects of endogenous ovarian hormones on tumor promotion, all rats were ovariectomized immediately after the initiation by irradiation with 2.6 Gy gamma-rays at day 21 of lactation, and were divided into 3 groups. For the control experiment, rats were implanted with a cholesterol pellet 1 month after the irradiation. Only one rat developed a fibroadenoma (4.3% mammary tumor incidence) during the 1 year period of the implantation. In the other two groups, chlormadinone acetate (CMA) to increase progestin level or diethylstilbestrol (DES) to increase estrogenic activity were administered, respectively, as tumor promoters for 1 year. Treatment with CMA did not significantly increase the incidence of mammary tumors as compared with the controls. However, administration of DES resulted in a significantly higher mammary tumor incidence (79.3%) than control treatment. Compared with cholesterol administration, DES treatment caused an increase in prolactin concentration in serum (5-fold), and reduction of estradiol-17beta concentration (22% of control). These results suggest that DES ia a potent effective promoter for tumorigenesis of radiation-initiated mammary cells, but CMA is not. DES may act directly on the irradiated mammary cells by binding to ER, and indirectly by stimulating prolactin secretion from the pituitary glands.

We investigated nitric oxide (NO) production and the presence of nitric oxide synthase (NOS) in the mammary gland by use of an organ culture system of rat mammary glands. Mammary glands were excised from the inguinal parts of female Wistar-MS rats primed by implantation with pellets of 17beta-estradiol and progesterone and were diced into approximately 3-mm cubes. Three of these cubes were cultured with 2 ml of 10% FCS/DMEM plus carboxy-PTIO (an NO scavenger, 100 microM) in the presence or absence of LPS (0.5 microgram/ml) for 2 days. The amount of NO produced spontaneously by the cultured mammary glands was relatively minute at the end of the 2-day culture period, and the NO production was significantly enhanced by the presence of LPS. This enhancement of NO production was completely eliminated by addition of hydrocortisone (3 microM), an inhibitor of inducible NOS (iNOS), to the incubation medium. Immunoblot analyses with specific antisera against NOS isoforms such as iNOS, endothelial NOS (eNOS), and brain NOS (bNOS) showed immunoreactive bands of iNOS (122 +/- 2 kD) and eNOS (152 +/- 3 kD) in extracts prepared from the mammary glands in the culture without LPS. The immunoreactive band of iNOS was highly intense after the treatment of mammary glands with LPS, whereas the corresponding eNOS immunoreactive band was faded. The immunohistochemical study of anti-iNOS antiserum on frozen sections of the cultured mammary glands showed that an immunoreactive substance with the antiserum was localized to the basal layer (composed of myoepithelial cells of alveoli and lactiferous ducts) of the mammary epithelia and to the endothelium of blood vessels that penetrated into the interstitium of the mammary glands. Histochemical staining for NADPH-diaphorase activity, which is identical to NOS, showed localization similar to that of iNOS in the mammary glands. Similar observations were noted in the immunohistochemistry of eNOS. In contrast, the immunoreactive signal with the bNOS antiserum was barely detected in the epithelial parts of alveoli and lactiferous ducts of the mammary glands. These observations demonstrate that three isoforms of NOS are present not only in the endothelium of blood vessels but also in the parenchymal cells (the glandular epithelium) of the rat mammary gland, such as epithelial cells and myoepithelial cells, and suggest that NO may have functional roles in the physiology of the mammary glands.

The effects of intravenous injection of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on circulating neutrophil numbers, pulmonary vascular permeability, and morphologic changes in the lung were examined in rabbits. Intravenous injection of rhG-CSF caused a rapid, profound neutropenia due to neutrophil sequestration primarily within capillaries but also in larger microvessels of the lungs. Examination of neutrophil deformability using microfilters revealed that granulocyte colony-stimulating factor (G-CSF) treatment caused a rapid stiffening of neutrophils through the polymerization of F-actin but not microtubule assembly. The expression of CD11b, CD11c, and CD18 on human neutrophils after G-CSF treatment increased, but CD11a did not. Intravenous injection of rhG-CSF did not induce neutrophil emigration or albumin leakage into alveolar space, wet/dry lung weight ratios were unchanged, and no pathologic changes in lung histology were observed. These studies indicate that injection of rhG-CSF caused a rapid neutropenia and neutrophil sequestration in the lungs that is likely to be mediated through a G-CSF-induced decrease in neutrophil deformability, although neutrophil-endothelial cell adhesion may also play a role. However, this G-CSF-induced neutrophil sequestration did not induce a massive lung injury.

Casein-like proteins were detected in various organs of rat by use of a specific antiserum raised against rat milk caseins. The antiserum specifically recognized alpha 1-, alpha 2-, beta-, and gamma-caseins in rat milk by Western blot analysis, whereas no immunoreactive band was observed in sera of rat and fetal bovine and in bovine caseins. Immunohistochemical studies of this antiserum on formalin-fixed mammary glands showed that immunoreactive caseins were localized to the apical portion of the cytoplasm in lactating mammary epithelial cells and in the luminal secretion, which indicates a directional secretion of caseins to the lumen by the mammary epithelial cells. With this antiserum, immunoreactive substances were detected in various organs, including the pancreatic ducts and islets of Langerhans, the secretory ducts of salivary glands, zona fasciculata cells and ganglion cells of adrenal gland, distal tubules and convoluted collecting tubules of kidney, epithelial cells of bronchioles and large pneumocytes of the lung, hair follicles, sebaceous glands, and the prickle cell layer of skin, uterine glands and epithelium of the endometrium, hepatic bile ducts, and brain. In Western blot analysis, major immunoreactive substances in the above organ extracts showed a similarity in molecular weight to alpha 2-casein of rat milk. Skin was the only tissue that expressed both alpha 2- and beta-caseins. There were no other immunoreactive bands with similarity to beta- and gamma-caseins in the other organ extracts, but higher molecular weight immunoreactive bands (> 100 kD) were detected in some organ extracts, such as salivary gland, kidney, liver, lung, and uterus. These findings suggest that the alpha 2-casein-like substance is localized not only in the mammary gland but also in a variety of organs and may play an important role as a functional molecule in those organs.

A 75-year-old woman had an irregularly shaped cavitary lesion in the right upper lung field on a chest X-ray film and a CT scan. Primary lung cancer was suspected, but no evidence of malignancy or of infection was found on examination of specimens obtained by transbronchial biopsy and by lavage. Seven months after the first examination the cavity was found to have enlarged and an intra-cavitary fungus ball like shadow was seen. On the basis of these findings, pulmonary aspergilloma with or without primary lung cancer was suspected. Examination of a specimen obtained by transbronchial biopsy revealed squamous cell carcinoma. Right upper lobectomy was done, and the resected tissue included a polypoid nodule and a cavity wall composed of a milky-white solid tumor. Microscopic examination revealed a moderately differentiated squamous cell carcinoma in both the cavity wall and the polypoid nodule, and no evidence of fungal involvement.