Development of novel steroid sulfatase inhibitors; II. TZS-8478 potently inhibits the growth of breast tumors in postmenopausal breast cancer model rats

In postmenopausal breast cancer tissue, steroid sulfatase (STS) activity is high and much estrone sulfate also exists; these facts reveal that estrone sulfate may be involved in the growth of breast cancer as an estrogen source. Steroid sulfatase is an enzyme, which catalyzes hydrolysis from estrone sulfate to estrone, and the development of steroid sulfatase inhibitors is expected as novel therapeutic drugs for postmenopausal breast cancer. We have developed a novel compound 2',4'-dicyanobiphenyl-4-O-sulfamate (TZS-8478), which has potent steroid sulfatase-inhibitory activity and exhibits no estrogenicity in vitro and in vivo. To elucidate its usefulness as a therapeutic drug for postmenopausal breast cancer, we examined the breast cancer cell proliferation- and breast tumor growth-inhibitory activity of TZS-8478 in postmenopausal breast cancer model rats. TZS-8478 dose-dependently suppressed the estrone sulfate-stimulated proliferation of MCF-7 cells. Regarding nitrosomethylurea (NMU)-induced postmenopausal breast cancer models, furthermore, TZS-8478 (0.5 mg/kg per day) markedly inhibited the estrone sulfate-stimulated growth of breast tumors similarly to estrone sulfate-depletion. TZS-8478 completely inhibited steroid sulfatase activity in tumor, uterus and liver, and also markedly lowered plasma concentrations of estrone and estradiol. The above mentioned results suggested that TZS-8478 may be useful as a therapeutic drug for estrogen-dependent postmenopausal breast cancer.     

Telephone cognitive-behavioral therapy for subthreshold depression and presenteeism in workplace: a randomized controlled trial

Background

Subthreshold depression is highly prevalent in the general population and causes great loss to society especially in the form of reduced productivity while at work (presenteeism). We developed a highly-structured manualized eight-session cognitive-behavioral program with a focus on subthreshold depression in the workplace and to be administered via telephone by trained psychotherapists (tCBT).

Methods

We conducted a parallel-group, non-blinded randomized controlled trial of tCBT in addition to the pre-existing Employee Assistance Program (EAP) versus EAP alone among workers with subthreshold depression at a large manufacturing company in Japan. The primary outcomes were depression severity as measured with Beck Depression Inventory-II (BDI-II) and presenteeism as measured with World Health Organization Health and Work Productivity Questionnaire (HPQ). In the course of the trial the follow-up period was shortened in order to increase acceptability of the study.

Results

The planned sample size was 108 per arm but the trial was stopped early due to low accrual. Altogether 118 subjects were randomized to tCBT+EAP (n = 58) and to EAP alone (n = 60). The BDI-II scores fell from the mean of 17.3 at baseline to 11.0 in the intervention group and to 15.7 in the control group after 4 months (p<0.001, Effect size = 0.69, 95%CI: 0.32 to 1.05). However, there was no statistically significant decrease in absolute and relative presenteeism (p = 0.44, ES = 0.15, −0.21 to 0.52, and p = 0.50, ES = 0.02, −0.34 to 0.39, respectively).

Conclusion

Remote CBT, including tCBT, may provide easy access to quality-assured effective psychotherapy for people in the work force who present with subthreshold depression. Further studies are needed to evaluate the effectiveness of this approach in longer terms. The study was funded by Sekisui Chemicals Co. Ltd.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00885014","term_id":"NCT00885014"}}NCT00885014     

An approach towards artificial quinone pools by use of photo- and redox-active dendritic molecules

Molecules with one porphyrin and multiple quinone groups are described. The molecules are based on dendritic frameworks, with the quinone groups attached at the "internal" positions and the porphyrin attached at the focal point, leading to a characteristic layer architecture. When irradiated with visible light in the presence of 4-tert-butylthiophenol, the quinones were converted to quinols. Such a behavior mimics the function of quinone pools in photosynthesis.     

Independent control of organogenesis and shoot tip abortion are key factors to developmental plasticity in kiwifruit (Actinidia)

BACKGROUND AND AIMS: In kiwifruit (Actinidia), the number of nodes per shoot is highly variable and is influenced by genotype and environmental conditions. To understand this developmental plasticity, three key processes were studied: organogenesis by the shoot apical meristem during shoot growth; expansion of phytomers; and shoot tip abortion. METHODS: Studies were made of organogenesis and shoot tip abortion using light and scanning electron microscopy. The effect of temperature on shoot growth cessation was investigated using temperature indices over the budbreak period, and patterns of shoot tip abortion were quantified using stochastic modelling. KEY RESULTS: All growing buds began organogenesis before budbreak. During shoot development, the number of phytomers initiated by the shoot apical meristem is correlated with the number of expanding phytomers and the mean internode length. Shoot tip abortion is preceded by growth cessation and is not brought about by the death of the shoot apical meristem, but occurs by tissue necrosis in the sub-apical zone. For most genotypes studied, the probability of shoot tip abortion is higher during expansion of the preformed part of the shoot. Lower temperatures during early growth result in a higher probability of shoot tip abortion. CONCLUSIONS: Organogenesis and shoot tip abortion are controlled independently. All buds have the potential to become long shoots. Conditions that increase early growth rate postpone shoot tip abortion.     

Tracking long‐distance migration of marine fishes using compound‐specific stable isotope analysis of amino acids

The long‐distance migrations by marine fishes are difficult to track by field observation. Here, we propose a new method to track such migrations using stable nitrogen isotopic composition at the base of the food web (δ¹⁵N_Base), which can be estimated by using compound‐specific isotope analysis. δ¹⁵N_Base exclusively reflects the δ¹⁵N of nitrate in the ocean at a regional scale and is not affected by the trophic position of sampled organisms. In other words, δ¹⁵N_Base allows for direct comparison of isotope ratios between proxy organisms of the isoscape and the target migratory animal. We initially constructed a δ¹⁵N_Base isoscape in the northern North Pacific by bulk and compound‐specific isotope analyses of copepods (n = 360 and 24, respectively), and then we determined retrospective δ¹⁵N_Base values of spawning chum salmon (Oncorhynchus keta) from their vertebral centra (10 sections from each of two salmon). We then estimated the migration routes of chum salmon during their skeletal growth by using a state‐space model. Our isotope tracking method successfully reproduced a known chum salmon migration route between the Okhotsk and Bering seas, and our findings suggest the presence of a new migration route to the Bering Sea Shelf during a later growth stage.     

Vertically structured prokaryotic community can control the efficiency of the biological pump in the oceans

Despite recent advances in molecular and metagenomic approaches, it is still unclear how spatiotemporal variations in microbial communities influence the biological pump, exporting organic carbon from the surface to the deep oceans. We address this important problem by constructing a simple model of a prokaryotic metacommunity in which two generalist ecotypes compete for two resources. The first and the second ecotypes have, respectively, a higher preference for particulate organic carbon (POC) and dissolved organic carbon. Sinking of POC would lead to a higher abundance of the first ecotype in the deep layer compared to the surface layer, but vertical mixing in turn generates a net upward flux of this ecotype to the surface layer. This upward movement accelerates the shifts in the community composition during the phytoplankton bloom, contributing to a higher efficiency in POC remineralization at the surface layer and reducing the carbon flux to the deep layer.     

Key flowering genes including FT-like genes are upregulated in the vasculature of apple dwarfing rootstocks

The Malling 9 (M.9) dwarfing rootstock is widely used in apple breeding and commercial cultivation to shorten the juvenile period, reduce vegetative growth and increase flowering of the scion. A segment of M.9 stem (interstock) or M.9 bark grafted into a compound tree can cause significant dwarfing of the scion, suggesting that the dwarfing signal may be vascular derived. To better understand how the M.9 rootstock alters the growth and development of the scion, we compared gene expression in vascular-enriched tissue from dwarfing and vigorous rootstocks. RNA sequencing indicated that key flowering genes were upregulated in M.9 relative to a vigorous rootstock, Malling 793 (M.793). An in-depth analysis of the apple FT/TFL1 gene family identified four new members: MdMFTa, MdMFTb, MdBFTa and MdBFTb. Quantitative RT-PCR analysis confirmed the higher expression of MdFT1/2, MdBFTa/b, MdCO, MdGI, and MdSOC1 in two different dwarfing rootstocks (M.9 and Malling 27 (M.27)) relative to M.793. Both MdFT1/2, and MdBFTa/b were expressed at higher levels in multiple dwarfing rootstock accessions relative to more vigorous genotypes. In perennial species, FT promotes flowering, and has additional roles in accelerating the transition from juvenility to maturity, and regulating cycles of seasonal growth and termination. Apple dwarfing rootstocks reduce the juvenile phase and promote both flowering and early shoot termination. Our work supports a role for MdFT in promoting flowering and earlier shoot termination. We suggest that upregulation of a suite of flowering genes including MdFT, and possibly MdBFT, in the vasculature is part of the underlying mechanism of apple dwarfing rootstocks. Genes involved with response to biotic and abiotic stress and disease were also upregulated in the M.9 rootstock, suggesting that stress, possibly mediated by JA and ABA signalling, also plays a role in the M.9-induced phenotype.     

Daily protein and energy intakes of infants fed a commercial infant formula with a reduced protein concentration of 2.2 g/100 kcal: an impact of feeding interval on energy intake

ABSTRACT

We evaluated the protein and energy intakes of infants fed commercial infant Formula A (protein, 2.2 g/100 kcal; energy, 68 kcal/100 mL) and examined whether changes in feeding intervals are involved in constant energy intake. Daily nutritional intake of 378 Formula A-fed infants was assessed using reference values and compared to that of infants fed Formulas B (protein: 2.3 g/100 kcal, energy: 68 kcal/100 mL) and C (protein: 2.4 g/100kcal, energy: 70 kcal/100 mL). From 15 to 149 days of age, the mean formula volume and protein intake were 758–887 mL/day and 11.4–13.3 g/day, respectively, higher than the protein intake of breast-fed infants. Daily energy intake (86–129 kcal/kg/day) was comparable to the estimated energy requirements. Feeding intervals were shorter in infants fed Formulas A and B than in those fed Formula C, whereas energy intake was similar. The protein intake of infants decreased as the protein concentration per energy in infant formula was reduced, and accordingly the protein intake of Formula A-fed infants was significantly lower than that of Formula C-fed infants. In conclusion, the new composition of Formula A is suitable in protein and energy intake of infants, and daily energy intake remains constant by shortening in feeding intervals when the energy concentration in infant formula is reduced.

Clinical Trial Registration: UMIN000023110     

HLA-A2 Antigen status predicts metastasis and response to immunotherapy in gastric cancer

 Our previous studies have shown that HLA-DR4 and -B52 antigens are associated with an increased risk of lymph node metastasis in patients with gastric cancer. We hypothesized that a putative HLA antigen, correlated with a low risk of lymph node metastasis, may also be correlated with the response to anticancer therapy. The microcytotoxicity assay was used to examine 49 HLA antigens of the A, B, C, DR, and DQ loci, and the association between HLA class I and II antigen status and lymph node metastasis in 847 patients with gastric cancer as well as the response to the therapy in 739 patients were analyzed. HLA-A2 antigen was significantly associated with a low risk of lymph node metastasis in patients with T2-T4 advanced cancer [58.8% compared to 37.0% in patients with lymph node metastasis; corrected P, P _c (98), =0.011], especially in those with moderately differentiated adenocarcinoma [71.0% compared to 26.4% in patients with lymph node metastasis, P _c (294)=0.00294] and with a better response to postoperative immunotherapy using protein-bound polysaccharide K (PSK), a nonspecific immunomodulator, than to chemotherapy. HLA alleles may be associated with resistance or susceptibility to lymph node metastasis and HLA-A2 antigen may be a useful predictor of the response to PSK. The data suggest that the predictive power of this HLA antigen may prove useful in the selection of anticancer therapy. Received: 29 May 1997 / Accepted: 15 July 1997     

Meta-analysis of effects and side effects of low dosage tricyclic antidepressants in depression: systematic review

ObjectiveTo compare the effects and side effects of low dosage tricyclic antidepressants with placebo and with standard dosage tricyclics in acute phase treatment of depression.DesignSystematic review of randomised trials comparing low dosage tricyclics (⩽100 mg/day) with placebo or with standard dosage tricyclics in adults with depression.Results35 studies (2013 participants) compared low dosage tricyclics with placebo, and six studies (551 participants) compared low dosage tricyclics with standard dosage tricyclics. Low dosage tricyclics, mostly between 75 and 100 mg/day, were 1.65 (95% confidence interval 1.36 to 2.0) and 1.47 (1.12 to 1.94) times more likely than placebo to bring about response at 4 weeks and 6-8 weeks, respectively. Standard dosage tricyclics failed, however, to bring about more response but produced more dropouts due to side effects than low dosage tricyclics.ConclusionsTreatment of depression in adults with low dose tricyclics is justified. However, more rigorous studies are needed to definitively establish the relative benefits and harms of various dosages.

What is already known on this topic

Tricyclics are still prescribed as often as selective serotonin reuptake inhibitors and other newer antidepressants worldwideExperts have often claimed that clinicians prescribe tricyclics at less than adequate dosages

What this study adds

Tricyclics at dosages below the recommended range are more effective than placeboThey may or may not be as effective as standard dosage tricyclics but result in fewer dropouts due to side effectsThe minimum effective dosage and ranges for antidepressants has not been established—a simple set of numbers that every practising doctor and patient would want to know