Efficacy and Safety of Radium-223 for Castration-resistant Prostate Cancer With Bone Metastasis Before and After Docetaxel.

BACKGROUND/AIM: Radium-223 (Ra-223) therapy provides a survival benefit for castration-resistant prostate cancer (CRPC) patients with bone metastasis. The optimal timing of using Ra-223 has not been determined. We evaluated the efficacy and safety of Ra-223 before and after docetaxel (DOC) therapy. PATIENTS AND METHODS: We retrospectively reviewed 36 CRPC patients with bone metastasis who were treated with Ra-223 in our institution and satellite hospitals. Ra-223 was used before DOC (pre-DOC group) in 17 patients (47%) and after DOC (post-DOC group) in 19 patients (53%). The treatment completion rate of 6 cycles, progression-free survival (PFS), cause-specific survival (CSS) and occurrence rate of adverse events were compared between the groups. RESULTS: The median follow-up duration was 45 months. In the pre-DOC compared with the post-DOC group, treatment completion rate was significantly higher (94% vs. 52%, p<0.01), PFS was significantly longer (median: 8 vs. 5 months, p=0.024) and CSS was significantly longer (median: 32 vs. 15 months, p=0.028). The difference in CSS was significant in multivariate analysis. In the pre-DOC compared with the post-DOC group, the occurrence rate of grade ≥3 adverse events tended to be lower (6% vs. 36%, p=0.322), and the CSS tended to be longer (median: not reached vs. 45 months, p=0.208). CONCLUSION: Ra-223 could be used more safely and more effectively for CRPC patients with bone metastasis before than after DOC therapy.

Development of Trifluoromethanesulfonic Acid-Immobilized Nitrogen-Doped Carbon-Incarcerated Niobia Nanoparticle Catalysts for Friedel-Crafts Acylation.

Heterogeneous trifluoromethanesulfonic acid-immobilized nitrogen-doped carbon-incarcerated niobia nanoparticle catalysts (NCI-Nb-TfOH) that show excellent catalytic performance with low niobium loading (1 mol %) in Friedel-Crafts acylation have been developed. These catalysts exhibit higher activity and higher tolerance to catalytic poisons compared with the previously reported TfOH-treated NCI-Ti catalysts, leading to a broader substrate scope. The catalysts were characterized via spectroscopic and microscopic studies.

Nitrogen-Doped Carbon Enables Heterogeneous Asymmetric Insertion of Carbenoids into Amines Catalyzed by Rhodium Nanoparticles.

Development of stable heterogeneous catalyst systems is a crucial subject to achieve sustainable society. Though metal nanoparticles are robust species, the study of asymmetric catalysis by them has been restricted because methods to activate metal nanoparticles without causing metal leaching were limited. We developed Rh nanoparticle catalysts (NCI-Rh) supported on nitrogen-doped carbon as a solid ligand to interact with metals for asymmetric insertion of carbenoids into N-H bonds cocatalyzed by chiral phosphoric acid. Nitrogen dopants played a crucial role in both catalytic activity and enantioselectivity while almost no catalysis was observed with Rh nanoparticles immobilized on supports without nitrogen dopants. Various types of chiral α-amino acid derivatives were synthesized in high yields with high enantioselectivities and NCI-Rh could be reused in seven runs. Furthermore, we demonstrated the corresponding continuous-flow reaction using a column packed with NCI-Rh. The desired product was obtained efficiently for over 90 h through the reactivation of NCI-Rh and the chiral source could be recovered.

N-terminal-pro-B-type-natriuretic peptide associated with 2-year mortality from both cardiovascular and non-cardiovascular origins in prevalent chronic hemodialysis patients.

N-terminal-pro-B-type-natriuretic peptide (NT-proBNP) was a predictive marker of cardiovascular disease (CVD)-related death in chronic dialysis patients. NT-proBNP was also correlated with markers of inflammation, malnutrition and protein-energy wasting. We hypothesized whether NT-proBNP was also associated with non-CVD death in chronic dialysis patients. A prospective observational study for incidence of death in chronic dialysis patients was conducted. Prevalent chronic dialysis patients (n = 1310) were enrolled and followed for 24 months. One hundred forty-four deaths were recorded. Area under the curve using ROC analysis for NT-proBNP showed: all causes of death (0.761), CVD-related (0.750), infection and malignancy-related (0.702) and others and unknown (0.745). After adjusting for age, sex, hemodialysis vintage, cardiothoracic ratio, mean pre-dialysis systolic blood pressure, dry weight and basal kidney disease, the hazard ratios (95% confidence intervals) per 1-log NT-proBNP calculated using multivariate Cox analysis were: all causes of death, 3.83 (2.51-5.85); CVD-related, 4.30 (2.12-8.75); infection and malignancy-related, 2.41 (1.17-4.93); and others and unknown origin, 5.63 (2.57-12.37). NT-proBNP was significantly associated not only with CVD-relate but also with non-CVD-related deaths in this population of prevalent chronic dialysis patients.

Apoprotein B/Apoprotein A-1 Ratio and Mortality among Prevalent Dialysis Patients.

BACKGROUND AND OBJECTIVES: In dialysis patients, the associations between apoprotein profile and all-cause or cardiovascular disease (CVD)-related mortality are not well known. We, therefore, investigated whether apoprotein levels are associated with these events. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We undertook a prospective observational cohort study of prevalent hemodialysis patients aged ≥18 years (n=1081), who were followed for 4 years (2011-2014). Outcomes were all-cause and CVD-related mortality. Predictors used were baseline apoprotein levels, particularly the apoprotein B (apo B)/ apoprotein A-1 (apo A-1) ratio. A Cox regression analysis was used to calculate the hazard ratios (HRs) for mortality. Apo A-1, apo B, and apo B/ apo A-1 ratio were analyzed with adjustments in three models: model 1, basic adjustment for age and sex; model 2, basic adjustments plus dialysis conditions (dialysis vintage, mean predialysis systolic blood pressure, dry weight, and mean intradialytic weight gain); and model 3, model 2 plus metabolic and inflammatory conditions (basal kidney disease, serum albumin, C-reactive protein level, and statin use). RESULTS: Of the 1081 patients included in the study, 203 deaths were recorded, 92 of which were related to CVD. The apo B/ apo A-1 ratio was significantly associated with all-cause and CVD-related mortality when analyzed by 1-SD increments or quartile IV versus I in all models. In model 3, HRs and 95% confidence intervals (95% CIs) for 1-SD increments of apo B/ apo A-1 ratio for all-cause mortality or CVD-related mortality were: HR, 1.16 (95% CI, 1.00 to 1.35), or HR, 1.38 (95% CI, 1.11 to 1.71), respectively, and for quartile IV versus I: HR, 1.65 (95% CI, 1.05 to 2.57), or HR, 2.56 (95% CI, 1.21 to 5.40), respectively. Apo A-1 was significantly associated with both mortalities in models 1 and 2. However, apo B was only significantly associated with CVD-related mortality in model 3. CONCLUSIONS: Apoprotein measurement, especially the apo B/ apo A-1 ratio, was significantly associated with all-cause and CVD-related mortality in prevalent dialysis patients.

[Effectiveness of acupuncture and moxibustion therapy for the treatment of refractory interstitial cystitis].

The efficacy of acupuncture and moxibustion treatment was examined on eight female patients with refractory interstitial cystitis (IC) who had been treated conservatively with hydrodistension, intravesical instillation of dimethyl sulfoxide, or oral medication. These patients had received hydrodistension on an average of 2.3±1.8 times. Moxa needles were applied to Ciliao in bladder meridian 32 and Xialiao in bladder meridian 34, and electroacupuncture was performed on Zhongliao in bladder meridian 33 at 3 Hz for 20 min once a week. The bladder condition was assessed by the visual analogue scale (VAS) score, the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI), the Interstitial Cystitis Problem Index (ICPI), and the maximum voided volume (MVV). After 3 months, patients who showed a reduction of >2 in their VAS score, reduction of <30% of ICSI and ICPI, and increase of >100 ml MVV were considered responders. There were three responders, and after repeated therapy to maintain these effects, they no longer required hydrodistension. Two responders had no recurrence for 48 months or more. Acupuncture and moxibustion resulted in improvement in 38% of the patients (3/8) with refractory IC, and repeated therapy maintained the therapeutic effects. This therapy is traditional and relatively noninvasive. Although its precise mechanism of action is unclear, this study suggests that acupuncture and moxibustion treatment may be a complementary and alternative therapeutic option for refractory IC.

Purification and characterization of HSP-inducers from Eupatorium lindleyanum.

The expression of heat shock proteins (HSPs), particularly HSP70, provides resistance to stressors. We recently reported that ultraviolet (UV)-induced melanin production and skin damage were suppressed in transgenic mice expressing HSP70 and that an extract of Eupatorium lindleyanum induces the expression of HSP70 in cells. Here we report the purification of eupalinolide A and B (EA and EB) from E. lindleyanum, and describe their actions as HSP-inducers. EA and EB both induced the expression of HSP70 in cells at concentrations that did not significantly affect cell viability. Treatment of cells with EA or EB activated heat shock factor 1 (HSF1), while the artificial suppression of HSF1 expression diminished the EA- or EB-mediated induction of HSP70 expression. Furthermore, EB inhibited the interaction between HSF1 and HSP90, which is known to inhibit the activity of HSF1. These findings suggest that EA and EB induce the expression of HSP70 via the activation of HSF1 by inhibiting the interaction between HSF1 and HSP90. EA and EB both induced the expression of HSP70 synergistically with other stressors. Furthermore, pre-treatment of cells with EA or EB suppressed melanin production and stressor-induced apoptosis. These effects were suppressed by the artificial suppression of HSP70 expression. In vivo, the percutaneous administration of EB induced the expression of HSP70 and suppressed UVB radiation-induced damage, inflammatory responses and melanin production in the skin. These results suggest that EA and EB could be beneficial for use in cosmetics and medicines as a consequence of their inhibitory action on UV-induced skin damage and melanin production.

Renal carcinoma with (6;11)(p21;q12) translocation: report of an adult case.

An extremely rare adult example of renal carcinoma with t(6;11)(p21;q12 or q13) is presented here. The tumor of a 45-year-old Japanese male, excised under the diagnosis of renal cell carcinoma, was a well circumscribed 7 cm mass with light brown sectioned surfaces. Histologically, it was composed of a major population of large polygonal epithelioid cells in a nested alveolar growth and a subpopulation of smaller cells clustering around hyaline basement membrane material. The former cells possessed ample, clear to eosinophilic granular cytoplasm with well-defined cell borders and the latter was frequently accompanied by psammomatous calcification. These tumor cells exhibited immunoreactivity for melanoma markers, transcription factor EB and cathepsin K, but were not reactive for epithelial markers and transcription factor E3. While pulmonary metastatic foci that were noted preoperatively progressed rapidly following interferon-based therapy, subsequent sunitinib malate yielded a partial response and stabilized the lung metastasis for 6 months after surgery. We could trace 20 cases of 6p21 translocation renal carcinoma, among which only four were in individuals older than 40 years. Description of a new case like this is important since little is known about the prognosis and treatment of adult patients with this condition.

HSP70 inducers from Chinese herbs and their effect on melanin production.

Skin hyperpigmentation disorders as a result of abnormal melanin production induced by ultraviolet (UV) irradiation are both a clinical and a cosmetic problem. This melanin production is mediated by tyrosinase whose expression is positively regulated by microphthalmia-associated transcription factor (MITF). We recently found that expression of heat shock protein 70 (HSP70) inhibits melanin production. In this study, we searched for HSP70 inducers from Chinese herbs and selected an ethanol extract of Eupatorium lindleyanum (E. lindleyanum). Not only melanin production but also the activity and expression of tyrosinase were significantly suppressed in cells treated with E. lindleyanum extract as well as in HSP70-overexpressing cells. The expression of MITF was clearly suppressed in cells treated with E. lindleyanum extract but not in HSP70-overexpressing cells. These results suggest that E. lindleyanum extract suppresses the expression of tyrosinase and melanin production through both HSP70-dependent and HSP70-independent mechanisms.

Suppression of melanin production by expression of HSP70.

Skin hyperpigmentation disorders due to abnormal melanin production induced by ultraviolet (UV) irradiation are both a clinical and cosmetic problem. UV irradiation stimulates melanin production in melanocytes by increasing intracellular cAMP. Expression of heat shock proteins (HSPs), especially HSP70, is induced by various stressors, including UV irradiation, to provide cellular resistance to such stressors. In this study we examined the effect of expression of HSP70 on melanin production both in vitro and in vivo. 3-Isobutyl-1-methylxanthine (IBMX), a cAMP-elevating agent, stimulated melanin production in cultured mouse melanoma cells, and this stimulation was suppressed in cells overexpressing HSP70. IBMX-dependent transcriptional activation of the tyrosinase gene was also suppressed in HSP70-overexpressing cells. Expression of microphthalmia-associated transcription factor (MITF), which positively regulates transcription of the tyrosinase gene, was up-regulated by IBMX; however, this up-regulation was not suppressed in HSP70-overexpressing cells. On the other hand, immunoprecipitation and immunostaining analyses revealed a physical interaction between and co-localization of MITF and HSP70, respectively. Furthermore, the transcription of tyrosinase gene in nuclear extract was inhibited by HSP70. In vivo, UV irradiation of wild-type mice increased the amount of melanin in the basal layer of the epidermis, and this increase was suppressed in transgenic mice expressing HSP70. This study provides the first evidence of an inhibitory effect of HSP70 on melanin production both in vitro and in vivo. This effect seems to be mediated by modulation of MITF activity through a direct interaction between HSP70 and MITF.

Prevention of UVB radiation-induced epidermal damage by expression of heat shock protein 70.

Irradiation with UV light, especially UVB, causes epidermal damage via the induction of apoptosis, inflammatory responses, and DNA damage. Various stressors, including UV light, induce heat shock proteins (HSPs) and the induction, particularly that of HSP70, provides cellular resistance to such stressors. The anti-inflammatory activity of HSP70, such as its inhibition of nuclear factor kappa B (NF-kappaB), was recently revealed. These in vitro results suggest that HSP70 protects against UVB-induced epidermal damage. Here we tested this idea by using transgenic mice expressing HSP70 and cultured keratinocytes. Irradiation of wild-type mice with UVB caused epidermal damage such as induction of apoptosis, which was suppressed in transgenic mice expressing HSP70. UVB-induced apoptosis in cultured keratinocytes was suppressed by overexpression of HSP70. Irradiation of wild-type mice with UVB decreased the cutaneous level of IkappaB-alpha (an inhibitor of NF-kappaB) and increased the infiltration of leukocytes and levels of pro-inflammatory cytokines and chemokines in the epidermis. These inflammatory responses were suppressed in transgenic mice expressing HSP70. In vitro, the overexpression of HSP70 suppressed the expression of pro-inflammatory cytokines and chemokines and increased the level of IkappaB-alpha in keratinocytes irradiated with UVB. UVB induced an increase in cutaneous levels of cyclobutane pyrimidine dimers and 8-hydroxy-2'-deoxyguanosine, both of which were suppressed in transgenic mice expressing HSP70. This study provides genetic evidence that HSP70 protects the epidermis from UVB-induced radiation damage. The findings here also suggest that the protective action of HSP70 is mediated by anti-apoptotic, anti-inflammatory, and anti-DNA damage effects.

Genetic aberration on chromosome 10 in human oral squamous cell carcinoma.

Recently a tumor suppressor gene, a deleted in malignant brain tumor gene (DMBT1), was detected on chromosome 10. In some types of tumors, the frequent deletion of DMBT1 locus have been reported as well as loss of heterozygosity (LOH) on chromosome 10. However, little is known relating to human oral squamous cell carcinoma (OSCC). To study the genetic aberrations on chromosome 10 in OSCC, we performed polymerase chain reaction (PCR) analysis of microsatellite polymorphisms corresponding to 16 loci, containing 2 DMBT1 loci. We examined 38 oral primary squamous cell carcinoma (SCC) tissues and corresponding normal tissues. Microsatellite instability (MI) was detected at least on 1 of the 16 loci in 15 (39.5%) of 38 cases, and loss of heterozygosity (LOH) at least 1 of the 16 loci was also observed in 28 (73.7%) of 38 cases. LOH was accumulated at D10S202 (34.6%) and D10S217 (28.6%), suggesting the presence of two putative tumor suppressor genes associated with OSCC. The 2 DMBT1 loci, D10S209 and D10S587, had comparatively high frequent LOH (20.0 and 22.7%, respectively), maybe indicating the important role of DMBT1 in OSCC. No significant correlation between histological differentiation and LOH was found. These results suggest that genetic aberrations on chromosome 10 play important roles in the oncogenesis of OSCC.