Osteoblasts Generate Testosterone From DHEA and Activate Androgen Signaling in Prostate Cancer Cells

Bone metastasis is a complication of prostate cancer in up to 90% of men afflicted with advanced disease. Therapies that reduce androgen exposure remain at the forefront of treatment. However, most prostate cancers transition to a state whereby reducing testicular androgen action becomes ineffective. A common mechanism of this transition is intratumoral production of testosterone (T) using the adrenal androgen precursor dehydroepiandrosterone (DHEA) through enzymatic conversion by 3β- and 17β-hydroxysteroid dehydrogenases (3βHSD and 17βHSD). Given the ability of prostate cancer to form blastic metastases in bone, we hypothesized that osteoblasts might be a source of androgen synthesis. RNA expression analyses of murine osteoblasts and human bone confirmed that at least one 3βHSD and 17βHSD enzyme isoform was expressed, suggesting that osteoblasts are capable of generating androgens from adrenal DHEA. Murine osteoblasts were treated with 100 nM and 1 μM DHEA or vehicle control. Conditioned media from these osteoblasts were assayed for intermediate and active androgens by liquid chromatography–tandem mass spectrometry. As DHEA was consumed, the androgen intermediates androstenediol and androstenedione were generated and subsequently converted to T. Conditioned media of DHEA-treated osteoblasts increased androgen receptor (AR) signaling, prostate-specific antigen (PSA) production, and cell numbers of the androgen-sensitive prostate cancer cell lines C4-2B and LNCaP. DHEA did not induce AR signaling in osteoblasts despite AR expression in this cell type. We describe an unreported function of osteoblasts as a source of T that is especially relevant during androgen-responsive metastatic prostate cancer invasion into bone. © 2021 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.     

A prognostic immune predictor,HLA-DRA,plays diverse roles in non-muscle invasive and muscle invasive bladder cancer

BackgroundThere is an increasing demand for prognostic immune biomarkers of cancer. The prognostic significance of immune markers has been shown for various cancers, but biomarkers of bladder cancer (BCa) have not been fully evaluated. To clarify the role of human leukocyte antigen DR alpha chain (HLA-DRA) in BCa development, we examined expression of HLA-DRA mRNA in tissue samples of non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC).Materials and MethodsTissues of 96 NMIBC, 43 MIBC and 59 controls comprising noncancerous BCa surrounding tissues were used to examine the expression of HLA-DRA gene by real-time polymerase chain reaction. The expression of up-stream genes regulating HLA-DRA were also measured to explain the role of HLA-DRA in BCa.ResultsPatients with high grade NMIBC showed higher expression of HLA-DRA than those with low grade NMIBC (P < 0.05). In addition, NMIBC patients who progressed to MIBC showed high expression of HLA-DRA mRNA. Kaplan-Meier analysis showed that NMIBC patients with low expression of HLA-DRA had better progression-free survival than those with high expression (P = 0.004). Moreover, the expression of genes regulating HLA-DRA varied in NMIBC and MIBC, indicating a different immunoregulation effect of HLA-DRA in both cancers.ConclusionsHigh expression of HLA-DRA in NMIBC patients has implications for patient stratification strategies, as well as for BCa tumor immunology.     

Bilateral immediate two-stage breast reconstruction in patients with unilateral breast cancer: Outcomes analysis and risk assessment

IntroductionContralateral prophylactic mastectomy has the potential to decrease the occurrence of cancer and reduce psychological burden. However, it is known that complications after bilateral mastectomy are higher compared with unilateral mastectomy. Our goal was to evaluate outcomes of immediate breast reconstruction in patients undergoing bilateral mastectomy and to compare complication rates between therapeutic and prophylactic sides.Patients and MethodsElectronic medical records of patients with unilateral breast cancer who underwent bilateral mastectomy and immediate reconstruction with expanders were reviewed. Postoperative complications were compared between therapeutic and prophylactic mastectomy sides.ResultsSixty-two patients were analyzed. The overall complication rate after both stages was 23.9% on the therapeutic side and 16.5% on the prophylactic side. Infection was the most common complication on both sides. All infections on the prophylactic mastectomy side were successfully treated with intravenous (IV) antibiotics (salvage rate of 100%), whereas 35.7% of infected tissue expander/implants on the therapeutic mastectomy side were explanted despite treatment.ConclusionCareful counselling of patients undergoing elective contralateral prophylactic mastectomy is essential as complications can develop in either breast after reconstruction.     

Leg-length discrepancy and associated risk factors after paediatric femur shaft fracture: a multicentre study

PurposeThis study was performed to investigate leg-length discrepancy (LLD) and associated risk factors after paediatric femur shaft fractures.MethodsA total of 72 consecutive patients under 13 years old (mean age 6.7 years; 48 boys, 24 girls) with unilateral femur shaft fracture, and a minimum follow-up of 18 months, were included. The amount of LLD was calculated by subtracting the length of the uninjured from that of the injured limb. Risk factors for an LLD ≥ 1 cm and ≥ 2 cm were analyzed using multivariable logistic regression analysis.ResultsHip spica casting, titanium elastic nailing and plating were performed on 22, 40 and ten patients, respectively. The mean LLD was 7.8 mm (sd 8.8) and 29 (40.3%) had a LLD of ≥ 1 cm, while nine (12.5%) had a LLD of ≥ 2 cm. There were significant differences in fracture stability (p = 0.005) and treatment methods (p = 0.011) between patients with LLD < 1 cm and ≥ 1 cm. There were significant differences in fracture site shortening (p < 0.001) and LLD (p < 0.001) between patients with length-stable and length-unstable fractures. Fracture stability was the only factor associated with LLD ≥ 1 cm (odds ratio of 4.0; p = 0.020) in the multivariable analysis.ConclusionThis study demonstrated that fracture stability was significantly associated with LLD after paediatric femur shaft fractures. Therefore, the surgeon should consider the possibility of LLD after length-stable femur shaft fracture in children.Level of EvidencePrognostic level III     

Association between Osteoporotic Vertebral Compression Fractures and Age,Bone Mineral Density,and European Quality of Life-5 Dimensions in Korean Postmenopausal Women: A Nationwide Cross-sectional Observational Study

BackgroudThe purpose of this study was to investigate the characteristics of osteoporotic vertebral compression fractures (OVCFs) in Korean postmenopausal women and the association between OVCFs and clinical factors such as age, bone mineral density (BMD), and quality of life.MethodsAccording to the population distribution in four regions in Korea, 1,281 postmenopausal female patients were recruited from nationwide orthopedic outpatient clinics. Radiologic, asymptomatic, and within 3 months of OVCF groups were analyzed based on age, fracture location, and prevalence according to BMD. In addition, BMD, T-score, body mass index, and European Quality of Life-5 Dimensions (EQ-5D) were investigated in the three groups, and the differences between groups were compared and analyzed.ResultsThe prevalence of radiologic OVCFs at the T11–L1 was 3.7 times higher in the 70s group (44.0%) than in the 50s group (11.9%). Femur and total hip BMD were significantly lower in patients with thoracolumbar junction fractures than in patients with L2–5 fractures, whereas no difference was observed in lumbar spine BMD. Of the three OVCF groups, the within 3 months of OVCF group had the lowest lumbar spine T-score of −2.445. The asymptomatic OVCF group also showed significantly lower lumbar spine T-score than did the group without radiologic OVCFs (p < 0.001). The EQ-5D showed a significant decrease in the radiologic OVCF group (p < 0.001) and within 3 months of OVCF group (p < 0.001).ConclusionsThe prevalence of OVCFs in the thoracolumbar junction rapidly increases with old age and low BMD in Korean postmenopausal women. Femur and total hip BMD are more predictive of thoracolumbar junction fractures than lumbar spine BMD. Patients with radiologic OVCFs had a significantly lower quality of life than no OVCF group. Therefore, this study shows it is important to treat and prevent osteoporosis before an OVCF occurs.     

The role of Ureaplasma parvum serovar-3 or serovar-14 infection in female patients with chronic micturition urethral pain and recurrent microscopic hematuria

BackgroundUreaplasma parvum (UP) is commonly isolated in the genitor-urinary tract and may cause various clinical features, including microscopic hematuria (MH). Some UP serovars are more commonly related with specific urogenital disease, but the evidences have been conflicting. This study primarily aimed to research the possible associations between specific UP serotypes and genito-urinary pathogenicity in female patients showing MH with/without chronic micturition urethral pain (CMP).MethodsThis study retrospectively reviewed 276 female patients having MH with/without CMP, who visited health screening center or female infertility clinic. All patients underwent multiplex polymerase chain reaction (PCR) tests with vaginal and urine samples to evaluate the infection rate and serotypes of UP. The antimicrobial susceptibility of UP and the predictors of CMP among UP infected patients were also analyzed. All patients were followed up at least for 6-months.ResultsForty-nine patients (17.8%) showed urinary UP infection. Urinary UP serotyping showed the prevalence of seorvar-1, -3, -6 and -14 were 24.5%, 30.6%, 18.4% and 26.5%, respectively. 79.6% of the urinary UP positive patients accompanied vaginal UP infection. 22 patients of the cohort (8.0%) had CMP whereas serovars-3 and -14 accompanied CMP in 54.5% and 41.0% cases, respectively. No serovars-6 infection case had CMP. 26.4% of the cohort were infertile whereas 10.9% of these infertile patients were positive for urinary tract infection with UP serotype-3 or -14. Doxycycline, josamycin and pristinamycin were the most active antibiotics with the lowest rate of resistance (0.0%) for treating UP. At 1-month post-initial treatment with doxycycline, all UP serotypes were eradicated and no patient complained of urethral discomfort. However, simultaneous urinary and vaginal reinfection of serovar-3 (5 cases) and serovar-5 (1 case) were confirmed at 3-months post-initial doxycycline therapy. The logistic regression analyses revealed that serovars-3 [hazard ratio (HR) 1.354, P value 0.018] and -14 (HR 1.103, P value 0.046) were significantly associated with CMP in female patients having MH.ConclusionsUP serovars-3 and -14 infections could be associated with CMP in female patients having MH. Doxycycline, josamycin and pristinamycin were effective for treating UP. Serovar-3 showed higher reinfection rate than other serotypes after antibiotics treatment.     

A 1993 Status Report on the Health Status of Asian Pacific Islander Americans: Comparisons with Healthy People 2000 Objectives

PURPOSE OF THE PAPER: The purpose of this paper is to offer a current assessment of the health status of Asian Pacific Islander Americans (APIAs) with respect to relevant Healthy People 2000 objectives and an assessment of Federal resource allocations targeted at APIAs. SUMMARY OF METHODS UTILIZED: The author reviewed documents from the relevant progress reports made to the Assistant Secretary on Health on Healthy People 2000 objectives, other Federal documents, and a review of the literature. PRINCIPAL FINDINGS: Adequate progress has been made on only one of the eight objectives targeted at APIAs; progress on the remaining objectives is either "not on target," require more data to evaluate, or inappropriate for APIAs at this time. Examples of APIA health problems not included in Healthy People 2000 objectives were documented. Illustrations of inadequate allocations of Federal health resources were cited. CONCLUSIONS: APIAs have been among the most neglected minority group with regards to health status surveillance, health services, and have been the most overlooked in Federal resource allocations. However, as greater awareness of data deficits and health status is presented, policy makers have the opportunity to improve the situation. A policy to improve the health status of APIAs must be multifaceted and minimally include the facets of data needs, intervention approaches, a research agenda, and advocacy. RELEVANCE TO ASIAN PACIFIC ISLANDER AMERICAN POPULATIONS: A 1993 review of the health status of APIAs with regards to the eight Healthy People 2000 and areas not covered by Healthy People 2000 were reviewed. KEY WORDS: Asian Americans, health status, health policy, health planning, tobacco, diet, diseases     

Differences in Caffeine 3-Demethylation Activity among Inbred Mouse Strains: A Comparison of Hepatic Cyp 1a2 Gene Expression between Two Inbred Strains

The 3-demethylation of caffeine can be used as an index of cytochromeP450 CYP1A2 activity in vivo. We compared the plasma levelsof caffeine and the 3-demethylated metabolite, 1,7-dimethylxanthine,in six common inbred strains (A/J, P/J, BALB/cJ, C3H/HeJ, AKR/J,and SWR/J) and one inbred strain (APN) derived in our laboratoryfrom outbred Swiss-Webster mice on the basis of its relativesusceptibility to acetaminophen-induced hepatotoxicity. We foundsignificant variations between a number of the common strains,all of which produced significantly higher caffeine 3-demethylationindices than our APN strain. In three of the six common strains,there was a significant difference between males and females,with the females having consistently lower 1,7-xanthine/caffeineratios. Hepatic Cyp1a2 expression was compared between APN andC3H/HeJ males. Microsomal methoxyresorufin O-demethylation,acetanilide 4-hydroxylation, and CYP1A2 immunoreactive proteinlevels were significantly higher in C3H/HeJ relative to APNmice, as were hepatic CYP1A2 mRNA levels. These results indicatethe importance of strain and gender to the outcome of pharmacologicalor toxicological studies involving CYP1A2-mediated metabolism,as well as the suitability of the plasma 1,7-dimethylxanthine/caffeineratio as a marker of CYP1A2 activity in the mouse. The strikingdifferences observed between the APN and C3H/HeJ mice suggestthat these strains may be suitable for a genetic analysis ofthe regulation of the basal expression of CYP1A2, a key enzymeIn procarcinogen activation.