Cellular prostatic acid phosphatase (cPAcP) serves as a useful biomarker of histone deacetylase (HDAC) inhibitors in prostate cancer cell growth suppression.

BACKGROUND: Prostate cancer (PCa) is the most commonly diagnosed solid tumor and the second leading cancer death in the United States, and also one of the major cancer-related deaths in Chinese. Androgen deprivation therapy (ADT) is the first line treatment for metastatic PCa. PCa ultimately relapses with subsequent ADT treatment failure and becomes castrate-resistant (CR). It is important to develop effective therapies with a surrogate marker towards CR PCa. METHOD: Histone deacetylase (HDAC) inhibitors were examined to determine their effects in androgen receptor (AR)/cellular prostatic acid phosphatase (cPAcP)-positive PCa cells, including LNCaP C-33, C-81, C4-2 and C4-2B and MDA PCa2b androgen-sensitive and androgen-independent cells, and AR/cPAcP-negative PCa cells, including PC-3 and DU 145 cells. Cell growth was determined by cell number counting. Western blot analyses were carried out to determine AR, cPAcP and PSA protein levels. RESULTS: cPAcP protein level was increased by HDAC inhibitor treatment. Valproic acid, a HDAC inhibitor, suppressed the growth of AR/cPAcP-positive PCa cells by over 50% in steroid-reduced conditions, higher than on AR/cPAcP-negative PCa cells. Further, HDAC inhibitor pretreatments increased androgen responsiveness as demonstrated by PSA protein level quantitation. CONCLUSION: Our results clearly demonstrate that HDAC inhibitors can induce cPAcP protein level, increase androgen responsiveness, and exhibit higher inhibitory activities on AR/cPAcP-positive PCa cells than on AR/cPAcP-negative PCa cells. Upon HDAC inhibitor pretreatment, PSA level was greatly elevated by androgens. This data indicates the potential clinical importance of cPAcP serving as a useful biomarker in the identification of PCa patient sub-population suitable for HDAC inhibitor treatment

Effects of recombinant adenovirus-mediated hypoxia-inducible factor-1alpha gene on proliferation and differentiation of endogenous neural stem cells in rats following intracerebral hemorrhage

AbstractObjectiveTo investigate the effects of adenovirus (Ad)-mediated hypoxia-inducible factor-1alpha (HIF-1α) gene on proliferation and differentiation of endogenous neural stem cells (NSCs) in rats following intracerebral hemorrhage (ICH) and the underlying mechanisms.MethodsA total of 120 specific pathogen-free, adult, male Sprague-Dawley rats were included in this study. After establishment of ICH models in rats, PBS, Ad, or Ad-HIF-1α was administered via the ischemic ventricle. On the 1st, 7th, 14th, 21st and 28th d after ICH, rat neurological deficits were scored, doublecortin (DCX) expression in the subventricular zone cells was detected by immunohistochemical staining, and 5-bromo-2'-deoxyuridine (BrdU)-, BrdU/DCX-, and BrdU/glial fibrillary acidic protein-positive cells in the subventricular zone were counted using immumofluorescence method among PBS, Ad, and Ad-HIF-1α groups.ResultsOn the 7th, 14th, 21st and 28th d after ICH, neurological deficit scores in the Ad-HIF-1α group were significantly lower than in the PBS and Ad groups (P<0.05). In the Ad-HIF-1α group, DCX expression was significantly increased on the 7th d, peaked on the 14th d, and then gradually decreased. In the Ad-HIF-1α group, BrdU-positive cells were significantly increased over time course, and significant difference in BrdU-positive cell counts was observed when compared with the PBS and Ad groups at each time point (P<0.01 or 0.05). On the 7th, 14th, 21st and 28th d after ICH, the number of DCX-, BrdU-, BrdU/DCX-, and BrdU/DCX-positive cells in the Ad-HIF-1α group was significantly greater than in the PBS and Ad groups (P<0.05).ConclusionsHIF-1α gene can promote the proliferation, migration and differentiation of endogenous neural stem cells after ICH, thereby contributing to neurofunctional recovery after ICH

Dissimilarity for functional data clustering based on smoothing parameter commutation.

Many studies measure the same type of information longitudinally on the same subject at multiple time points, and clustering of such functional data has many important applications. We propose a novel and easy method to implement dissimilarity measure for functional data clustering based on smoothing splines and smoothing parameter commutation. This method handles data observed at regular or irregular time points in the same way. We measure the dissimilarity between subjects based on varying curve estimates with pairwise commutation of smoothing parameters. The intuition is that smoothing parameters of smoothing splines reflect the inverse of the signal-to-noise ratios and that when applying an identical smoothing parameter the smoothed curves for two similar subjects are expected to be close. Our method takes into account the estimation uncertainty using smoothing parameter commutation and is not strongly affected by outliers. It can also be used for outlier detection. The effectiveness of our proposal is shown by simulations comparing it to other dissimilarity measures and by a real application to methadone dosage maintenance levels

Histone deacetylase inhibitor valproic acid suppresses the growth and increases the androgen responsiveness of prostate cancer cells.

We identified the molecular target by histone deacetylase (HDAC) inhibitors for exploring their potential prostate cancer (PCa) therapy. Upon HDAC inhibitors-treatment, LNCaP cell growth was suppressed, correlating with increased cellular prostatic acid phosphatase (cPAcP) expression, an authentic protein tyrosine phosphatase. In those cells, ErbB-2 was dephosphorylated, histone H3/H4 acetylation and methylation increased and cyclin proteins decreased. In PAcP shRNA-transfected C-81 cells, valproic acid (VPA) efficacy of growth suppression was diminished. Further, VPA pre-treatment enhanced androgen responsiveness of C-81, C4-2 and MDA PCa2b-AI cells. Thus, cPAcP expression is involved in growth suppression by HDAC inhibitors in PCa cells, and VPA pre-treatments increase androgen responsiveness

Malignant phyllodes tumors display mesenchymal stem cell features and aldehyde dehydrogenase/disialoganglioside identify their tumor stem cells.

IntroductionAlthough breast phyllodes tumors are rare, there is no effective therapy other than surgery. Little is known about their tumor biology. A malignant phyllodes tumor contains heterologous stromal elements, and can transform into rhabdomyosarcoma, liposarcoma and osteosarcoma. These versatile properties prompted us to explore their possible relationship to mesenchymal stem cells (MSCs) and to search for the presence of cancer stem cells (CSCs) in phyllodes tumors.MethodsParaffin sections of malignant phyllodes tumors were examined for various markers by immunohistochemical staining. Xenografts of human primary phyllodes tumors were established by injecting freshly isolated tumor cells into the mammary fat pad of non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice. To search for CSCs, xenografted tumor cells were sorted into various subpopulations by flow cytometry and examined for their in vitro mammosphere forming capacity, in vivo tumorigenicity in NOD-SCID mice and their ability to undergo differentiation.ResultsImmunohistochemical analysis revealed the expression of the following 10 markers: CD44, CD29, CD106, CD166, CD105, CD90, disialoganglioside (GD2), CD117, Aldehyde dehydrogenase 1 (ALDH), and Oct-4, and 7 clinically relevant markers (CD10, CD34, p53, p63, Ki-67, Bcl-2, vimentin, and Globo H) in all 51 malignant phyllodes tumors examined, albeit to different extents. Four xenografts were successfully established from human primary phyllodes tumors. In vitro, ALDH+ cells sorted from xenografts displayed approximately 10-fold greater mammosphere-forming capacity than ALDH- cells. GD2+ cells showed a 3.9-fold greater capacity than GD2- cells. ALDH+/GD2+cells displayed 12.8-fold greater mammosphere forming ability than ALDH-/GD2- cells. In vivo, the tumor-initiating frequency of ALDH+/GD2+ cells were up to 33-fold higher than that of ALDH+ cells, with as few as 50 ALDH+/GD2+ cells being sufficient for engraftment. Moreover, we provided the first evidence for the induction of ALDH+/GD2+ cells to differentiate into neural cells of various lineages, along with the observation of neural differentiation in clinical specimens and xenografts of malignant phyllodes tumors. ALDH+ or ALDH+/GD2+ cells could also be induced to differentiate into adipocytes, osteocytes or chondrocytes.ConclusionsOur findings revealed that malignant phyllodes tumors possessed many characteristics of MSC, and their CSCs were enriched in ALDH+ and ALDH+/GD2+ subpopulations

Exploring Asian Female Pastors\u27 Leadership Roles in the Church: Using Deborah\u27s Story

Women in many Christian cultures are told that men are strong and should lead the church. Consequently, some women rationalize that they should not assume top leadership roles in the church. When they do assume such roles, many female pastors experience challenges. The purpose of our qualitative case study was to give voice to Asian female pastors (AFPs) by having them share challenges they experienced in the Taiwanese Presbyterian Church and relate those challenges to the experiences of Deborah in the biblical story found in Judges 4 and 5. Reported in this paper are the results of focus groups centered on a feminist commentary of Deborah\u27s story. The voices of the AFPs speak to reconstruct traditional patriarchal theological thought