Prospection deficits in patients with first-episode schizophrenia: a cross-sectional comparative study.

Prospection refers to the ability to simulate and pre-experience future events. Schizophrenia patients have difficulty in anticipating pleasure in future events, but previous studies examined prospection deficits in chronic schizophrenia patients. This study aimed to investigate prospection deficits in first-episode schizophrenia patients. Thirty first-episode schizophrenia patients and 31 healthy controls completed the Affective Prospection Task, which utilized pictorial cues to involve positive, neutral and negative prospection. Participants' ratings regarding the phenomenal characteristics of their prospected events were collected, and their prospected narratives were coded using a valid scoring manual. We also assessed intelligence, working memory and logical memory. The results showed, in all participants, valence of the cues significantly influenced participants' sense of pre-experience, temporal distance, emotion experience, vividness and participation of the prospected events, as well as the richness of sensory details. The two groups did not differ in self-report phenomenal characteristics of their prospected events. For coded characteristics, schizophrenia patients' prospected narratives were less rich in thought/emotion than controls, even after controlling for intelligence and memory deficits. We extended empirical evidence for prospection deficits from chronic schizophrenia samples to first-episode schizophrenia patients.

Targeting PIN1 as a Therapeutic Approach for Hepatocellular Carcinoma.

PIN1 is a peptidyl-prolyl cis/trans isomerase that specifically binds and catalyzes the cis/trans isomerization of the phosphorylated serine or threonine residue preceding a proline (pSer/Thr-Pro) motif of its interacting proteins. Through this phosphorylation-dependent prolyl isomerization, PIN1 is involved in the regulation of various important cellular processes including cell cycle progression, cell proliferation, apoptosis and microRNAs biogenesis; hence its dysregulation contributes to malignant transformation. PIN1 is highly expressed in hepatocellular carcinoma (HCC). By fine-tuning the functions of its interacting proteins such as cyclin D1, x-protein of hepatitis B virus and exportin 5, PIN1 plays an important role in hepatocarcinogenesis. Growing evidence supports that targeting PIN1 is a potential therapeutic approach for HCC by inhibiting cell proliferation, inducing cellular apoptosis, and restoring microRNAs biogenesis. Novel formulation of PIN1 inhibitors that increases in vivo bioavailability of PIN1 inhibitors represents a promising future direction for the therapeutic strategy of HCC treatment. In this review, the mechanisms underlying PIN1 over-expression in HCC are explored. Furthermore, we also discuss the roles of PIN1 in HCC tumorigenesis and metastasis through its interaction with various phosphoproteins. Finally, recent progress in the therapeutic options targeting PIN1 for HCC treatment is examined and summarized.

PIN1 in Cell Cycle Control and Cancer.

Cell cycle progression is tightly controlled by many cell cycle-regulatory proteins that are in turn regulated by a family of cyclin-dependent kinases (CDKs) through protein phosphorylation. The peptidyl-prolyl cis/trans isomerase PIN1 provides a further post-phosphorylation modification and functional regulation of these CDK-phosphorylated proteins. PIN1 specifically binds the phosphorylated serine or threonine residue preceding a proline (pSer/Thr-Pro) motif of its target proteins and catalyzes the cis/trans isomerization on the pSer/Thr-Pro peptide bonds. Through this phosphorylation-dependent prolyl isomerization, PIN1 fine-tunes the functions of various cell cycle-regulatory proteins including retinoblastoma protein (Rb), cyclin D1, cyclin E, p27, Cdc25C, and Wee1. In this review, we discussed the essential roles of PIN1 in regulating cell cycle progression through modulating the functions of these cell cycle-regulatory proteins. Furthermore, the mechanisms underlying PIN1 overexpression in cancers were also explored. Finally, we examined and summarized the therapeutic potential of PIN1 inhibitors in cancer therapy.

The peptidyl-prolyl isomerase PIN1 relieves cyclin-dependent kinase 2 (CDK2) inhibition by the CDK inhibitor p27.

PIN1 is a peptidyl-prolyl isomerase that catalyzes the cis/trans isomerization of peptide bonds between proline and phosphorylated serine/threonine residues. By changing the conformation of its protein substrates, PIN1 increases the activities of key proteins that promote cell cycle progression and oncogenesis. Moreover, it has been shown that PIN1 stabilizes and increases the level of the cyclin-dependent kinase (CDK) inhibitor p27, which inhibits cell cycle progression by binding cyclin A- and cyclin E-CDK2. Notwithstanding the associated increase in the p27 level, PIN1 expression promotes rather than retards cell proliferation. To explain the paradoxical effects of PIN1 on p27 levels and cell cycle progression, we hypothesized that PIN1 relieves CDK2 inhibition by suppressing the CDK inhibitory activity of p27. Here, we confirmed that PIN1-expressing cells exhibit higher p27 levels but have increased CDK2 activities and higher proliferation rates in the S-phase compared with Pin1-null fibroblasts or PIN1-depleted hepatoma cells. Using co-immunoprecipitation and CDK kinase activity assays, we found that PIN1 binds the phosphorylated Thr187-Pro motif in p27 and reduces p27's interaction with cyclin A- or cyclin E-CDK2, leading to increased CDK2 kinase activity. In conclusion, our results indicate that although PIN1 increases p27 levels, it also attenuates p27's inhibitory activity on CDK2 and thereby contributes to increased G1-S phase transitions and cell proliferation.

miR-874-3p is down-regulated in hepatocellular carcinoma and negatively regulates PIN1 expression.

PIN1 is a peptidyl-prolyl cis/trans isomerase (PPIase) that regulates multiple signaling pathways to control cell fate and is found to be over-expressed in cancers, including hepatocellular carcinoma (HCC). However, the regulation of PIN1 in HCC remains poorly defined. Micro-RNAs (miRNAs) have been reported to play a pivotal role in oncogenesis by targeting the 3'-untranslated region (UTR) of mRNAs encoded by oncogenes and tumour suppressor genes, thereby suppressing the levels of both oncoproteins and tumour suppressors. In this report, we aimed to identify miRNAs that suppress PIN1 expression and to determine their role in HCC. By searching the TargetScan database, miR-874-3p was identified as a potential negative regulator of PIN1. miR-874-3p was demonstrated to bind the 3'UTR of PIN1 mRNA directly to suppress expression of PIN1. Functionally, over-expression of miR-874-3p in HCC cell line PLC/PRF/5 inhibited cell growth and colony formation in-vitro, and promoted cellular apoptosis. Furthermore, these tumour suppressive functions conferred by miR-874-3p were abrogated by over-expression of PIN1. Similarly, expression of miR-874-3p in PLC/PRF/5 with PIN1 knocked-down did not further suppress cellular proliferation, suggesting that PIN1 was a major target of miR-874-3p. More importantly, miR-874-3p was found to be down-regulated in HCC tissues and its expression was negatively correlated with that of PIN1. Down-regulation of miR-874-3p was also associated with poorly differentiated tumour cells, more advanced staging, and inferior patient outcomes. In addition, over-expression of miR-874-3p suppressed tumour growth in vivo. Taken together, our data suggested that miR-874-3p plays a tumour suppressive role in HCC through down-regulation of PIN1.

Understanding the role of PIN1 in hepatocellular carcinoma.

PIN1 is a peptidyl-prolyl cis/trans isomerase that binds and catalyses isomerization of the specific motif comprising a phosphorylated serine or threonine residue preceding a proline (pSer/Thr-Pro) in proteins. PIN1 can therefore induce conformational and functional changes of its interacting proteins that are regulated by proline-directed serine/threonine phosphorylation. Through this phosphorylation-dependent prolyl isomerization, PIN1 fine-tunes the functions of key phosphoproteins (e.g., cyclin D1, survivin, ß-catenin and x-protein of hepatitis B virus) that are involved in the regulation of cell cycle progression, apoptosis, proliferation and oncogenic transformation. PIN1 has been found to be over-expressed in many cancers, including human hepatocellular carcinoma (HCC). It has been shown previously that overexpression of PIN1 contributes to the development of HCC in-vitro and in xenograft mouse model. In this review, we first discussed the aberrant transcription factor expression, miRNAs dysregulation, PIN1 gene promoter polymorphisms and phosphorylation of PIN1 as potential mechanisms underlying PIN1 overexpression in cancers. Furthermore, we also examined the role of PIN1 in HCC tumourigenesis by reviewing the interactions between PIN1 and various cellular and viral proteins that are involved in ß-catenin, NOTCH, and PI3K/Akt/mTOR pathways, apoptosis, angiogenesis and epithelial-mesenchymal transition. Finally, the potential of PIN1 inhibitors as an anti-cancer therapy was explored and discussed.

Patients with bipolar disorder show differential executive dysfunctions: A case-control study.

Executive deficits in euthymic bipolar I disorder were examined in a fractionated manner based on the "Supervisory Attentional System" (SAS) model, and the relationship between the degree of executive impairment and the demographic and clinical characteristics of bipolar I participants was explored. A battery of neurocognitive tests capturing specific components of executive function was administered on 30 patients with bipolar I disorder in euthymic state, and compared with 30 healthy controls who were matched by age, gender and IQ. A differential impairment in executive function was demonstrated in euthymic bipolar I participants by using a fractionated approach of the SAS. Euthymic bipolar I patients were found to have significantly poorer performance in immediate and delayed visual memory; and in the executive domains of "initiation", "sustained attention", and "attention allocation and planning". Those with a greater number of executive impairments had lower IQ and higher negative sub-scores on PANSS. These findings might provide a the basis for further studies on identifying the executive components that are associated with particular disease characteristics of bipolar disorder, and those with poorer functional outcome, so that rehabilitation can be focused on the selective domains concerned.

PIN1 inhibits apoptosis in hepatocellular carcinoma through modulation of the antiapoptotic function of survivin.

PIN1, a peptidyl-prolyl-isomerase, binds a specific motif comprising a phosphorylated serine or threonine preceding a proline (p-Ser/Thr-Pro) residue in proteins. Through cis-trans isomerization, it induces conformational changes and modulates functions of many proteins that are involved in cell cycle progression, cell proliferation, and oncogenesis. PIN1 is overexpressed in hepatocellular carcinomas (HCC) and contributes to hepatocarcinogenesis. We investigated the role of PIN1 and the significance of its interaction with the inhibitor of apoptosis protein survivin in evading apoptosis in HCC cells. Using cell line and xenograft models, we determined that PIN1 overexpression inhibits apoptosis through suppression of caspase-3 and caspase-9 activity. In addition, down-regulation of survivin in PIN1-overexpressing cells attenuated the antiapoptotic effect induced by PIN1, suggesting that the inhibition of apoptosis is mediated through PIN1-survivin interaction. Coimmunoprecipitation assays showed that PIN1 interacted with survivin via the phosphorylated Thr34-Pro35 motif and enhanced binding among survivin phosphorylated at Thr34, hepatitis B X-interacting protein (HBXIP), and pro-caspase-9. Taken together, these results suggest that the inhibition of apoptosis by PIN1 in HCC cells is mediated through modulation of the antiapoptotic function of survivin by increasing its binding to pro-caspase-9 via HBXIP. Such functional interaction between PIN1 and survivin may therefore play an important role in hepatocarcinogenesis and chemoresistance.

The CDK subunit CKS2 counteracts CKS1 to control cyclin A/CDK2 activity in maintaining replicative fidelity and neurodevelopment.

CKS proteins are evolutionarily conserved cyclin-dependent kinase (CDK) subunits whose functions are incompletely understood. Mammals have two CKS proteins. CKS1 acts as a cofactor to the ubiquitin ligase complex SCF(SKP2) to promote degradation of CDK inhibitors, such as p27. Little is known about the role of the closely related CKS2. Using a Cks2(-/-) knockout mouse model, we show that CKS2 counteracts CKS1 and stabilizes p27. Unopposed CKS1 activity in Cks2(-/-) cells leads to loss of p27. The resulting unrestricted cyclin A/CDK2 activity is accompanied by shortening of the cell cycle, increased replication fork velocity, and DNA damage. In vivo, Cks2(-/-) cortical progenitor cells are limited in their capacity to differentiate into mature neurons, a phenotype akin to animals lacking p27. We propose that the balance between CKS2 and CKS1 modulates p27 degradation, and with it cyclin A/CDK2 activity, to safeguard replicative fidelity and control neuronal differentiation.

Purple acid phosphatase-like sequences in prokaryotic genomes and the characterization of an atypical purple alkaline phosphatase from Burkholderia cenocepacia J2315.

Purple acid phosphatases (PAP) are a group of dimetallic phosphohydrolase first identified in eukaryotes. Bioinformatics analysis revealed 57 prokaryotic PAP-like sequences in the genomes of 43 bacteria and 4 cyanobacteria species. A putative PAP gene (BcPAP) from the bacteria Burkholderia cenocepacia J2315 was chosen for further studies. Synteny analysis showed that this gene is present as an independent gene in most of the members of the genus Burkholderia. The predicted 561 a.a. polypeptide of BcPAP was found to harbour all the conserved motifs of the eukaryotic PAPs and an N-terminal twin-arginine translocation signal. Expression and biochemical characterization of BcPAP in Escherichia coli revealed that this enzyme has a relatively narrow substrate spectrum, preferably towards phosphotyrosine, phosphoserine and phosphoenolpyruvate. Interestingly, this enzyme was found to have a pH optimum at 8.5, rather than an acidic optima exhibited by eukaryotic PAPs. BcPAP contains a dimetallic ion centre composed of Fe and Zn, and site-directed mutagenesis confirmed that BcPAP utilizes the invariant residues for metal-ligation and catalysis. The enzyme is secreted by the wild type bacteria and its expression is regulated by the availability of orthophosphate. Our findings suggest that not all members in the PAP family have acidic pH optimum and broad substrate specificity.

Effect of vardenafil on blood pressure profile of patients with erectile dysfunction concomitantly treated with doxazosin gastrointestinal therapeutic system for benign prostatic hyperplasia.

PURPOSE: We investigated the effect of the combination of the doxazosin gastrointestinal therapeutic system and 10 mg vardenafil on the hemodynamic status of patients with benign prostatic hyperplasia and erectile dysfunction. MATERIALS AND METHODS: This was a double-blinded, randomized, placebo controlled crossover trial. Patients with benign prostatic hyperplasia and erectile dysfunction treated with the doxazosin gastrointestinal therapeutic system on a regular basis, with no other antihypertensive events, were recruited. Subjects took 10 mg vardenafil or placebo in a randomized crossover fashion with a washout period of at least 7 days between each treatment. The supine and standing blood pressure of the subjects was recorded from 1 hour before to 6 hours after the administration of vardenafil or placebo. The primary outcome of the study was the maximal change in standing systolic blood pressure of the subjects from 1 half hour before to 6 hours after the administration of drugs. RESULTS: A total of 37 patients, 25 (67.6%) and 12 (32.4%) on the doxazosin gastrointestinal therapeutic system at 4 mg and 8 mg, respectively, completed the trial. The combination drug therapy resulted in a maximal decrease in standing systolic blood pressure of 6.18 mm Hg (95% CI -12.02, -0.33; p = 0.039). Only 1 patient had an asymptomatic standing systolic blood pressure of less than 85 mm Hg. Otherwise no symptomatic hypotension or clinically significant adverse cardiovascular event was observed during the study. CONCLUSIONS: In patients on the doxazosin gastrointestinal therapeutic system for benign prostatic hyperplasia a single 10 mg dose of vardenafil had no symptomatic hemodynamic effects.

Stabilization of beta-propeller phytase by introducing Xaa-->Pro and Gly-->Ala substitutions at consensus positions.

Phytases play important roles in agricultural and feed industries. In this study, the stability of a beta-propeller phytase, PhyL, from Bacillus licheniformis was successfully improved by introducing Xaa-->Pro and Gly-->Ala substitutions at consensus positions. Our results suggest that Gly-->Ala substitution is a more promising strategy to improve protein stability.

Distribution and diversity of phytate-mineralizing bacteria.

Phytate, the most abundant organic phosphorus compound in soil, dominates the biotic phosphorus input from terrestrial runoffs into aquatic systems. Microbial mineralization of phytate by phytases is a key process for recycling phosphorus in the biosphere. Bioinformatic studies were carried out on microbial genomes and environmental metagenomes in the NCBI and the CAMERA databases to determine the distribution of the four known classes of phytase in the microbial world. The beta-propeller phytase is the only phytase family that can be found in aquatic environments and it is also distributed in soil and plant bacteria. The beta-propeller phytase-like genes can be classified into several subgroups based on their domain structure and the positions of their conserved cysteine residues. Analysis of the genetic contexts of these subgroups showed that beta-propeller phytase genes exist either as an independent gene or are closely associated with a TonB-dependent receptor-like gene in operons, suggesting that these two genes are functionally linked and thus may play an important role in the cycles of phosphorus and iron. Our work suggests that beta-propeller phytases play a major role in phytate-phosphorus cycling in both soil and aquatic microbial communities.

Pathway of phytate dephosphorylation by beta-propeller phytases of different origins.

Using a combination of high-performance ion chromatography analysis and kinetic studies, the pathway of myo-inositol hexakisphosphate dephosphorylation by the beta-propeller phytase of Shewanella oneidensis was established, which was then compared with that of Bacillus subtilis 168, Bacillus amyloliquefaciens ATCC 15841, and B. amyloliquefaciens 45 beta-propeller phytases. The data demonstrate that all of these beta-propeller phytases dephosphorylate myo-inositol hexakisphosphate in a stereospecific way by sequential removal of phosphate groups via d-Ins(1,2,4,5,6)P5, Ins(2,4,5,6)P4 to finally Ins(2,4,6)P3. Thus, the beta-propeller phytases prefer the hydrolysis of every second phosphate over that of adjacent ones. This finding does not support previous phytate degradation models proposed by J. Kerovuo, J. Rouvinen, and F. Hatzack (2000. Biochem. J. 352: 623-628) and R. Greiner, A. Farouk, M. Larsson Alminger, and N.G. Carlsson (2002. Can. J. Microbiol. 48: 986-994), but seems to fit with the structural model given by S. Shin, N.C. Ha, B.C. Oh, T.K. Oh, and B.H. Oh (2001. Structure, 9: 851-858).

The effect of disulfide bond on the conformational stability and catalytic activity of beta-propeller phytase.

While beta-propeller phytases (BPPs) from Gram-positive bacteria do not carry disulfide bonding, their counterparts from Gram-negative bacteria contain cysteine residues that may form disulfide bonds. By molecular modeling, two amino acid residues of B. subtilis 168 phytase (168PhyA), Ser-161 and Leu-212, were mutated to cysteine residues. Although the double cysteine mutant was secreted from B. subtilis at an expression level that was 3.5 times higher than that of the wild type, the biochemical and enzymatic properties were unaltered. In CD spectrometric analysis, both enzymes exhibited similar apparent melting temperatures and mid-points of transition under thermal and guanidine hydrochloride induced denaturation, respectively. In enzyme assays, the mutant phytase exhibited a poor refolding ability after thermal denaturation. We postulate that the disulfide bond in BPP sequences from Gram-negative bacteria is beneficial to their stability in the periplasmic compartment. In contrast, the lack of periplasmic space in Bacillus species and the fact that Bacillus BPPs are released extracellularly may render disulfide bonds unnecessary. This may explain why in evolution, BPPs in Bacillus species do not carry disulfide bonds.

Undifferentiated sex cord-stromal tumor in a young adult.

Undifferentiated sex cord-stromal tumor in post-puberty male is extremely rare. There were only three reported cases in the literature. We reported a 19-year-old patient presented with an asymptomatic right testicular nodule with normal level of serum marker for germ cell tumor. Excisional biopsy and subsequent orchidectomy was preformed and the final pathology supported the diagnosis of undifferentiated sex cord-stromal tumor. He was then put on regular surveillance with no adjuvant therapy given. He remained disease free 18 months after the operation. A summary of the literatures and discussion on the management of this rare tumor was provided.

Use of the University of California Los Angeles Integrated Staging System (UISS) to predict survival in localized renal cell carcinoma in an Asian population.

OBJECTIVES: To evaluate the applicability of the University of California Los Angeles Integrated Staging System (UISS) in predicting the prognosis of Chinese patients with localized renal cell carcinoma after radical nephrectomy, with reference to that reported by Patard et al in an international multicenter study (J Clin Oncol 2004, 22:3316-3322). METHODOLOGY: One hundred and twenty-eight Chinese patients with localized renal cell carcinoma were stratified into low risk (LR), intermediate risk (IR) and high risk (HR) groups according to the UISS, based on the TMN staging and Fuhrman grading of the tumor and the Eastern Cooperative Oncology Group performance status of the patients. The survival curves of each risk group were then calculated. RESULTS: The number of patients in the LR, IR and HR was 24 (18.8%), 94 (73.4%) and 10 (7.8%) respectively. The estimated 2-year survival rates were 100%, 89.9% and 100% for the LR, IR and HR groups respectively. Whereas the estimated 5-year survival rates were 93.3%, 72.4% and 80% for the LR, IR and HR groups respectively. The LR and IR patients had comparable 2-year and 5-year estimated survival rates with those reported by Patard et al. However, the estimated survival rate for HR patients was better than that reported. CONCLUSIONS: UISS provided a valuable tool in predicting the survival of Chinese patients with localized renal cell carcinoma of LR and IR groups, as reported in other international centers. Further large scale study may be needed to confirm the applicability in HR population.

Breast metastasis from prostate cancer and interpretation of immunoreactivity to prostate-specific antigen.

A case of prostate cancer metastasized to the breast is presented, the latter being prostate-specific antigen (PSA) positive. This is the first of such cases reported in Hong Kong and China in the English literature. As PSA expression also can be found in primary breast cancer, prostatic acid phosphatase staining was employed to confirm the diagnosis. The relationship of PSA and non-prostatic tissues is reviewed. The differential diagnosis of breast enlargement in patients known to have prostate malignancy also is discussed.

Beta-propeller phytases in the aquatic environment.

Phytate, which is one of the dominant organic phosphorus compounds in nature, is very stable in soils. Although a substantial amount of phytate is carried from terrestrial to aquatic systems, it is a minor component of organic phosphorus in coastal sediments. The ephemeral nature of phytate implies the rapid hydrolysis of phytate under aquatic conditions. Among the four classes of known phytases that have been identified in terrestrial organisms, only beta-propeller phytase-like sequences have been identified in the aquatic environment. A novel beta-propeller phytase gene (phyS), cloned from Shewanella oneidensis MR-1, was found to encode a protein with two beta-propeller phytase domains. The characterization of recombinant full-length PhyS and its domains demonstrated that Domain II was the catalytic domain responsible for phytate hydrolysis. The full-length PhyS displayed a K(m) of 83 microM with a kcat of 175.9 min(-1) and the Domain II displayed a K(m) of 474 microM with a kcat of 10.6 min(-1). These results confirm that the phyS gene encodes a functional beta-propeller phytase, which is expressed in S. oneidensis under phosphorus deficient condition. The presence of multiple sequences with a high similarity to phyS in aquatic environmental samples and the widespread occurrence of the Shewanella species in nature suggest that the beta-propeller phytase family is the major class of phytases in the aquatic environment, and that it may play an important role in the recycling of phosphorus.