Disease-related complications in patients with metastatic hormone-sensitive prostate cancer.

INTRODUCTION: Prostate-specific antigen-based screening for prostate cancer reportedly does not improve cancer-specific survival. However, there remain concerns about the increasing incidence of advanced disease at initial presentation. Here, we investigated the incidences and types of complications that occur during the course of disease in patients with metastatic hormone-sensitive prostate cancer (mHSPC). METHODS: This study included 100 consecutive patients who were diagnosed with mHSPC at five hospitals from January 2016 to August 2017. Analyses were conducted using patient data extracted from a prospectively collected database, along with information about complications and readmission obtained from electronic medical records. RESULTS: The median patient age was 74 years and the median serum prostate-specific antigen level at diagnosis was 202.5 ng/mL. Ninety-nine patients received androgen deprivation therapy; 17 of these patients also received chemotherapy. During a mean follow-up period of 32.9 months, 41 patients reported bone pain; of these patients, 21 developed pathologic fractures and eight had cord compression. Twenty-eight patients developed retention of urine; of these patients, 10 (36%) required surgery and 11 (39%) required long-term urethral catheter use. Among 15 patients who developed ureteral obstruction, four (27%) required ureteral stenting and four (27%) required long-term nephrostomy drainage. Other complications included anaemia (41%) and deep vein thrombosis (4%). Fifty-nine (59%) patients had ≥1 unplanned hospital admission during the course of disease; 16% of such patients had >5 episodes of readmission. CONCLUSION: Among patients with mHSPC, 70% experienced disease-related complications and unplanned hospital admissions, which substantially burdened both patients and the healthcare system.

Outcomes of transperineal and transrectal ultrasound-guided prostate biopsy.

OBJECTIVE: To compare the clinical outcomes and pathological findings of transperineal ultrasound-guided prostate biopsy (TPUSPB) and transrectal ultrasound-guided prostate biopsy (TRUSPB) in a secondary referral hospital. METHODS: This was a retrospective study of 100 TPUSPBs and 100 TRUSPBs performed in our centre. Pre-biopsy patient parameters (eg, patient age, clinical staging, serum prostate-specific antigen [PSA] level, prostate size, and PSA density), as well as pathological results and 30-day complication and readmission rates, were retrieved from the patients' medical records and compared between the two groups. RESULTS: One hundred TPUSPBs performed from January 2018 to May 2018 and 100 TRUSPBs performed from January 2016 to April 2016 were included for analysis. Mean age did not significantly differ between the groups. The TPUSPB group had a higher mean PSA level, smaller prostate size, and higher PSA density, compared with the TRUSPB group. The overall prostate cancer detection rate was similar between the TPUSPB and TRUSPB groups (35% vs 25%, P=0.123). There were no significant differences between the groups in prostate cancer detection rates after stratification according to PSA density and clinical staging. With respect to complications, no patients developed fever in the TPUSPB group, while 4% of patients in the TRUSPB group had fever and required at least 1-week admission for intravenous antibiotic administration. CONCLUSION: For prostate biopsy, TPUSPB is safer, with no infection complications, and has similar prostate cancer detection rate compared with TRUSPB.

Intracerebroventricular delivery of self-complementary adeno-associated virus serotype 9 to the adult rat brain.

Gene therapy for the central nervous system is poised to become a powerful treatment for numerous neurological disorders. Adeno-associated viral vectors based on serotype 9 (AAV9) have proven themselves to be strong candidates for delivering gene-based therapies throughout the brain and spinal cord when administered intravenously, intrathecally, intracisternally, and intracerebroventricularly (i.c.v.). Previous studies of i.c.v.-delivered self-complimentary AAV9 have been performed in neonatal mice with delivery of a single dose. However, before clinical trials can be considered, more information is required about the dose-response relationship for transduction efficiency in adult animals. In the current study, three doses of self-complementary AAV9 were administered to adult rats. High levels of transduction were observed in the hippocampus, cerebellum and cerebral cortex, and transduction increased with increasing dosage. Both neurons and astrocytes were transduced. There was no evidence of astrocytosis at the doses tested. Preliminary results from pigs receiving i.c.v. self-complementary AAV9 are also presented. The results of this study will serve to inform dosing studies in large animal models before clinical testing.

Effect of remote ischemic conditioning on the immune-inflammatory profile in patients with traumatic hemorrhagic shock in a randomized controlled trial.

Resuscitation induced ischemia/reperfusion predisposes trauma patients to systemic inflammation and organ dysfunction. We investigated the effect of remote ischemic conditioning (RIC), a treatment shown to prevent ischemia/reperfusion injury in experimental models of hemorrhagic shock/resuscitation, on the systemic immune-inflammatory profile in trauma patients in a randomized trial. We conducted a prospective, single-centre, double-blind, randomized, controlled trial involving trauma patients sustaining blunt or penetrating trauma in hemorrhagic shock admitted to a Level 1 trauma centre. Patients were randomized to receive RIC (four cycles of 5-min pressure cuff inflation at 250 mmHg and deflation on the thigh) or a Sham intervention. The primary outcomes were neutrophil oxidative burst activity, cellular adhesion molecule expression, and plasma levels of myeloperoxidase, cytokines and chemokines in peripheral blood samples, drawn at admission (pre-intervention), 1 h, 3 h, and 24 h post-admission. Secondary outcomes included ventilator, ICU and hospital free days, incidence of nosocomial infections, 24 h and 28 day mortality. 50 eligible patients were randomized; of which 21 in the Sham group and 18 in the RIC group were included in the full analysis. No treatment effect was observed between Sham and RIC groups for neutrophil oxidative burst activity, adhesion molecule expression, and plasma levels of myeloperoxidase and cytokines. RIC prevented significant increases in Th2 chemokines TARC/CCL17 (P < 0.01) and MDC/CCL22 (P < 0.05) at 24 h post-intervention in comparison to the Sham group. Secondary clinical outcomes were not different between groups. No adverse events in relation to the RIC intervention were observed. Administration of RIC was safe and did not adversely affect clinical outcomes. While trauma itself modified several immunoregulatory markers, RIC failed to alter expression of the majority of markers. However, RIC may influence Th2 chemokine expression in the post resuscitation period. Further investigation into the immunomodulatory effects of RIC in traumatic injuries and their impact on clinical outcomes is warranted.ClinicalTrials.gov number: NCT02071290.

Comparative in vitro cytotoxicity study on uncoated magnetic nanoparticles: effects on cell viability, cell morphology, and cellular uptake.

Magnetic iron oxide nanoparticles (MIONPs) must be biocompatible, and a thorough knowledge on their potential cytotoxicity is crucial for their biomedical applications. However, the detailed study about the effects of iron oxide nanoparticles on cell viability, cell morphology, and cellular uptake of different mammalian cells is still insufficient. In this paper, comparative cytotoxicity study of uncoated magnetite nanoparticles at different concentrations was performed on human cervical cancer cell line (HeLa) and immortalized normal human retinal pigment epithelial cell line (RPE). The size, structure, and magnetic behavior of the MIONPs were characterized using transmission electron microscopy (TEM), X-ray diffractometry (XRD), and vibrating sample magnetometry (VSM) respectively. After 24-hour incubation with the MIONPs, the cell viability was determined by live/dead assay, the cell morphology at high magnification was observed under scanning electron microscopy (SEM), and the cellular uptake of MIONPs was measured under TEM and verified by energy-dispersive X-ray spectroscopy (EDX) analysis. Our results indicate that the uncoated MIONPs at a high concentration (0.40 mg/ml) were toxic to both HeLa and RPE cells. However, the cytotoxicity of uncoated MIONPs at low concentrations was cell-type specific, and RPE cells were more susceptible to these MIONPs than HeLa cells. The effects of the MIONPs on cell morphology and the nanoparticles uptake also showed different features between these two cell lines. Hence cell type should be taken into consideration in the in vitro cytotoxicity study of uncoated MIONPs. Additionally, it should be noticed that the cell morphological changes and the uptake of nanoparticles can take place even though no toxic effect of these MIONPs at low concentrations was reflected in the traditional cell viability assay.

Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1.

Histone deacetylases (HDACs) 1 and 2 share a high degree of homology and coexist within the same protein complexes. Despite their close association, each possesses unique functions. We show that the upregulation of HDAC2 in colorectal cancer occurred early at the polyp stage, was more robust and occurred more frequently than HDAC1. Similarly, while the expression of HDACs1 and 2 were increased in cervical dysplasia and invasive carcinoma, HDAC2 expression showed a clear demarcation of high-intensity staining at the transition region of dysplasia compared to HDAC1. Upon HDAC2 knockdown, cells displayed an increased number of cellular extensions reminiscent of cell differentiation. There was also an increase in apoptosis, associated with increased p21Cip1/WAF1 expression that was independent of p53. These results suggest that HDACs, especially HDAC2, are important enzymes involved in the early events of carcinogenesis, making them candidate markers for tumor progression and targets for cancer therapy.

Management of spinal injury.

Spinal injury often affects young adults and results in debilitating neurological status, which in turn places a significant burden on society. This review article describes the current practice and controversies surrounding the management of spinal injury. General principles of pre-hospital management, resuscitation, medical treatment, surgical intervention and future advancement are reviewed.

Validation of the Hong Kong Cantonese Version of World Health Organization Five Well-Being Index for People with Severe Mental Illness.

OBJECTIVE: The World Health Organization Five Well-Being Index (WHO-5) has been developed to measure psychological wellbeing. Translation and linguistic validation of the WHO-5 into a Cantonese version has been accomplished for local use but it is not yet validated in people with severe mental illness in Hong Kong. This study aimed to examine the applicability of WHO-5 in measuring the psychological wellbeing dimension of people with severe mental illness. A brief and easily administrated tool to measure psychological wellbeing of people with severe mental illness can be used to provide an outcome measure in research studies and clinical trials. METHODS: Subjects were randomly recruited from the Extended-Care Patient Intensive Treatment, Early Diversion and Rehabilitation Stepping-Stone Project (EXITERS) and the Rehabilitation Activity Centre (RAC) of Kwai Chung Hospital in Hong Kong. They were invited to complete the abbreviated version of Hong Kong Chinese World Health Organization Quality of Life (WHOQOL-BREF [HK]) and WHO-5 (Cantonese version) separately and concurrent validity was examined. RESULTS: A total of 84 subjects were recruited, 42 each from EXITERS and RAC. In all, 49 (58%) were male and 35 (42%) were female. The mean ± standard deviation age was 43.2 ± 9.7 years. Their mean duration of mental illness was 16.4 ± 10.5 years and the mean years of education was 10.17 ± 2.5 years, i.e. about junior secondary school level in Hong Kong. The internal consistency of the WHO-5 was satisfactory (0.86) and was comparable with previous reports. Regarding validity, 1-factor structure with an eigenvalue of 3.24 explained 64.8% of total variance of WHO-5 for people with severe mental illness. Concurrent validity was established with moderate correlation (0.41-0.51) between WHO-5 and 4 domains of the WHOQOL-BREF (HK). CONCLUSION: The WHO-5 (Cantonese version) is a reliable and valid tool to assess the psychological wellbeing of people with severe mental illness in Hong Kong. It can be used to monitor the effectiveness of psychological intervention aimed at improving the wellbeing of such patients.

Epidermal growth factor induces Gadd45 (growth arrest and DNA damage inducible protein) expression in A431 cells.

Epidermal growth factor (EGF) receptor over-expressing, p53-deficient A431 cells response to toxic dose of EGF by G1 arrest and apoptosis. Applying cDNA expression array technology we demonstrated that EGF increased the levels of Gadd45 mRNA. Northern blot and Western blot analyses confirmed that both Gadd45 mRNA and protein were increased. Concurrently half-lives of Gadd45 mRNA and protein also increased. Nuclear run-on experiments did not show a large increase of Gadd45 mRNA transcription rate. Gadd45 mRNA and protein started to increase after 1 h of EGF treatment and remained high for up to 10 h. We have also confirmed previous studies which showed that in EGF-stimulated A431 cells p21(Cip1/Waf1) (cyclin-dependent kinase interacting protein 1) was up-regulated within the same time frame. Thus it appears that in addition to inducing G2 arrest by directly disrupting Cdc2/Cyclin B1 complex in genotoxic-stressed cells, Gadd45 may also participate in G1 arrest in growth factor overexposed cells.

Characterization and regulation of a mRNA encoding the prostaglandin F2alpha receptor in the rat ovary.

The recent cloning of several cDNAs encoding prostaglandin (PG) receptors has paved the way for a more detailed investigation of the postulated regulatory role of prostaglandins in corpus luteum function. We have utilized the reverse transcription-polymerase chain reaction (RT-PCR) to isolate a mRNA encoding the ovarian PGF(2alpha) (FP) receptor, using oligonucleotides based on the recently cloned mouse cDNA as primers. The 5'-untranslated region of the rat ovarian mRNA was isolated following 5'-RACE (rapid amplification of cDNA ends). The isolated 1526 base-pair sequence, which spans the entire open reading frame, was found 100% identical in the protein coding region to a similar sequence isolated from a rat astrocyte cDNA library, but different in the first 32 nucleotides of the 5'-untranslated region, possibly due to tissue-specific splicing heterogeneity. Using ribonuclease protection assay, a quantitative analysis of FP receptor mRNA levels was performed in corpora lutea excised from adult pseudopregnant rats (Day 8) at different timepoints (0.5-48 h) following the in vivo s.c. regimen of a luteolytic dose of the FP receptor agonist cloprostenol (5 microg). Already 3 h after cloprostenol injection, FP receptor mRNA levels exhibited a pronounced increase to values 4.0-fold higher (P < 0.01) than before injection. At 7 h through 24 h, the amount of luteal FP receptor mRNA decreased, approaching preinjection levels, whereafter they were again 3.0-fold higher (P < 0.01) at 48 h than before injection. We conclude that following homologous stimulation of the FP receptor, abundance of this mRNA is tissue-specifically regulated in a dynamic pattern, suggestive of an important role for FP receptor-mediated action on gene expression during the demise of corpus luteum function.

Rapid detection of the mecA gene in methicillin resistant staphylococci using a colorimetric cycling probe technology.

A Cycling Probe Technology (CPT) assay was developed for the detection of the mecA gene from methicillin resistant staphylococcal cultures. The assay is based on a colorimetric enzyme-immuno-assay (EIA) and uses a mecA probe (DNA-RNA-DNA) labeled with fluorescein at the 5'-terminus and biotin at the 3'-terminus. The reaction occurs at a constant temperature that allows the target DNA to anneal to the probe. RNase H cuts the RNA portion, allowing the cut fragments to dissociate from the target, making it available for further cycling. CPT-EIA uses streptavidin-coated microplate wells to capture uncut probe followed by detection with horseradish-peroxidase conjugated anti-fluorescein antibody. The assay was compared to PCR and shown to accurately detect the presence or absence of the mecA gene in 159 staphylococcal clinical isolates. The CPT-EIA assay takes two hours starting from cultured cells compared with the 24-48 h required for detection of methicillin resistance by conventional susceptibility tests.

Neurochemical changes in ventilated head-injured patients with cerebral perfusion pressure treatment failure.

The goal of intensive care management of patients with head injury is to provide them with a favourable physiological and metabolic environment for recovery of injury-compromised cells, and to prevent secondary brain insults. Clinical intracerebral microdialysis has enabled documentation of the metabolic derangement after head injury. Treatment targeted at this derangement has emphasized maintenance of optimal cerebral perfusion pressure (CPP). To determine the relationships between CPP and five clinically relevant intracerebral extracellular metabolites (glucose, lactate, glycerol, glutamate and pyruvate) in relation to different therapy intensities, 23 moderate to severe head-injury patients with hourly microdialysis samples were studied. These five metabolites were correlated with CPP and showed a biphasic relation at CPP of 65 to 67 mmHg, which was believed to be the critical CPP indicating irreversible brain damage. Relationship between intracerebral metabolites and CPP in relation to different therapy intensities was studied and suggests the critical CPP threshold in head-injured patients with high ICP and maximum therapy is elevated and should be maintained above 70 mmHg to prevent irreversible brain damage.

Spinal cord pilocytic astrocytoma with cranial meningeal metastases.

Dissemination of tumour cells along the cerebrospinal fluid (CSF) pathway has been reported mostly in medulloblastomas, germ cell tumours or high grade gliomas. Juvenile pilocytic astrocytoma (JPA) is usually a benign astrocytoma. However, drop metastases of indolent nature from intracranial tumours to the spinal cord are documented. All of the previously reported cases represent metastases of cerebellar or hypothalamic tumours spreading to the spinal cord. We document in this paper the first report of a spinal cord pilocytic astrocytoma spreading via the CSF to the cerebral meninges. A 9 year old girl had a JPA of C5 to C7 subtotally resected. Two and a half years later she presented with hydrocephalus with radiologically meningeal enhancement. The meninges were biopsied which showed metastatic JPA. The girl was relatively well 4 years after initial surgery with residual tumour. Spinal cord JPA can rarely metastasize to the cranial meninges. Similar to intracranial tumours which spread to the spinal cord, such metastatic lesions are indolent.

The comparative impact of video-consultation on neurosurgical health services.

This study evaluated the impact of telemedicine technology on the provision of neurosurgical health services. We focused on the differences between the use of real time audio-visual teleconferencing and teleradiology versus conventional telephone consultations in the referral of neurosurgical patients from a large district general hospital. All patients requiring emergency neurosurgical consultation were included for randomization into telephone consultation only (Mode A), teleradiology and telephone consultation (Mode B) and video-consultation (Mode C). Measures of effectiveness included diagnostic accuracy and adverse events during the transfer and Glasgow Outcome Score. In a 10-month period, 327 patients were recruited and randomized into the study: the male/female ratio was 2:1 and the number of patients required to be transferred to the neurosurgical unit was 125 (38%). There was a trend towards a more favourable outcome in the video-consultation mode (44%, Mode C), versus teleradiology (31%, Mode B), versus telephone consultation (38%, Mode A). The interim data of this prospective randomized trial suggests that video-consultation may have a favourable impact on emergency neurosurgical consultations.

Matching of complex patterns by energy minimization.

Two patterns are matched by putting one on top of the other and iteratively moving their individual parts until most of their corresponding parts are aligned. An energy function and a neighborhood of influence are defined for each iteration. Initially, a large neighborhood is used such that the movements result in global features being coarsely aligned. The neighborhood size is gradually reduced in successive iterations so that finer and finer details are aligned. Encouraging results have been obtained when applied to match complex Chinese characters. It has been observed that computation increases with the square of the number of moving parts which is quite favorable compared with other algorithms. The method was applied to the recognition of handwritten Chinese characters. After performing the iterative matching, a set of similarity measures are used to measure the similarity in topological features between the input and template characters. An overall recognition rate of 96.1% is achieved.

Identification of a natural product-like STAT3 dimerization inhibitor by structure-based virtual screening.

STAT3 regulates a variety of genes involved with cell proliferation, differentiation, apoptosis, angiogenesis, metastasis, inflammation, and immunity. The purpose of this study was to apply molecular docking techniques to identify STAT3 inhibitors from a database of over 90000 natural product and natural product-like compounds. The virtual screening campaign furnished 14 hit compounds, from which compound 1 emerged as a top candidate. Compound 1 inhibited STAT3 DNA-binding activity in vitro and attenuated STAT3-directed transcription in cellulo with selectivity over STAT1 and with comparable potency to the well-known STAT3 inhibitor S3I-201. Furthermore, compound 1 inhibited STAT3 dimerization and decreased STAT3 phosphorylation in cells without affecting STAT1 dimerization and phosphorylation. Compound 1 also exhibited selective anti-proliferative activity against cancer cells over normal cells in vitro. Molecular docking analysis suggested that compound 1 might putatively function as an inhibitor of STAT3 dimerization by binding to the SH2 domain. This study also validates the use of in silico techniques to identify inhibitors of protein-protein interactions, which are typically considered difficult to target with small molecules.

A cyclometallated iridium(III) complex as a c-myc G-quadruplex stabilizer and down-regulator of c-myc oncogene expression.

A new cyclometallated iridium(III) complex with the 2,2'-biquinoline N-donor ligand has been synthesized and characterized. The interaction and affinity of the complex towards c-myc G-quadruplex and duplex DNA have been investigated using UV/Vis spectroscopy and gel mobility shift assay. These studies revealed that complex 1 binds to c-myc G-quadruplexes (Pu22 and Pu27) with high affinity but does not interact with duplex DNA either by intercalation or groove binding. The ability of 1 to stabilize c-myc G-quadruplex DNA in vitro has also been examined through a PCR stop assay and a cell-based luciferase reporter assay. Complex 1 displays promising cytotoxic activity against the HeLa cell line with sub-micromolar potency.

PRAP1 is a novel executor of p53-dependent mechanisms in cell survival after DNA damage.

p53 has a crucial role in governing cellular mechanisms in response to a broad range of genotoxic stresses. During DNA damage, p53 can either promote cell survival by activating senescence or cell-cycle arrest and DNA repair to maintain genomic integrity for cell survival or direct cells to undergo apoptosis to eliminate extensively damaged cells. The ability of p53 to execute these two opposing cell fates depends on distinct signaling pathways downstream of p53. In this study, we showed that under DNA damage conditions induced by chemotherapeutic drugs, gamma irradiation and hydrogen peroxide, p53 upregulates a novel protein, proline-rich acidic protein 1 (PRAP1). We identified functional p53-response elements within intron 1 of PRAP1 gene and showed that these regions interact directly with p53 using ChIP assays, indicating that PRAP1 is a novel p53 target gene. The induction of PRAP1 expression by p53 may promote resistance of cancer cells to chemotherapeutic drugs such as 5-fluorouracil (5-FU), as knockdown of PRAP1 increases apoptosis in cancer cells after 5-FU treatment. PRAP1 appears to protect cells from apoptosis by inducing cell-cycle arrest, suggesting that the induction of PRAP1 expression by p53 in response to DNA-damaging agents contributes to cancer cell survival. Our findings provide a greater insight into the mechanisms underlying the pro-survival role of p53 in response to cytotoxic treatments.