Prostate cancer: a presentation of clinicopathologic prognosticators among Filipino and American men at radical prostatectomy / 亚洲男科学杂志(英文版)

Lower incidence and mortality rates from prostate cancer (PCa) have been shown in Asian men in general compared to Westerners. This is the first study detailing the clinicopathologic features of resected prostate cancer in Filipino men living in the Philippines (PH). This study investigated the supposed "lower risk" Filipino and "higher risk" American PCa patients from the PH and the United States of America (USA), respectively. We examined 348 (176 from PH, 172 from USA) radical prostatectomy cases. The clinicopathologic features of both groups (age at time of diagnosis, preoperative prostate-specific antigen [pre-op PSA] level, Gleason score [GS], Grade groups [GG], margin involvement, extraprostatic extension [EPE], seminal vesicle invasion [SVI], and regional lymph node [RLN] metastasis) were compared. Six of seven prognosticators examined were more strongly associated with Filipinos than with Americans. Filipinos were older at diagnosis (PH: 64.32 ± 6.56 years vs USA: 58.98 ± 8.08 years) and had higher pre-op PSA levels (PH: 21.39 ± 46.40 ng ml

Elastohydrodynamic lubricant flow with nanoparticle tracking.

Lubricants operating in elastohydrodynamic (EHD) contacts exhibit local variations in rheological properties when the contact pressure rises. Direct evidence of this behaviour has only been obtained by examining through-thickness velocity profiles U(z) of lubricants in a contact using luminescence-based imaging velocimetry. In the present study, nanoparticles (NPs) are added to polybutene (PB) as tracers to investigate the effect of pressure on the flow of PB in an EHD contact. By tracking NPs in the contact, particle velocity distributions f(U) under various pressures are obtained and found to be pressure dependent. Results show quantitatively that f(U) and U(z) are correlated and thus confirm that U(z) of PB changes from Couette flow to partial plug flow above a critical pressure. This confirmation highlights the complexity of lubricant rheology in a high pressure contact.

The Role of Consolidation Chemoradiotherapy in Locally Advanced Pancreatic Cancer Receiving Chemotherapy: An Updated Systematic Review and Meta-Analysis / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The role of consolidation chemoradiation (CCRT) after systemic chemotherapy in locally advanced pancreatic cancer (LAPC) is still controversial. We aim to evaluate the effectiveness of CCRT in LAPC using systematic review and meta-analysis of prospective studies. MATERIALS AND METHODS: Prospective clinical trials of LAPC receiving chemotherapy with or without subsequent CCRT were included in the analysis. We systematically searched in PubMed, MEDLINE, Embase, and Web of Science. The primary outcome of interest was 1-year survival. Secondary end-points were median overall survival, progression-free survival, toxicity, and resection rate. RESULTS: Forty-one studies with 49 study arms were included with a total of 1,018 patients receiving CCRT after induction chemotherapy (ICT) and 954 patients receiving chemotherapy alone. CCRT after ICT did not improve 1-year survival significantly in LAPC patients compared with chemotherapy alone (58% vs. 52%). ICT lasted for at least 3 months revealed significantly improved survival of additional CCRT to LAPC patients compared to chemotherapy alone (65% vs. 52%). A marginal survival benefit of consolidation CCRT was noted in studies using maintenance chemotherapy (59% vs. 52%), and fluorouracil-based CCRT (64% vs. 52%), as well as in studies conducted after the 2010 (64% vs. 55%). CONCLUSION: The survival benefit of ICT+CCRT over chemotherapy alone in treating LAPC was noted when ICT lasted for at least 3 months. Fluorouracil-based CCRT, and maintenance chemotherapy were associated with improved clinical outcomes.

The Effect of Antidepressants on Mesenchymal Stem Cell Differentiation

BACKGROUND: Use of antidepressant medications has been linked to detrimental impacts on bone mineral density and osteoporosis; however, the cellular basis behind these observations remains poorly understood. The effect does not appear to be homogeneous across the whole class of drugs and may be linked to affinity for the serotonin transporter system. In this study, we hypothesized that antidepressants have a class- and dose-dependent effect on mesenchymal stem cell (MSC) differentiation, which may affect bone metabolism. METHODS: Human MSCs (hMSCs) were committed to differentiate when either adipogenic or osteogenic media was added, supplemented with five increasing concentrations of amitriptyline (0.001–10 µM), venlafaxine (0.01–25 µM), or fluoxetine (0.001–10 µM). Alizarin red staining (mineralization), alkaline phosphatase (osteoblastogenesis), and oil red O (adipogenesis) assays were performed at timed intervals. In addition, cell viability was assessed using a MTT. RESULTS: We found that fluoxetine had a significant inhibitory effect on mineralization. Furthermore, adipogenic differentiation of hMSC was affected by the addition of amitriptyline, venlafaxine, and fluoxetine to the media. Finally, none of the tested medications significantly affected cell survival. CONCLUSIONS: This study showed a divergent effect of three antidepressants on hMSC differentiation, which appears to be independent of class and dose. As fluoxetine and amitriptyline, but not venlafaxine, affected both osteoblastogenesis and adipogenesis, this inhibitory effect could be associated to the high affinity of fluoxetine to the serotonin transporter system.

Engineering of Anti-CD133 Trispecific Molecule Capable of Inducing NK Expansion and Driving Antibody-Dependent Cell-Mediated Cytotoxicity / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The selective elimination of cancer stem cells (CSCs) in tumor patients is a crucial goal because CSCs cause drug refractory relapse. To improve the current conventional bispecific immune-engager platform, a 16133 bispecific natural killer (NK) cell engager (BiKE), consisting of scFvs binding FcγRIII (CD16) on NK cells and CD133 on carcinoma cells, was first synthesized and a modified interleukin (IL)-15 crosslinker capable of stimulating NK effector cells was introduced. MATERIALS AND METHODS: DNA shuffling and ligation techniques were used to assemble and synthesize the 1615133 trispecific NK cell engager (TriKE). The construct was tested for its specificity using flow cytometry, cytotoxic determinations using chromium release assays, and lytic degranulation. IL-15–mediated expansion was measured using flow-based proliferation assays. The level of interferon (IFN)-γ release was measured because of its importance in the anti-cancer response. RESULTS: 1615133 TriKE induced NK cell–mediated cytotoxicity and NK expansion far greater than that achieved with BiKE devoid of IL-15. The drug binding and induction of cytotoxic degranulation was CD133+ specific and the anti-cancer activity was improved by integrating the IL-15 cross linker. The NK cell–related cytokine release measured by IFN-γ detection was higher than that of BiKE. NK cytokine release studies showed that although the IFN-γ levels were elevated, they did not approach the levels achieved with IL-12/IL-18, indicating that release was not at the supraphysiologic level. CONCLUSION: 1615133 TriKE enhances the NK cell anti-cancer activity and provides a self-sustaining mechanism via IL-15 signaling. By improving the NK cell performance, the new TriKE represents a highly active drug against drug refractory relapse mediated by CSCs.

Lumen apposing metal stents: A review of current uses and outcomes

Lumen-apposing metal stents (LAMS) represent a new innovation in gastrointestinal endoscopy. These devices have a saddle-shaped design and larger inner lumen diameter than either plastic or metal biliary stents, which should decrease the risk of migration and allows for an endoscope to pass into pancreatic fluid collections as well as the ability to perform direct endoscopic necrosectomy. LAMS were originally conceived and designed for transmural pancreatic fluid collection drainage but are currently also being used for many off label indications. There are three different LAMS available at this time around the globe. This manuscript will review the current state of the art with regards to LAMS and their indications, usage, and outcomes.

Nurse-delivered focused echocardiography to determine intravascular volume status in a deployed maritime critical care unit.

Focused echocardiography is increasingly used by clinicians to guide fluid resuscitation. The UK Defence Medical Services (DMS) have adopted focused echocardiography as a tool to guide flow assessment and resuscitation in deployed critical care. We aimed to explore whether two focused echo techniques, namely Inferior Vena Cava (IVC) and Left Ventricular Outflow Tract Velocity Time integer (LVOT VTi) respiratory variability could be taught to a group of critical care nurses without previous exposure to ultrasound imaging. After a five-week program of training, validation was carried out on healthy volunteers. The mentor, an accredited focused echo trainer, and six nurses performed a total of forty-eight scans on eleven volunteers. The mentor and students acquired subcostal long axis views of the IVC and apical five chamber views using a high frequency linear ultrasound probe. Mean values from three measurements were obtained for IVC diameter and LVOT VTi. Minimum and maximum values were recorded for both variables across a full respiratory cycle. Echo images were saved and at least two images for each student were reviewed offline by an accredited echo-training supervisor. In all cases students were able to obtain adequate echo windows. There was good correlation between values recorded by the mentor and students for both IVC diameter (r = 0.90, p < 0.001) and LVOT VTi (r = 0.77, p < 0.001). Bland Altman analysis showed good correlation with minimal bias for VTi measurements. There was some increase in bias for IVC measurements below 1.2 cm. In summary, we found that these skills for assessing intravascular volume status could be acquired in a relatively short time by specialist nurses without previous experience, and that results were comparable to those produced by an experienced practitioner.

Implications and limitations of cellular reprogramming for psychiatric drug development

Human-induced pluripotent stem cells (hiPSCs) derived from somatic cells of patients have opened possibilities for in vitro modeling of the physiology of neural (and other) cells in psychiatric disease states. Issues in early stages of technology development include (1) establishing a library of cells from adequately phenotyped patients, (2) streamlining laborious, costly hiPSC derivation and characterization, (3) assessing whether mutations or other alterations introduced by reprogramming confound interpretation, (4) developing efficient differentiation strategies to relevant cell types, (5) identifying discernible cellular phenotypes meaningful for cyclic, stress induced or relapsing-remitting diseases, (6) converting phenotypes to screening assays suitable for genome-wide mechanistic studies or large collection compound testing and (7) controlling for variability in relation to disease specificity amidst low sample numbers. Coordination of material for reprogramming from patients well-characterized clinically, genetically and with neuroimaging are beginning, and initial studies have begun to identify cellular phenotypes. Finally, several psychiatric drugs have been found to alter reprogramming efficiency in vitro, suggesting further complexity in applying hiPSCs to psychiatric diseases or that some drugs influence neural differentiation moreso than generally recognized. Despite these challenges, studies utilizing hiPSCs may eventually serve to fill essential niches in the translational pipeline for the discovery of new therapeutics.

A cone-beam computed tomography evaluation of buccal bone thickness following maxillary expansion

PURPOSE: This study was performed to determine the buccal alveolar bone thickness following rapid maxillary expansion (RME) using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: Twenty-four individuals (15 females, 9 males; 13.9 years) that underwent RME therapy were included. Each patient had CBCT images available before (T1), after (T2), and 2 to 3 years after (T3) maxillary expansion therapy. Coronal multiplanar reconstruction images were used to measure the linear transverse dimensions, inclinations of teeth, and thickness of the buccal alveolar bone. One-way ANOVA analysis was used to compare the changes between the three times of imaging. Pairwise comparisons were made with the Bonferroni method. The level of significance was established at p<0.05. RESULTS: The mean changes between the points in time yielded significant differences for both molar and premolar transverse measurements between T1 and T2 (p<0.05) and between T1 and T3 (p<0.05). When evaluating the effect of maxillary expansion on the amount of buccal alveolar bone, a decrease between T1 and T2 and an increase between T2 and T3 were found in the buccal bone thickness of both the maxillary first premolars and maxillary first molars. However, these changes were not significant. Similar changes were observed for the angular measurements. CONCLUSION: RME resulted in non-significant reduction of buccal bone between T1 and T2. These changes were reversible in the long-term with no evident deleterious effects on the alveolar buccal bone.

Optimized mixture of hops rho iso-alpha acids-rich extract and acacia proanthocyanidins-rich extract reduces insulin resistance in 3T3-L1 adipocytes and improves glucose and insulin control in db/db mice

Rho iso-alpha acids-rich extract (RIAA) from Humulus lupulus (hops) and proanthocyanidins-rich extracts (PAC) from Acacia nilotica exert anti-inflammatory and anti-diabetic activity in vitro and in vivo. We hypothesized that a combination of these two extracts would exert enhanced effects in vitro on inflammatory markers and insulin signaling, and on nonfasting glucose and insulin in db/db mice. Over 49 tested combinations, RIAA:PAC at 5:1 (6.25 microg/mL) exhibited the greatest reductions in TNFalpha-stimulated lipolysis and IL-6 release in 3T3-L1 adipocytes, comparable to 5 microg/mL troglitazone. Pretreatment of 3T3-L1 adipocytes with this combination (5 microg/mL) also led to a 3-fold increase in insulin-stimulated glucose uptake that was comparable to 5 microg/mL pioglitazone or 901 microg/mL aspirin. Finally, db/db mice fed with RIAA:PAC at 5:1 (100 mg/kg) for 7 days resulted in 22% decrease in nonfasting glucose and 19% decrease in insulin that was comparable to 0.5 mg/kg rosiglitazone and better than 100 mg/kg metformin. RIAA:PAC mixture may have the potential to be an alternative when conventional therapy is undesirable or ineffective, and future research exploring its long-term clinical application is warranted.

Hydrogen sulfide protects colon cancer cells from chemopreventative agent beta-phenylethyl isothiocyanate induced apoptosis.

AIM: Hydrogen sulfide (H(2)S) is a prominent gaseous constituent of the gastrointestinal (GI) tract with known cytotoxic properties. Endogenous concentrations of H(2)S are reported to range between 0.2-3.4 mmol/L in the GI tract of mice and humans. Considering such high levels we speculate that, at non-toxic concentrations, H(2)S may interact with chemical agents and alter the response of colonic epithelium cells to such compounds. The GI tract is a major site for the absorption of phytochemical constituents such as isothiocyanates, flavonoids, and carotenoids, with each group having a role in the prevention of human diseases such as colon cancer. The chemopreventative properties of the phytochemical agent beta-phenyethyl isothiocyanate (PEITC) are well recognized. However, little is currently known about the physiological or biochemical factors present in the GI tract that may influence the biological properties of ITCs. The current study was undertaken to determine the effects of H(2)S on PEITC mediated apoptosis in colon cancer cells. METHODS: Induction of apoptosis by PEITC in human colon cancer HCT116 cells was assessed using classic apoptotic markers namely SubG1 population analysis, caspase-3 like activity and nuclear fragmentation and condensation coupled with the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide) viability assay and LDH leakage. RESULTS: PEITC significantly induced apoptosis in HCT116 cells as assessed by SubG1 population formation, nuclear condensation, LDH leakage and caspase-3 activity after 24 h, these data being significant from control groups (P<0.01). In contrast, co-treatment of cells with physiological concentrations of H2S (0.1-1 mmol/L) prevented PEITC mediated apoptosis as assessed using the parameters described. CONCLUSION: PEITC effectively induced cell death in the human adenocarcinoma cell line HCT116 in vitro through classic apoptotic mechanisms. However, in the presence of H(2)S, apoptosis was abolished. These data suggest that H(2)S may play a significant role in the response of colonic epithelial cells to beneficial as well as toxic agents present within the GI tract.

The Effect of 7.5% Hypertonic Saline Resuscitation and Normal Saline Resuscitation on Acute Lung Injury after Hemorrhagic Shock

PURPOSE: To investigate the hypothesis that resuscitation with hypertonic saline (HTS) in hemorrhagic shock (HS) will improve the pulmonary function and inflammatory changes in post-hemorrhage induced acute lung injury. METHODS: HS was induced in anesthetized Swiss-Webster mice by removing 0.025cc blood/g. body weight via the carotid artery while under blood pressure monitoring. Mice were divided into 5 groups: Group I (n=12) were cannulated but not bled (sham); Group II (n=12) were bled and received 4mL/kg 7.5% HTS; Group III (n=10) were bled and received 3 times their shed blood (SB) volume of normal saline (NS); Group IV (n=11) were bled and received SB and 4mL/kg 7.5% HTS; Group V (n=9) were bled and received SB and two times their SB volume of NS after 30 minutes shock. Serum lactates (LA) were evaluated at the end of the shock period and after resuscitation. Pulmonary function was measured by whole-body plethysmography prior to any instrumentation and again 24hr, 48hr and 72hr after resuscitation. Pulmonary inflammation was assessed by quantifying bronchoalveolar lavage neutrophil infiltration (BALN) and myeloperoxidase (MPO) activity after 72hr of observation. RESULTS: There were no differences in baseline BP, shock BP, shock LA and LA after resuscitation in each shock group. The survival rates were as follows: Group I, 75.0%; Group II, 33.3%; Group III, 60%; Group IV, 81.8%; and Group V, 88.8% (p=0.046). There were no significant differences in the changes of airway resistance after resuscitation in each group. BALN and MPO activity in Group III were increased. CONCILUSION: HTS resuscitation alone was associated with higher mortality. HTS was decreased pulmonary inflammation but it did not alter respiratory function.

The Hampstead Schizophrenia Survey 1991. I: Prevalence and service use comparisons in an inner London health authority, 1986-1991.

BACKGROUND: A point prevalence study of schizophrenia was carried out in 1986 in the former Hampstead Health District using a key informant method to identify cases. The point prevalence of broadly defined schizophrenia was 4.7 per 1000. METHOD: A repeat census of people with schizophrenia, using the same method, was carried out in 1991 and the point prevalence calculated. The accuracy of the census method was estimated. Contact with services, social and occupational activity, and medication usage in the 1986 and 1991 samples were compared. RESULTS: The point prevalence rate of broadly defined schizophrenia in 1991 was 5.1 per 1000. The results of both censuses showed we underestimated the number of individuals with DSM-III-R positive schizophrenia by about 14%. The level of contact with specialist services was greater in 1991 than 1986. Patients in 1991 were discharged on higher doses of medication, and their most recent admission was more likely to be due to non-compliance, than the 1986 group. CONCLUSION: The point prevalence confirmed the high rate reported in 1986. The accuracy of the census was within acceptable limits for service planning. Contact with specialist services increased between 1986 and 1991.

The Hampstead Schizophrenia Survey 1991. II: Incidence and migration in inner London.

BACKGROUND: The previous paper reports a high prevalence of schizophrenia (broad definition) in an inner London area. In this paper we test hypotheses for this finding and examine the characteristics of people with schizophrenia who move frequently. METHOD: People with schizophrenia in the Hampstead area were identified by key informant methodology, at two censuses five years apart. This allowed identification of incident cases during these five years and identification of people who had moved into and out of the area. RESULTS: The incidence of DSM-III-R schizophrenia in Hampstead between 1986 and 1991 was at least 0.21 per 1000 of the population aged 15 to 54. There was a significant movement of people with schizophrenia to this inner London area from outer London between 1986 and 1991. People with schizophrenia who were relatively mobile were significantly more likely to be male, to suffer with prominent hallucinations, and to have no contact with a GP. CONCLUSIONS: The high prevalence of broad schizophrenia in this inner London area is, in part, due to geographical drift. A significant excess of the people with schizophrenia who move frequently are men with positive symptoms.