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1.  Contemporaneous comparison of open vs minimally-invasive radical prostatectomy for high-risk prostate cancer 
BJU international  2013;112(6):751-757.
Objectives
• To analyze pathological and short-term oncological outcomes in men undergoing open and minimally-invasive radical prostatectomy (MIRP) for high-risk prostate cancer (HRPC; prostate-specific antigen level [PSA] >20 ng/mL, ≥cT2c, Gleason score 8–10) in a contemporaneous series.
Patients and Methods
• In total, 913 patients with HRPC were identified in the Johns Hopkins Radical Prostatectomy Database subsequent to the inception of MIRP at this institution (2002–2011)
• Of these, 743 (81.4%) underwent open radical retropubic prostatectomy (ORRP), 105 (11.5%) underwent robot-assisted laparoscopic radical prostatectomy (RALRP) and 65 (7.1%) underwent laparoscopic radical prostatectomy (LRP) for HRPC.
• Appropriate comparative tests were used to evaluate patient and prostate cancer characteristics.
• Proportional hazards regression models were used to predict biochemical recurrence.
Results
• Age, race, body mass index, preoperative PSA level, clinical stage, number of positive cores and Gleason score at final pathology were similar between ORRP and MIRP.
• On average, men undergoing MIRP had smaller prostates and more organ-confined (pT2) disease (P = 0.02).
• The number of surgeons and surgeon experience were greatest for the ORRP cohort.
• Overall surgical margin rate was 29.4%, 34.3% and 27.7% (P = 0.52) and 1.9%, 2.9% and 6.2% (P = 0.39) for pT2 disease in men undergoing ORRP, RALRP and LRP, respectively.
• Biochemical recurrence-free survival among ORRP, RALRP and LRP was 56.3%, 67.8% and 41.1%, respectively, at 3 years (P = 0.6) and the approach employed did not predict biochemical recurrence in regression models.
Conclusions
• At an experienced centre, MIRP is comparable to open radical prostatectomy for HRPC with respect to surgical margin status and biochemical recurrence.
doi:10.1111/j.1464-410X.2012.11757.x
PMCID: PMC3978171  PMID: 23356390
high-risk; minimally-invasive surgery; prostate cancer; radical prostatectomy
2.  Preservation of renal function in the modern staged repair of classic bladder exstrophy 
Journal of pediatric urology  2012;9(2):169-173.
Objective
To compare the estimated glomerular filtration rate (eGFR) in bladder exstrophy patients with published normative GFR estimates.
Patients and Methods
eGFR was calculated using the Schwartz formula at three timepoints, with mean eGFR at each timepoint compared to normative values.
Results
At primary closure (n = 53) the mean eGFR (ml/min/1.73 m2) in exstrophy patients was similar to norms at 0–7 days (exstrophy vs norm: 42.5 vs 40.6, p > 0.05) and after 2 years of age (108.8 vs 133, p > 0.05). However, the mean eGFR in exstrophy patients was significantly lower than norms between 8 days (44.8 vs 65.8, p < 0.0001) and 2 years of life (68 vs 95.7, p = 0.01). At bladder neck reconstruction (n = 13) no statistically significant difference existed between the exstrophy and normative eGFR values (137.1 vs 133, p >0.05). Similarly, among 27 patients with at least 1 year follow-up after bladder neck reconstruction, the mean exstrophy eGFR was no worse or higher than normative values (2–12 years: 124.5 vs 133, p > 0.05; males ≥ 13 years 175.6 vs 140, p = 0.04; females ≥ 13 years 128.8 vs 126, p >0.05).
Conclusion
The staged reconstruction of exstrophy does not appear to negatively impact renal function in most patients. As eGFR detects only significant changes, surgical reconstruction may still cause more subtle renal damage.
doi:10.1016/j.jpurol.2012.01.014
PMCID: PMC3378802  PMID: 22365973
Bladder Exstrophy; Estimated Glomerular Filtration Rate; Modern Staged Repair of Exstrophy
3.  Novel Hsp90 inhibitor NVP-AUY922 radiosensitizes prostate cancer cells 
Cancer Biology & Therapy  2013;14(4):347-356.
Outcomes for poor-risk localized prostate cancers treated with radiation are still insufficient. Targeting the “non-oncogene” addiction or stress response machinery is an appealing strategy for cancer therapeutics. Heat-shock-protein-90 (Hsp90), an integral member of this machinery, is a molecular chaperone required for energy-driven stabilization and selective degradation of misfolded “client” proteins, that is commonly overexpressed in tumor cells. Hsp90 client proteins include critical components of pathways implicated in prostate cancer cell survival and radioresistance, such as androgen receptor signaling and the PI3K-Akt-mTOR pathway. We examined the effects of a novel non-geldanamycin Hsp90 inhibitor, AUY922, combined with radiation (RT) on two prostate cancer cell lines, Myc-CaP and PC3, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γ-H2AX foci kinetics and client protein expression in pathways important for prostate cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined treatment (RT-AUY922) on the PI3K-Akt-mTOR and AR pathways in a hind-flank tumor graft model. We observed that AUY922 caused supra-additive radiosensitization in both cell lines at low nanomolar doses with enhancement ratios between 1.4–1.7 (p < 0.01). RT-AUY922 increased apoptotic cell death compared with either therapy alone, induced G2-M arrest and produced marked changes in client protein expression. These results were confirmed in vivo, where RT-AUY922 combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in Myc-CaP and PC3 tumor grafts (both p < 0.0001). Our data suggest that combined RT-AUY922 therapy exhibits promising activity against prostate cancer cells, which should be investigated in clinical studies.
doi:10.4161/cbt.23626
PMCID: PMC3667875  PMID: 23358469
prostate cancer; Hsp90; NVP-AUY922; radiosensitizer; DNA damage response
5.  Optimal Media for Use in Air Sampling To Detect Cultivable Bacteria and Fungi in the Pharmacy 
Journal of Clinical Microbiology  2013;51(10):3172-3175.
Current guidelines for air sampling for bacteria and fungi in compounding pharmacies require the use of a medium for each type of organism. U.S. Pharmacopeia (USP) chapter <797> (http://www.pbm.va.gov/linksotherresources/docs/USP797PharmaceuticalCompoundingSterileCompounding.pdf) calls for tryptic soy agar with polysorbate and lecithin (TSApl) for bacteria and malt extract agar (MEA) for fungi. In contrast, the Controlled Environment Testing Association (CETA), the professional organization for individuals who certify hoods and clean rooms, states in its 2012 certification application guide (http://www.cetainternational.org/reference/CAG-009v3.pdf?sid=1267) that a single-plate method is acceptable, implying that it is not always necessary to use an additional medium specifically for fungi. In this study, we reviewed 5.5 years of data from our laboratory to determine the utility of TSApl versus yeast malt extract agar (YMEA) for the isolation of fungi. Our findings, from 2,073 air samples obtained from compounding pharmacies, demonstrated that the YMEA yielded >2.5 times more fungal isolates than TSApl.
doi:10.1128/JCM.00944-13
PMCID: PMC3811631  PMID: 23903551
6.  Depletion of Cutaneous Macrophages and Dendritic Cells Promotes Growth of Basal Cell Carcinoma in Mice 
PLoS ONE  2014;9(4):e93555.
Basal cell carcinoma (BCC) belongs to the group of non-melanoma skin tumors and is the most common tumor in the western world. BCC arises due to mutations in the tumor suppressor gene Patched1 (Ptch). Analysis of the conditional Ptch knockout mouse model for BCC reveals that macrophages and dendritic cells (DC) of the skin play an important role in BCC growth restraining processes. This is based on the observation that a clodronate-liposome mediated depletion of these cells in the tumor-bearing skin results in significant BCC enlargement. The depletion of these cells does not modulate Ki67 or K10 expression, but is accompanied by a decrease in collagen-producing cells in the tumor stroma. Together, the data suggest that cutaneous macrophages and DC in the tumor microenvironment exert an antitumor effect on BCC.
doi:10.1371/journal.pone.0093555
PMCID: PMC3972151  PMID: 24691432
7.  A first-in-class, first-in-human, phase I trial of p28, a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in patients with advanced solid tumours 
British Journal of Cancer  2013;108(5):1061-1070.
Background:
This first-in-human, phase I clinical trial of p28 (NSC745104), a 28-amino-acid fragment of the cupredoxin azurin, investigated the safety, tolerability, pharmacokinetics and preliminary activity of p28 in patients with p53+ metastatic solid tumours.
Methods:
A total of 15 patients were administered p28 i.v. as a short infusion three times per week for 4 weeks followed by a 2-week rest under an accelerated titration 3+3 dose escalation design until either a grade 3-related adverse event occurred or the maximum tolerated dose (MTD) was reached. Single-dose and steady-state serum pharmacokinetics were characterised. Assessments included toxicity, best objective response by RECIST 1.1 Criteria, and overall survival.
Results:
No patients exhibited any dose-limiting toxicities (DLTs), significant adverse events or exhibited an immune response (IgG) to the peptide. The No Observed Adverse Effect Level (NOAEL) and MTD were not reached. Seven patients demonstrated stable disease for 7–61 weeks, three a partial response for 44–125 weeks, and one a complete response for 139 weeks. Three patients are still alive at 158, 140, and 110 weeks post therapy completion.
Conclusion:
p28 was tolerated with no significant adverse events. An MTD was not reached. Evidence of anti-tumour activity indicates a highly favourable therapeutic index and demonstrates proof of concept for this new class of non-HDM2-mediated peptide inhibitors of p53 ubiquitination.
doi:10.1038/bjc.2013.74
PMCID: PMC3619084  PMID: 23449360
p28; p53; metastatic solid tumours
8.  Performance Asymmetries in Tool Use are Associated with Corpus Callosum Integrity in Chimpanzees (Pan troglodytes): A Diffusion Tensor Imaging Study 
Behavioral neuroscience  2013;127(1):106-113.
We examined the relationship of corpus callosum morphology and organization to hand preference and performance on a motor skill task in chimpanzees. Handedness was assessed using a complex tool use task that simulated termite fishing. Chimpanzees were initially allowed to perform the task wherein they could choose which hand to use (preference measure); then they were required to complete trials using each hand (performance measure). Two measures were used to assess the corpus callosum: midsagittal area obtained from in vivo magnetic resonance images and density of transcallosal connections as determined by fractional anisotropy values obtained from diffusion tensor imaging. We hypothesized that chimpanzees would perform better on their preferred hand compared to the non-preferred hand, and that strength of behavioral lateralization (rather the direction) on this task would be negatively correlated to regions of the corpus callosum involved in motor processing. Our results indicate that the preferred hand was the most adept hand. Performance asymmetries correlated with FA measures but not area measures of the CC.
doi:10.1037/a0031089
PMCID: PMC3939601  PMID: 23398443
Corpus callosum; DTI; chimpanzee; handedness; tool use
9.  Self-Association of the Gal4 Inhibitor Protein Gal80 Is Impaired by Gal3: Evidence for a New Mechanism in the GAL Gene Switch 
Molecular and Cellular Biology  2013;33(18):3667-3674.
The DNA-binding transcriptional activator Gal4 and its regulators Gal80 and Gal3 constitute a galactose-responsive switch for the GAL genes of Saccharomyces cerevisiae. Gal4 binds to GAL gene UASGAL (upstream activation sequence in GAL gene promoter) sites as a dimer via its N-terminal domain and activates transcription via a C-terminal transcription activation domain (AD). In the absence of galactose, a Gal80 dimer binds to a dimer of Gal4, masking the Gal4AD. Galactose triggers Gal3-Gal80 interaction to rapidly initiate Gal4-mediated transcription activation. Just how Gal3 alters Gal80 to relieve Gal80 inhibition of Gal4 has been unknown, but previous analyses of Gal80 mutants suggested a possible competition between Gal3-Gal80 and Gal80 self-association interactions. Here we assayed Gal80-Gal80 interactions and tested for effects of Gal3. Immunoprecipitation, cross-linking, and denaturing and native PAGE analyses of Gal80 in vitro and fluorescence imaging of Gal80 in live cells show that Gal3-Gal80 interaction occurs concomitantly with a decrease in Gal80 multimers. Consistent with this, we find that newly discovered nuclear clusters of Gal80 dissipate in response to galactose-triggered Gal3-Gal80 interaction. We discuss the effect of Gal3 on the quaternary structure of Gal80 in light of the evidence pointing to multimeric Gal80 as the form required to inhibit Gal4.
doi:10.1128/MCB.00646-12
PMCID: PMC3753875  PMID: 23858060
10.  SAR analysis of novel non-peptidic NPBWR1 (GPR7) antagonists 
In this Letter we report on the advances in our NPBWR1 antagonist program aimed at optimizing the 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one lead molecule previously obtained from a high-throughput screening (HTS)-derived hit. Synthesis and structure–activity relationships (SAR) studies around the 3,5-dimethylphenyl and 4-methoxyphenyl regions resulted in the identification of a novel series of non-peptidic submicromolar NPBWR1 antagonists based on a 5-chloro-4-(4-alkoxyphenoxy)-2-(benzyl)pyridazin-3(2H)-one chemotype. Amongst them, 5-chloro-2-(9H-fluoren-9-yl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one 9h (CYM50769) inhibited NPW activation of NPBWR1 with a submicromolar IC50, and displayed high selectivity against a broad array of off-targets with pharmaceutical relevance. Our medicinal chemistry study provides innovative non-peptidic selective NPBWR1 antagonists that may enable to clarify the biological role and therapeutic utility of the target receptor in the regulation of feeding behavior, pain, stress, and neuroendocrine function.
doi:10.1016/j.bmcl.2012.12.030
PMCID: PMC3621982  PMID: 23287738
NPBWR1 (GPR7) antagonists; Anorexia; Analgesia; Stress
11.  Poor receptive joint attention skills are associated with atypical gray matter asymmetry in the posterior superior temporal gyrus of chimpanzees (Pan troglodytes) 
Clinical and experimental data have implicated the posterior superior temporal gyrus as an important cortical region in the processing of socially relevant stimuli such as gaze following, eye direction, and head orientation. Gaze following and responding to different socio-communicative signals is an important and highly adaptive skill in primates, including humans. Here, we examined whether individual differences in responding to socio-communicative cues was associated with variation in either gray matter (GM) volume and asymmetry in a sample of chimpanzees. Magnetic resonance image scans and behavioral data on receptive joint attention (RJA) was obtained from a sample of 191 chimpanzees. We found that chimpanzees that performed poorly on the RJA task had less GM in the right compared to left hemisphere in the posterior but not anterior superior temporal gyrus. We further found that middle-aged and elderly chimpanzee performed more poorly on the RJA task and had significantly less GM than young-adult and sub-adult chimpanzees. The results are consistent with previous studies implicating the posterior temporal gyrus in the processing of socially relevant information.
doi:10.3389/fpsyg.2014.00007
PMCID: PMC3905213  PMID: 24523703
joint attention; chimpanzees; superior temporal gyrus; brain asymmetry in cognition; brain development
12.  Genetic Influences on Receptive Joint Attention in Chimpanzees (Pan troglodytes) 
Scientific Reports  2014;4:3774.
Despite their genetic similarity to humans, our understanding of the role of genes on cognitive traits in chimpanzees remains virtually unexplored. Here, we examined the relationship between genetic variation in the arginine vasopressin V1a receptor gene (AVPR1A) and social cognition in chimpanzees. Studies have shown that chimpanzees are polymorphic for a deletion in a sequence in the 5′ flanking region of the AVPR1A, DupB, which contains the variable RS3 repetitive element, which has been associated with variation in social behavior in humans. Results revealed that performance on the social cognition task was significantly heritable. Furthermore, males with one DupB+ allele performed significantly better and were more responsive to socio-communicative cues than males homozygous for the DupB- deletion. Performance on a non-social cognition task was not associated with the AVPR1A genotype. The collective findings show that AVPR1A polymorphisms are associated with individual differences in performance on a receptive joint attention task in chimpanzees.
doi:10.1038/srep03774
PMCID: PMC3895903  PMID: 24440967
13.  Abuse-Deterrent Formulations, an Evolving Technology Against the Abuse and Misuse of Opioid Analgesics 
Journal of Medical Toxicology  2012;8(4):400-407.
The increased use of opioid pain medication has been mirrored by the increased misuse and abuse of these drugs. As part of a multidisciplinary approach to this epidemic, pharmaceutical companies, with the encouragement of the Food and Drug Administration, have increased the development of abuse-deterrent formulations. While all have the goal of treating pain while mitigating misuse and abuse, there are different technologies utilized to impart the abuse-deterrent properties. The goal of this paper is to review the basis of abuse-deterrent formulations, the different types and approaches of some of the abuse-deterrent products, and their current regulatory status in the USA.
doi:10.1007/s13181-012-0270-y
PMCID: PMC3550267  PMID: 23073726
Abuse deterrent formulation; Opioid abuse; Opioid misuse
14.  Design, synthesis and SAR analysis of novel potent and selective small molecule antagonists of NPBWR1 (GPR7) 
Novel small molecule antagonists of NPBWR1 (GPR7) are herein reported. A high-throughput screening (HTS) of the Molecular Libraries-Small Molecule Repository library identified 5-chloro-4-(4-methoxyphenoxy)-2-(p-tolyl)pyridazin-3(2H)-one as a NPBWR1 hit antagonist with micromolar activity. Design, synthesis and structure–activity relationships study of the HTS-derived hit led to the identification of 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one lead molecule with submicromolar antagonist activity at the target receptor and high selectivity against a panel of therapeutically relevant off-target proteins. This lead molecule may provide a pharmacological tool to clarify the molecular basis of the in vivo physiological function and therapeutic utility of NPBWR1 in diverse disease areas including inflammatory pain and eating disorders.
doi:10.1016/j.bmcl.2012.09.074
PMCID: PMC3601546  PMID: 23079522
NPBWR1 (GPR7); Selective small molecule antagonists; Feeding behavior and energy homeostasis; Inflammatory pain
15.  Wnt Signaling Though Beta-catenin is Required for Prostate Lineage Specification 
Developmental biology  2012;371(2):246-255.
Androgens initiate a complex network of signals within the UGS that trigger prostate lineage commitment and bud formation. Given its contributions to organogenesis in other systems, we investigated a role for canonical Wnt signaling in prostate development. We developed a new method to achieve complete deletion of beta-catenin, the transcriptional coactivator required for canonical Wnt signaling, in early prostate development. Beta-catenin deletion abrogated canonical Wnt signaling and yielded prostate rudiments that exhibited dramatically decreased budding and failed to adopt prostatic identity. This requirement for canonical Wnt signaling was limited to a brief critical period during the initial molecular phase of prostate identity specification. Deletion of beta-catenin in the adult prostate did not significantly affect organ homeostasis. Collectively, these data establish that beta-catenin and Wnt signaling play key roles in prostate lineage specification and bud outgrowth.
doi:10.1016/j.ydbio.2012.08.016
PMCID: PMC3472417  PMID: 22960283
Wnt signaling; Prostate development; Urogenital sinus; Mouse
16.  Modulating the RNA Processing and Decay by the Exosome: Altering Rrp44/Dis3 Activity and End-Product 
PLoS ONE  2013;8(11):e76504.
In eukaryotes, the exosome plays a central role in RNA maturation, turnover, and quality control. In Saccharomyces cerevisiae, the core exosome is composed of nine catalytically inactive subunits constituting a ring structure and the active nuclease Rrp44, also known as Dis3. Rrp44 is a member of the ribonuclease II superfamily of exoribonucleases which include RNase R, Dis3L1 and Dis3L2. In this work we have functionally characterized three residues located in the highly conserved RNB catalytic domain of Rrp44: Y595, Q892 and G895. To address their precise role in Rrp44 activity, we have constructed Rrp44 mutants and compared their activity to the wild-type Rrp44. When we mutated residue Q892 and tested its activity in vitro, the enzyme became slightly more active. We also showed that when we mutated Y595, the final degradation product of Rrp44 changed from 4 to 5 nucleotides. This result confirms that this residue is responsible for the stacking of the RNA substrate in the catalytic cavity, as was predicted from the structure of Rrp44. Furthermore, we also show that a strain with a mutation in this residue has a growth defect and affects RNA processing and degradation. These results lead us to hypothesize that this residue has an important biological role. Molecular dynamics modeling of these Rrp44 mutants and the wild-type enzyme showed changes that extended beyond the mutated residues and helped to explain these results.
doi:10.1371/journal.pone.0076504
PMCID: PMC3827031  PMID: 24265673
17.  Contrast of hemispheric lateralization for oro-facial movements between learned attention-getting sounds and species-typical vocalizations in chimpanzees: Extension in a second colony 
Brain and language  2012;123(1):10.1016/j.bandl.2012.07.002.
Studies involving oro-facial asymmetries in nonhuman primates have largely demonstrated a right hemispheric dominance for communicative signals and conveyance of emotional information. A recent study on chimpanzee reported the first evidence of significant left-hemispheric dominance when using attention-getting sounds and rightward bias for species-typical vocalizations (Losin, Russell, Freeman, Meguerditchian, Hopkins & Fitch, 2008). The current study sought to extend the findings from Losin et al. (2008) with additional oro-facial assessment in a new colony of chimpanzees. When combining the two populations, the results indicated a consistent leftward bias for attention-getting sounds and a right lateralization for species-typical vocalizations. Collectively, the results suggest that both voluntary- controlled oro-facial and gestural communication might share the same left-hemispheric specialization and might have coevolved into a single integrated system present in a common hominid ancestor.
doi:10.1016/j.bandl.2012.07.002
PMCID: PMC3823530  PMID: 22867751
Hemispheric specialization; Oro-facial asymmetry; Communicative behaviors; Gestural communication; Oro-facial communication; Emotions; Primates
18.  A New Synthetic FGF Receptor Antagonist Inhibits Arteriosclerosis in a Mouse Vein Graft Model and Atherosclerosis in Apolipoprotein E-Deficient Mice 
PLoS ONE  2013;8(11):e80027.
Objective
The role of fibroblast growth factors (FGFs) in the development of vascular diseases remains incompletely understood. The objective of this study was to examine the effects of a new small-molecule multi-FGF receptor blocker with allosteric properties, SSR128129E, on neointimal proliferation after a vein graft procedure in mice and on the development of atherosclerosis in atherosclerosis-prone apolipoprotein E (apoE)-deficient mice.
Methods and Results
Vein grafts were performed in 3 month-old male C57BL6 mice. Segments of the vena cava were interposed at the level of the carotid artery. In SSR128129E (50 mg/kg/d)-treated animals, a dramatic decrease in neointimal proliferation was observed 2 and 8 weeks after the graft (72.5 %, p<0.01, and 47.8 %, p<0.05, respectively). Four-week old male apoE-deficient mice were treated with SSR128129E (50 mg/kg/d) for 3 and 5 months in comparison with a control group. SSR128129E treatment resulted in a reduction of lesion size in the aortic sinus (16.4 % (ns) at 3 months and 42.9 % (p<0.01) at 5 months, without any change in serum lipids. SSR128129 significantly reduced FGFR2 mRNA levels in the aortic sinus (p<0.05, n=5-6), but did not affect the mRNA expression levels of other FGF receptors or ligands.
Conclusion
These studies indicate that FGFs have an important role in the development of vascular diseases like atherosclerosis and graft arteriosclerosis. These data suggest that inhibition of FGF receptors by compounds like SSR128129E might be useful as a new therapeutic approach for these vascular pathologies.
doi:10.1371/journal.pone.0080027
PMCID: PMC3817113  PMID: 24224032
19.  Stimulation of autophagy is neuroprotective in a mouse model of human tauopathy 
Autophagy  2012;8(11):1686-1687.
The most common neurodegenerative diseases are characterized by the accumulation of misfolded proteins. Tauopathies, which include Alzheimer disease, progressive supranuclear palsy, corticobasal degeneration, Pick disease and cases of frontotemporal dementia and parkinsonism linked to chromosome 17, are characterized by the accumulation of hyperphosphorylated and filamentous MAPT/tau protein. The pathological mechanisms involved in MAPT protein accumulation are not well understood, but a possible impairment of protein degradation pathways has been suggested. We investigated the effects of autophagy stimulation on MAPT pathology in a model tauopathy, the human mutant P301S MAPT transgenic mouse line. In the brain of the trehalose-treated mutant mice, autophagy is activated and a reduced number of neurons containing MAPT inclusions, as well as a decreased amount of insoluble MAPT, are observed. The improvement of MAPT pathology is associated with increased nerve cell survival. Moreover, MAPT inclusions colocalize with SQSTM1/p62- and LC3-positive puncta, suggesting the colocalization of MAPT aggregates with autophagic vacuoles. Autophagy is not activated in the spinal cord of the human P301S MAPT transgenic mice and neuronal survival, as well as MAPT pathology, is unaffected. This study supports a role for autophagy stimulation in the degradation of MAPT aggregates and opens new perspectives for the investigation of autophagy as a pathological mechanism involved in neurodegenerative diseases.
doi:10.4161/auto.21488
PMCID: PMC3494601  PMID: 22874558
autophagy; neurodegenerative diseases; neuroprotection; protein aggregation; protein degradation; tau
20.  Severe cholestasis due to adalimumab in a Crohn’s disease patient 
World Journal of Hepatology  2013;5(10):592-595.
Elevation of liver biochemistry has been reported with anti-tumor necrosis factor agents, but overt liver failure rarely reported. Autoimmune hepatitis has been more commonly reported with infliximab than adalimumab (ADA). Our case, however, describes the first reported case of ADA-associated severe cholestatic injury. A 39-year-old female with Crohn’s disease developed severe jaundice after initiation of ADA. All serologic tests and imaging studies were normal. Liver biopsy showed prominent pericentral canalicular cholestasis, without features of steatosis or sclerosing cholangitis, consistent with drug-induced cholestasis. The serum total bilirubin peaked at 280 μmol/L, and improvement was seen after 5 wk with eventual normalization of liver enzymes at 10 wk. Our case describes the first reported case of ADA-associated severe cholestatic liver disease and the first histopathologic examination of this adverse drug effect. Clinicians need to be aware of this potential drug-induced liver injury when prescribing this commonly used biologic medication.
doi:10.4254/wjh.v5.i10.592
PMCID: PMC3812463  PMID: 24179620
Crohn’s disease; Cholestasis; Adalimumab; Anti-tumor necrosis factor agents; Drug-induced liver injury
21.  Dipeptidyl Peptidase-4 Inhibition in Patients with Type 2 Diabetes Treated with Saxagliptin, Sitagliptin, or Vildagliptin 
Diabetes Therapy  2013;4(2):431-442.
Introduction
Saxagliptin, sitagliptin, and vildagliptin are dipeptidyl peptidase-4 (DPP-4) inhibitors widely approved for use in patients with type 2 diabetes. Using a crossover design, the present study compared trough levels of DPP-4 inhibition provided by these agents in a single cohort of patients with type 2 diabetes.
Methods
This was a randomized, placebo-controlled, open-label, five-period crossover study. Eligible patients were 18–65 years of age, either treatment-naïve or off prior antihyperglycemic agent therapy for at least 6 or 12 weeks (depending on the prior therapy), and had glycated hemoglobin (HbA1C) ≥6.5% and ≤10.0%. In separate study periods, patients received 5 mg saxagliptin q.d. (saxa-5), 100 mg sitagliptin q.d. (sita-100), 50 mg vildagliptin q.d. (vilda-50-q.d.), 50 mg vildagliptin b.i.d. (vilda-50-b.i.d.), or placebo for 5 days. The primary endpoint was trough %DPP-4 inhibition, derived by comparing DPP-4 activity 24 h after the Day-5 morning dose with predose activity in the same period and analyzed using a linear mixed-effects model with fixed-effects terms for treatment and period.
Results
Mean (range) baseline HbA1C was 7.4% (6.4–9.0%; N = 22). Least-squares (LS) mean trough %DPP-4 inhibition was 73.5%, 91.7%, 28.9%, 90.6%, and 3.5% after saxa-5, sita-100, vilda-50-q.d., vilda-50-b.i.d., and placebo, respectively. In patients treated with sita-100, the LS-mean difference in trough %DPP-4 inhibition was 18.2% greater than with saxa-5 (p < 0.001), 62.9% greater than with vilda-50-q.d. (p < 0.001), 1.1% greater than with vilda-50-b.i.d. (p = 0.128), and 87.8% greater than with placebo (p < 0.001). Mean %DPP-4 inhibition was nearly maximal at 12 h postdose regardless of active treatment. Thus, these between-group comparisons at trough primarily reflected differences in duration of action. Adverse events reported during the study were transient and mild or moderate in intensity.
Conclusion
Once daily treatment with sitagliptin provided trough DPP-4 inhibition significantly greater than saxagliptin or vildagliptin administered once daily, and similar to that provided by vildagliptin administered twice daily.
doi:10.1007/s13300-013-0045-8
PMCID: PMC3889317  PMID: 24163113
Dipeptidyl peptidase-4; Enzyme inhibition; Saxagliptin; Sitagliptin; Type 2 diabetes; Vildagliptin
22.  Proteomics profiling reveals novel proteins and functions of the plant stigma exudate 
Journal of Experimental Botany  2013;64(18):5695-5705.
Proteomic analysis of the stigmatic exudate of Lilium longiflorum and Olea europaea led to the identification of 51 and 57 proteins, respectively, most of which are described for the first time in this secreted fluid. These results indicate that the stigmatic exudate is an extracellular environment metabolically active, participating in at least 80 different biological processes and 97 molecular functions. The stigma exudate showed a markedly catabolic profile and appeared to possess the enzyme machinery necessary to degrade large polysaccharides and lipids secreted by papillae to smaller units, allowing their incorporation into the pollen tube during pollination. It may also regulate pollen-tube growth in the pistil through the selective degradation of tube-wall components. Furthermore, some secreted proteins were involved in pollen-tube adhesion and orientation, as well as in programmed cell death of the papillae cells in response to either compatible pollination or incompatible pollen rejection. Finally, the results also revealed a putative cross-talk between genetic programmes regulating stress/defence and pollination responses in the stigma.
doi:10.1093/jxb/ert345
PMCID: PMC3871823  PMID: 24151302
Eastern lily; exudate; olive; proteomics; stigma; secretome.
23.  Temporal control of self-organized pattern formation without morphogen gradients in bacteria 
The generation of self-organized ring patterns of gene expression in the absence of a morphogen gradient was demonstrated using bacteria programmed by a synthetic gene circuit. This work presents a timing mechanism of pattern formation.
Using Escherichia coli programmed by a synthetic gene circuit, we demonstrate the generation of robust, self-organized ring patterns of gene expression in the absence of an apparent morphogen gradient.Instead of being a spatial cue, the morphogen serves as a timing cue to trigger the formation and maintenance of the ring patterns.The timing mechanism enables the system to sense the domain size of the environment and generate patterns that scale accordingly.
Diverse mechanisms have been proposed to explain biological pattern formation. Regardless of their specific molecular interactions, the majority of these mechanisms require morphogen gradients as the spatial cue, which are either predefined or generated as a part of the patterning process. However, using Escherichia coli programmed by a synthetic gene circuit, we demonstrate here the generation of robust, self-organized ring patterns of gene expression in the absence of an apparent morphogen gradient. Instead of being a spatial cue, the morphogen serves as a timing cue to trigger the formation and maintenance of the ring patterns. The timing mechanism enables the system to sense the domain size of the environment and generate patterns that scale accordingly. Our work defines a novel mechanism of pattern formation that has implications for understanding natural developmental processes.
doi:10.1038/msb.2013.55
PMCID: PMC3817405  PMID: 24104480
morphogen; pattern formation; synthetic biology; systems biology; temporal control
25.  Pregabalin for the Treatment of Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome 
Archives of internal medicine  2010;170(17):1586-1593.
Background
Evidence suggests that the urogenital pain of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) may be neuropathic.
Methods
This randomized, double-blind, placebo-controlled trial was conducted across 10 tertiary care centers in North America to determine whether pregabalin, which has been proved effective in other chronic pain syndromes, is effective in reducing CP/CPPS symptoms. In 2006–2007, 324 men with pelvic pain for at least 3 of the previous 6 months were enrolled in this study. Men were randomly assigned to receive pregabalin or placebo in a 2:1 ratio and were treated for 6 weeks. Pregabalin dosage was increased from 150 to 600 mg/d during the first 4 weeks. The primary outcome was a 6-point decrease in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) total score. Multiple secondary outcomes were assessed.
Results
Of 218 men assigned to receive pregabalin, 103 (47.2%) reported at least a 6-point decrease in the NIHCPSI total score at 6 weeks compared with 35.8% (38 of 106 men) assigned to receive placebo (P = .07, exact Mantel-Haenszel test, adjusting for clinical sites). Compared with the placebo group, men assigned to receive pregabalin experienced reductions in the NIH-CPSI total score and sub-scores (P < .05), a higher Global Response Assessment response rate (31.2% and 18.9%; P = .02), and improvement in total McGill Pain Questionnaire score (P = .01). Results for the other outcomes did not differ between groups.
Conclusion
Pregabalin therapy for 6 weeks was not superior to placebo use in the rate of a 6-point decrease (improvement) in the NIH-CPSI total score in men with CP/CPPS.
Trial Registration
clinicaltrials.gov Identifier: NCT00371033
doi:10.1001/archinternmed.2010.319
PMCID: PMC3767281  PMID: 20876412

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