Now showing items 1-20 of 8573

    • twenty one @ 601 [exhibit]: Celebrating HS/HSL's 21 Years at 601 W. Lombard

      University of Maryland, Baltimore. Health Sciences and Human Services Library (2019)
    • Delta Vs Gamma auditory steady state synchrony in schizophrenia

      Puvvada, K.C.; Summerfelt, A.; Du, X. (Oxford University Press, 2018)
      Background: Delta band (1-4 Hz) neuronal responses support the precision and stability of auditory processing, and a deficit in delta band synchrony may be relevant to auditory domain symptoms in schizophrenia patients. Methods: Delta band synchronization elicited by a 2.5 Hz auditory steady state response (ASSR) paradigm, along with those from theta (5 Hz), alpha (10 Hz), beta (20 Hz), gamma (40 Hz), and high gamma (80 Hz) frequency ASSR, were compared in 128 patients with schizophrenia, 108 healthy controls, and 55 first-degree relatives (FDR) of patients. Results: Delta band synchronization was significantly impaired in patients compared with controls (F = 18.3, P < .001). There was a significant 2.5 Hz by 40 Hz ASSR interaction (P = .023), arising from a greater reduction of 2.5 Hz ASSR than of 40 Hz ASSR, in patients compared with controls. Greater deficit in delta ASSR was associated with auditory perceptual abnormality (P = .007) and reduced verbal working memory (P < .001). Gamma frequency ASSR impairment was also significant but more modest (F = 8.7, P = .004), and this deficit was also present in FDR (P = .022). Conclusions: The ability to sustain delta band oscillation entrainment in the auditory pathway is significantly reduced in schizophrenia patients and appears to be clinically relevant. Copyright The Author(s) 2017.
    • Characterization of the Theileria parva sporozoite proteome

      Nyagwange, J.; Tijhaar, E.; Ternette, N. (Elsevier Ltd, 2018)
      East Coast fever is a lymphoproliferative disease caused by the tick-borne protozoan parasite Theileria parva. The sporozoite stage of this parasite, harboured and released from the salivary glands of the tick Rhipicephalus appendiculatus during feeding, invades and establishes infection in bovine lymphocytes. Blocking this initial stage of invasion presents a promising vaccine strategy for control of East Coast fever and can in part be achieved by targeting the major sporozoite surface protein p67. To support research on the biology of T. parva and the identification of additional candidate vaccine antigens, we report on the sporozoite proteome as defined by LC�MS/MS analysis. In total, 4780 proteins were identified in an enriched preparation of sporozoites. Of these, 2007 were identified as T. parva proteins, representing close to 50% of the total predicted parasite proteome. The remaining 2773 proteins were derived from the tick vector. The identified sporozoite proteins include a set of known T. parva antigens targeted by antibodies and cytotoxic T cells from cattle that are immune to East Coast fever. We also identified proteins predicted to be orthologs of Plasmodium falciparum sporozoite surface molecules and invasion organelle proteins, and proteins that may contribute to the phenomenon of bovine lymphocyte transformation. Overall, these data establish a protein expression profile of T. parva sporozoites as an important starting point for further study of a parasitic species which has considerable agricultural impact. Copyright 2018 The Authors
    • Novel self-etch adhesive with antibacterial and protein-repellent functions to prevent enamel demineralization

      Wang, B.; Zhang, N.; Wang, X. (Japanese Society for Dental Materials and Devices, 2018)
      Enamel demineralization is the most undesired side-effect of fixed orthodontic treatments. This study were to develop a novel adhesive that is self-etching instead of using the traditional etching method, and to form a sealant on the enamel to prevent demineralization. 2-methacryloyloxyethyl phosphorylcholine (MPC) and quaternary ammonium dimethylaminohexadecyl methacrylate (DMAHDM) were mixed into a self-etch adhesive (Adper Easy One, 3M, St. Paul, MN, USA; referred to as AEO). Enamel shear bond strength (SBS) was measured. Protein adsorption onto the resins was measured. An oral microcosm biofilm model with saliva was tested. Incorporation of 7.5% MPC and 5% DMAHDM into AEO did not reduce the SBS (p>0.1). AEO with 7.5% MPC+5% DMAHDM had protein adsorption that was only 1/18 that of AEO control. AEO with 7.5% MPC+5% DAMHDM had much stronger antibacterial properties (p<0.05). In conclusion, the new self-etch adhesive with MPC and DAMHDM greatly reduced protein adsorption and inhibited biofilm viability. Copyright 2018, Japanese Society for Dental Materials and Devices. All rights reserved.
    • Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse

      Yousaf, R.; Gu, C.; Ahmed, Z.M. (Public Library of Science, 2018)
      Autosomal recessive nonsyndromic hearing loss is a genetically heterogeneous disorder. Here, we report a severe-to-profound sensorineural hearing loss locus, DFNB100 on chromosome 5q13.2-q23.2. Exome enrichment followed by massive parallel sequencing revealed a c.2510G>A transition variant in PPIP5K2 that segregated with DFNB100-associated hearing loss in two large apparently unrelated Pakistani families. PPIP5Ks enzymes interconvert 5-IP7 and IP8, two key members of the inositol pyrophosphate (PP-IP) cell-signaling family. Their actions at the interface of cell signaling and bioenergetic homeostasis can impact many biological processes. The c.2510G>A transition variant is predicted to substitute a highly invariant arginine residue with histidine (p.Arg837His) in the phosphatase domain of PPIP5K2. Biochemical studies revealed that the p.Arg837His variant reduces the phosphatase activity of PPIP5K2 and elevates its kinase activity. We found that in mouse inner ear, PPIP5K2 is expressed in the cochlear and vestibular sensory hair cells, supporting cells and spiral ganglion neurons. Mice homozygous for a targeted deletion of the Ppip5k2 phosphatase domain exhibit degeneration of cochlear outer hair cells and elevated hearing thresholds. Our demonstration that PPIP5K2 has a role in hearing in humans indicates that PP-IP signaling is important to hair cell maintenance and function within inner ear. Copyright 2018 Public Library of Science. All Rights Reserved.
    • Cell-based reference samples designed with specific differences in microRNA biomarkers

      Pine, P.S.; Lund, S.P.; Stass, S.A. (BioMed Central Ltd., 2018)
      Background: We demonstrate the feasibility of creating a pair of reference samples to be used as surrogates for clinical samples measured in either a research or clinical laboratory setting. The reference sample paradigm presented and evaluated here is designed to assess the capability of a measurement process to detect true differences between two biological samples. Cell-based reference samples can be created with a biomarker signature pattern designed in silico. Clinical laboratories working in regulated applications are required to participate in proficiency testing programs; research laboratories doing discovery typically do not. These reference samples can be used in proficiency tests or as process controls that allow a laboratory to evaluate and optimize its measurement systems, monitor performance over time (process drift), assess changes in protocols, reagents, and/or personnel, maintain standard operating procedures, and most importantly, provide evidence for quality results. Results: The biomarkers of interest in this study are microRNAs (miRNAs), small non-coding RNAs involved in the regulation of gene expression. Multiple lung cancer associated cell lines were determined by reverse transcription (RT)-PCR to have sufficiently different miRNA profiles to serve as components in mixture designs as reference samples. In silico models based on the component profiles were used to predict miRNA abundance ratios between two different cell line mixtures, providing target values for profiles obtained from in vitro mixtures. Two reference sample types were tested: total RNA mixed after extraction from cell lines, and intact cells mixed prior to RNA extraction. MicroRNA profiling of a pair of samples composed of extracted RNA derived from these cell lines successfully replicated the target values. Mixtures of intact cells from these lines also approximated the target values, demonstrating potential utility as mimics for clinical specimens. Both designs demonstrated their utility as reference samples for inter- or intra-laboratory testing. Conclusions: Cell-based reference samples can be created for performance assessment of a measurement process from biomolecule extraction through quantitation. Although this study focused on miRNA profiling with RT-PCR using cell lines associated with lung cancer, the paradigm demonstrated here should be extendable to genome-scale platforms and other biomolecular endpoints. Copyright 2018 The Author(s).
    • Primordial origin and diversification of plasmids in Lyme disease agent bacteria

      Casjens, S.R.; Di, L.; Akther, S. (BioMed Central Ltd., 2018)
      Background: With approximately one-third of their genomes consisting of linear and circular plasmids, the Lyme disease agent cluster of species has the most complex genomes among known bacteria. We report here a comparative analysis of plasmids in eleven Borreliella (also known as Borrelia burgdorferi sensu lato) species. Results: We sequenced the complete genomes of two B. afzelii, two B. garinii, and individual B. spielmanii, B. bissettiae, B. valaisiana and B. finlandensis isolates. These individual isolates carry between seven and sixteen plasmids, and together harbor 99 plasmids. We report here a comparative analysis of these plasmids, along with 70 additional Borreliella plasmids available in the public sequence databases. We identify only one new putative plasmid compatibility type (the 30th) among these 169 plasmid sequences, suggesting that all or nearly all such types have now been discovered. We find that the linear plasmids in the non-B. burgdorferi species have undergone the same kinds of apparently random, chaotic rearrangements mediated by non-homologous recombination that we previously discovered in B. burgdorferi. These rearrangements occurred independently in the different species lineages, and they, along with an expanded chromosomal phylogeny reported here, allow the identification of several whole plasmid transfer events among these species. Phylogenetic analyses of the plasmid partition genes show that a majority of the plasmid compatibility types arose early, most likely before separation of the Lyme agent Borreliella and relapsing fever Borrelia clades, and this, with occasional cross species plasmid transfers, has resulted in few if any species-specific or geographic region-specific Borreliella plasmid types. Conclusions: The primordial origin and persistent maintenance of the Borreliella plasmid types support their functional indispensability as well as evolutionary roles in facilitating genome diversity. The improved resolution of Borreliella plasmid phylogeny based on conserved partition-gene clusters will lead to better determination of gene orthology which is essential for prediction of biological function, and it will provide a basis for inferring detailed evolutionary mechanisms of Borreliella genomic variability including homologous gene and plasmid exchanges as well as non-homologous rearrangements. Copyright 2018 The Author(s).
    • Online advertising and marketing claims by providers of proton beam therapy: Are they guideline-based?

      Corkum, M.T.; Liu, W.; Palma, D.A. (BioMed Central Ltd., 2018)
      Background: Cancer patients frequently search the Internet for treatment options, and hospital websites are seen as reliable sources of knowledge. Guidelines support the use of proton radiotherapy in specific disease sites or on clinical trials. This study aims to evaluate direct-to-consumer advertising content and claims made by proton therapy centre (PTC) websites worldwide. Methods: Operational PTC websites in English were identified through the Particle Therapy Co-Operative Group website. Data abstraction of website content was performed independently by two investigators. Eight international guidelines were consulted to determine guideline-based indications for proton radiotherapy. Univariate and multivariate logistic regression models were used to determine the characteristics of PTC websites that indicated proton radiotherapy offered greater disease control or cure rates. Results: Forty-eight PTCs with 46 English websites were identified. 60�9% of PTC websites claimed proton therapy provided improved disease control or cure. U.S. websites listed more indications than international websites (15�5 � 5�4 vs. 10�4 � 5�8, p = 0�004). The most common disease sites advertised were prostate (87�0%), head and neck (87�0%) and pediatrics (82�6%), all of which were indicated in least one international guideline. Several disease sites advertised were not present in any consensus guidelines, including pancreatobiliary (52�2%), breast (50�0%), and esophageal (43�5%) cancers. Multivariate analysis found increasing number of disease sites and claiming their centre was a local or regional leader in proton radiotherapy was associated with indicating proton radiotherapy offers greater disease control or cure. Conclusions: Information from PTC websites often differs from recommendations found in international consensus guidelines. As online marketing information may have significant influence on patient decision-making, alignment of such information with accepted guidelines and consensus opinion should be adopted by PTC providers. Copyright 2018 The Author(s).
    • Overexpressing TPTE2 (TPIP), a homolog of the human tumor suppressor gene PTEN, rescues the abnormal phenotype of the PTEN-/- mutant

      Lusche, D.F.; Buchele, E.C.; Russell, K.B. (Impact Journals LLC, 2018)
      One possible approach to normalize mutant cells that are metastatic and tumorigenic, is to upregulate a functionally similar homolog of the mutated gene. Here we have explored this hypothesis by generating an overexpressor of TPTE2 (TPIP), a homolog of PTEN, in PTEN-/- mutants, the latter generated by targeted mutagenesis of a human epithelial cell line. Overexpression of TPTE2 normalized phenotypic changes associated with the PTEN mutation. The PTEN-/--associated changes rescued by overexpressing TPTE2 included 1) accelerated wound healing in the presence or absence of added growth factors (GFs), 2) increased division rates on a 2D substrate in the presence of GFs, 3) adhesion and viability on a 2D substrate in the absence of GFs, 4) viability in a 3D Matrigel model in the absence of GFs and substrate adhesion 5) loss of apoptosis-associated annexin V cell surface binding sites. The results justify further exploration into the possibility that upregulating TPTE2 by a drug may reverse metastatic and tumorigenic phenotypes mediated in part by a mutation in PTEN. This strategy may also be applicable to other tumorigenic mutations in which a homolog to the mutated gene is present and can substitute functionally. Copyright Lusche et al.
    • The dysregulation of tRNAs and tRNA derivatives in cancer

      Huang, S.-Q.; Sun, B.; Xiong, Z.-P. (BioMed Central Ltd., 2018)
      Transfer RNAs (tRNAs), traditionally considered to participate in protein translation, were interspersed in the entire genome. Recent studies suggested that dysregulation was observed in not only tRNAs, but also tRNA derivatives generated by the specific cleavage of pre- and mature tRNAs in the progression of cancer. Accumulating evidence had identified that certain tRNAs and tRNA derivatives were involved in proliferation, metastasis and invasiveness of cancer cell, as well as tumor growth and angiogenesis in several malignant human tumors. This paper reviews the importance of the dysregulation of tRNAs and tRNA derivatives during the development of cancer, such as breast cancer, lung cancer, and melanoma, aiming at a better understanding of the tumorigenesis and providing new ideas for the treatment of these cancers. Copyright 2018 The Author(s).
    • Oral health knowledge, behavior, and care seeking among pregnant and recently-delivered women in rural Nepal: A qualitative study

      Lubon, A.J.; Erchick, D.J.; Khatry, S.K. (BioMed Central Ltd., 2018)
      Background: Oral health behavior and attitudes of pregnant women in low-income countries are rarely examined, yet should be considered when designing preventative or therapeutic studies to reduce burden of oral diseases. We aimed to understand dental care-seeking behavior, as well as oral health knowledge and attitudes of oral health among pregnant women in rural Nepal. Methods: Semi-structured in-depth interviews (n = 16) and focus group discussions (3 groups, n = 23) were conducted among pregnant and recently-delivered women in Sarlahi, Nepal. Transcripts were translated from the local language to English then analyzed using a hybrid approach to thematic coding with Atlas.ti version 7. Results: Women felt confident describing the signs and symptoms of tooth decay and gum disease, but were not knowledgeable about where to receive care for tooth and/or gum pain and relied heavily on the knowledge of their community. Some women used a toothbrush and toothpaste at least once a day to clean their teeth, but many reported the traditional use of a branch of a local shrub or tree as their teeth cleaning instrument. Women suggested a willingness to consider using an oral rinse throughout pregnancy, perceiving that it might have a positive impact on infant health. Conclusions: Future studies should focus on providing adequate and sustainable resources for pregnant women in Nepal and other low income settings to engage in good oral health behaviors (possibly supported through community-based workers), to maintain dental hygiene, and to access qualified dentists as a means of improving their oral health. Copyright 2018 The Author(s).
    • Atrial fibrillation after transhiatal esophagectomy with transcervical endoscopic esophageal mobilization: One institution's experience

      Colwell, E.M.; Encarnacion, C.O.; Rein, L.E. (BioMed Central Ltd., 2018)
      Background: There have been numerous studies regarding atrial fibrillation (AF) associated with cardiac and pulmonary surgery; however, studies looking at esophagectomy and atrial fibrillation are sparse. The goal of this study was to review our institution's atrial fibrillation rate following esophagectomy in order to better define the incidence and predisposing factors in this patient population. Methods: A retrospective chart review of all patients undergoing esophagectomy with transcervical endoscopic mobilization of the esophagus (TEEM) at the Medical College of Wisconsin and Affiliated Hospitals from July 2009 through December 2012. Results: Seventy-one patients underwent TEEM esophagectomy during the study period. Of those, 23 (32.4%) patients developed new atrial fibrillation postoperatively. ICU (Intensive Care Unit) length of stay was 7.1 days for those that did not receive amiodarone, compared to 5.3 days for those that did receive amiodarone (p < 0.025). Those that went into AF spent on average 9.3 days in the ICU compared to 4.7 days for their counterparts that did not go into AF (p < 0.006). Total length of stay was not statistically different between populations [15.1 +/- 11.3 days compared to 13.5 +/- 9.4 days for those who did not go into AF (p < 0.281)]. Receiving preoperative amiodarone was found to reduce the overall incidence of AF. There was a trend towards decreased risk of going into AF in those who received preoperative amiodarone with an adjusted hazard ratio of 0.555 (p = 0.057). Conclusion: Similar to data reported in previous literature, postoperative atrial fibrillation was found to increase ICU length of stay as well as overall length of hospital stay. Preoperative amiodarone administration displayed a trend toward decreasing the rates of atrial fibrillation in patients undergoing TEEM. Copyright 2018 The Author(s).
    • Financial hardship and drug use among men who have sex with men

      Park, S.H.; Al-Ajlouni, Y.; Palamar, J.J. (BioMed Central Ltd., 2018)
      Background: Little is known about the role of financial hardship as it relates to drug use, especially among men who have sex with men (MSM). As such, this study aimed to investigate potential associations between financial hardship status and drug use among MSM. Methods: We conducted a cross-sectional survey of 580 MSM in Paris recruited using a popular geosocial-networking smartphone application (GSN apps). Descriptive analyses and multivariate analyses were performed. A modified Poisson model was used to assess associations between financial hardship status and use of drugs (any drugs, tobacco, alcohol, marijuana, inhalant nitrites, and club drugs). Results: In our sample, 45.5% reported that it was somewhat, very, or extremely difficult to meet monthly payments of bills (high financial hardship). In multivariate analyses, a high level of financial hardship was significantly associated with an increased likelihood of reporting use of any substance use (adjusted risk ratio [aRR]=1.15; 95% CI=1.05-1.27), as well as use of tobacco (aRR=1.45; 95% CI=1.19-1.78), marijuana (aRR=1.48; 95% CI =1.03-2.13), and inhalant nitrites (aRR=1.24; 95% CI=1.03-1.50). Conclusions: Financial hardship was associated with drug use among MSM, suggesting the need for interventions to reduce the burden of financial hardship in this population. Copyright 2018 The Author(s).
    • Meta-analysis of Exercise Training on Vascular Endothelial Function in Cancer Survivors

      Beaudry, R.I.; Liang, Y.; Boyton, S.T. (SAGE Publications Inc., 2018)
      Cancer and cardiovascular disease (CVD) are leading causes of morbidity and mortality in the United States. Vascular endothelial dysfunction, an important contributor in the development of CVD, improves with exercise training in patients with CVD. However, the role of regular exercise to improve vascular function in cancer survivors remains equivocal. We performed a meta-analysis to determine the effect of exercise training on vascular endothelial function in cancer survivors. We searched PubMed (1975 to 2016), EMBASE CINAHL (1937 to 2016), OVID MEDLINE (1948 to 2016), and Cochrane Central Registry of Controlled Trials (1991 to 2016) using search terms: vascular function, endothelial function, flow-mediated dilation [FMD], reactive hyperemia, exercise, and cancer. Studies selected were randomized controlled trials of exercise training on vascular endothelial function in cancer survivors. We calculated pooled effect sizes and performed a meta-analysis. We identified 4 randomized controlled trials (breast cancer, n=2; prostate cancer, n=2) measuring vascular endothelial function by FMD (n=3) or reactive hyperemia index (n=1), including 163 cancer survivors (exercise training, n=82; control, n=81). Aerobic exercise training improved vascular function (n=4 studies; standardized mean difference [95% CI]=0.65 [0.33, 0.96], I2=0%; FMD, weighted mean difference [WMD]=1.28 [0.22, 2.34], I2=23.2%) and peak exercise oxygen uptake (3 trials; WMD [95% CI]=2.22 [0.83, 3.61] mL/kg/min; I2=0%). Our findings indicate that exercise training improves vascular endothelial function and exercise capacity in breast and prostate cancer survivors. Copyright 2018, Copyright The Author(s) 2018.
    • Correction to: Top Down Tandem Mass Spectrometric Analysis of a Chemically Modified Rough-Type Lipopolysaccharide Vaccine Candidate (Journal of The American Society for Mass Spectrometry, (2018), 29, 6, (1221-1229), 10.1007/s13361-018-1897-y)

      Oyler, B.L.; Khan, M.M.; Smith, D.F. (Springer New York LLC, 2018)
      In the preceding article �Top Down Tandem Mass Spectrometric Analysis of a Chemically Modified Rough-Type Lipopolysaccharide Vaccine Candidate� by Oyler et al., an error in the J5 E. coli LPS chemical structure (Figs.�2 and 4) was introduced and propagated into the final revision. Copyright 2018, American Society for Mass Spectrometry.
    • Overcoming Ovarian Cancer Drug Resistance with a Cold Responsive Nanomaterial

      Wang, H.; Agarwal, P.; Zhao, G. (American Chemical Society, 2018)
      Drug resistance due to overexpression of membrane transporters in cancer cells and the existence of cancer stem cells (CSCs) is a major hurdle to effective and safe cancer chemotherapy. Nanoparticles have been explored to overcome cancer drug resistance. However, drug slowly released from nanoparticles can still be efficiently pumped out of drug-resistant cells. Here, a hybrid nanoparticle of phospholipid and polymers is developed to achieve cold-triggered burst release of encapsulated drug. With ice cooling to below ?12 �C for both burst drug release and reduced membrane transporter activity, binding of the drug with its target in drug-resistant cells is evident, while it is minimal in the cells kept at 37 �C. Moreover, targeted drug delivery with the cold-responsive nanoparticles in combination with ice cooling not only can effectively kill drug-resistant ovarian cancer cells and their CSCs in vitro but also destroy both subcutaneous and orthotopic ovarian tumors in vivo with no evident systemic toxicity. Copyright Copyright 2018 American Chemical Society.
    • Effect of Patiromer on Hyperkalemia Recurrence in Older Chronic Kidney Disease Patients Taking RAAS Inhibitors

      Weir, M.R.; Bushinsky, D.A.; Benton, W.W. (Elsevier Inc., 2018)
      Background: Older people are predisposed to hyperkalemia because of impaired renal function, comorbid conditions, and polypharmacy. Renin�angiotensin�aldosterone system inhibitors (RAASi), which are recommended to treat chronic kidney disease and heart failure augment the risk. Patiromer, a nonabsorbed potassium binder, was shown in the phase 3 OPAL-HK study to decrease serum potassium in patients with chronic kidney disease taking RAASi. We studied the efficacy and safety of patiromer in a prespecified subgroup of patients aged ?65 years from OPAL-HK. Methods: Chronic kidney disease patients with mild or moderate-to-severe hyperkalemia received patiromer, initially 8.4 g/d or 16.8 g/d, respectively, for 4 weeks (treatment phase, part A). Eligible patients entered an 8-week randomized withdrawal phase (part B) and continued patiromer or switched to placebo. Results: Mean � standard error change in serum potassium from baseline to week 4 of part A (primary endpoint) in patients aged ?65 years was ?1.01 � 0.05 mEq/L (P <.001); 97% achieved serum potassium 3.8-<5.1 mEq/L. The serum potassium increase during the first 4 weeks of part B was greater in patients taking placebo than in those taking patiromer (P <.001). Fewer patients taking patiromer (30%) than placebo (92%) developed recurrent hyperkalemia (serum potassium ?5.1 mEq/L). Mild-to-moderate constipation occurred in 15% (part A) and 7% (part B) of patients aged ?65 years. Serum potassium <3.5 mEq/L and serum magnesium <1.4 mg/dL were infrequent (4% each in patients aged ?65 years in part A). Conclusions: Patiromer reduced recurrent hyperkalemia and was well tolerated in older chronic kidney disease patients taking RAASi. Copyright 2018 The Authors
    • Superior metastasis-free survival for patients with high-risk prostate cancer treated with definitive radiation therapy compared to radical prostatectomy: A propensity score-matched analysis

      Markovina, S.; Meeks, M.W.; Badiyan, S. (Elsevier Inc, 2018)
      Purpose: For high-risk prostate cancer (HR-PCa) in men with a life expectancy of at least 10 years, the National Comprehensive Cancer Network recommends radiation therapy (RT) plus androgen deprivation therapy (ADT) with category 1 evidence or radical prostatectomy (RP) as an acceptable initial therapy. Randomized evidence regarding which therapy is optimal for disease control is lacking for men with HR-PCa. We performed a propensity-score-matched comparison of outcomes for men with localized HR-PCa treated with primary RT or RP. Methods and materials: The medical records of patients with localized HR-PCa who were treated at our institution between 2002 and 2011 were reviewed. Patient and disease characteristics, treatment details, and outcomes were collected. A combination of nearest-neighbor propensity score matching on age, Adult Comorbidity Evaluation-27 comorbidity index, prostate-specific antigen, biopsy Gleason scores, and clinical T-stage as well as exact matching on prostate-specific antigen, biopsy Gleason scores, and clinical T-stage was performed. Outcomes were measured from diagnosis. Multivariate Cox proportional hazards regression was used to compare metastasis-free and overall survival. Results: A total of 246 patients were identified with 62 propensity-score-matched pairs. ADT was administered to 6.5% and 80.6% of patients receiving RP and RT, respectively. Five-year rates of metastasis for RP and RT were 33% and 8.9%, respectively (P =.003). Overall survival was not different. Delay of salvage therapy was longer for patients undergoing primary RT (P <.001). Findings were similar when only those patients who did not receive ADT were compared. Conclusions: At our institution, treatment with primary RT resulted in superior metastasis-free survival over RP. This was not accompanied by an improvement in OS. Copyright 2017 The Authors
    • Loss of S100A1 expression leads to Ca2+ release potentiation in mutant mice with disrupted CaM and S100A1 binding to CaMBD2 of RyR1

      Hern�ndez-Ochoa, E.O.; Melville, Z.; Vanegas, C. (American Physiological Society, 2018)
      Calmodulin (CaM) and S100A1 fine-tune skeletal muscle Ca2+ release via opposite modulation of the ryanodine receptor type 1 (RyR1). Binding to and modulation of RyR1 by CaM and S100A1 occurs predominantly at the region ranging from amino acid residue 3614-3640 of RyR1 (here referred to as CaMBD2). Using synthetic peptides, it has been shown that CaM binds to two additional regions within the RyR1, specifically residues 1975-1999 and 4295-4325 (CaMBD1 and CaMBD3, respectively). Because S100A1 typically binds to similar motifs as CaM, we hypothesized that S100A1 could also bind to CaMBD1 and CaMBD3. Our goals were: (1) to establish whether S100A1 binds to synthetic peptides containing CaMBD1 and CaMBD3 using isothermal calorimetry (ITC), and (2) to identify whether S100A1 and CaM modulate RyR1 Ca2+ release activation via sites other than CaMBD2 in RyR1 in its native cellular context. We developed the mouse model (RyR1D-S100A1KO), which expresses point mutation RyR1-L3625D (RyR1D) that disrupts the modulation of RyR1 by CaM and S100A1 at CaMBD2 and also lacks S100A1 (S100A1KO). ITC assays revealed that S100A1 binds with different affinities to CaMBD1 and CaMBD3. Using high-speed Ca2+ imaging and a model for Ca2+ binding and transport, we show that the RyR1D-S100A1KO muscle fibers exhibit a modest but significant increase in myoplasmic Ca2+ transients and enhanced Ca2+ release flux following field stimulation when compared to fibers from RyR1D mice, which were used as controls to eliminate any effect of binding at CaMBD2, but with preserved S100A1 expression. Our results suggest that S100A1, similar to CaM, binds to CaMBD1 and CaMBD3 within the RyR1, but that CaMBD2 appears to be the primary site of RyR1 regulation by CaM and S100A1. Copyright 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
    • Regulation of intestinal epithelial barrier function by long noncoding RNA uc.173 through interaction with microRNA 29b

      Wang, J.-Y.; Cui, Y.-H.; Xiao, L. (American Society for Microbiology, 2018)
      The mammalian intestinal epithelium establishes a selectively permeable barrier that supports nutrient absorption and prevents intrusion by noxious luminal substances and microbiota. The effectiveness and integrity of the barrier function are tightly regulated via well-controlled mechanisms. Long noncoding RNAs transcribed from ultraconserved regions (T-UCRs) control diverse cellular processes, but their roles in the regulation of gut permeability remain largely unknown. Here we report that the T-UCR uc.173 enhances intestinal epithelial barrier function by antagonizing microRNA 29b (miR-29b). Decreasing the levels of uc.173 by gene silencing led to dysfunction of the intestinal epithelial barrier in cultured cells and increased the vulnerability of the gut barrier to septic stress in mice. uc.173 specifically stimulated translation of the tight junction (TJ) claudin-1 (CLDN1) by associating with miR-29b rather than by binding directly to CLDN1 mRNA. uc.173 acted as a natural decoy RNA for miR-29b, which interacts with CLDN1 mRNA via the 3= untranslated region and represses its translation. Ectopically expressed uc.173 abolished the association of miR-29b with CLDN1 mRNA and restored claudin-1 expression to normal levels in cells overexpressing miR-29b, thus rescuing the barrier function. These results highlight a novel function of uc.173 in controlling gut permeability and define a mechanism by which uc.173 stimulates claudin-1 translation, by decreasing the availability of miR-29b to CLDN1 mRNA. Copyright 2018 American Society for Microbiology.