Head and Neck Diseases by Alexandros G.Sfakianakis: 01/15/16

Παρασκευή 15 Ιανουαρίου 2016

Protocol for the Evaluation of Speech Intelligibility in Dysarthrias: Evidence of Reliability and Validity

Background/Aims: Studies about the reliability and validity of intelligibility measures are fundamental to direct their use and interpretation in both clinical and research settings. The present study assessed inter-rater reliability, internal consistency and criterion validity of scores for the sentence and word subtests of the Protocol for the Evaluation of Speech Intelligibility (PESI). Methods: This study included 180 adult volunteers who were divided into three groups: 30 speakers with dysarthria, 30 control speakers and 120 listeners. Intelligibility scores were calculated according to the percentage of words correctly transcribed in each subtest: words in sentences and single words. Results: The intelligibility measurements exhibited a high level of inter-rater reliability for sentences [intraclass correlation coefficient (ICC) = 0.94] and for single words (ICC = 0.96). The items from the single words subtest of the PESI revealed high internal consistency (Cronbach's alpha = 0.93). The measurement of intelligibility of sentences and single words had a high discriminatory power (0.82 and 0.95, respectively), with high sensitivity and specificity, particularly for scores in the single words subtest. Conclusion: This study provides preliminary evidence of the reliability and validity of the PESI.
Folia Phoniatr Logop 2015;67:212-218

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A Participatory Design Approach to Develop a Web-Based Self-Care Program Supporting Early Rehabilitation among Patients after Total Laryngectomy

Aim: To develop a Web-based self-care program for patients after total laryngectomy according to a participatory design approach. Methods: We conducted a needs assessment with laryngectomees (n = 9) and their partners (n = 3) by means of a focus group interview. In 4 focus group sessions, a requirement plan was formulated by a team of health care professionals (n = 10) and translated into a prototype. An e-health application was built including illustrated information on functional changes after total laryngectomy as well as video demonstrations of skills and exercises. Usability of the prototype was tested by end users (n = 4) and expert users (n = 10). Interviews were held to elicit the intention to use and the desired implementation strategy. Results: Six main self-care topics were identified: (1) nutrition, (2) tracheostomy care, (3) voice prosthesis care, (4) speech rehabilitation, (5) smell rehabilitation, and (6) mobility of head, neck, and shoulder muscles. Expert users expressed concerns regarding tailored exercises, indicated a positive intent to implement the intervention in routine care, and expressed a need for guidance when implementing the intervention. End users and expert users appreciated the content completeness and multimedia-based information built into the application. Conclusion: The participatory design is a valuable approach to develop a self-care program to help meet users' needs.
Folia Phoniatr Logop 2015;67:193-201

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1{alpha},25(OH)2D3 and Skeletal Muscle Genomics and Proteomics

Muscle weakness and myopathy are observed in vitamin D deficiency and chronic renal failure, where concentrations of the active vitamin D3 metabolite, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), are low. To evaluate the mechanism of action of 1α,25(OH)2D3 in skeletal muscle, we examined mitochondrial oxygen consumption, dynamics, and biogenesis and changes in expression of nuclear genes encoding mitochondrial proteins in human skeletal muscle cells following treatment with 1α,25(OH)2D3. The mitochondrial oxygen consumption rate (OCR) increased in 1α,25(OH)2D3-treated cells. Vitamin D3 metabolites lacking a 1α-hydroxyl group (vitamin D3, 25-hydroxyvitamin D3, and 24R,25-dihydroxyvitamin D3) decreased or failed to increase OCR. 1α-Hydroxyvitamin D3 did not increase OCR. In 1α,25(OH)2D3-treated cells, mitochondrial volume and branching and expression of the pro-fusion protein OPA1 (optic atrophy 1) increased, whereas expression of the pro-fission proteins Fis1 (fission 1) and Drp1 (dynamin 1-like) decreased. Phosphorylated pyruvate dehydrogenase (PDH) (Ser-293) and PDH kinase 4 (PDK4) decreased in 1α,25(OH)2D3-treated cells. There was a trend to increased PDH activity in 1α,25(OH)2D3-treated cells (p = 0.09). 83 nuclear mRNAs encoding mitochondrial proteins were changed following 1α,25(OH)2D3 treatment; notably, PDK4 mRNA decreased, and PDP2 mRNA increased. MYC, MAPK13, and EPAS1 mRNAs, which encode proteins that regulate mitochondrial biogenesis, were increased following 1α,25(OH)2D3 treatment. Vitamin D receptor-dependent changes in the expression of 1947 mRNAs encoding proteins involved in muscle contraction, focal adhesion, integrin, JAK/STAT, MAPK, growth factor, and p53 signaling pathways were observed following 1α,25(OH)2D3 treatment. Five micro-RNAs were induced or repressed by 1α,25(OH)2D3. 1α,25(OH)2D3 regulates mitochondrial function, dynamics, and enzyme function, which are likely to influence muscle strength.

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A Programmed Metabolic Event Determines Aging Metabolism

Aging involves progressive loss of cellular function and integrity, presumably caused by accumulated stochastic damage to cells. Alterations in energy metabolism contribute to aging, but how energy metabolism changes with age, how these changes affect aging, and whether they can be modified to modulate aging remain unclear. In locomotory muscle of post-fertile Caenorhabditis elegans, we identified a progressive decrease in cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), a longevity-associated metabolic enzyme, and a reciprocal increase in glycolytic pyruvate kinase (PK) that were necessary and sufficient to limit lifespan. Decline in PEPCK-C with age also led to loss of cellular function and integrity including muscle activity, and cellular senescence. Genetic and pharmacologic interventions of PEPCK-C, muscle activity, and AMPK signaling demonstrate that declines in PEPCK-C and muscle function with age interacted to limit reproductive life and lifespan via disrupted energy homeostasis. Quantifications of metabolic flux show that reciprocal changes in PEPCK-C and PK with age shunted energy metabolism toward glycolysis, reducing mitochondrial bioenergetics. Last, calorie restriction countered changes in PEPCK-C and PK with age to elicit anti-aging effects via TOR inhibition. Thus, a programmed metabolic event involving PEPCK-C and PK is a determinant of aging that can be modified to modulate aging.

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GTP Hydrolysis on Sar1 Is Regulated by Membrane Curvature and Facilitates Vesicle Formation♦ Papers of the Week

♦ See referenced article, J. Biol. Chem. 2016, 291, 1014–1027Many proteins travel through the secretory pathway in lipid-bound transport carriers. Most of the transport carriers are generated at specific locations on the endoplasmic reticulum where the cytosolic coat protein II (COPII) complex plays a role. A GTPase called Sar1 is a member of the COPII complex. It is involved in membrane bending, recruitment of other COPII coat proteins, and vesicle formation. However, the coordination of these different activities by Sar1 is not well understood. In this Paper of the Week, Anjon Audhya at the University of Wisconsin-Madison School of Medicine and Public Health and colleagues showed that Sar1 senses membrane curvature to bind more avidly to highly curved membranes. The investigators also showed that the GTPase activity of Sar1 increases when the membranes are more curved. The authors comment, "Taken together, our data support a stepwise model in which the amino-terminal amphipathic helix of GTP-bound Sar1 stably penetrates the endoplasmic reticulum membrane, promoting local membrane deformation. As membrane bending increases, Sar1 membrane binding is elevated, ultimately culminating in GTP hydrolysis, which may destabilize the bilayer sufficiently to facilitate membrane fission."jbc;291/3/1028/FU1F1FU1Representative atomic force microscopy images of supported lipid bilayers composed of 70% phosphatidylcholine, 15% phosphatidylethanolamine, and 15% phosphatidylserine imaged over time, following assembly in the presence of GDP-bound Sar1 (400 nm) and supplementation with a buffer containing 1 mm GTP. The times shown are relative to the timing of GTP addition. Scale bar, 250 nm.

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Rab32/38 Inactivation by RUTBC1 in Melanocytes Membrane Biology

Two cell type-specific Rab proteins, Rab32 and Rab38 (Rab32/38), have been proposed as regulating the trafficking of melanogenic enzymes, including tyrosinase and tyrosinase-related protein 1 (Tyrp1), to melanosomes in melanocytes. Like other GTPases, Rab32/38 function as switch molecules that cycle between a GDP-bound inactive form and a GTP-bound active form; the cycle is thought to be regulated by an activating enzyme, guanine nucleotide exchange factor (GEF), and an inactivating enzyme, GTPase-activating protein (GAP), which stimulates the GTPase activity of Rab32/38. Although BLOC-3 has already been identified as a Rab32/38-specific GEF that regulates the trafficking of tyrosinase and Tyrp1, no physiological GAP for Rab32/38 in melanocytes has ever been identified, and it has remained unclear whether Rab32/38 is involved in the trafficking of dopachrome tautomerase, another melanogenic enzyme, in mouse melanocytes. In this study we investigated RUTBC1, which was originally characterized as a Rab9-binding protein and GAP for Rab32 and Rab33B in vitro, and the results demonstrated that RUTBC1 functions as a physiological GAP for Rab32/38 in the trafficking of all three melanogenic enzymes in mouse melanocytes. The results of this study also demonstrated the involvement of Rab9A in the regulation of the RUTBC1 localization and in the trafficking of all three melanogenic enzymes. We discovered that either excess activation or inactivation of Rab32/38 achieved by manipulating RUTBC1 inhibits the trafficking of all three melanogenic enzymes. These results collectively indicate that proper spatiotemporal regulation of Rab32/38 is essential for the trafficking of all three melanogenic enzymes in mouse melanocytes.

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Significance of HIV-1 Exosomal TAR RNA in Cytokine Regulation Cell Biology

HIV-1 infection results in a chronic illness because long-term highly active antiretroviral therapy can lower viral titers to an undetectable level. However, discontinuation of therapy rapidly increases virus burden. Moreover, patients under highly active antiretroviral therapy frequently develop various metabolic disorders, neurocognitive abnormalities, and cardiovascular diseases. We have previously shown that exosomes containing trans-activating response (TAR) element RNA enhance susceptibility of undifferentiated naive cells to HIV-1 infection. This study indicates that exosomes from HIV-1-infected primary cells are highly abundant with TAR RNA as detected by RT-real time PCR. Interestingly, up to a million copies of TAR RNA/μl were also detected in the serum from HIV-1-infected humanized mice suggesting that TAR RNA may be stable in vivo. Incubation of exosomes from HIV-1-infected cells with primary macrophages resulted in a dramatic increase of proinflammatory cytokines, IL-6 and TNF-β, indicating that exosomes containing TAR RNA could play a direct role in control of cytokine gene expression. The intact TAR molecule was able to bind to PKR and TLR3 effectively, whereas the 5′ and 3′ stems (TAR microRNAs) bound best to TLR7 and -8 and none to PKR. Binding of TAR to PKR did not result in its phosphorylation, and therefore, TAR may be a dominant negative decoy molecule in cells. The TLR binding through either TAR RNA or TAR microRNA potentially can activate the NF-κB pathway and regulate cytokine expression. Collectively, these results imply that exosomes containing TAR RNA could directly affect the proinflammatory cytokine gene expression and may explain a possible mechanism of inflammation observed in HIV-1-infected patients under cART.

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NDRG1 Inhibits ErbB Receptor Activation Cell Biology

N-MYC downstream-regulated gene-1 (NDRG1) is a potent growth and metastasis suppressor that acts through its inhibitory effects on a wide variety of cellular signaling pathways, including the TGF-β pathway, protein kinase B (AKT)/PI3K pathway, RAS, etc. To investigate the hypothesis that its multiple effects could be regulated by a common upstream effector, the role of NDRG1 on the epidermal growth factor receptor (EGFR) and other members of the ErbB family, namely human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 3 (HER3), was examined. We demonstrate that NDRG1 markedly decreased the expression and activation of EGFR, HER2, and HER3 in response to the epidermal growth factor (EGF) ligand, while also inhibiting formation of the EGFR/HER2 and HER2/HER3 heterodimers. In addition, NDRG1 also decreased activation of the downstream MAPKK in response to EGF. Moreover, novel anti-tumor agents of the di-2-pyridylketone class of thiosemicarbazones, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, which markedly up-regulate NDRG1, were found to inhibit EGFR, HER2, and HER3 expression and phosphorylation in cancer cells. However, the mechanism involved appeared dependent on NDRG1 for di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, but was independent of this metastasis suppressor for di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone. This observation demonstrates that small structural changes in thiosemicarbazones result in marked alterations in molecular targeting. Collectively, these results reveal a mechanism for the extensive downstream effects on cellular signaling attributed to NDRG1. Furthermore, this study identifies a novel approach for the treatment of tumors resistant to traditional EGFR inhibitors.

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Connexins in Zebrafish Skin Patterning Developmental Biology

The zebrafish has a striped skin pattern on its body, and Connexin41.8 (Cx41.8) and Cx39.4 are involved in striped pattern formation. Mutations in these connexins change the striped pattern to a spot or labyrinth pattern. In this study, we characterized Cx41.8 and Cx39.4 after expression in Xenopus oocytes. In addition, we analyzed Cx41.8 mutants Cx41.8I203F and Cx41.8M7, which caused spot or labyrinth skin patterns, respectively, in transgenic zebrafish. In the electrophysiological analysis, the gap junctions formed by Cx41.8 and Cx39.4 showed distinct sensitivity to transjunctional voltage. Analysis of non-junctional (hemichannel) currents revealed a large voltage-dependent current in Cx39.4-expressing oocytes that was absent in cells expressing Cx41.8. Junctional currents induced by both Cx41.8 and Cx39.4 were reduced by co-expression of Cx41.8I203F and abolished by co-expression of Cx41.8M7. In the transgenic experiment, Cx41.8I203F partially rescued the Cx41.8 null mutant phenotype, whereas Cx41.8M7 failed to rescue the null mutant, and it elicited a more severe phenotype than the Cx41.8 null mutant, as evidenced by a smaller spot pattern. Our results provide evidence that gap junctions formed by Cx41.8 play an important role in stripe/spot patterning and suggest that mutations in Cx41.8 can effect patterning by way of reduced function (I203F) and dominant negative effects (M7). Our results suggest that functional differences in Cx41.8 and Cx39.4 relate to spot or labyrinth mutant phenotypes and also provide evidence that these two connexins interact in vivo and in vitro.

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Fc{gamma}RIIIa (CD16a) Co-localizes with TLRs in CD4+ T-cells Cell Biology

CD4+ T-cells in systemic lupus erythematosus (SLE) patients show altered T-cell receptor signaling, which utilizes Fc-receptor γ-chain FcRγ-Syk. A role for FcγRIIIa activation from immune complex (IC) ligation and sublytic terminal complement complex (C5b-9) in CD4+ T-cell responses is not investigated. In this study, we show that the ICs present in SLE patients by ligating to FcγRIIIa on CD4+ T-cells phosphorylate Syk and provide a co-stimulatory signal to CD4+ T-cells in the absence of CD28 signal. This led to the development of pathogenic IL-17A+ and IFN-γhigh CD4+ T-cells in vitro. Cytokines IL-1β, IL-6, TGF-β1, and IL-23 were the only requirement for the development of both populations. SLE patients CD4+ T-cells that expressed CD25, CD69, and CD98 bound to ICs showed pSyk and produced IFN-γ and IL-17A. This FcγRIIIa-mediated co-signal differentially up-regulated the expression of IFN pathway genes compared with CD28 co-signal. FcγRIIIa-pSyk up-regulated several toll-like receptor genes as well as the HMGB1 and MyD88 gene transcripts. ICs co-localized with these toll-like receptor pathway proteins. These results suggest a role for the FcγRIIIa-pSyk signal in modulating adaptive immune responses.

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Novel treatment of severe combined immunodeficiency utilizing ex-vivo T-cell depleted haploidentical hematopoietic stem cell transplantation and CD45RA+ depleted donor lymphocyte infusions

Abstract

Background

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment available for severe combined immunodeficiency (SCID); although, there is a high incidence of severe infections and an increased risk of graft-versus host-disease (GvHD) with HSCT. Early intervention is a crucial prognostic factor and a HLA-haploidentical parental donor is often available. Haploidentical HSCT protocols utilizing extensively ex vivo T-cell depleted grafts (CliniMACs system) have proven efficient in preventing GvHD, but cause a delay in early T-cell recovery that increases the risk of viral infections. Here, we present a novel approach for treating SCID that combines selective depletion of GvHD-inducing alpha/beta (α/β) T-cells from the haploidentical HSCT graft with a subsequent donor lymphocyte infusion (DLI) enriched for CD45RO+ memory T-cells.

Results

Our patient was diagnosed with SCID (T-B + NK+ phenotype). At 9 months of age, he received a T cell receptor(TCR)α/β-cell depleted graft from his haploidentical mother, following a reduced intensity conditioning regimen with no additional GvHD prophylaxis. Engraftment was rapid with complete donor chimerism and no signs of GvHD. However, at 12 weeks post HSCT, the patient was still T-cell lymphopenic with clinical symptoms of multiple severe viral infections. Consequently, therapeutic DLIs were initiated for enhanced anti-viral immunity. The patient was treated with CD45RA+ depleted haploidentical maternal donor lymphocytes enriched from unmobilized whole blood, and a total T-cell dose of no more than 25 x103 CD3+ cells/kg with >99.9 % purity of CD3 + CD45RO+ memory T-cells was transferred. Following the DLI, a prompt increase in CD3 + CD4+ and CD3 + CD8+ counts was observed with a subsequent clearance of viral infections. No acute or chronic GvHD was observed.

Conclusions

Automated depletion of CD45RA+ naïve T-cells from unmobilized whole blood is a simple and rapid strategy to provide unmanipulated DLIs, with a potentially broad repertoire of pathogen specific memory T-cells. In the haploidentical setting, CD45RA+ depleted DLIs can be safely administered at low T-cell doses for efficient enhancement of viral immunity and limited risk of GvHD. We demonstrate the successful use of this approach following TCR-α/β-cell depleted HSCT for the treatment of SCID.

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Antibiotics, Vol. 5, Pages 7: Evaluation of a Computerized Decision Support Intervention to Decrease Use of Anti-Pseudomonal Carbapenems in Penicillin Allergic Patients

Allergies to β-lactam antibiotics are commonly documented in hospitalized patients; however, true allergy is uncommon. Cross-reactivity rates for advanced generation cephalosporins and carbapenems are low; particularly for patients without a history of symptoms consistent with type 1 hypersensitivity. We observed that providers preferentially prescribed antipseudomonal carbapenems (APC) over advanced generation cephalosporins for patients with β-lactam allergy history, including those with low risk for antimicrobial-resistant infections. Information was inserted into the computerized decision support system (CDSS) to aid clinicians in assessing β-lactam cross-reactivity risk and selecting appropriate therapy. A retrospective evaluation was conducted in a small hospital to assess the impact of the CDSS changes in APC prescribing. Inpatients (n = 68) who received at least one APC dose during hospitalization over a 13 month pre-intervention period were compared to inpatients who received an APC during the 15 month post-intervention period (n = 59) for documented APC indications and β-lactam allergy history. APC initiations were measured and corrected per 1000 patient-days; interrupted time-series analysis was performed to assess changes in use before and after implementation. Aggregate monthly APC initiations decreased from 7.01 to 6.14 per 1000 patient-days after the implementation (p = 0.03). Post-intervention APC initiations for patients with low-risk β-lactam histories decreased from 92% to 83% (p = 0.17). No adverse events were observed in patients with low-risk β-lactam histories. The intervention was associated with a reduction in APC initiations.

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Return to Play After Hamstring Injuries: A Qualitative Systematic Review of Definitions and Criteria

Abstract

Background

More than half of the recurrent hamstring injuries occur within the first month after return-to-play (RTP). Although there are numerous studies on RTP, comparisons are hampered by the numerous definitions of RTP used. Moreover, there is no consensus on the criteria used to determine when a person can start playing again. These criteria need to be critically evaluated, in an attempt to reduce recurrence rates and optimize RTP.

Objective

To carry out a systematic review of the literature on (1) definitions of RTP used in hamstring research and (2) criteria for RTP after hamstring injuries.

Study Design

Systematic review.

Methods

Seven databases (PubMed, EMBASE/MEDLINE, CINAHL, PEDro, Cochrane, SPORTDiscus, Scopus) were searched for articles that provided a definition of, or criteria for, RTP after hamstring injury. There were no limitations on the methodological design or quality of articles. Content analysis was used to record and analyze definitions and criteria for RTP after hamstring injury.

Results

Twenty-five papers fulfilled inclusion criteria, of which 13 provided a definition of RTP and 23 described criteria to support the RTP decision. "Reaching the athlete's pre-injury level" and "being able to perform full sport activities" were the primary content categories used to define RTP. "Absence of pain", "similar strength", "similar flexibility", "medical staff clearance", and "functional performance" were core themes to describe criteria to support the RTP decision after hamstring injury.

Conclusion

Only half of the included studies provided some definition of RTP after hamstring injury, of which reaching the athlete's pre-injury level and being able to perform full sport activities were the most important. A wide variety of criteria are used to support the RTP decision, none of which have been validated. More research is needed to reach a consensus on the definition of RTP and to provide validated RTP criteria to facilitate hamstring injury management and reduce hamstring injury recurrence.

PROSPERO systematic review registration number: CRD42015016510.

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Antibiotics, Vol. 5, Pages 7: Evaluation of a Computerized Decision Support Intervention to Decrease Use of Anti-Pseudomonal Carbapenems in Penicillin Allergic Patients

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Avdøde legers rekvisisjoner anses ugyldig

Skal apotekene kunne overprøve lovlig utstedte resepter?

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River Dikes in Agricultural Landscapes: The Importance of Secondary Habitats in Maintaining Landscape-Scale Diversity

Abstract

Lowland rivers and their floodplains have changed markedly over the last centuries. River dikes have become among the most extensive secondary habitats of former floodplains. Our main question was, what role do secondary habitats on river dikes play in harbouring plant species and maintaining plant diversity of lowland landscapes dominated by agricultural areas? We compared historical maps and current habitat maps to understand the effects of landscape changes on the vegetation pattern of the study region, in southern Hungary. Dikes and primary vegetation of the landscape were selected for intensive vegetation sampling. We compared the floristic similarity and the Shannon diversity of the vegetation types. We used ordinations to visualize relationships among the vegetation types and among dike vegetation and environmental variables. Our results indicated that profound changes have been brought about in the vegetation during the last 150 years, resulting in a transition from marshland to agricultural land. The species composition and pattern of dike vegetation strongly depended on their relative position to the river and their aspect. We conclude that dikes can harbour many vascular plants that are absent or rare in the surrounding habitats and therefore play a decisive role in maintaining plant diversity in agricultural landscapes.

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Biomolecules, Vol. 6, Pages 11: Multidisciplinary View of Alcohol Use Disorder: From a Psychiatric Illness to a Major Liver Disease

Alcohol use disorder is a significant health problem being a cause of increased morbidity and mortality worldwide. Alcohol-related illness has a relevant economic impact on the society and a negative influence on the life of patients and their family members. Psychosocial support might be useful in the management of people affected by alcohol use disorder since psychiatric and pharmaceutical approaches show some limits. In fact, many drugs are accessible for the treatment of alcohol disorder, but only Baclofen is functional as an anti-craving drug in patients with advanced liver disease. The alcohol-related liver damage represents the most frequent cause of advanced liver disease in Europe, and it is the main cause of death among adults with high alcohol consumption. The multidisciplinary action of clinical-psychologists, psychiatrics and hepatologists, is essential in the management of patients with alcohol liver disease especially in the case of liver transplantation. In general, the multidisciplinary approach is necessary in prevention, in framing patients and in the treatment. More resources should be used in prevention and research with the main aim of decreasing the harmful alcohol consumption.

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MiR-205 suppresses autophagy and enhances radiosensitivity of prostate cancer cells by targeting TP53INP1

OBJECTIVE: This study aimed to investigate the role of miR-205 in radiosensitivity and autophagy of prostate cancer cells and to explore its regulative effect on TP53INP1.

MATERIALS AND METHODS: MiR-205 expression was compared in three prostate cancer cell lines (DU145, PC-3 and LNCaP) and one normal human prostate epithelial cell line (RWPE-1). The effect of irradiation-induced autophagy on radiosensitivity of the cancer cells and the effect of miR-205 on irradiation-induced autophagy were explored. The regulative effect of miR-205 on TP53INP1 and the function of this axis was further studied.

RESULTS: Ectopic expression of miR-205 substantially reduced the survival fraction of both DU145 and LNCaP cells to irradiation and inhibited irradiation-induced autophagy. Irradiation-induced autophagy acted as a protective mechanism in prostate cancer cells. TP53INP1 is a direct functional target of miR-205 in irradiation-induced autophagy and radiosensitivity regulation.

CONCLUSIONS: The miR-205/TP53INP1 mediated autophagy pathway might be an important molecular mechanism regulating radiosensitivity of prostate cancer cells and represents a potential therapeutic target for prostate cancer.

L'articolo MiR-205 suppresses autophagy and enhances radiosensitivity of prostate cancer cells by targeting TP53INP1 sembra essere il primo su European Review.

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Clinical significance of sCIP2A levels in breast cancer

OBJECTIVE: It has previously found that human oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) was overexpressed in breast cancer, and was positively correlated with lymph node metastasis of the patients. This study aimed to investigate the association between serum CIP2A and prognosis of breast cancer. Then, we investigated whether CIP2A could be as a therapeutic target in breast cancer treatment.

PATIENTS AND METHODS: Preoperative CIP2A levels of 240 patients with breast cancer and 480 cases of controls were measured by ELISA method. The association of CIP2A levels with clinicopathological outcomes was investigated by univariate and multivariate analyses. The effect of CIP2A on breast cancer MDA-MB-231 cells was evaluated by CIP2A siRNA-mediated depletion of the CIP2A protein followed by an analysis of cell proliferation, invasion, colony growth, and xenograft growth and metastasis.

RESULTS: The serum CIP2A levels in patients with breast cancer were (79.0±74.2) ng/mL, which was significantly higher than that in those controls (25.6±21.4) ng/mL for male and (24.8±20.6) ng/mL for female control. Higher preoperative CIP2A levels were significantly associated with the American Joint Committee on Cancer (AJCC) stage, histological grade and lymph node metastasis. Patients with elevated CIP2A levels showed worse survival. In multivariate analysis, elevated preoperative CIP2A levels were independent prognostic factors. Patients with high CIP2A levels had significantly shorter overall survival (OS) and disease-free survival (DFS) times. Knockdown of CIP2A by stable CIP2A siRNA transfection inhibited MDA-MB-231 cell proliferation, invasion, colony growth in vitro, and xenograft growth and metastasis in vivo.

CONCLUSIONS: Our results suggest that serum CIP2A is significantly higher in patients with breast cancer, which is a potential biomarker to make a distinction between breast cancer patients and healthy controls. Higher serum CIP2A levels positively associated with the aggressive phenotype of breast cancer, and forecasts poor prognosis for patients with breast cancer. Knockdown of CIP2A may be a novel target for prevention and treatment of breast cancer.

L'articolo Clinical significance of sCIP2A levels in breast cancer sembra essere il primo su European Review.

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Correlation between intensity modulated radiotherapy and bone marrow suppression in breast cancer

OBJECTIVE: To study the correlation factors of bone marrow suppression in breast cancer radiotherapy and find out the method to guide the target area, dose limitation for breast cancer to reduce the risk of bone marrow suppression.

PATIENTS AND METHODS: 72 cases of breast cancer patients were collected through retrospective, clinical control study. For patients with Grade 0-3, bone marrow suppression in the course of radiotherapy, the dose-volume parameters (V5, V10, V20, V30, V50, D20, D40, D60, D80, D100, Min, Max, Dmean) of the chest and rib of each patient were collected and analyzed from multiple points including tumor stage, age, lesion location, surgical approach, chemotherapy regimen and the number of cycles, bone dose-volume parameters.

RESULTS: The relative parameters of the rib in the middle and severe bone marrow suppression group were significantly higher than those in the mild bone marrow depression group and the p values of V5, V10, V20, V30, Dmean, D40, D60, D80, D100 were less than 0.05. The difference of V50 in the two groups was statistically significant (p <0.05). For chemotherapy regimens containing doxorubicin, epirubicin, cyclophosphamide, the differences between bone marrow suppression group and non-bone marrow suppression were statistically significant (p =0.002).

CONCLUSIONS: The dose-volume parameters of the rib radiation is one of the main factors causing the suppression of bone marrow in radiotherapy, and the volume of the 50Gy irradiation is also a contribution to the bone marrow. For patients accepted chemotherapy with doxorubicin, epirubicin, cyclophosphamide before radiotherapy, bone marrow suppression is more likely to occur during radiotherapy. After radical mastectomy or the volume of thoracic rib is increased because of the small breast, the occurrence of bone marrow suppression is increased. The effects of radiation on the bone marrow suppression were small, while its effect on the ribs was more evident, especially on the ribs V20 and Dmean and the difference was statically significant.

L'articolo Correlation between intensity modulated radiotherapy and bone marrow suppression in breast cancer sembra essere il primo su European Review.

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The multiple sclerosis susceptibility genes TAGAP and IL2RA are regulated by … – Nature.com

The multiple sclerosis susceptibility genes TAGAP and IL2RA are regulated by …
Nature.com
This bioactive form of vitamin D was originally described as an essential hormone for mineral and bone homeostasis, and its biological effects are mediated by the nuclear receptor vitamin D receptor (VDR). The discovery of VDR ….. Genome-wide VDR …

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IJERPH, Vol. 13, Pages 130: Built Environment Influences of Children’s Physical Activity: Examining Differences by Neighbourhood Size and Sex

Neighbourhoods can facilitate or constrain moderate-to-vigorous physical activity (MVPA) among children by providing or restricting opportunities for MVPA. However, there is no consensus on how to define a child's neighbourhood. This study examines the influence of the neighbourhood built environment on objectively measured MVPA among 435 children (aged 9–14 years) in London (ON, Canada). As there is no consensus on how to delineate a child's neighbourhood, a geographic information system was used to generate measures of the neighbourhood built environment at two buffer sizes (500 m and 800 m) around each child's home. Linear regression models with robust standard errors (cluster) were used to analyze the relationship between built environment characteristics and average daily MVPA during non-school hours on weekdays. Sex-stratified models assessed sex-specific relationships. When accounting for individual and neighbourhood socio-demographic variables, park space and multi-use path space were found to influence children's MVPA. Sex-stratified models found significant associations between MVPA and park space, with the 800 m buffer best explaining boys' MVPA and the 500 m buffer best explaining girls' MVPA. Findings emphasize that, when designing built environments, programs, and policies to facilitate physical activity, it is important to consider that the size of the neighbourhood influencing a child's physical activity may differ according to sex.

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IJERPH, Vol. 13, Pages 131: Spatiotemporal Pattern Analysis of Scarlet Fever Incidence in Beijing, China, 2005–2014

Objective: To probe the spatiotemporal patterns of the incidence of scarlet fever in Beijing, China, from 2005 to 2014. Methods: A spatiotemporal analysis was conducted at the district/county level in the Beijing region based on the reported cases of scarlet fever during the study period. Moran's autocorrelation coefficient was used to examine the spatial autocorrelation of scarlet fever, whereas the Getis-Ord Gi* statistic was used to determine the hotspot incidence of scarlet fever. Likewise, the space-time scan statistic was used to detect the space-time clusters, including the relative risk of scarlet fever incidence across all settings. Results: A total of 26,860 scarlet fever cases were reported in Beijing during the study period (2005–2014). The average annual incidence of scarlet fever was 14.25 per 100,000 population (range, 6.76 to 32.03 per 100,000). The incidence among males was higher than that among females, and more than two-thirds of scarlet fever cases (83.8%) were among children 3–8 years old. The seasonal incidence peaks occurred from March to July. A higher relative risk area was mainly in the city and urban districts of Beijing. The most likely space-time clusters and secondary clusters were detected to be diversely distributed in every study year. Conclusions: The spatiotemporal patterns of scarlet fever were relatively unsteady in Beijing from 2005 to 2014. The at-risk population was mainly scattered in urban settings and dense districts with high population, indicating a positive relationship between population density and increased risk of scarlet fever exposure. Children under 15 years of age were the most susceptible to scarlet fever.

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Lead protects pacemakers from radiation

2013_10_28_14_20_06_962_Pacemaker_200.jp Lead shields provide a simple and inexpensive way to reduce radiation delivered…

Issue Information

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Evaluation of 188 Re-labeled NGR–VEGI protein for radioimaging and radiotherapy in mice bearing human fibros arcoma HT-1080 xenografts

Abstract

Vascular endothelial growth inhibitor (VEGI) is an anti-angiogenic protein, which includes three isoforms: VEGI-174, VEGI-192, and VEGI-251. The NGR (asparagine–glycine–arginine)-containing peptides can specifically bind to CD13 (Aminopeptidase N) receptor which is overexpressed in angiogenic blood vessels and tumor cells. In this study, a novel NGR–VEGI fusion protein was prepared and labeled with 188Re for radioimaging and radiotherapy in mice bearing human fibrosarcoma HT-1080 xenografts. Single photon emission computerized tomography (SPECT) imaging results revealed that 188Re-NGR–VEGI exhibits good tumor-to-background contrast in CD13-positive HT-1080 tumor xenografts. The CD13 specificity of 188Re-NGR–VEGI was further verified by significant reduction of tumor uptake in HT-1080 tumor xenografts with co-injection of the non-radiolabeled NGR–VEGI protein. The biodistribution results demonstrated good tumor-to-muscle ratio (4.98 ± 0.25) of 188Re-NGR–VEGI at 24 h, which is consistent with the results from SPECT imaging. For radiotherapy, 18.5 MBq of 188Re-NGR–VEGI showed excellent tumor inhibition effect in HT-1080 tumor xenografts with no observable toxicity, which was confirmed by the tumor size change and hematoxylin and eosin (H&E) staining of major mouse organs. In conclusion, these data demonstrated that 188Re-NGR–VEGI has the potential as a theranostic agent for CD13-targeted tumor imaging and therapy.

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MicroRNA-503 represses epithelial–mesenchymal transition and inhibits metastasis of osteosarcoma by targeting c-myb

Abstract

Deregulated expression of miRNAs contributes to the development of osteosarcoma. Our previous study has showed that miR-503 was downregulated in osteosarcoma tissues. However, the mechanism of the miR-503 in osteosarcoma development still remains largely undefined. In our study, we found that miR-503 overexpression suppressed cell invasion and migration and inhibited epithelial-to-mesenchymal transition (EMT) of MG-63. Furthermore, we identified that c-myb, an oncogene, was a direct target of miR-503. Moreover, overexpression of c-myb could rescue miR-503-suppressed invasion and EMT. The expression of c-myb was upregulated in osteosarcoma cell lines. Therefore, we conclude that high miR-503 expression suppressed osteosarcoma cell mobility and EMT through targeting c-myb, and this may serve as a therapeutic target.

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Caveolin-1 affects tumor drug resistance in esophageal squamous cell carcinoma by regulating expressions of P-gp and MRP1

Abstract

Esophageal squamous cell carcinoma (ESCC) is the most common cancer in China, and multidrug resistance (MDR) remains one of the biggest problems in ESCC chemotherapy. In this study, we aimed to investigate the mechanism of Caveolin-1, an integral membrane protein, on regulating ESCC MDR. First, immunohistochemistry was used to check the protein expression of Caveolin-1, MDR-related protein of P-glycoprotein (P-gp), and multidrug resistance protein 1 (MRP1) in 84 pathologically characterized ESCC tissues, matched adjacent tumor, and adjacent normal-looking tissues. The results showed that Caveolin-1 expression level was elevated in ESCC tissues than that of matched adjacent tumor and adjacent normal-looking tissues (P < 0.05), and the expression of Caveolin-1 has close correlation with P-gp and MRP1 during tumor genesis of ESCC (P = 0.034, P = 0.009, respectively). Then, Caveolin-1 overexpression and knockdown were used to investigate its effect on expressions of P-gp and MRP1 in ESCC cell line Ec9706. The messenger RNA (mRNA) and protein expression levels of P-gp and MRP1 were checked by real-time quantitative reverse transcription-PCR (qRT-PCR) and Western blot (WB). The results showed that Caveolin-1 overexpression significantly promotes the mRNA and protein expression of MRP1 (P < 0.05), while almost has no effect on the mRNA and protein expression of P-gp (P > 0.05); Cavoelin-1 knockdown inhibits the mRNA and protein expressions of both P-gp and MRP1 (P < 0.05). The similar result was found in another ESCC cell line Eca109. So, it is concluded that Caveolin-1 affects ESCC MDR by regulating the expressions of P-gp and MRP1; therefore, it can be taken as a significant marker and target in tumor therapy.

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The proliferation impairment induced by AQP3 deficiency is the result of glycerol uptake and metabolism inhibition in gastric cancer cells

Abstract

Gastric cancer is a big threat to human health. Effective therapeutic cancer target remains to be discovered. Aquaporin 3 (AQP3) belongs to a family of transmembrane channels that are important in transporting water, glycerol, and other small molecules across the cell membrane. Glycerol that is transported by AQP3 is necessary for cell energy generation and lipid synthesis which fulfill the cell biological processes. Previous studies have shown that AQP3 is implicated in disease progression in several cancer types. However, whether AQP3-regulated glycerol uptake and metabolism were involved in cancer progression remains to be further studied. Our study demonstrated that the expression of AQP3 was positively correlated with glycerol level in human gastric cancer tissues. AQP3 inhibition induced proliferation impairment in gastric cancer cells both in vitro and in vivo. AQP3 inhibition that induced glycerol uptake reduction and glycerol administration would rehabilitate the cell proliferation. The energy and lipid production decreased when AQP3 was knocked down since the cellular glycerol level and several lipogenesis enzymes were downregulated. PI3K/Akt signaling pathway, which was involved in the impaired lipid and ATP production, was also inhibited after AQP3 knockdown. Our study indicated that the energy and lipid production inhibition, which were responsible for gastric cancer cell proliferation impairment, were induced by glycerol uptake reduction after AQP3 knockdown.

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Lin28: an emerging important oncogene connecting several aspects of cancer

Abstract

RNA-binding protein Lin28 was originally found as a heterochronic gene which played a significant role in the development of Caenorhabditis elegans. The tumor suppressor let-7 is a downstream target of Lin28, which has a wide variety of target genes which are involved in many aspects of cellular activities. By inhibition of let-7 and directly binding the target RNAs, Lin28 plays an important role in different biological and pathological processes including differentiation, metabolism, proliferation, pluripotency, and tumorigenesis. Overexpression of Lin28 has been reported in several kinds of cancers and is correlated with poor outcomes. It has been shown that Lin28 could affect the progression of cancers in several ways, such as promoting proliferation, increasing glucose metabolism, and inducing epithelial-mesenchymal transition (EMT) and cancer stem cells. Decrease of Lin28 expression or reactivation of let-7 in cancer cells could induce a reverse effect, indicating their therapeutic values in developing novel strategies for cancer treatment. Here, we will overview the regulatory mechanisms and functions of Lin28 in cancers.

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These new articles for The Journal of Clinical Endocrinology & Metabolism are available online

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Effect of exercise intensity on glucose requirements to maintain euglycaemia during exercise in type 1 diabetes

Vinutha B Shetty, et al. | The Journal of Clinical Endocrinology & Metabolism | Jan 14, 2016

Obesity is associated with gene expression and imaging markers of iron accumulation in skeletal muscle

José María Moreno-Navarrete, et al. | The Journal of Clinical Endocrinology & Metabolism | Jan 14, 2016

A 6 bp In Frame Germline Deletion In Exon 7 Of RET Leads To Increased RET Phosphorylation, ERK Activation And MEN2A

S Latteyer, et al. | The Journal of Clinical Endocrinology & Metabolism | Jan 14, 2016

Molecular Heterogeneity in Aldosterone-Producing Adenomas

Kazutaka Nanba, et al. | The Journal of Clinical Endocrinology & Metabolism | Jan 14, 2016

Effect of Dapagliflozin With and Without Acipimox on Insulin Sensitivity and Insulin Secretion in T2DM Males

Aurora Merovci, et al. | The Journal of Clinical Endocrinology & Metabolism | Jan 14, 2016

Serum PTHrP predicts weight loss in cancer patients independent of hypercalcemia, inflammation, and tumor burden

Namki Hong, et al. | The Journal of Clinical Endocrinology & Metabolism | Jan 14, 2016

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Classification of fibroglandular tissue distribution in the breast based on radiotherapy planning CT

Abstract

Background

Accurate segmentation of breast tissues is required for a number of applications such as model based deformable registration in breast radiotherapy. The accuracy of breast tissue segmentation is affected by the spatial distribution (or pattern) of fibroglandular tissue (FT). The goal of this study was to develop and evaluate texture features, determined from planning computed tomography (CT) data, to classify the spatial distribution of FT in the breast.

Methods

Planning CT data of 23 patients were evaluated in this study. Texture features were derived from the radial glandular fraction (RGF), which described the distribution of FT within three breast regions (posterior, middle, and anterior). Using visual assessment, experts grouped patients according to FT spatial distribution: sparse or non-sparse. Differences in the features between the two groups were investigated using the Wilcoxon rank test. Classification performance of the features was evaluated for a range of support vector machine (SVM) classifiers.

Results

Experts found eight patients and 15 patients had sparse and non-sparse spatial distribution of FT, respectively. A large proportion of features (>9 of 13) from the individual breast regions had significant differences (p <0.05) between the sparse and non-sparse group. The features from middle region had most significant differences and gave the highest classification accuracy for all the SVM kernels investigated. Overall, the features from middle breast region achieved highest accuracy (91 %) with the linear SVM kernel.

Conclusion

This study found that features based on radial glandular fraction provide a means for discriminating between fibroglandular tissue distributions and could achieve a classification accuracy of 91 %.

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An open source software for analysis of dynamic contrast enhanced magnetic resonance images: UMMPerfusion revisited

Abstract

Background

Perfusion imaging has become an important image based tool to derive the physiological information in various applications, like tumor diagnostics and therapy, stroke, (cardio-) vascular diseases, or functional assessment of organs. However, even after 20 years of intense research in this field, perfusion imaging still remains a research tool without a broad clinical usage. One problem is the lack of standardization in technical aspects which have to be considered for successful quantitative evaluation; the second problem is a lack of tools that allow a direct integration into the diagnostic workflow in radiology.

Results

Five compartment models, namely, a one compartment model (1CP), a two compartment exchange (2CXM), a two compartment uptake model (2CUM), a two compartment filtration model (2FM) and eventually the extended Toft's model (ETM) were implemented as plugin for the DICOM workstation OsiriX. Moreover, the plugin has a clean graphical user interface and provides means for quality management during the perfusion data analysis. Based on reference test data, the implementation was validated against a reference implementation. No differences were found in the calculated parameters.

Conclusion

We developed open source software to analyse DCE-MRI perfusion data. The software is designed as plugin for the DICOM Workstation OsiriX. It features a clean GUI and provides a simple workflow for data analysis while it could also be seen as a toolbox providing an implementation of several recent compartment models to be applied in research tasks. Integration into the infrastructure of a radiology department is given via OsiriX. Results can be saved automatically and reports generated automatically during data analysis ensure certain quality control.

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Combination of 5T4-ADC with PI3K/mTOR Inhibitors or Taxanes

Purpose: Targeted treatment of solid or liquid tumors with antibody–drug conjugates (ADCs) can lead to promising clinical benefit. The aim of the study is to investigate combination regimens of auristatin-based ADCs in preclinical models of cancer.

Experimental Design: An auristatin-based anti-5T4 antibody conjugate (5T4-ADC) and auristatin payloads were combined with the dual PI3K/mTOR catalytic site inhibitor PF-05212384 (PF-384) or taxanes in a panel of tumor cell lines. Drug interactions in vitro were evaluated using cell viability assays, apoptosis induction, immunofluorescence, mitotic index, and immunoblotting. Breast cancer cells treated with auristatin analogue or 5T4-ADC were profiled by total- and phospho-proteomics. Antitumor efficacy of selected combinations was evaluated in 5T4-positive human breast or lung tumor xenografts in vivo.

Results: In vitro, auristatin-based agents displayed strong synergistic or additive activity when combined with PF-384 or taxanes, respectively. Further, treatment of 5T4-ADC plus PF-384 resulted in stronger induction of apoptosis and cell line–specific attenuation of pAKT and pGSK. Interestingly, proteomic analysis revealed unique effects of auristatins on multiple components of mRNA translation. Addition of PF-384 further amplified effects of 5T4-ADC on translational components, providing a potential mechanism of synergy between these drugs. In human tumor xenografts, dual targeting with 5T4-ADC/PF-384 or 5T4-ADC/paclitaxel produced substantially greater antitumor effects with longer average survival as compared with monotherapy treatments.

Conclusions: Our results provide a biologic rationale for combining 5T4-ADC with either PI3K/mTOR pathway inhibitors or taxanes and suggest that mechanisms underlying the synergy may be attributed to cellular effects of the auristatin payload. Clin Cancer Res; 22(2); 383–94. ©2015 AACR.

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Response to Letter to the Editor, “Wnt Signaling and Its Contribution to Craniofacial Tissue Homeostasis”

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SRC3-pS543 in ER-Positive Breast Cancer

Purpose: The steroid receptor coactivator SRC3 is essential for the transcriptional activity of estrogen receptor α (ERα). SRC3 is sufficient to cause mammary tumorigenesis, and has also been implicated in endocrine resistance. SRC3 is posttranslationally modified by phosphorylation, but these events have not been investigated with regard to functionality or disease association. Here, we investigate the spatial selectivity of SRC3-pS543/DNA binding over the human genome and its expression in primary human breast cancer in relation with outcome.

Experimental Design: Chromatin immunoprecipitation, coupled with sequencing, was used to determine the chromatin binding patterns of SRC3-pS543 in the breast cancer cell line MCF7 and two untreated primary breast cancers. IHC was used to assess the expression of SRC3 and SRC3-pS543 in 1,650 primary breast cancers. The relationship between the expression of SRC3 and SRC3-pS543, disease-free survival (DFS), and breast cancer specific survival (BCSS) was assessed.

Results: Although total SRC3 is selectively found at enhancer regions, SRC3-pS543 is recruited to promoters of ERα responsive genes, both in the MCF7 cell line and primary breast tumor specimens. SRC3-pS543 was associated with both improved DFS (P = 0.003) and BCSS (P = 0.001) in tamoxifen untreated high-risk patients, such a correlation was not seen in tamoxifen-treated cases, the interaction was statistically significant (P = 0.001). Multivariate analysis showed SRC3-pS543 to be an independent prognostic factor.

Conclusions: Phosphorylation of SRC3 at S543 affects its genomic interactions on a genome-wide level, where SRC3-pS543 is selectively recruited to promoters of ERα-responsive genes. SRC3-pS543 is a prognostic marker, and a predictive marker of response to endocrine therapy. Clin Cancer Res; 22(2); 479–91. ©2015 AACR.

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PD-L1 and HLA Class I in Intrahepatic Cholangiocarcinoma

Purpose: More effective therapy is needed for intrahepatic cholangiocarcinoma (ICC). The encouraging clinical results obtained with checkpoint molecule-specific monoclonal antibodies (mAb) have prompted us to investigate whether this type of immunotherapy may be applicable to ICC. The aims of this study were to determine whether (i) patients mount a T-cell immune response to their ICC, (ii) checkpoint molecules are expressed on both T cells and tumor cells, and (iii) tumor cells are susceptible to recognition by cognate T cells.

Experimental Design: Twenty-seven ICC tumors were analyzed for (i) lymphocyte infiltrate, (ii) HLA class I and HLA class II expression, and (iii) PD-1 and PD-L1 expression by T cells and ICC cells, respectively. The results of this analysis were correlated with the clinicopathologic characteristics of the patients investigated.

Results: Lymphocyte infiltrates were identified in all tumors. PD-L1 expression and HLA class I antigen expression by ICC cells was observed in 8 and 11, respectively, of the 27 tumors analyzed. HLA class I antigen expression correlated with CD8+ T-cell infiltrate. Furthermore, positive HLA class I antigen expression in combination with negative/rare PD-L1 expression was associated with favorable clinical course of the disease.

Conclusions: ICC patients are likely to mount a T-cell immune response against their own tumors. Defects in HLA class I antigen expression in combination with PD-L1 expression by ICC cells provide them with an immune escape mechanism. This mechanism justifies the implementation of immunotherapy with checkpoint molecule-specific mAbs in patients bearing ICC tumors without defects in HLA class I antigen expression. Clin Cancer Res; 22(2); 470–8. ©2015 AACR.

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Mechanoresponsive Properties of the Periodontal Ligament

The periodontal ligament (PDL) functions as an enthesis, a connective tissue attachment that dissipates strains created by mechanical loading. Entheses are mechanoresponsive structures that rapidly adapt to changes in their mechanical loading; here we asked which features of the PDL are sensitive to such in vivo loading. We evaluated the PDL in 4 physiologically relevant mechanical environments, focusing on mitotic activity, cell density, collagen content, osteogenic protein expression, and organization of the tissue. In addition to examining PDLs that supported teeth under masticatory loading and eruptive forces, 2 additional mechanical conditions were created and analyzed: hypoloading and experimental tooth movement. Collectively, these data revealed that the adult PDL is a remarkably quiescent tissue and that only when it is subjected to increased loads—such as those associated with mastication, eruption, and orthodontic tooth movement—does the tissue increase its rate of cell proliferation and collagen production. These data have relevance in clinical scenarios where PDL acclimatization can be exploited to optimize tooth movement.

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Enamel Surface with Pit and Fissure Sealant Containing 45S5 Bioactive Glass

Enamel demineralization adjacent to pit and fissure sealants leads to the formation of marginal caries, which can necessitate the replacement of existing sealants. Dental materials with bioactive glass, which releases ions that inhibit dental caries, have been studied. The purpose of this study was to evaluate the enamel surface adjacent to sealants containing 45S5 bioactive glass (BAG) under simulated microleakage between the material and the tooth in a cariogenic environment. Sealants containing 45S5BAG filler were prepared as follows: 0% 45S5BAG + 50.0% glass (BAG0 group), 12.5% 45S5BAG + 37.5% glass (BAG12.5 group), 25.0% 45S5BAG + 25.0% glass (BAG25.0 group), 37.5% 45S5BAG + 12.5% glass (BAG37.5 group), and 50.0% 45S5BAG + 0% glass (BAG50.0 group). A cured sealant disk was placed over a flat bovine enamel disk, separated by a 60-µm gap, and immersed in lactic acid solution (pH 4.0) at 37 °C for 15, 30, and 45 d. After the storage period, each enamel disk was separated from the cured sealant disk, and the enamel surface was examined with optical 3-dimensional surface profilometer, microhardness tester, and scanning electron microscopy. The results showed a significant increase in roughness and a decrease in microhardness of the enamel surface as the proportion of 45S5BAG decreased (P < 0.05). In the scanning electron microscopy images, enamel surfaces with BAG50.0 showed a smooth surface, similar to those in the control group with distilled water, even after prolonged acid storage. Additionally, an etched pattern was observed on the surface of the demineralized enamel with a decreasing proportion of 45S5BAG. Increasing the 45S5BAG filler contents of the sealants had a significant impact in preventing the demineralization of the enamel surface within microgaps between the material and the tooth when exposed to a cariogenic environment. Therefore, despite some marginal leakage, these novel sealants may be effective preventive dental materials for inhibiting secondary caries at the margins.

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Letter to the Editor, “Wnt Signaling and Its Contribution to Craniofacial Tissue Homeostasis”

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Wnt-5 in CLL Pathogenesis

Purpose: ROR1, a receptor in the noncanonical Wnt/planar cell polarity (PCP) pathway, is upregulated in malignant B cells of chronic lymphocytic leukemia (CLL) patients. It has been shown that the Wnt/PCP pathway drives pathogenesis of CLL, but which factors activate the ROR1 and PCP pathway in CLL cells remains unclear.

Experimental Design: B lymphocytes from the peripheral blood of CLL patients were negatively separated using RosetteSep (StemCell) and gradient density centrifugation. Relative expression of WNT5A, WNT5B, and ROR1 was assessed by quantitative real-time PCR. Protein levels, protein interaction, and downstream signaling were analyzed by immunoprecipitation and Western blotting. Migration capacity of primary CLL cells was analyzed by the Transwell migration assay.

Results: By analyzing the expression in 137 previously untreated CLL patients, we demonstrate that WNT5A and WNT5B genes show dramatically (five orders of magnitude) varying expression in CLL cells. High WNT5A and WNT5B expression strongly associates with unmutated IGHV and shortened time to first treatment. In addition, WNT5A levels associate, independent of IGHV status, with the clinically worst CLL subgroups characterized by dysfunctional p53 and mutated SF3B1. We provide functional evidence that WNT5A-positive primary CLL cells have increased motility and attenuated chemotaxis toward CXCL12 and CCL19 that can be overcome by inhibitors of Wnt/PCP signaling.

Conclusions: These observations identify Wnt-5a as the crucial regulator of ROR1 activity in CLL and suggest that the autocrine Wnt-5a signaling pathway allows CLL cells to overcome natural microenvironmental regulation. Clin Cancer Res; 22(2); 459–69. ©2015 AACR.

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Germline ASPN Variants and Metastatic Progression

Purpose: Prostate cancers incite tremendous morbidity upon metastatic growth. We previously identified Asporin (ASPN) as a potential mediator of metastatic progression found within the tumor microenvironment. ASPN contains an aspartic acid (D)-repeat domain and germline polymorphisms in D-repeat-length have been associated with degenerative diseases. Associations of germline ASPN D polymorphisms with risk of prostate cancer progression to metastatic disease have not been assessed.

Experimental Design: Germline ASPN D-repeat-length was retrospectively analyzed in 1,600 men who underwent radical prostatectomy for clinically localized prostate cancer and in 548 noncancer controls. Multivariable Cox proportional hazards models were used to test the associations of ASPN variations with risk of subsequent oncologic outcomes, including metastasis. Orthotopic xenografts were used to establish allele- and stroma-specific roles for ASPN D variants in metastatic prostate cancer.

Results: Variation at the ASPN D locus was differentially associated with poorer oncologic outcomes. ASPN D14 [HR, 1.72; 95% confidence interval (CI), 1.05–2.81, P = 0.032] and heterozygosity for ASPN D13/14 (HR, 1.86; 95% CI, 1.03–3.35, P = 0.040) were significantly associated with metastatic recurrence, while homozygosity for the ASPN D13 variant was significantly associated with a reduced risk of metastatic recurrence (HR, 0.44; 95% CI, 0.21–0.94, P = 0.035) in multivariable analyses. Orthotopic xenografts established biologic roles for ASPN D14 and ASPN D13 variants in metastatic prostate cancer progression that were consistent with patient-based data.

Conclusions: We observed associations between ASPN D variants and oncologic outcomes, including metastasis. Our data suggest that ASPN expressed in the tumor microenvironment is a heritable modulator of metastatic progression. Clin Cancer Res; 22(2); 448–58. ©2015 AACR.

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PD1 Blockade Augments TCR-Engineered Adoptive T-cell Therapy

Purpose: Tumor-infiltrating lymphocytes (TILs) become hypofunctional, although the mechanisms are not clear. Our goal was to generate a model of human tumor-induced TIL hypofunction to study mechanisms and to test anti-human therapeutics.

Experimental Design: We transduced human T cells with a published, optimized T-cell receptor (TCR) that is directed to a peptide within the cancer testis antigen, NY-ESO-1. After demonstrating antigen-specific in vitro activity, these cells were used to target a human lung cancer line that expressed NY-ESO-1 in the appropriate HLA context growing in immunodeficient mice. The ability of anti-PD1 antibody to augment efficacy was tested.

Results: Injection of transgenic T cells had some antitumor activity, but did not eliminate the tumors. The injected T cells became profoundly hypofunctional accompanied by upregulation of PD1, Tim3, and Lag3 with coexpression of multiple inhibitory receptors in a high percentage of cells. This model allowed us to test reagents targeted specifically to human T cells. We found that injections of an anti-PD1 antibody in combination with T cells led to decreased TIL hypofunction and augmented the efficacy of the adoptively transferred T cells.

Conclusions: This model offers a platform for preclinical testing of adjuvant immunotherapeutics targeted to human T cells prior to transition to the bedside. Because the model employs engineering of human T cells with a TCR clone instead of a CAR, it allows for study of the biology of tumor-reactive TILs that signal through an endogenous TCR. The lessons learned from TCR-engineered TILs can thus be applied to tumor-reactive TILs. Clin Cancer Res; 22(2); 436–47. ©2015 AACR.

See related commentary by Yang, p. 275

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Blood transcriptome changes after stroke in an African American population

Abstract

Objective

Molecular diagnostic medicine holds much promise to change point of care treatment. An area where additional diagnostic tools are needed is in acute stroke care, to assist in diagnosis and prognosis. Previous studies using microarray-based gene expression analysis of peripheral blood following stroke suggests this approach may be effective. Next-generation sequencing (NGS) approaches have expanded genomic analysis and are not limited to previously identified genes on a microarray chip. Here, we report on a pilot NGS study to identify gene expression and exon expression patterns for the prediction of stroke diagnosis and prognosis.

Methods

We recruited 28 stroke patients and 28 age- and sex-matched hypertensive controls. RNA was extracted from 3 mL blood samples, and RNA-Seq libraries were assembled and sequenced.

Results

Bioinformatical analysis of the aligned RNA data reveal exonic (30%), intronic (36%), and novel RNA components (not currently annotated: 33%). We focused our study on patients with confirmed middle cerebral artery occlusion ischemic stroke (n = 17). On the basis of our observation of differential splicing of gene transcripts, we used all exonic RNA expression rather than gene expression (combined exons) to build prediction models using support vector machine algorithms. Based on model building, these models have a high predicted accuracy rate >90% (spec. 88% sen. 92%). We further stratified outcome based on the improvement in NIHss scores at discharge; based on model building we observe a predicted 100% accuracy rate.

Interpretation

NGS-based exon expression analysis approaches have a high potential for patient diagnosis and outcome prediction, with clear utility to aid in clinical patient care.

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Afatinib + Cetuximab First-line in EGFR-Mutant Lung Cancer

Purpose: The EGFR tyrosine kinase inhibitors (TKIs), erlotinib and afatinib, have transformed the treatment of advanced EGFR-mutant lung adenocarcinoma. However, almost all patients who respond develop acquired resistance on average approximately 1 year after starting therapy. Resistance is commonly due to a secondary mutation in EGFR (EGFRT790M). We previously found that the combination of the EGFR TKI afatinib and the EGFR antibody cetuximab could overcome EGFRT790M-mediated resistance in preclinical models. This combination has shown a 29% response rate in a clinical trial in patients with acquired resistance to first-generation TKIs. An outstanding question is whether this regimen is beneficial when used as first-line therapy.

Experimental Design: Using mouse models of EGFR-mutant lung cancer, we tested whether the combination of afatinib plus cetuximab delivered upfront to mice with TKI-naïve EGFRL858R-induced lung adenocarcinomas delayed tumor relapse and drug-resistance compared with single-agent TKIs.

Results: Afatinib plus cetuximab markedly delayed the time to relapse and incidence of drug-resistant tumors, which occurred in only 63.6% of the mice, in contrast to erlotinib or afatinib treatment where 100% of mice developed resistance. Mechanisms of tumor escape observed in afatinib plus cetuximab resistant tumors include the EGFRT790M mutation and Kras mutations. Experiments in cell lines and xenografts confirmed that the afatinib plus cetuximab combination does not suppress the emergence of EGFRT790M.

Conclusions: These results highlight the potential of afatinib plus cetuximab as an effective treatment strategy for patients with TKI-naïve EGFR-mutant lung cancer and indicate that clinical trial development in this area is warranted. Clin Cancer Res; 22(2); 426–35. ©2015 AACR.

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Registers of the Swedish total population and their use in medical research

Abstract

The primary aim of the Swedish national population registration system is to obtain data that (1) reflect the composition, relationship and identities of the Swedish population and (2) can be used as the basis for correct decisions and measures by government and other regulatory authorities. For this purpose, Sweden has established two population registers: (1) The Population Register, maintained by the Swedish National Tax Agency ("Folkbokföringsregistret"); and (2) The Total Population Register (TPR) maintained by the government agency Statistics Sweden ("Registret över totalbefolkningen"). The registers contain data on life events including birth, death, name change, marital status, family relationships and migration within Sweden as well as to and from other countries. Updates are transmitted daily from the Tax Agency to the TPR. In this paper we describe the two population registers and analyse their strengths and weaknesses. Virtually 100 % of births and deaths, 95 % of immigrations and 91 % of emigrations are reported to the Population Registers within 30 days and with a higher proportion over time. The over-coverage of the TPR, which is primarily due to underreported emigration data, has been estimated at up to 0.5 % of the Swedish population. Through the personal identity number, assigned to all residents staying at least 1 year in Sweden, data from the TPR can be used for medical research purposes, including family design studies since each individual can be linked to his or her parents, siblings and offspring. The TPR also allows for identification of general population controls, participants in cohort studies, as well as calculation of follow-up time.

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Stromal Depletion by Minnelide in Pancreatic Cancer

Purpose: Pancreatic cancer stromal microenvironment is considered to be the major reason for failure of conventional and targeted therapy for this disease. The desmoplastic stroma, comprising mainly collagen and glycosaminoglycans like hyaluronan (HA), is responsible for compression of vasculature in the tumor resulting in impaired drug delivery and poor prognosis. Minnelide, a water-soluble prodrug of triptolide currently in phase I clinical trial, has been very effective in multiple animal models of pancreatic cancer. However, whether Minnelide will have efficacious delivery into the tumor despite the desmoplastic stroma has not been evaluated before.

Experiment Design: Patient tumor-derived xenografts (PDX) and spontaneous pancreatic cancer mice were treated with 0.42 and 0.21 mg/kg body weight for 30 days. Stromal components were determined by IHC and ELISA-based assays. Vascular functionality and drug delivery to the tumor were assessed following treatment with Minnelide.

Result: Our current study shows that treatment with Minnelide resulted in reduction of ECM components like HA and collagen in the pancreatic cancer stroma of both the spontaneous KPC mice as well as in patient tumor xenografts. Furthermore, treatment with Minnelide improved functional vasculature in the tumors resulting in four times more functional vessels in the treated animals compared with untreated animals. Consistent with this observation, Minnelide also resulted in increased drug delivery into the tumor compared with untreated animals. Along with this, Minnelide also decreased viability of the stromal cells along with the tumor cells in pancreatic adenocarcinoma.

Conclusions: In conclusion, these results are extremely promising as they indicate that Minnelide, along with having anticancer effects is also able to deplete stroma in pancreatic tumors, which makes it an effective therapy for pancreatic cancer. Clin Cancer Res; 22(2); 415–25. ©2015 AACR.

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Universal newborn hearing screening in Umbria region, Italy

Publication date: Available online 14 January 2016
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Egisto Molini, Lucia Calzolaro, Ruggero Lapenna, Giampietro Ricci
ObjectiveIn Italy, universal newborn hearing screening (UNHS) was first introduced in some regions from 1997. Umbria Region has launched a UNHS program in all hospitals, which has been implemented throughout the region since July 2010. Before UNHS implementation in Umbria region, the average age of identification of congenital hearing loss was around 32 months of age with an average age of initial amplification treatment at least 2 months later. The coverage rate of newborn screening was only 34.4% in 2006.The aim of this study was to examine the results of this program and its evolution in the first 2.5 years since implementation in our region.MethodsSince July 2010, all 11 birth centers and hospitals in Umbria region have been involved in a UNHS program. The screening involves the automated otoacoustic emissions (AOAE) test and automatic auditory brain stem response (AABR) audiometry. The number of screening stages and tests used were different depending on whether the infants had audiological risk factors or not.ResultsA total of 20,841 babies were born in the hospitals involved of whom 20,051 were well born babies (WB), while 790 babies (3.8%) presented identified audiological risk factors (BRF). The overall coverage rate in the study period was 93.8%. The prevalence of hearing loss was 2‰ for WB infants and 4.3% for BRF. Mean age at diagnosis was 5.31±3.95 and 11.28±7.73 months in the WB and BRF groups, respectively.ConclusionsUNHS has allowed us to substantially increase the coverage rates and decrease the mean age at diagnosis and subsequent treatment. The identification of audiological risk factors is very important for adequate screening and follow-up. However the Joint Committee on Infant Hearing 2007 quality indicators and benchmarks for screening have not yet been fully achieved and there is still scope for some improvement. This could be achieved with a closer cooperation among institutions, parents, pediatricians, and ENT doctors.

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Midline nasofrontal dermoids in children: A review of 29 cases managed at Mansoura University Hospitals

Publication date: Available online 14 January 2016
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Ahmed Musaad Abd El-fattah, Ahmed Naguib, Hossam El-Sisi, Elsharawy Kamal, Ali Tawfik
ObjectivesNasal dermoids are congenital anomalies constituting 3.7–12.6% of dermoids in the head and neck. Most of lesions are superficial but there is always a risk that it may end blindly within the deep structures of the nose or extend intracranially. Complete excision, regardless of extension, is essential and must be balanced against cosmoses. This study reviews the clinical characteristics and imaging findings as well as the appropriate surgical approach adopted for 29 cases managed at Mansoura University Hospitals.MethodsA retrospective analysis was performed in 29 patients admitted for management of nasal dermoid between Jan 2001 and Jan 2015 at the Otolaryngology department of our tertiary referral university hospital. Recorded data included patient's demographics, complaint, lesion's site, pre-operative radiological findings, surgical technique, intra-operative findings, and post-operative squeal.ResultsThis series included 12 (41%) female and 17 (59%) male children, with a mean age of 2.5 years. Twenty seven children presented with a nasofrontal swelling of which 20 had an apparent sinus. Other presentations included a swelling in the inner canthum (1), nasal tip and columella (1). Nine (31%) patients had a history of infection and two patients gave a positive history of meningitis. Intracranial extradural extension was identified in 10 patients (34.5%) during preoperative imaging. Surgical modalities included local excision and direct closure (12), open rhinoplasty (7), bicoronal excision and craniotomy (10). In 9 cases, the tract was adherent to the dura but was carefully dissected and in one case resection required excision of a segment of dura and reconstruction. In a follow up period of 1-8 years, recurrence was detected in one case and the cosmetic results were satisfactory.ConclusionsThose lesions are rare and require early precise surgical planning to achieve complete en bloc excision. This study reports a low morbidity associated with management of nasal dermoids with intracranial extension.

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Παρασκευή 15 Ιανουαρίου 2016

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