Skin microbiota and human 3D skin models

Abstract

Although the role of the microbiota in skin homeostasis is still emerging there is growing evidence that an intact microbiota supports the skin barrier. The increasing number of research efforts that are trying to shed more light on the human skin-microbiota interaction require the use of suitable experimental models. Three-dimensional (3D) skin equivalents have been established as a valuable tool in dermatological research because they contain a fully differentiated epidermal barrier that reflects the morphological and molecular characteristics of normal human epidermis. In this review we provide an overview of current 3D skin models and illustrate the potential of 3D skin models to study the human skin-microbiota interplay.

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Activation of Wnt/β-catenin signaling is involved in hair growth-promoting effect of 655-nm red light and LED in in vitro culture model

Abstract

Activation of the Wnt/β-catenin signaling pathway plays an important role in hair follicle morphogenesis and hair growth. Recently, low-level laser therapy (LLLT) was evaluated for stimulating hair growth in numerous clinical studies, in which 655-nm red light was found to be most effective and practical for stimulating hair growth. We evaluated whether 655-nm red light + light-emitting diode (LED) could promote human hair growth by activating Wnt/β-catenin signaling. An in vitro culture of human hair follicles (HFs) was irradiated with different intensities of 655-nm red light + LED, 21 h7 (an inhibitor of β-catenin), or both. Immunofluorescence staining was performed to assess the expression of β-catenin, GSK3β, p-GSK3β, and Lef1 in the Wnt/β-catenin signaling. The 655-nm red light + LED not only enhanced hair shaft elongation, but also reduced catagen transition in human hair follicle organ culture, with the greatest effectiveness observed at 5 min (0.839 J/cm²). Additionally, 655-nm red light + LED enhanced the expression of β-catenin, p-GSK3β, and Lef1, signaling molecules of the Wnt/β-catenin pathway, in the hair matrix. Activation of Wnt/β-catenin signaling is involved in hair growth-promoting effect of 655-nm red light and LED in vitro and therefore may serve as an alternative therapeutic option for alopecia.

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Progressive osseous heteroplasia caused by a mosaic gnas mutation

Abstract

Progressive osseous heteroplasia (POH, OMIM#166350) is an "ultrarare" genetic condition characterized by plaque-like heterotopic ossification, beginning in infancy in the dermis and subsequently progressing to involve deep connective tissues such as muscles and joints, sometimes resulting in loss of mobility ¹. It is usually associated with paternal inheritance of an inactivating mutation at the GNAS gene but in some patients (around 30% of cases) with identical clinical characteristics of POH no mutations have been detected ². On the other hand, the same mutation on the paternal allele can be responsible for pseudopseudohypoparathyroidism (PPHP, OMIM#612463), or, if maternally inherited, pseudohypoparathyroidism type 1A (PHP1A, OMIM#103580) ^.

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Accuracy of adrenal computed tomography in predicting the unilateral subtype in young patients with hypokalaemia and elevation of aldosterone in primary aldosteronism

Summary

Context

The current Endocrine Society Guideline suggests that patients aged <35 years with marked primary aldosteronism (PA) and unilateral adrenal lesions on adrenal computed tomography (CT) scan may not need adrenal vein sampling (AVS) before proceeding to unilateral adrenalectomy. This suggestion is, however, based on the data from only one report in the literature.

Objective

We sought to determine the accuracy of CT findings in young PA patients who had unilateral adrenal disease on CT with hypokalaemia and elevation of aldosterone.

Design and Patients

We retrospectively studied 358 PA patients (n=30, aged <35 years; n=39, aged 35-40 years; n=289, aged ≥40 years) with hypokalaemia and elevation of aldosterone and unilateral disease on CT who had successful AVS.

Main outcome measure

Accuracy of CT findings determined by AVS findings and/or surgical outcomes in patients aged <35 years.

Results

Concordance of the diagnosis between CT and AVS was 90% (27/30) in patients aged <35 years, 79% (31/39) in patients aged 35-40 years, and 69% (198/289) in those aged ≥40 years (Trend for p<0.01). Surgical benefit was confirmed in three patients aged <35 years and in three patients aged 35-40 years with available surgical data who had discordance between CT and AVS findings. Collectively, the diagnostic accuracy of CT findings was 100% (30/30) if aged <35 years and 87% (34/39) if aged 35-40 years.

Conclusion

PA patients aged <35 years with hypokalaemia and elevation of aldosterone and unilateral disease on adrenal CT could be spared AVS.

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Copeptin role in polyuria-polydipsia syndrome (PPS) differential diagnosis and reference range in paediatric age

Summary

Objective

Plasma arginine-vasopressin (AVP) analysis can help in the differential diagnosis of the polyuria-polydipsia syndrome (PPS), even if such investigation is hampered by technical difficulties, conversely to its surrogate copeptin. This study aims to enlarge the existing data on normal copeptin levels in childhood, to evaluate the correlation between copeptin, serum sodium and plasma and urine osmolality, and to assess the utility of the copeptin analysis in the diagnostic work-up of PPS in the paediatric age.

Patients and methods

Plasma copeptin levels were evaluated in 53 children without AVP disorders (control population), in 12 hypopituitaric children and in 15 patients with PPS after water deprivation test (WDT).

Results

Mean basal copeptin levels were 5.2±1.56 (range 2.4-8.6 pmol/L) in the control population, 2.61±0.49 pmol/L in the hypopituitaric children with complete diabetes insipidus (CDI) (p=0.04), and 6.21±1.17 pmol/L in the hypopituitaric patients without DI (p=0.02). After WDT, among 15 naïve polyuric/polydipsic children copeptin values greater than 20 pmol/liter allowed to identify nephrogenic diabetes insipidus (NDI), concentrations below 2.2 pmol/liter complete central DI (CCDI) and between 5-20 pmol/l primary polydipsia (PP). Copeptin cut-off level of 3.5 pmol/l distinguished CDI from PP, with a sensitivity and specificity of 75% and 83.3%, respectively.

Conclusion

Copeptin evaluation holds promises as a diagnostic tool in paediatric PPS; its interpretation might be useful to promptly distinguish NDI, even avoiding the WDT need.

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Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature

Summary

Objective

Mutations in the aggrecan gene (ACAN) have been identified in two autosomal dominant skeletal dysplasias, Spondyloepiphyseal dysplasia, Kimberley type (SEDK) and osteochondritis dissecans, as well as in a severe recessive dysplasia, Spondyloepimetaphyseal dysplasia, aggrecan type. Next generation sequencing (NGS) has aided the identification of heterozygous ACAN mutations in individuals with short stature, minor skeletal defects and mild facial dysmorphisms, some of whom have advanced bone age (BA), poor pubertal spurt and early growth cessation as well as precocious osteoarthritis.

Design & methods

Clinical and genetic characterization of 16 probands with heterozygous ACAN variants, 14 with short stature and mild skeletal defects (group 1) and two with SEDK (group 2). Subsequently, we reviewed the literature to determine the frequency of the different clinical characteristics in ACAN positive individuals.

Results

A total of 16 ACAN variants were located throughout the gene, six pathogenic mutations and 10 variants of unknown significance (VUS). Interestingly, brachydactyly was observed in all probands. Probands from group 1, with a pathogenic mutation tended to be shorter and 60% had an advanced BA compared to 0% in those with a VUS. A higher incidence of coxa valga was observed in individuals with a VUS (37% v 0%). Nevertheless, other features were present at similar frequencies.

Conclusions

ACAN should be considered as a candidate gene in patients with short stature and minor skeletal defects, particularly those with brachydactyly, and in patients with spondyloepiphyseal dysplasia. It is also important to note that advanced BA and osteoarticular complications are not obligatory conditions for aggrecanopathies/aggrecan-associated dysplasias.

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Issue Information - Cover and Editorial Board

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Issue Information - TOC

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Editorial: Oncolytic Virus and Gene Thearapy Application: Update 2018.

Related Articles

Editorial: Oncolytic Virus and Gene Thearapy Application: Update 2018.

Curr Cancer Drug Targets. 2018;18(2):108

Authors: Abei M

PMID: 29457568 [PubMed - in process]

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STING activation enhances cetuximab-mediated NK cell activation and DC maturation and correlates with HPV+ status in head and neck cancer

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Shanhong Lu, Fernando Concha-Benavente, Gulidanna Shayan, Raghvendra M. Srivastava, Sandra P. Gibson, Lin Wang, William E. Gooding, Robert L. Ferris
ObjectivesThe intracellular DNA sensor stimulator of interferon genes (STING) has recently been shown to play a vital role in anti-viral and anti-tumor immune responses stimulating cytokine production. While human papillomavirus (HPV) is a causative agent for a subset of head and neck squamous cell carcinoma (HNSCC) with unique etiology and clinical outcome, how the STING pathway is regulated in a virus-induced tumor microenvironment is not well understood. Since STING inactivation likely reflects immunoescape via innate immunity, we hypothesized that its restoration would improve efficacy of the immune modulatory monoclonal antibody (mAb), cetuximab.Materials and methodsWe correlated STING protein expression with clinical parameters by immunohistochemistry (n = 106) and its mRNA expression from The Cancer Genome Atlas (TCGA) in HNSCC tissue specimens. STING protein expression was tested for association with cancer-specific survival (CSS). We further examined the impact of STING activation on cetuximab-mediated immunity using an in vitro NK:DC:tumor cells co-culture system.ResultsIn this study, we found that expression of STING both at the protein and mRNA level was higher in HPV positive (HPV⁺) specimens but unrelated to TNM stage or cancer-specific survival. Our in vitro studies verified that STING activation enhanced cetuximab mediated NK cell activation and DC maturation.ConclusionOur findings suggest a novel role of STING in HPV-related carcinogenesis, in which activation of the STING signaling pathway may facilitate anti-tumor response in HNSCC patients, particularly in combination with therapeutic monoclonal antibodies (mAbs) such as cetuximab, an epidermal growth factor receptor (EGFR) inhibitor.



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Podoplanin emerges as a functionally relevant oral cancer biomarker and therapeutic target

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Edward P. Retzbach, Stephanie A. Sheehan, Evan M. Nevel, Amber Batra, Tran Phi, Angels T.P. Nguyen, Yukinari Kato, Soly Baredes, Mahnaz Fatahzadeh, Alan J. Shienbaum, Gary S. Goldberg
Oral cancer has become one of the most aggressive types of cancer, killing 140,000 people worldwide every year. Current treatments for oral cancer include surgery and radiation therapies. These procedures can be very effective; however, they can also drastically decrease the quality of life for survivors. New chemotherapeutic treatments are needed to more effectively combat oral cancer. The transmembrane receptor podoplanin (PDPN) has emerged as a functionally relevant oral cancer biomarker and chemotherapeutic target. PDPN expression promotes tumor cell migration leading to oral cancer invasion and metastasis. Here, we describe the role of PDPN in oral squamous cell carcinoma progression, and how it may be exploited to prevent and treat oral cancer.



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Oncologic and functional outcomes of pretreatment tracheotomy in advanced laryngeal squamous cell carcinoma: A multi-institutional analysis

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Serena A. Byrd, Mary J. Xu, Lauren M. Cass, Daniel J. Wehrmann, Matthew Naunheim, Kara Christopher, John J. Dombrowski, Ronald J. Walker, Lori Wirth, John Clark, Paul Busse, Annie Chan, Daniel G. Deschler, Kevin Emerick, Derrick T. Lin, Mark A. Varvares
ObjectivesDescribe the influence of pretreatment tracheotomy and treatment modality (surgical versus non-surgical) on oncologic and functional outcomes.Materials and methodsRetrospective study of previously untreated advanced-stage laryngeal squamous cell carcinoma patients at two academic tertiary care institutions from 1995 to 2014.ResultsPrimary outcomes evaluated were disease-free survival, disease-specific survival, and overall survival of pretreatment tracheotomy versus no pretreatment tracheotomy cohorts. Functional status, measured by tracheotomy decannulation and gastrostomy tube placement/removal, was assessed. Of the 226 patients, 31.4% underwent pretreatment tracheotomy. Five-year disease-specific survival was 72.9%, and overall survival was 48.8% for entire cohort. There was a statistically significant decrease in overall survival (p = .03) and disease-free survival (p = .02) for the pretreatment tracheotomy group compared to no pretreatment tracheotomy, which was largely explained by primary tumor stage. Pretreatment tracheotomy was associated with gastrostomy tube placement and was an independent predictor of worse odds of gastrostomy tube removal. Disease stage, distant metastasis, and age independently conferred worse odds of gastrostomy tube removal.ConclusionPatients undergoing pretreatment tracheotomy for primary T4 laryngeal cancer had decreased overall survival compared to patients without pretreatment tracheotomy. There was no difference in local recurrence rates based on tracheotomy status. Organ preservation with chemotherapy and radiation did not result in better functional outcomes than surgery in the pretreatment tracheotomy group as nearly half of patients treated with organ preservation remained tracheotomy dependent. Based on this data, pretreatment tracheotomy may impact oncologic and functional outcomes in advanced disease, and it should be a consideration in an informed decision-making process.



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Role of sequential chemoradiotherapy in stage II and low-risk stage III–IV nasopharyngeal carcinoma in the era of intensity-modulated radiotherapy: A propensity score-matched analysis

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Cheng Xu, Rui Sun, Ling-Long Tang, Lei Chen, Wen-Fei Li, Yan-Ping Mao, Guan-Qun Zhou, Rui Guo, Ai-Hua Lin, Ying Sun, Jun Ma, Wei-Han Hu
ObjectivesTo investigate the role of sequential chemoradiotherapy (SCRT; induction chemotherapy [IC] followed by intensity-modulated radiotherapy [IMRT]) in stage II and low-risk stage III–IV nasopharyngeal carcinoma (NPC).Materials and methodsFour well-matched groups were individually generated using propensity score matching in patients (n = 689) with stage II (SCRT vs. concurrent chemoradiotherapy [CCRT], SCRT vs. IMRT alone) and low-risk stage III–IV NPC (SCRT vs. CCRT, SCRT vs. IC + CCRT). Five-year overall/disease-free/locoregional relapse-free/distant metastasis-free survival (OS/DFS/LRRFS/DMFS) and acute hematological toxicities were compared between groups. The value of SCRT was further investigated in multivariate analysis and subgroup analysis by adjusting for covariates and limiting IC-to-IMRT time interval, respectively.ResultsSCRT led to equivalent survival outcomes compared to CCRT/IMRT alone and CCRT/IC + CCRT in stage II and low-risk stage III–IV NPC, respectively (all P > .050). In multivariate analysis, patients with stage II NPC treated by SCRT obtained higher DMFS (AHR = 0.22, 95% CI = 0.05–1.00, P = .050), but not OS, DFS or LRRFS, compared to patients receiving CCRT; non-significant differences were observed between SCRT and other treatments. SCRT with short IC-to-IMRT time interval (≤70 days) achieved higher 5-year survival rates than IMRT alone (DMFS: P = .046), CCRT (stage II NPC; OS: P = .047; DMFS: P = .020) and IC + CCRT (DFS: P = .041). Moreover, SCRT was associated with higher, equivalent and lower frequencies of acute hematological toxicities than IMRT alone, CCRT and IC + CCRT, respectively.ConclusionSCRT is mainly beneficial in stage II NPC, leading to better DMFS and/or equivalent acute hematological toxicities compared to CCRT/IMRT alone. CCRT is still the best choice for low-risk stage III–IV NPC.



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Induction chemotherapy followed by concurrent chemoradiation versus concurrent chemoradiation alone in the definitive management of p16-positive oropharyngeal squamous cell carcinoma with low-neck or N3 disease

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Onita Bhattasali, Jeannie Han, Lester D.R. Thompson, Gary L. Buchschacher, Iman A. Abdalla, Shawn Iganej
ObjectiveThe addition of induction chemotherapy (ICT) to concurrent chemoradiation (CCRT) has been investigated as a method of improving outcomes among patients with locally advanced head and neck squamous cell carcinoma. Previous studies have consisted of heterogeneous populations with both p16-positive and p16-negative disease and varying extent of nodal disease burden. We evaluated the role of ICT in p16-positive oropharyngeal squamous cell carcinoma (OPSCC) at high-risk of distant failure.Materials and methodsA retrospective review was conducted of 88 consecutive patients with p16-positive OPSCC with low-neck and/or N3 lymphadenopathy. Among these patients, 44 received ICT followed by CCRT, and 44 received CCRT alone with concurrent agents including Cisplatin, Carboplatin, and Cetuximab. Disease control and survival outcomes were reported after adjusting for age, T stage, N stage, and smoking status.ResultsMedian follow-up for surviving patients was 47 (range: 13–115) months. Patients who received CCRT alone were older than those who received ICT (61 years vs. 56 years; p = 0.02); the groups were otherwise similarly balanced. 3-year distant metastasis: 38% vs. 18% (adjusted hazard ratio (HR) = 0.32 [0.13–0.82]; p = 0.02). 3-year progression-free survival: 49% vs. 74% (adjusted HR = 0.46 [0.22–0.93]; p = 0.03). 3-year overall survival: 67% vs. 83% (adjusted HR = 0.48 [0.21–1.12]; p = 0.09).ConclusionAmong patients with p16-positive OPSCC with low-neck and/or N3 lymphadenopathy, ICT followed by CCRT may reduce the risk for distant failure over CCRT alone and lead to improved progression-free survival. Future trials should concentrate on patients at the highest risk of distant metastasis in order to appropriately assess the benefit of ICT.



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Baseline peripheral blood leukocytosis: Biological marker predicts outcome in oropharyngeal cancer, regardless of HPV-status

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Zeno A.R. Gouw, Jan Paul de Boer, Arash Navran, Michiel W.M. van den Brekel, Jan-Jakob Sonke, Abrahim Al-Mamgani
ObjectivesTo study the prognostic value of abnormalities in baseline complete blood count in patients with oropharyngeal cancer (OPC) treated with (chemo) radiation.Methods and materialsThe prognostic value of baseline complete blood count on outcome in 234 patients with OPC treated between 2010 and 2015 was examined in multivariate analysis together with other conventional prognostic variables including HPV-status, tumor stage, tumor and nodal size.ResultsThe 3-year overall survival (OS), disease-free survival (DFS), locoregional control (LRC), and distant control (DC) of the whole group were 74%, 64%, 79%, and 88%, respectively. Leukocytosis and HPV-status were the only significant prognosticators for OS and DFS at the multivariate analysis. Patients without leukocytosis had a significantly better DC compared to those with leukocytosis (92% and 70%, respectively, p < 0.001). Patients with HPV-negative OPC had significantly worse LRC compared to HPV-positive patients (67% and 90%, respectively, p < 0.001). The 3-year OS in HPV-positive group with leukocytosis compared to those without leukocytosis were 69% and 95%, respectively (p < 0.001). The figures for HPV-negative patients were 41% vs. 61%, respectively (p = 0.010).ConclusionsThis is the first study to date reporting the independent impact of leukocytosis and HPV-status on outcome of patients with OPC. The poor outcome of patients with leukocytosis is mainly caused by the worse DC. The significant impact of leukocytosis on outcome was even more pronounced in HPV-positive patients. These biomarkers could help identifying patients with poor prognosis at baseline requiring intensification of local and/or systemic treatment while treatment de-intensification might be offered to the low-risk group.



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Phosphorylation of PI3K regulatory subunit p85 contributes to resistance against PI3K inhibitors in radioresistant head and neck cancer

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Myung Woul Han, In Sun Ryu, Jong Cheol Lee, Song Hee Kim, Hyo Won Chang, Yoon Sun Lee, Seulkina Lee, Seong Who Kim, Sang Yoon Kim
Objectives: PI3K/Akt/mTOR pathway is commonly activated in most cancers and is correlated with resistance to anticancer therapies such as radiotherapy. Therefore, PI3K is an attractive target for treating PI3K-associated cancers. Material and Methods: We investigated the basal expression and the expression after treatment of PI3K inhibitor or Src inhibitor of PI3K/Akt pathway-related proteins in AMC-HN3, AMC-HN3R, HN30 and HN31 cells by performing immunoblotting analysis. The sensitivity to PI3K inhibitors or Src inhibitor was analyzed by MTT assay and clonogenic assay. To determine the antitumoral activity of combination treatment with PI3K inhibitor and Src inhibitor, we used using xenograft mouse model. Results: We found that PI3K regulatory subunit p85 was predominantly phosphorylated in radioresistant head and neck cancer cell line (HN31), which showed resistance to PI3K inhibitors. Next, we investigated mechanism through which PI3K p85 phosphorylation modulated response to PI3K inhibitors. Of note, constitutive activation of Src was found in HN31 cells and upon PI3K inhibitor treatment, restoration of p-Src was occurred. Src inhibitor improved the efficacy of PI3K inhibitor treatment and suppressed the reactivation of both Src and PI3K p85 in HN31 cells. Furthermore, downregulation of PI3K p85 expression by using a specific siRNA suppressed Src phosphorylation. Conclusions: Together, our results imply the novel role of the PI3K regulatory subunit p85 in the development of resistance to PI3K inhibitors and suggest the presence of a regulatory loop between PI3K p85 and Src in radioresistant head and neck cancers with constitutively active PI3K/Akt pathway.



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Comparison of clinical, radiological and morphological features including the distribution of HPV E6/E7 oncogenes in resection specimens of oropharyngeal squamous cell carcinoma

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Hani Ibrahim Channir, Katalin Kiss, Niclas Rubek, Jane Andersen, Jeanette Bæhr Georgsen, Gulla Søby Rathje, Birgitte Wittenborg Charabi, Christian von Buchwald, Christel Bræmer Lajer
BackgroundHuman papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) represents a distinct tumour entity in comparison to HPV-negative OPSCC. The clinical, radiological, morphological features and distribution of HPV E6/E7 mRNA were investigated in resected specimens of OPSCC.MethodsWe retrieved formalin-fixed, paraffin-embedded whole section slides from 24 p16/HPV-DNA positive and 18 p16/HPV-DNA negative primary tumours and 16 corresponding metastases in patients with early-stage OPSCC who underwent planned curative or diagnostic primary transoral robotic surgery. A detailed clinicoradiological and histopathological investigation of the tumours was performed along with detection of HPV E6/E7 mRNA by in situ hybridisation.ResultsHPV-driven OPSCC was characterised by non-keratinising morphology and was dominated by a cohesive invasion pattern at the leading edge of the tumour. Dysplastic zones of the squamous epithelium were strictly located in the tonsillar crypts in contrast to HPV-negative OPSCC which predominantly arised from the dysplastic surface epithelium. Thirteen HPV-driven OPSCC invaded through the tonsillar lymphoid compartment and into soft tissue, causing a stromal desmoplastic reaction. HPV mRNA was consistently but inhomogenously expressed in the entire tumour area and in the dysplastic squamous epithelium. There was no HPV expression in the adjacent normal epithelium and in the non-neoplastic tissues.ConclusionsThis study enhances the current understanding of HPV-driven OPSCC. Only tumours that invade through the lymphoid compartment induce a stromal desmoplastic reaction. A consistent but inhomogenous expression of E6 and E7 mRNA was found in tumour and dysplastic areas, emphasizing that the E6/E7 oncogenes are the driving factors in HPV-driven OPSCC.



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Do we need a different staging system for tongue and gingivobuccal complex squamous cell cancers?

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Piyush Gupta, Jocelyn C. Migliacci, Pablo H. Montero, Daniella Karassawa Zanoni, Jatin P. Shah, Snehal G. Patel, Ian Ganly
ObjectivesTo determine the need for a separate staging system for gingivobuccal complex squamous cell cancers (GBCSCC) based on 5-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) data from one institution.Patients and methodsAn Institutional Review Board (IRB)-approved retrospective analysis was performed on an oral cavity cancer patient database. Patients from 1985 to 2012 with primary surgical treatment for biopsy-proven squamous cell cancer (SCC) from either the oral tongue (TSCC Group) or gingivobuccal complex (GBCSCC Group), were selected as two separate subgroups. The clinicopathologic data were used to stage the patients based on the American Joint Committee on Cancer 7th edition. Survival outcomes including 5-year OS, RFS, and DSS were calculated and analyzed. A multivariate analysis was performed to identify if subsite was an independent predictor for the survival outcomes, adjusting for other variables. A p-value of less than .05 was considered statistically significant.Results936 patients with TSCC and 486 patients with GBCSCC were considered eligible for the analysis. Patients with GBCSCC were more likely to be older (p < .001) and presented with more advanced disease (p < .001) compared to patients with TSCC. Unadjusted hazard ratio (HR) suggested GBCSCC had poor OS compared to TSCC. However, after adjusting for other variables, the adjusted HR was not significant (p = .593). There was no difference in 5-year DSS or RFS in either of the study groups.ConclusionWith similar survival outcomes by stage, there is no justification for using a different staging system for GBCSCC.



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Evaluating oropharyngeal carcinoma with transcervical ultrasound, CT, and MRI

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Farhoud Faraji, Stephanie F. Coquia, Meghan B. Wenderoth, Ericka S. Padilla, Dana Blitz, M. Robert DeJong, Nafi Aygun, Ulrike M. Hamper, Carole Fakhry
ObjectiveTo compare transcervical ultrasonography (US) to standard cross-sectional imaging for the visualization of human papillomavirus-related oropharyngeal cancer (HPV-OPC).Materials and methodsPatients with HPV-OPC and available standard imaging (CT and/or MRI) were identified in clinic and prospectively enrolled. US was performed to visualize the oropharynx and lymph nodes. Tumor characteristics across imaging modalities were evaluated (CT versus MRI, and US versus standard imaging (SI)).ResultsForty-three patients were included. The overall blinded detection rates for CT and MRI were 83% and 71%, respectively. The unblinded detection rate for US was 98%. Agreement of tumor anatomic subsite was moderate for both CT vs MRI (κ = 0.59) and US vs SI (κ = 0.47). Comparison of tumor size by CT and MRI showed statistically significant correlations in craniocaudal (CC), anteroposterior (AP), and mediolateral (ML) dimensions (RhoCC = 0.51, pCC = 0.038; RhoAP = 0.81, pAP < 0.0001; RhoML = 0.57, pML = 0.012). Tumor size estimates by US and SI showed statistically significant correlations in CC and AP, but not ML (RhoCC = 0.60, pCC = 0.003; RhoAP = 0.71, pAP < 0.0001; RhoML = 0.30, pML = 0.08). Tumor volume estimates improved correlations between US and SI (Rho = 0.66, p < 0.0001). Stratification of US patients into early and late imaging studies demonstrated an increase in correlation strength from early (Rho = 0.32, p = 0.32) to late groups (Rho = 0.77, p < 0.0001) demonstrating that ultrasound accuracy improved with experience.ConclusionsOur findings suggest that transcervical ultrasonography is a sensitive and relatively accurate adjunct to standard imaging for the evaluation of oropharyngeal tumors. Its cost, portability, and potential for in-clinic and serial imaging render US an attractive modality to further develop for imaging oropharyngeal tumors.



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Identification of a gene expression signature predicting survival in oral cavity squamous cell carcinoma using Monte Carlo cross validation

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): John Schomberg, Argyrios Ziogas, Hoda Anton-Culver, Trina Norden-Krichmar
ObjectivesThis study aims to identify a robust signature that performs well in predicting overall survival across tumor phenotypes and treatment strata, and validates the application of Monte Carlo cross validation (MCCV) as a means of identifying molecular signatures when utilizing small and highly heterogeneous datasets.Materials and methodsRNA sequence gene expression data for 264 patient tumors were acquired from The Cancer Genome Atlas (TCGA). 100 iterations of Monte Carlo cross validation were applied to differential expression and Cox model validation. The association between the gene signature risk score and overall survival was measured using Kaplan-Meier survival curves, univariate, and multivariable Cox regression analyses.ResultsPathway analysis findings indicate that ligand-gated ion channel pathways are the most significantly enriched with the genes in the aggregated signature. The aggregated signature described in this study is predictive of overall survival in oral cancer patients across demographic and treatment strata.ConclusionThis study reinforces previous findings supporting the role of ion channel gating, interleukin, calcitonin receptor, and keratinization pathways in tumor progression and treatment response in oral cancer. These results strengthen the argument that differential expression of genes within these pathways reduces tumor susceptibility to treatment. Conducting differential gene expression (DGE) with Monte Carlo cross validation, as this study describes, offers a potential solution to decreasing the variability in DGE results across future studies that are reliant upon highly heterogeneous datasets. This improves the ability of studies reliant upon similarly structured datasets to reach results that are reproducible.



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Submental artery island flap versus free flap reconstruction of lateral facial soft tissue and parotidectomy defects: Comparison of outcomes and patient factors

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Akshay V. Patel, Jason E. Thuener, Kate Clancy, Mustafa Ascha, Nauman F. Manzoor, Chad A. Zender
ObjectivesThe submental artery island flap (SIF) has recently been described in temporal bone defects. At our institution we have broadened the application of the SIF and modified the harvest technique for complex lateral facial and skull base defects. Our primary aim is to evaluate the outcomes of patients undergoing complex lateral facial soft tissue, parotidectomy, and temporal bone defects who are reconstructed with the SIF to a similar cohort undergoing free tissue transfer reconstruction.Materials and methodsNineteen patients undergoing SIF and 54 patients undergoing free tissue flaps for oncologic lateral facial, parotidectomy and temporal bone defects were retrospectively identified. Comparative statistics were used to analyze variables between the two cohorts, specifically operative time, flap size, length of stay, regional recurrence, disease free survival, and overall survival.ResultsNo significant difference in demographic and disease related variables was observed. Operative time was significantly lower in SIF group with mean of 412.9 (SD 93.4) minutes compared to 544.1 (SD 139.9) minutes in free flap group. Flap size was significantly larger in free tissue transfer, 32.4 (SD 17.5) cm² (SIF) compared to mean area of 105.2 (SD 53.2) cm² (Free tissue transfer). A significant difference in length of stay was also noted between groups. There was no regional recurrence of disease in level I–III in SIF group. There was no significant difference in DFS or OS between the two groups.ConclusionSIF is an oncologically sound option for reconstruction of lateral facial soft tissue, parotidectomy, and temporal bone defects.



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Refining the eighth edition AJCC TNM classification and prognostic groups for papillary thyroid cancer with lateral nodal metastasis

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Hye In Kim, Kyunga Kim, So Young Park, Jun-Ho Choe, Jung-Han Kim, Jee Soo Kim, Young Lyun Oh, Soo Yeon Hahn, Jung Hee Shin, Hyeon Seon Ahn, Sun Wook Kim, Tae Hyuk Kim, Jae Hoon Chung
BackgroundIn the eighth edition, TNM staging system omits location of nodal metastasis as a criterion for staging patients with papillary thyroid cancer (PTC). Accordingly, all of non-metastatic N1b PTC patients are classified as stage I or II solely according to an age-cutoff of 55 years. We hypothesized that incorporating other lymph node (LN) factors into TNM staging system would better predict cancer-specific mortality (CSM) in N1b patients.MethodsWe enrolled 745 N1b PTC patients without distant metastasis. Alternative prognostic LN factors and cut-off points were assessed using Cox regression and time-dependent ROC analysis. Alternative prognostic groupings were derived based on minimal hazard differences for CSM among groups stratified by LN risk and age. We assessed accuracy of CSM prediction.ResultsLateral LN ratio (LNR) >0.3 and largest LN size >3 cm were prognostic factors for CSM. Stage II patients (eighth edition) with LN risk (lateral LNR >0.3 or largest LN size >3 cm) had a much higher CSM rate (20.9%) than those in the same stage without LN risk (3.2%). Alternative prognostic grouping (Group 1, <55 years without LN risk; Group 2, <55 years with LN risk or ≥55 years without LN risk; and Group 3, ≥55 with LN risk) achieved higher proportions of variance explained (PVEs) for predicting CSM (10.7%) than those of the eighth edition TNM staging system (4.8%).ConclusionsThe proposed grouping for N1b patients using LN risk can distinguish patients with poor prognosis from those with good prognosis better than the eighth edition TNM staging system.



http://ift.tt/2GsRnYv

Proteome analysis reveals that de novo regenerated mucosa over fibula flap-reconstructed mandibles resembles mature keratinized oral mucosa

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Vinay V. Kumar, Bonney L. James, Manuela Ruß, Stefan Mikkat, Amritha Suresh, Peer W. Kämmerer, Michael O. Glocker
AimThe aim of this study was to determine whether intra-oral de novo regenerated mucosa (D) that grew over free fibula flap reconstructed-mandibles resembled the donor tissue i.e. external skin (S) of the lateral leg, or the recipient site tissue, i.e. keratinized oral mucosa (K).Materials and methodsDifferential proteome analysis was performed with ten tissue samples from each of the three groups: de novo regenerated mucosa (D), external skin (S), and keratinized oral mucosa (K). Expression differences of cornulin and involucrin were validated by Western blot analysis and their spatial distributions in the respective tissues were ascertained by immunohistochemistry.ResultsFrom all three investigated tissue types a total of 1188 proteins were identified, 930 of which were reproducibly and robustly quantified by proteome analysis. The best differentiating proteins were assembled in an oral mucosa proteome signature that encompasses 56 differentially expressed proteins. Principal component analysis of both, the 930 quantifiable proteins and the 56 oral mucosa signature proteins revealed that the de novo regenerated mucosa resembles keratinized oral mucosa much closer than extra-oral skin. Differentially expressed cornification-related proteins comprise proteins from all subclasses of the cornified cell envelope. Prominently expressed in intra-oral mucosa tissues were (i) cornifin-A, cornifin-B, SPRR3, and involucrin from the cornified-cell-envelope precursor group, (ii) S100A9, S100A8 and S100A2 from the S100 group, and (iii) cornulin which belongs to the fused-gene-protein group.ConclusionAccording to its proteome signature de novo regenerated mucosa over the free fibula flap not only presents a passive structural surface layer but has adopted active tissue function.



http://ift.tt/2Hx3WDp

Prognostic significance and optimal candidates of primary tumor resection in major salivary gland carcinoma patients with distant metastases at initial presentation: A population-based study

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Xiao Shi, Fan Dong, Wenjun Wei, Kehan Song, Naisi Huang, Zhongwu Lu, Bowen Lei, Pengcheng Yu, Wanlin Liu, Yu Wang, Guohua Sun, Yulong Wang, Qinghai Ji
ObjectivesTo investigate the prognostic significance and identify optimal candidates of primary tumor resection (PTR) for patients with metastatic major salivary gland carcinoma (MaSGC) at diagnosis.Materials and methodsPatients with metastatic MaSGC were identified from the Surveillance, Epidemiology and End Results (SEER) database. Kaplan-Meier analyses, log-rank tests and multivariate Cox regression models were employed to evaluate the therapeutic roles of PTR in the overall cohort and different subgroups.ResultsOverall, 255 patients were included in our study, among whom 80 (31.4%) received PTR. PTR was associated with decreased overall mortality (OM) and cancer-specific mortality (CSM) in the overall cohort (PTR vs No-PTR, HR: 0.363, 95%CI: 0.204–0.646, p = .001 for OM; HR: 0.439, 95%CI: 0.243–0.794, p = .006 for CSM). When we focused on site-specific metastases, receipt of PTR significantly reduced the risk of OM for patients with lung, bone or distant lymph node involvement (all p < .05), whereas this surgical procedure not only failed to bring survival benefit, but even seemed to insignificantly increase the mortality risk once liver metastases were presented (PTR vs No-PTR, HR: 1.109, 95%CI: 0.279–4.412 for OM; HR: 1.596, 95%CI: 0.364–7.004 for CSM). In addition, subgroup analyses showed that patients with stage T1-3 disease, younger age (<65), single-site metastases and high-risk pathologies might benefit from PTR.ConclusionOur study for the first time verifies the favorable prognostic impact of PTR for highly-selected patients with metastatic MaSGC at diagnosis and has the potential to be adopted in future clinical practice, although long-term prospective studies are warranted.



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Neck recurrence in clinically node-negative oral cancer: 27-year experience at a single institution

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Aviram Mizrachi, Jocelyn C. Migliacci, Pablo H. Montero, Sean McBride, Jatin P. Shah, Snehal G. Patel, Ian Ganly
ObjectivesNeck failure in patients with oral squamous cell carcinoma (OSCC) carries a poor outcome, yet the management of patients who initially present with clinically node-negative (cN0) neck is not clearly defined.Patients and methodsRetrospective review of patients with cN0 OSCC treated at Memorial Sloan Kettering Cancer Center from 1985 to 2012, focusing on rate, pattern and predictors of neck failure, salvage treatment, and survival outcomes.ResultsOf 1,302 patients, 806 (62%) underwent elective neck dissection (END) and 496 (38%) had observation. 190 patients (15%) developed neck recurrence. Median follow-up was 58.5 months (range 1–343); 5-year neck recurrence-free survival (NRFS) was 85% and 80% for the END and observation group respectively (p = .06). Patients with neck failure had poorer outcomes than patients without neck failure (5-year overall survival, 37% vs. 74% [p < .001]; disease-specific survival [DSS], 41% vs. 91% [p < .001]). Independent predictors of neck failure were smoking, primary tumor subsite (hard palate and upper gum), and extranodal extension. 87% of patients underwent salvage treatment (END: 81.1%; observation: 94%). Salvage surgery with adjuvant (chemo) radiation had better DSS than surgery alone or nonsurgical salvage.ConclusionsIn our cohort of patients with initially cN0 OSCC triaged to END vs. observation using clinical parameters, 15% developed neck failure. Salvage treatment was feasible in most cases but survival was poorer compared to patients without neck failure. Surgery followed by adjuvant (chemo) radiation resulted in the best outcome.



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Combination of post-operative radiotherapy and cetuximab for high-risk cutaneous squamous cell cancer of the head and neck: A propensity score analysis

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Joshua D. Palmer, Charles J. Schneider, Neil Hockstein, Alexandra L. Hanlon, Jordan Silberg, Jon Strasser, Elizabeth A. Mauer, Michael Dzeda, Robert Witt, Adam Raben
ObjectivesThe objective of this study was to investigate the safety, tolerability and preliminary efficacy of radiotherapy plus cetuximab in high risk CSCC patients.Materials and MethodsPatients with high-risk CSCC diagnosed between 2006 and 2013 were analyzed. Patients were divided into two groups: radiotherapy alone versus radiotherapy plus cetuximab. Among 68 patients meeting study criteria, we identified 29 treated with cetuximab plus RT and 39 with RT alone. Primary analysis examined disease-free and overall survival, freedom from local and distant recurrence in the propensity score matched cohort. Propensity score analysis was performed with weighted factors including: Charlson Comorbidity Index score, age. KPS, primary location, T and N stage, recurrent status, margin status, LVSI, PNI and grade. Toxicity was assessed using the CTCAE v4.0.ResultsMedian follow-up for living patients was 30 months. Patients in the cetuximab group were more likely to have advanced N stage, positive margins and recurrent disease. After propensity score matching the groups were well balanced. Six patients experienced ≥ grade 3 acute toxicity in the cetuximab group. The 1-year, 2-year and 5-year progression free survival (PFS) for patients in the cetuximab group were 86%, 72% and 66%, respectively. The 1-year, 2-year and 5-year overall survival (OS) for patients in the cetuximab group was 98%, 80% and 80%, respectively.ConclusionsAlthough limited by small numbers, the combination of cetuximab and radiotherapy in CSCC appears well tolerated there were more long-term survivors and less distant metastasis in the cetuximab group. These promising finding warrant further studies.



http://ift.tt/2GyvcAf

Pitfalls of post-treatment PET after de-intensified chemoradiotherapy for HPV-associated oropharynx cancer: Secondary analysis of a phase 2 trial

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Kyle Wang, Terence Z. Wong, Robert J. Amdur, William M. Mendenhall, Nathan C. Sheets, Rebecca Green, Brian D. Thorp, Samip N. Patel, Trevor G. Hackman, Adam M. Zanation, Mark C. Weissler, Bhishamjit S. Chera
ObjectivesWe evaluated patterns of nodal response and positive predictive value (PPV) of 3 month post-treatment PET in patients with HPV-associated oropharyngeal cancer treated on a multi-institutional de-intensification trial.Materials and methodsEligibility criteria included: (1) T0-3, N0-2c, M0, (2) HPV+/p16+ oropharyngeal squamous cell carcinoma, and (3) ≤10 pack-years smoking or ≤30 pack-years and abstinent ≥5 years. Patients received 60 Gy radiation alone (T0-2, N0-1) or with concurrent weekly cisplatin 30 mg/m² and surveillance PET three months post-radiation. Nodal responses were categorized as complete (CR), equivocal (ER), or incomplete (IR) using both local and central radiographic review. A "true positive" was ER/IR with clinical/radiographic progression or positive pathology.Results79 node-positive pts (84% N2) were analyzed. Distribution of nodal CR, ER, and IR was 44 (56%), 27 (34%), and 8 (10%), respectively. 29 (37%) had ER/IR in pre-treatment node-positive neck levels, whereas 14 (18%) had ER/IR in pre-treatment node-negative levels. Of patients with ER/IR, 5 were observed clinically, 19 received repeat imaging, and 11 received either biopsy (1) or neck dissection (10). The PPV was 9% for ER/IR and 13% for IR, with 3 patients found to have persistent disease on neck dissection. There was no difference in nodal relapse rate in patients with nodal CR vs. nodal ER/IR.ConclusionPost-treatment PET may not accurately predict the presence of persistent disease in patients with favorable-risk oropharynx cancer. These results support close surveillance rather than surgical evaluation in most favorable-risk patients.



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Comparison between magnetic resonance and computed tomography in detecting mandibular invasion in oral cancer: A systematic review and diagnostic meta-analysis

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): José de Souza Brandão Neto, Felipe Toyama Aires, Rogério Aparecido Dedivitis, Leandro Luongo Matos, Claudio Roberto Cernea
BackgroundSuspicion of mandibular invasion directly influences perioperative strategy, requiring marginal or segmental mandibulectomy, or reconstruction in some cases. This has a considerable impact on outcome and quality of life. The aim of this study was to evaluate the accuracy of magnetic resonance and computed tomography in the prediction of mandibular invasion in patients with oral cavity cancer.MethodA systematic review was conducted, including diagnostic studies comparing magnetic resonance imaging with computed tomography in the prediction of bone invasion. Sensitivity, specificity, positive and negative likelihood values and summary receiver operating characteristic (sROC) curves were calculated.ResultsThe electronic and manual search identified 346 articles. Of these, 11 studies were included in the systematic review for a total of 477 patients. The sensitivity, specificity, and positive and negative likelihood values for MRI were 78%, 86%, 5.29 and 0.23, respectively. For CT, they were 76%, 89%, 6.00 and 0.28, respectively. The sROC curves for MRI and CT were 82.3% and 82.5%, respectively.ConclusionNo superiority was observed between the diagnostic methods regarding mandibular invasion detection.



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The efficacy of botulinum neurotoxin A in the treatment of plaque psoriasis

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Clinical efficacy of oral administration of finasteride at a dose of 2.5 mg/day in women with female pattern hair loss

Abstract

Female pattern hair loss (FPHL) presents with diffuse thinning over the mid-frontal scalp, for which various treatment modalities have been tried. Although currently, oral 5 α-reductase inhibitors such as finasteride are being used, their clinical efficacy remains controversial. We retrospectively investigated 544 premenopausal or postmenopausal patients with FPHL who were prescribed finasteride at a dose of 2.5 mg/day. Our study excluded patients with a follow-up period of < 3 months and patients who were prescribed other FPHL treatment modalities including topical minoxidil. Finally, 112 patients were evaluated based on their medical records and clinical photographs. Based on assessment using the Ludwig scale at the time of their initial visit, among 112 patients studied, 59 patients were classified as belonging to grade I, 47 were grade II, and 6 were grade III. Using global photographs, we found that 33 (29.5%) of the 112 patients studied showed slight improvement, 73 (65.2%) showed significant improvement, whereas no change was recorded in 6 (5.4%). We could demonstrate efficacy of administration of finasteride at a dose of 2.5 mg/day for patients with FPHL and also found that finasteride has a better effect on hair growth when patients had a lower Ludwig score and an older age at onset

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The efficacy of botulinum neurotoxin A in the treatment of plaque psoriasis

http://ift.tt/2oeOFzg

Desmoplastic transformation of a nodular melanoma arising from a speckled lentiginous nevus

http://ift.tt/2CaRgCI

Monitoring of immunoglobulin A antibodies to epidermal and tissue transglutaminases over an 18-month period in a Japanese patient with dermatitis herpetiformis

http://ift.tt/2omvHpm

Promising therapeutic option for cutaneous plasmacytosis: 308-nm excimer lamp

http://ift.tt/2CaRfPa

pH-Dependent production of himeic acid A and its non-enzymatic conversions to himeic acids B and C

Publication date: Available online 20 February 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Ayako Katsuki, Hikaru Kato, Yurika Tahara, Makoto Hashimoto, Isao Fujii, Sachiko Tsukamoto
The fungus Aspergillus japonicus MF275 produces himeic acid A (1), containing a 4-pyrone ring, along with its congeners, himeic acids B (2) and C (3). During culture, 1 was gradually converted to 3, the corresponding 4-pyridone derivative. A study of the relationship between the culture pH and the fungal metabolites showed that a decrease from pH 6.5 to pH 2 is essential for production of 1, while a subsequent increase to pH 5 is necessary for production of 3. In addition, we revealed that 1 was non-enzymatically converted to 3 by the incorporation of an ammonium nitrogen atom in a pH 5 buffer, and that 1 was converted to 2 at a conversion ratio of 50% during incubation in MeOH for five days.

Graphical abstract

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Design, synthesis and biological evaluation of novel 7-azaspiro[3.5]nonane derivatives as GPR119 agonists

Publication date: Available online 20 February 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Daisuke Matsuda, Madoka Kawamura, Yohei Kobashi, Fumiyasu Shiozawa, Youichirou Suga, Keiko Fusegi, Shinichi Nishimoto, Kayo Kimura, Masako Miyoshi, Noriko Takayama, Hiroyuki Kakinuma, Norikazu Ohtake
The design and synthesis of a novel class of 7-azaspiro[3.5]nonane GPR119 agonists are described. In this series, optimization of the right piperidine N-capping group (R²) and the left aryl group (R³) led to the identification of compound 54g as a potent GPR119 agonist. Compound 54g showed a desirable PK profile in Sprague-Dawley (SD) rats and a favorable glucose lowering effect in diabetic rats.

Graphical abstract

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Comparison of stratum corneum thickness between two proposed methods of calculation using Raman spectroscopic depth profiling of skin water content

Abstract

Background/purpose

The stratum corneum (SC) is the most important layer for the barrier function of skin, so investigation of the SC is very important in cosmetic and medical research. Here, we calculated the SC thickness using the depth profile of the skin's water concentration based on previously described methods, and then compared the results.

Methods

Seven Korean women in their 30s participated in this study. Raman spectroscopy was used to measure the in vivo depth profile of skin water concentration. A total of 21 areas were measured at forearm. Microsoft Excel 2007 was used to calculate SC thickness based on the slope and intersection methods.

Results

The slope method and the intersection method gave a forearm SC thickness calculated at 21.3 ± 2.6 μm and 17.6 ± 2.8 μm, respectively. There was a significant difference between the two calculation methods but the two methods showed strong correlation of SC thickness results (r = .899).

Conclusion

Although there was a difference in calculated SC thickness of about 20% between the two methods, these results reveal that the two SC thickness calculation methods using Raman spectroscopy were suitable for measuring SC thickness, a finding consistent with other published results.

http://ift.tt/2FhkWNc

Inflammatory Biomarkers During Bacterial Acute Rhinosinusitis

Abstract

Purpose of Review

Diagnosis of bacterial acute rhinosinusitis is difficult. Several attempts have been made to clarify the diagnostic criteria. Inflammatory biomarkers are easily obtainable variables that could shed light on both the pathophysiology and diagnosis of bacterial acute rhinosinusitis. The purpose of this review article is to assess literature concerning the course of inflammatory biomarkers during acute rhinosinusitis and the use of inflammatory biomarkers in diagnosing bacterial acute rhinosinusitis.

Recent Findings

We included C-reactive protein, erythrocyte sedimentation rate, white blood cell counts, procalcitonin, and nasal nitric oxide in this review and found that especially elevated C-reactive protein and erythrocyte sedimentation rate are related to a higher probability of a bacterial cause of acute rhinosinusitis. Still, normal levels of these two biomarkers are quite common as well, or the levels can be heightened even during viral respiratory infection without suspicion of bacterial involvement.

Summary

Elevated levels of C-reactive protein or erythrocyte sedimentation rate support diagnosis of bacterial acute rhinosinusitis, but due to a lack of sensitivity, they should not be used to screen patients for bacterial acute rhinosinusitis.

http://ift.tt/2GvOUMP

Novel splice site mutation in the LIPH gene in a patient with autosomal recessive woolly hair/hypotrichosis: Case report and published work review

Abstract

Autosomal recessive woolly hair is a relatively rare hereditary hair disorder characterized by sparse, short, curly hair. This condition is known to be caused by mutations in the LIPH gene, LPAR6 gene or KRT25 gene. In the Japanese population, most patients with autosomal recessive woolly hair carry one of two founder mutations in the LIPH gene, c.736T>A (p.Cys246Ser) or c.742C>A (p.His248Asn). However, occasionally, individuals with this condition carry compound heterozygous mutations, typically one founder mutation and another mutation. In this study, we describe a patient with a compound heterozygous mutation in the LIPH gene at c.736T>A and c.1095-3C>G. The latter mutation created a novel splice site. This was the fourth splice site mutation to be described in the LIPH gene. Furthermore, we performed an in vitro transcription assay in cultured cells, and demonstrated that the c.1095-3C>G mutation led to a frame-shift, which created a premature termination codon at the protein level (p.Glu366Ilefs*7). Finally, we summarized the mutations previously reported for the LIPH gene. Our findings provide further clues as to the molecular basis of autosomal recessive woolly hair.

http://ift.tt/2BGLw2D

Safety and efficacy of nivolumab in Japanese patients with malignant melanoma: An interim analysis of a postmarketing surveillance

Abstract

A postmarketing surveillance study is ongoing to evaluate nivolumab treatment for Japanese patients with malignant melanoma and accumulate data on all adverse events (AE) and efficacy. In this interim analysis, we evaluated data from approximately 100 Japanese medical institutions obtained from the nivolumab approval date in Japan (4 July 2014) through 3 July 2016. Patients were monitored during the first 12 months of treatment. Nivolumab was administrated by i.v. infusion (2 mg/kg every 3 weeks). A total of 680 and 610 patients were evaluated for safety and efficacy, respectively. The incidences of adverse drug reactions (ADR) and grade 3 or higher ADR were 53.53% and 12.35%, respectively. Predominant ADR included hypothyroidism (11.32%) and abnormal enzyme activity, such as increase of aspartate aminotransferase (7.79%), alanine aminotransferase (6.76%), alkaline phosphatase (6.18%) and γ-glutamyltransferase (5.44%). Grade 3 or higher ADR of special interest with an incidence of 1% or higher were hepatic function disorder (2.50%), colitis/diarrhea (2.06%) and infusion reaction (1.32%). No cases of encephalitis or venous thromboembolism, other AE of special interest, were observed. The estimated median overall survival was 379 days (95% confidence interval [CI], 290–not reached [NR]) in the overall population, NR (95% CI, 305–NR) for cutaneous melanoma and 340 days (95% CI, 275–NR) for mucosal melanoma. The improvement rate based on the antitumor response at the last evaluation was 22.2% (131/590 patients). No new safety concerns were raised, and serious ADR of special interest were infrequent. Nivolumab showed equivalent efficacy in patients with mucosal melanoma and those with cutaneous melanoma.

http://ift.tt/2C93T13

Enlarged Size and Impaired Elastic Properties of the Ascending Aorta are Associated with Endothelial Dysfunction and Elevated Plasma Matrix Metalloproteinase-2 Level in Patients with Bicuspid Aortic Valve

Publication date: Available online 20 February 2018
Source:Ultrasound in Medicine & Biology
Author(s): Yi-Bin Wang, Yang Li, You-Bin Deng, Ya-Ni Liu, Jun Zhang, Jie Sun, Ying Zhu, Li Li, Qiao-Ying Tang, Wei Zhou
The aim of this study was to test whether enlarged size and impaired elastic properties of the ascending aorta are associated with impaired endothelial function and increases in plasma matrix metalloproteinase (MMP)-2 concentrations in patients with bicuspid aortic valve (BAV) without significant valvular dysfunction. The size and the elasticity of the ascending aorta and the flow-mediated vasodilation (FMD) in the brachial artery in response to hyperemia were evaluated with 2-D echocardiography and high-frequency linear ultrasound in 42 patients with BAV without significant valvular dysfunction and 30 age- and sex-matched healthy controls. In the BAV group, diastolic ascending aortic diameter (AoD) (32.1 ± 8.1 mm vs. 25.3 ± 3.6 mm, p < 0.001) and aortic stiffness index (8.0 ± 5.3 vs. 4.0 ± 1.8, p < 0.001) were significantly higher, and aortic strain (7.4 ± 3.6% vs. 11.1 ± 3.0%, p < 0.001) and aortic distensibility (7.4 ± 4.1 × 10⁻⁶cm²/dyn vs. 11.1 ± 4.3 × 10⁻⁶cm²/dyn, p < 0.001) were significantly lower than those in the control group. The BAV group also had lower FMD (6.5 ± 2.2% vs. 11.9 ± 2.7%, p < 0.001) and higher plasma MMP-2 levels (226.7 ± 55.0 ng/mL vs. 177.0 ± 45.3 ng/mL, p < 0.001) compared with the control group. In the BAV group, AoD, aortic strain, aortic stiffness index and aortic distensibility significantly correlated with FMD and MMP-2 (all p < 0.05). The multivariable linear regression analysis further indicated that FMD and MMP-2 were independently associated with AoD (β = −1.1, p = 0.005, and β = 0.09, p < 0.001, respectively). These findings suggest that enlarged size and impaired elastic properties of the ascending aorta are associated with endothelial dysfunction and elevated plasma MMP-2 level in patients with BAV without significant valvular dysfunction. FMD and plasma MMP-2 level are the significant and independent predictors of dilation of the ascending aorta in patients with BAV.



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American Heart Association Precision Medicine Platform.

Author: Kass-Hout, Taha A. MD, MS; Stevens, Laura M. BS; Hall, Jennifer L. PhD

Page: 647-649

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Upper Limits of Aerobic Power and Performance in Heart Transplant Recipients: Legacy Effect of Prior Endurance Training.

Author: Haykowsky, Mark J. PhD; Halle, Martin MD; Baggish, Aaron MD

Page: 650-652

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Genetic Predisposition to High Blood Pressure and Lifestyle Factors: Associations With Midlife Blood Pressure Levels and Cardiovascular Events.

Author: Pazoki, Raha MD, PhD; Dehghan, Abbas MD, PhD; Evangelou, Evangelos PhD; Warren, Helen PhD; Gao, He PhD; Caulfield, Mark MD, PhD; Elliott, Paul MD, PhD; Tzoulaki, Ioanna PhD

Page: 653-661

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Hypertension, Genes, and Environment: Challenges for Prevention and Risk Prediction.

Author: Cooper, Richard MD

Page: 662-664

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Value of Progression of Coronary Artery Calcification for Risk Prediction of Coronary and Cardiovascular Events: Result of the HNR Study (Heinz Nixdorf Recall).

Author: Lehmann, Nils PhD *,; Erbel, Raimund MD *,; Mahabadi, Amir A. MD; Rauwolf, Michael MD; Mohlenkamp, Stefan MD; Moebus, Susanne PhD; Kalsch, Hagen MD; Budde, Thomas MD; Schmermund, Axel MD; Stang, Andreas MD; Fuhrer-Sakel, Dagmar MD; Weimar, Christian MD; Roggenbuck, Ulla CRA; Dragano, Nico PhD; Jockel, Karl-Heinz PhD; on behalf of the Heinz Nixdorf Recall Study Investigators; Meinertz, T.; Bode, C.; de Feyter, P.J.; Guntert, B.; Gutzwiller, F.; Heinen, H.; Hess, O.; Klein, B.; Lowel, H.; Reiser, M.; Schmidt, G.; Schwaiger, M.; Steinmuller, C.; Theorell, T.; Willich, S.N.; Bode, C.; Berger, K.; Figulla, H.R.; Hamm, C.; Hanrath, P.; Kopcke, W.; Ringelstein, B.; Dichgans, M.; Zeiher, A.

Page: 665-679

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Coronary Artery Calcium: If Measuring Once Is Good, Is Twice Better?.

Author: Khera, Amit MD, MSc; Greenland, Philip MD

Page: 680-683

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Frequency, Predictors, and Impact of Combined Antiplatelet Therapy on Venous Thromboembolism in Patients With Symptomatic Atherosclerosis.

Author: Cavallari, Ilaria MD; Morrow, David A. MD, MPH; Creager, Mark A. MD; Olin, Jeffrey MD; Bhatt, Deepak L. MD, MPH; Steg, P. Gabriel MD; Storey, Robert F. MD, PhD; Cohen, Marc MD; Scirica, Benjamin S. MD; Piazza, Gregory MD, MS; Goodrich, Erica L. MS; Braunwald, Eugene MD; Sabatine, Marc S. MD, MPH; Bonaca, Marc P. MD, MPH

Page: 684-692

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Prognostic Value of Follow-Up Hemodynamic Variables After Initial Management in Pulmonary Arterial Hypertension.

Author: Weatherald, Jason MD; Boucly, Athenais MD; Chemla, Denis MD, PhD; Savale, Laurent MD, PhD; Peng, Mingkai PhD; Jevnikar, Mitja MD; Jais, Xavier MD; Taniguchi, Yu MD, PhD; O'Connell, Caroline MD; Parent, Florence MD; Sattler, Caroline MD; Herve, Philippe MD; Simonneau, Gerald MD; Montani, David MD, PhD; Humbert, Marc MD, PhD; Adir, Yochai MD *,; Sitbon, Olivier MD, PhD *,,,

Page: 693-704

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Assessing Prognosis of Pulmonary Arterial Hypertension in the Therapeutic Era: Importance of Serial Hemodynamic Measurements.

Author: Rubin, Lewis J. MD

Page: 705-706

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Developing a Clinical Approach to Air Pollution and Cardiovascular Health.

Author: Hadley, Michael B. MD, MScPH; Baumgartner, Jill PhD; Vedanthan, Rajesh MD, MPH

Page: 725-742

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Broad[horizontal ellipsis] Narrow[horizontal ellipsis] Broad QRS Tachycardia.

Author: Ballesteros, Gabriel MD; Menendez, Diego MD; Ramos, Pablo MD; Garcia-Bolao, Ignacio MD, PhD

Page: 743-746

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Impact of Coronary Remodeling on Fractional Flow Reserve.

Author: Collet, Carlos MD; Katagiri, Yuki MD; Miyazaki, Yosuke MD, PhD; Asano, Taku MD; Sonck, Jeroen MD; van Geuns, Robert-Jan MD, PhD; Andreini, Daniele MD, PhD; Bittencourt, Marcio S. MD, PhD; Kitslaar, Pieter MSc; Tenekeciouglu, Erhan MD; Tijssen, Jan G.P. PhD; Piek, Jan J. MD, PhD; de Winter, Robbert J. MD, PhD; Cosyns, Bernard MD, PhD; Rogers, Campbell MD; Zarins, Christopher K. MD, PhD; Taylor, Charles PhD; Onuma, Yoshinobu MD, PhD; Serruys, Patrick W. MD, PhD

Page: 747-749

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Proefferocytic Therapy Promotes Transforming Growth Factor-[beta] Signaling and Prevents Aneurysm Formation.

Author: Kojima, Yoko MD, PhD; Werner, Norna MD; Ye, Jianqin MD, PhD; Nanda, Vivek PhD; Tsao, Noah; Wang, Ying PhD; Flores, Alyssa M. BS; Miller, Clint L. PhD; Weissman, Irving MD; Deng, Hongping MD, PhD; Xu, Baohui MD, PhD; Dalman, Ronald L. MD; Eken, Suzanne M. MD, PhD; Pelisek, Jaroslav PhD; Li, Yuhuang MD, PhD; Maegdefessel, Lars MD, PhD; Leeper, Nicholas J. MD

Page: 750-753

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Letter by Jin-shan and Xue-bin Regarding Article, "Physiology of Angina and Its Alleviation With Nitroglycerin: Insights From Invasive Catheter Laboratory Measurements During Exercise".

Author: Jin-shan, He MD; Xue-bin, Li MD

Page: 754

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Response by Asrress et al to Letter Regarding Article, "Physiology of Angina and Its Alleviation With Nitroglycerin: Insights From Invasive Catheter Laboratory Measurements During Exercise".

Author: Asrress, Kaleab N. PhD; Williams, Rupert PhD; Lockie, Timothy PhD; Khawaja, Muhammed Z. PhD; Patterson, Tiffany MBBS; Arri, Satpal MBBS; De Silva, Kalpa PhD; Perera, Divaka MD; Marber, Michael S. PhD; Redwood, Simon R. MD

Page: 755-756

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Letter by Galyfos and Filis Regarding Article, "Effect of Obesity and Underweight Status on Perioperative Outcomes of Congenital Heart Operations in Children, Adolescents, and Young Adults: An Analysis of Data From the Society of Thoracic Surgeons Database".

Author: Galyfos, George MD, PhD; Filis, Konstantinos MD, PhD

Page: 757-758

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Response by O'Byrne et al to Letter Regarding Article, "Effect of Obesity and Underweight Status on Perioperative Outcomes of Congenital Heart Operations in Children, Adolescents, and Young Adults: An Analysis of Data From the Society of Thoracic Surgeons Database".

Author: O'Byrne, Michael L. MD, MSCE; Jacobs, Jeffrey P. MD; Jacobs, Marshall L. MD; Jonas, Richard A. MD

Page: 759

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Correction to: Efficacy and Safety of a Pharmaco-Invasive Strategy With Half-Dose Alteplase Versus Primary Angioplasty in ST-Segment-Elevation Myocardial Infarction: EARLY-MYO Trial (Early Routine Catheterization After Alteplase Fibrinolysis Versus Primary PCI in Acute ST-Segment-Elevation Myocardial Infarction).

Author:

Page: e29

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Comparison between male and female rats in a model of self-administration of a chocolate-flavored beverage: Behavioral and neurochemical studies

Publication date: 15 May 2018
Source:Behavioural Brain Research, Volume 344
Author(s): Andrea Contini, Fabrizio Sanna, Paola Maccioni, Giancarlo Colombo, Antonio Argiolas
The existence of sex differences was studied in a rat model of operant self-administration of a chocolate-flavored beverage (CFB), which possesses strong reinforcing properties and is avidly consumed by rats. Whether these differences occurred concomitantly to changes in extracellular dopamine in the dialysate obtained from the nucleus accumbens, was assessed by intracerebral microdialysis. Male, ovariectomized and intact female rats showed similar self-administration profiles, with minor differences in both acquisition and maintenance phases. Intact females self-administered larger amounts of CFB, when expressed per body weight, than males and ovariectomized females, in spite of similar values of lever-responding, latency to the first lever-response and consumption efficiency (a measure of rat's licking effectiveness) in males, ovariectomized and intact females and no difference in breakpoint value and number of lever-responses emerged when males, ovariectomized and intact females were exposed to a progressive ratio schedule of reinforcement. Intracerebral microdialysis revealed a slight but significant increase in dopamine activity in the shell of the nucleus accumbens of male rats when compared to intact female rats during CFB self-administration. The above differences may be caused by the hormonal (mainly estradiol) fluctuations that occur during the estrus cycle in intact females. Accordingly, in intact females CFB self-administration and dopamine activity were found to fluctuate across the estrus cycle, with lower parameters of CFB self-administration and lower dopamine activity in the Proestrus and Estrus phases vs. the Metestrus and Diestrus phases of the cycle.



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Development of novel tasks for studying view-invariant object recognition in rodents: Sensitivity to scopolamine

Publication date: 15 May 2018
Source:Behavioural Brain Research, Volume 344
Author(s): Krista A. Mitchnick, Cassidy E. Wideman, Andrew E. Huff, Daniel Palmer, Bruce L. McNaughton, Boyer D. Winters
The capacity to recognize objects from different view-points or angles, referred to as view-invariance, is an essential process that humans engage in daily. Currently, the ability to investigate the neurobiological underpinnings of this phenomenon is limited, as few ethologically valid view-invariant object recognition tasks exist for rodents. Here, we report two complementary, novel view-invariant object recognition tasks in which rodents physically interact with three-dimensional objects. Prior to experimentation, rats and mice were given extensive experience with a set of 'pre-exposure' objects. In a variant of the spontaneous object recognition task, novelty preference for pre-exposed or new objects was assessed at various angles of rotation (45°, 90° or 180°); unlike control rodents, for whom the objects were novel, rats and mice tested with pre-exposed objects did not discriminate between rotated and un-rotated objects in the choice phase, indicating substantial view-invariant object recognition. Secondly, using automated operant touchscreen chambers, rats were tested on pre-exposed or novel objects in a pairwise discrimination task, where the rewarded stimulus (S+) was rotated (180°) once rats had reached acquisition criterion; rats tested with pre-exposed objects re-acquired the pairwise discrimination following S+ rotation more effectively than those tested with new objects. Systemic scopolamine impaired performance on both tasks, suggesting involvement of acetylcholine at muscarinic receptors in view-invariant object processing. These tasks present novel means of studying the behavioral and neural bases of view-invariant object recognition in rodents.



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Graded 6-OHDA-induced dopamine depletion in the nigrostriatal pathway evokes progressive pathological neuronal activities in the subthalamic nucleus of a hemi-parkinsonian mouse

Publication date: 15 May 2018
Source:Behavioural Brain Research, Volume 344
Author(s): Sunghee Estelle Park, Kang-Il Song, Hyungmin Kim, Seok Chung, Inchan Youn
Recent studies have established methods for establishing a rodent model that mimics progressive stages of human Parkinson's disease (PD), via injection of graded doses of 6-hydroxydopamine (6-OHDA) into regions within the nigrostriatal pathway. However, the electrophysiological characteristics of the subthalamic nucleus (STN) in this model have not been fully elucidated in this model. This study aimed to investigate changes in the neuronal activity of the STN in a graded mouse model of PD. Increasing doses of 6-OHDA were unilaterally injected into the medial forebrain bundle (MFB) to produce a hemi-parkinsonian mouse model, mimicking early, moderate, advanced, and severe stages of human PD. Mice treated with higher doses of 6-OHDA demonstrated significantly lower rates of use of the impaired (contralateral) forelimb during wall contact, relative to sham mice. The STN firing rate was significantly increased in groups with >75% dopaminergic cell loss in the substantia nigra pars compacta (SNc), whereas little increase was observed in groups with partial lesions of the SNc, relative to the sham group. In addition, firing patterns of the STN in groups treated with higher doses of 6-OHDA became more irregular and exhibited burst-like patterns of activity, with dominant slow wave oscillations in the frequency range of 0.3–2.5 Hz. Our results demonstrated a strong correlation between neuronal activities in the STN and dopamine depletion in the nigrostriatal pathway, which can be manipulated by variation of 6-OHDA doses.



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Destruction of noradrenergic terminals increases dopamine concentration and reduces dopamine metabolism in the medial prefrontal cortex

Publication date: 15 May 2018
Source:Behavioural Brain Research, Volume 344
Author(s): Rita Gálosi, Zoltán Petykó, Veronika Kállai, Attila Tóth, Tamás Ollmann, László Péczely, Anita Kovács, Beáta Berta, László Lénárd
Effects of destroyed noradrenergic (NE) innervation in the medial prefrontal cortex (mPFC) were examined on dopamine (DA) content and metabolism. Six-hydroxy-DOPA (6-OHDOPA) or 6-hydroxy-dopamine (6-OHDA) in combination with a potent DA reuptake inhibitor GBR 12935 or 6-OHDA were injected bilaterally into the mPFC in separate groups of animals. In addition, GBR 12935 or vehicle was injected into the mPFC in two other groups of animals as control experiments. NE and DA concentrations from postmortem tissue of the mPFC were measured using HPLC with electrochemical detection. In addition, extracellular NE, DA and DOPAC levels were determined using in vivo microdialysis after the 6-OHDA lesion in combination with GBR 12935 pretreatment in the mPFC. Using reverse microdialysis of alpha-2-adrenoreceptor antagonist yohimbine, we tested the remaining activity of NE innervation and the extracellular concentration of DA and DOPAC. NE and DA concentrations from postmortem tissue of the mPFC showed that 6-OHDOPA lesion reduced NE concentration to 76%, which was a non-significant alteration, however it enhanced significantly DA concentration to 186% compared to vehicle. After 6-OHDA lesion with GBR 12935 pretreatment, concentration of NE significantly decreased to 51% and DA level increased to 180%. 6-OHDA lesion without GBR 12635 pretreatment decreased NE concentration to 23% and DA concentration to 67%. In the microdialysis experiment, after 6-OHDA lesion with GBR 12935 pretreatment, extracellular NE levels were not detectable, whereas extracellular DA levels were increased and DOPAC levels were decreased compared to controls. Reverse microdialysis of yohimbine demonstrated that the residual NE innervation was able to increase NE level and DA levels, but DOPAC concentration remained low after lesion of the NE terminals. These findings suggest that the damage of NE innervation in the mPFC may alter extracellular DA level due to a reduced DA clearance.



http://ift.tt/2BFWUvx

Speech Intelligibility Predicted from Neural Entrainment of the Speech Envelope

Abstract

Speech intelligibility is currently measured by scoring how well a person can identify a speech signal. The results of such behavioral measures reflect neural processing of the speech signal, but are also influenced by language processing, motivation, and memory. Very often, electrophysiological measures of hearing give insight in the neural processing of sound. However, in most methods, non-speech stimuli are used, making it hard to relate the results to behavioral measures of speech intelligibility. The use of natural running speech as a stimulus in electrophysiological measures of hearing is a paradigm shift which allows to bridge the gap between behavioral and electrophysiological measures. Here, by decoding the speech envelope from the electroencephalogram, and correlating it with the stimulus envelope, we demonstrate an electrophysiological measure of neural processing of running speech. We show that behaviorally measured speech intelligibility is strongly correlated with our electrophysiological measure. Our results pave the way towards an objective and automatic way of assessing neural processing of speech presented through auditory prostheses, reducing confounds such as attention and cognitive capabilities. We anticipate that our electrophysiological measure will allow better differential diagnosis of the auditory system, and will allow the development of closed-loop auditory prostheses that automatically adapt to individual users.

http://ift.tt/2C9ItRv

Optimal Human Passive Vestibulo-Ocular Reflex Adaptation Does Not Rely on Passive Training

Abstract

The vestibulo-ocular reflex (VOR) is the main vision-stabilising system during rapid head movements in humans. A visual-vestibular mismatch stimulus can be used to train or adapt the VOR response because it induces a retinal image slip error signal that drives VOR motor learning. The training context has been shown to affect VOR adaptation. We sought to determine whether active (self-generated) versus passive (externally imposed) head rotation vestibular training would differentially affect adaptation and short-term retention of the active and passive VOR responses. Ten subjects were tested, each over six separate 1.5-h sessions. We compared active versus passive head impulse (transient, rapid head rotations with peak velocity ~ 150 °/s) VOR adaptation training lasting 15 min with the VOR gain challenged to increment, starting at unity, by 0.1 every 90 s towards one side only (this adapting side was randomised to be either left or right). The VOR response was tested/measured in darkness at 10-min intervals, 20-min intervals, and two single 60-min interval sessions for 1 h post-training. The training was active or passive for the 10- and 20-min interval sessions, but only active for the two single 60-min interval sessions. The mean VOR response increase due to training was ~ 10 % towards the adapting side versus ~2 % towards the non-adapting side. There was no difference in VOR adaptation and retention between active and passive VOR training. The only factor to affect retention was exposure to a de-adaptation stimulus. These data suggest that active VOR adaptation training can be used to optimally adapt the passive VOR and that adaptation is completely retained over 1 h as long as there is no visual feedback signal driving de-adaptation.

http://ift.tt/2sMd6Zu

Editorial Board

Publication date: March 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 177





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Vitamin D3 supplementation decreases a unique circulating monocyte cholesterol pool in patients with type 2 diabetes

Publication date: March 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 177
Author(s): Amy E. Riek, Jisu Oh, Isra Darwech, Veronica Worthy, Xiaobo Lin, Richard E. Ostlund, Rong M. Zhang, Carlos Bernal-Mizrachi
Cross-sectional studies indicate consistent associations between low 25(OH)D concentration and increased risk of cardiovascular disease (CVD), but results of randomized control trials (RCTs) are mixed. However, the majority of the RCTs do not focus on type 2 diabetics, potentially obscuring the effects of vitamin D in this population. In vitro 1,25(OH)2D3 downregulates macrophage cholesterol deposition, but the in vivo effects are unknown. To explore potential mechanisms of the effects of vitamin D on CVD risk in patients with type 2 diabetes, we isolated monocytes in a subset of 26 patients from our RCT of diabetics with baseline serum 25(OH)D <25ng/mL randomized to vitamin D3 4000 IU/day or placebo for 4 months. Upon enrollment, the mean 25(OH)D level was 17ng/mL, which increased to 36ng/mL after vitamin D and remained unchanged in the placebo group. Before randomization, groups demonstrated similar mean hemoglobin A1c and plasma lipids levels, none of which was significantly altered by vitamin D supplementation. Moreover, assessment of oxidized LDL uptake in monocytes cultured in the patient's own serum before vs. after treatment resulted in >50% reduction in the vitamin D group with no change in the placebo group. This was mediated through suppression of endoplasmic reticulum stress and scavenger receptor CD36 protein expression. The reduction in monocyte cholesterol uptake was reflected in a 19% decrease in total monocyte cholesterol content. Interestingly, cross-sectional analysis of circulating monocytes from vitamin D-deficient vs. sufficient diabetic patients revealed 8-fold higher cholesteryl ester content, confirming the capacity of these monocytes to uptake and carry cholesterol in the circulation. This study identifies a unique circulating cholesterol pool within monocytes that is modulated by vitamin D and has the potential to contribute to CVD in type 2 diabetes.



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Deletion of JNK2 prevents vitamin-D-deficiency-induced hypertension and atherosclerosis in mice

Publication date: March 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 177
Author(s): Jisu Oh, Amy E. Riek, Rong M. Zhang, Samantha A.S. Williams, Isra Darwech, Carlos Bernal-Mizrachi
The c-Jun N-terminal kinase 2 (JNK2) signaling pathway contributes to inflammation and plays a key role in the development of obesity-induced insulin resistance and cardiovascular disease. Macrophages are key cells implicated in these metabolic abnormalities. Active vitamin D downregulates macrophage JNK activation, suppressing oxidized LDL cholesterol uptake and foam cell formation and promoting an anti-inflammatory phenotype. To determine whether deletion of JNK2 prevents high blood pressure and atherosclerosis known to be induced by vitamin D deficiency in mice, we generated mice with knockout of JNK2 in a background susceptible to diet-induced atherosclerosis (LDLR^−/−). JNK2^−/− LDLR^−/− and LDLR^−/− control mice were fed vitamin D-deficient chow for 8 weeks followed by vitamin D-deficient high fat diet (HFD) for 10 weeks and assessed before and after HFD. There was no difference in fasting glucose, cholesterol, triglycerides, or free fatty acid levels. However, JNK2^−/− mice, despite vitamin D-deficient diet, had 20–30mmHg lower systolic (SBP) and diastolic (DBP) blood pressure before HFD compared to control mice fed vitamin D-deficient diets, with persistent SBP differences after HFD. Moreover, deletion of JNK2 reduced HFD-induced atherosclerosis by 30% in the proximal aorta when compared to control mice fed vitamin D-deficient diets. We have previously shown that peritoneal macrophages obtained from LDLR^−/− mice fed vitamin D-deficient HFD diets have higher foam cell formation compared to those from mice on vitamin D-sufficient HFD. The increased total cellular cholesterol and modified cholesterol uptake in macrophages from mice on vitamin D-deficient HFD were blunted by deletion of JNK2. These data suggest that JNK2 signaling activation is necessary for the atherosclerosis and hypertension induced by vitamin D deficiency.



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Vitamin D prevents lipid accumulation in murine muscle through regulation of PPARγ and perilipin-2 expression

Publication date: March 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 177
Author(s): Jiarong Li, Milton Mihalcioiu, Lifeng Li, Mahvash Zakikhani, Anne Camirand, Richard Kremer
Vitamin D plays an important role in regulation of skeletal muscle tone and contraction. Serum vitamin D status is linked to muscle power and force in adolescent girls, and vitamin D deficiency is associated with myopathies in children and poorer physical performance in the elderly. We previously reported that vitamin D deficiency is linked to a significant increase in muscle fatty infiltration in healthy young women, and studies in patients with neuromuscular disorders also associate muscle weakening and lipid content. In order to better understand the link between vitamin D status and skeletal muscle lipid metabolism, we compared the effect of a low (25IU/kg) or normal (1000IU/kg) vitamin D3 diet on muscle fat in female FVB mice maintained in a room without UVB lighting to minimize endogenous vitamin D production. Animals on low vitamin D diet displayed lower circulating 25(OH)D levels and a dramatic increase (287±52% compared to normal diet, p<0.0001) in lipid deposition in skeletal muscle accompanied by muscle fiber disorganization. Lipid droplet staining increased by 242±23% (p<0.0001) in low vitamin D diet, and lipid droplet coat protein perilipin-2 and nuclear receptor transcription factor PPARγ expression levels were increased compared to mice fed the normal vitamin D diet: average staining for PLIN2: 0.22±0.08 (25IU/kg diet) vs 0.10±0.02 (1000IU/kg). Average staining for PPARγ: 0.24±0.06 (25IU/kg diet) vs 0.07±0.04 (1000IU/kg) p<0.0001. Tissue mass spectrometry imaging revealed major differences in muscle phospholipids profile depending on diet. In vitro, 1,25(OH)2D3 treatment of 3T3-L1 pre-adipocytes inhibited appearance of lipid droplets by 79±9.3%, and caused a 80±10% and 25±8% (p=0.001) reduction in PPARγ and perilipin-2 mRNA levels (by qPCR) compared to control cells. In summary, we report here the first in vivo model illustrating the important structural muscle fiber disorganization and fat accumulation inside and outside muscle fibers that accompany vitamin D deficiency. Furthermore, we show that the underlying mechanisms involve PPARγ and perilipin-2.

Graphical abstract

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Vitamin D status in relation to physical performance, falls and fractures in the Longitudinal Aging Study Amsterdam: A reanalysis of previous findings using standardized serum 25-hydroxyvitamin D values

Publication date: March 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology, Volume 177
Author(s): N.M. Van Schoor, M.W. Heymans, P. Lips
The Longitudinal Aging Study Amsterdam (LASA) is an ongoing prospective cohort study in a representative sample of Dutch older persons. In previous LASA studies, lower serum 25-hydroxyvitamin D (25(OH)D) values, as assessed by a competitive protein binding assay or radioimmunoassay, have been associated with decreased physical functioning, falls and fractures. Recently, serum 25(OHD) values in LASA were standardized using the Vitamin D Standardization Program (VDSP) protocol as part of the European ODIN project. In the current manuscript, the influence of standardizing serum 25(OH)D values will be discussed using the associations with physical functioning, falls and fractures as examples.



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Hochauflösungsmanometrische Evaluation des velopharyngealen Verschlussdrucks beim Trompetenspiel

Laryngo-Rhino-Otol
DOI: 10.1055/s-0043-124971

Hintergrund Bei etwa einem Drittel der Blasmusiker kommt es zu belastungsbedingten Insuffizienzen des velopharyngealen Abschlusses (VPA), d. h. der intraorale Druck übersteigt die durch den VPA gebildete Barriere. In dieser Studie sollte der Verschlussdruck im VPA beim Spielen einer Trompete gemessen und über prüft werden, welchen Einfluss eine 30-minütige Belastungssequenz auf die muskulären Aktivitäten im VPA hat. Material und Methoden Stichprobe: 6 gesunde Probanden. Aufgabe: Spielen des Tons h1 über 5 Sekunden mit 85 dB(A) und mit 100 dB(A). Methodik: Hochauflösungsmanometrie (HRM); Messzeitpunkte: t0: Messung ohne Einspielphase, t1 nach 30 min Trompetenspiel mit vorgegebenen Musikstücken. Variablen: mittlere Drücke (pmit), Minimal-(pmin)- sowie Maximaldrücke (pmax) zu t0 und t1 im VPA. Statistik: Prüfung auf Normalverteilung, t-test. Ergebnisse Alle gemessenen Drücke im VPA sanken von t0 zu t1 für produzierte 85 dB(A) Töne. Für 100 dB(A) Töne sanken nur die pmin. Die Drücke im VPA waren bei 100 dB(A) Tönen insgesamt höher als bei 85 dB(A) Tönen, signifikant war dieser Unterschied nur für pmin und pmax zu t0. Schlussfolgerung Lauter gespielte Töne erfordern eine stärkere muskuläre Kontraktion im VPA. Der niedrigere Verschlussdruck im VPA zum Zeitpunkt t1 kann Folge einer physiologischen muskulären Adaptation an das für den VPA notwendige Druckniveau oder bereits Zeichen einer muskulären Ermüdung sein. Dies ist möglicherweise für den Einsatz der HRM zur Beurteilung der Berufsfähigkeit von Blasinstrumentalisten von Bedeutung. Wie schon für die Phonation beschrieben, ließ sich auch hier mit einem dreiphasigen Modell, bestehend aus Initiation, stabiler Phase und Terminierung, der VPA Druckverlauf beschreiben.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Kinetics, isotherms, and thermodynamic studies of lead, chromium, and cadmium bio-adsorption from aqueous solution onto Picea smithiana sawdust

Abstract

Lead (Pb), chromium (Cr), and cadmium (Cd) removal capacity of sawdust (Picea smithiana) from aqueous solution was investigated by conducting batch experiments. Thermodynamic parameters, like change in standard free energy (ΔG^Θ), enthalpy (ΔH^Θ) and entropy (ΔS^Θ) during bio-adsorption process were estimated using the Van't Hoff equation. The maximum metals adsorption was observed at pH 8, 20 g L⁻¹ bio-adsorbent and at 60 min of contact time. The metal adsorption kinetics was examined by fitting the pseudo-first-order as well as four forms of pseudo-second-order kinetic models. Type 1 pseudo-second-order equation described adsorption kinetics better than others. Langmuir model and Freundlich equations were used for calculation of sorption parameters. The Langmuir maximum adsorption capacity of Pb, Cr, and Cd was 6.35, 3.37, and 2.87 mg g⁻¹ at room temperature, respectively. The values of the separation factor (RL) were in between 0 and 1, indicating that bio-adsorption was favorable. Thermodynamics study revealed that the Pb, Cr, and Cd uptake reactions were endothermic and spontaneous. Results of the study asserted that the removal of heavy metal ions from aqueous solution is viable and the sawdust could be used in the treatment of effluents from industries, thereby reducing the level of water pollution.

http://ift.tt/2C9NpFT

Computer-Aided Surgical Simulation in Head and Neck Reconstruction: A Cost Comparison among Traditional, In-House, and Commercial Options

J reconstr Microsurg
DOI: 10.1055/s-0037-1621735

Background Computer-aided surgical simulation (CASS) has redefined surgery, improved precision and reduced the reliance on intraoperative trial-and-error manipulations. CASS is provided by third-party services; however, it may be cost-effective for some hospitals to develop in-house programs. This study provides the first cost analysis comparison among traditional (no CASS), commercial CASS, and in-house CASS for head and neck reconstruction. Methods The costs of three-dimensional (3D) pre-operative planning for mandibular and maxillary reconstructions were obtained from an in-house CASS program at our large tertiary care hospital in Northern Virginia, as well as a commercial provider (Synthes, Paoli, PA). A cost comparison was performed among these modalities and extrapolated in-house CASS costs were derived. The calculations were based on estimated CASS use with cost structures similar to our institution and sunk costs were amortized over 10 years. Results Average operating room time was estimated at ten hours, with an average of two hours saved with CASS. The hourly cost to the hospital for the operating room (including anesthesia and other ancillary costs) was estimated at $4,614/hour. Per case, traditional cases were $46,140, commercial CASS cases were $40,951, and in-house CASS cases were $38,212. Annual in-house CASS costs were $39,590. Conclusions CASS reduced operating room time, likely due to improved efficiency and accuracy. Our data demonstrate that hospitals with similar cost structure as ours, performing greater than 27 cases of 3D head and neck reconstructions per year can see a financial benefit from developing an in-house CASS program.
[...]

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Article in Thieme eJournals:
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Small, Smart Technology Opens a World of Sound for Kaci Mueller

Between the 4th and 8th grades, Kaci Mueller suffered repeated ear infections and underwent more than 10 surgeries for cholesteatoma,... Read the full article...

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Citardi and Luong Named to Best Doctors List for Otorhinolaryngology

Two of the nation's top otorhinolaryngologists practice at UT Physicians, the clinical practice of McGovern Medical School at The University... Read the full article...

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The GRP78/BiP inhibitor HA15 synergizes with mitotane action against adrenocortical carcinoma cells through convergent activation of ER stress pathways

Publication date: Available online 20 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Carmen Ruggiero, Mabrouka Doghman-Bouguerra, Cyril Ronco, Rachid Benhida, Stéphane Rocchi, Enzo Lalli
Many types of cancer cells present constitutively activated ER stress pathways because of their significant burden of misfolded proteins coded by mutated and rearranged genes. Further increase of ER stress by pharmacological intervention may shift the balance towards cell death and can be exploited therapeutically. Recent studies have shown that an important component in the mechanism of action of mitotane, the only approved drug for the medical treatment of adrenocortical carcinoma (ACC), is represented by activation of ER stress through inhibition of the SOAT1 enzyme and accumulation of toxic lipids. Here we show that HA15, a novel inhibitor of the essential ER chaperone GRP78/BiP, inhibits ACC H295R cell proliferation and steroidogenesis and is able to synergize with mitotane action. These results suggest that convergent activation of ER stress pathways by drugs acting via different mechanisms represents a valuable therapeutic option for ACC.



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Table of Contents

Publication date: March 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 3, Supplement 1





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Editorial Board

Publication date: March 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 3, Supplement 1





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Dupilumab: A review of its use in the treatment of atopic dermatitis

Publication date: March 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 3, Supplement 1
Author(s): Melinda J. Gooderham, H. Chih-ho Hong, Panteha Eshtiaghi, Kim A. Papp
Atopic dermatitis (AD) is a chronic, pruritic immune-mediated inflammatory dermatosis characterized by a T helper 2 (Th2) immune response phenotype and may be associated with systemic inflammation. Dupilumab is an interleukin 4 (IL-4) receptor α-antagonist that inhibits IL-4 and IL-13 signaling through blockade of the shared IL-4α subunit. Blockade of IL-4/13 is effective in reducing Th2 response. Dupilumab has recently been approved in the United States and Europe for the treatment of adult patients with moderate-to-severe AD. Clinical trials have shown that adults with moderate-to-severe AD who receive weekly or biweekly dupilumab injections have significantly improved clinical and patient-reported outcomes, including Eczema Area Severity Index, SCORing Atopic Dermatitis, Dermatology Life Quality Index, and itch Numeric Rating Scale scores. Concomitant use of topical corticosteroids along with dupilumab results in a greater improvement in signs and symptoms of AD than with use of dupilumab alone. Biomarker analyses show that dupilumab modulates the AD molecular signature and other Th2-associated biomarkers. Common adverse events reported in the clinical trials were nasopharyngitis, upper respiratory tract infection, injection site reactions, skin infections, and conjunctivitis. These were mild-to-moderate in nature, and overall rates of adverse events occurred with similar frequency between the treatment and placebo groups. There were no significant serious safety concerns identified in phase III clinical trials. Dupilumab, as monotherapy or with concomitant use of topical corticosteroids, can significantly improve clinical outcomes and quality of life in patients suffering from moderate-to-severe AD. Ongoing studies of dupilumab will help determine the clinical efficacy and safety profile of its long-term use.



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New therapies for atopic dermatitis: Additional treatment classes

Publication date: March 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 3, Supplement 1
Author(s): Paras P. Vakharia, Jonathan I. Silverberg
BackgroundA wide array of miscellaneous agents is being studied for the treatment of atopic dermatitis (AD), including targeted topical, oral systemic, and biologic agents.ObjectiveTo review the known efficacy and safety to date for such agents being studied for the treatment of AD.MethodsA nonsystematic review of the literature was performed. PubMed and ClinicalTrials.gov were searched for studies assessing agents not described previously for the treatment of AD. Randomized controlled trials were primarily sought, but other study types were also included if they contained pertinent data. Agents are presented by mechanism of action, with analysis of mechanism of action and data regarding efficacy and safety in patients with AD.ResultsData regarding the following agents are presented: omiganan (an antimicrobial peptide), tapinarof (a nonsteroidal anti-inflammatory agent), PR022 (hypochlorous acid), asimadoline (a κ-opioid agonist), DS107 (dihomo-γ-linolenic acid), ZPL-389 (a histamine H4 receptor antagonist), secukinumab (an interleukin 17A inhibitor), and fezakinumab (interleukin 22 inhibitor).LimitationsLimited clinical data exist for many of the described agents.ConclusionsAs recent research has improved our understanding of AD pathogenesis, various agents with unique mechanisms of action have been studied for the treatment of AD. Many of these hold great therapeutic promise for AD, and continued research and development is warranted.



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Phosphodiesterase 4 inhibitors

Publication date: March 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 3, Supplement 1
Author(s): Rema Zebda, Amy S. Paller
Historically, drugs available for treating atopic dermatitis (AD) have been limited to topical corticosteroids and topical calcineurin inhibitors, with systemic immunosuppressants and phototherapy reserved for severe AD. Despite their efficacy and infrequent adverse events, phobia about the use of topical steroids and calcineurin inhibitors has limited their use. More targeted options with fewer systemic and cutaneous side effects are needed for treating AD. Phosphodiesterase 4 (PDE4) is involved in the regulation of proinflammatory cytokines via the degradation of cyclic adenosine monophosphate. PDE4 activity is increased in the inflammatory cells of patients with AD, leading to increased production of proinflammatory cytokines and chemokines. Targeting PDE4 reduces the production of these proinflammatory mediators in AD. Both topical and oral PDE4 inhibitors have a favorable safety profile. Crisaborole 2% ointment, a topical PDE4, is now US Food and Drug Administration–approved for children older than 2 years and adults in the treatment of AD. Crisaborole 2% ointment shows early and sustained improvement in disease severity and pruritus and other AD symptoms, with burning and/or stinging upon application as the only related adverse event. Other PDE4 inhibitors are currently in trials with promising efficacy and safety.



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Emerging therapies for atopic dermatitis: JAK inhibitors

Publication date: March 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 3, Supplement 1
Author(s): David G. Cotter, David Schairer, Lawrence Eichenfield
The Janus kinase–signal transducer and activator of transcription pathway is a conserved master regulator of immunity and myeloproliferation. Advanced understanding of this pathway has led to development of targeted inhibitors of Janus kinases (Jakinibs). As a class, JAK inhibitors effectively treat a multitude of hematologic and inflammatory diseases. Given such success, use of JAK inhibitors for mitigation of atopic dermatitis is under active investigation. Herein, we review the evolving data on the safety and efficacy of JAK inhibitors in treatment of atopic dermatitis. Although it is still early in the study of JAK inhibitors for atopic dermatitis, evidence identifies JAK inhibitors as effective alternatives to conventional therapies. Nonetheless, multiple large safety and efficacy trials are needed before widespread use of JAK inhibitors can be advocated for atopic dermatitis.



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