Head and Neck Diseases by Alexandros G.Sfakianakis: 10/30/16

Κυριακή 30 Οκτωβρίου 2016

Head impacts in a junior rugby league team measured with a wireless head impact sensor: an exploratory analysis.

Head impacts in a junior rugby league team measured with a wireless head impact sensor: an exploratory analysis.

J Neurosurg Pediatr. 2016 Oct 28;:1-11

Authors: King D, Hume P, Gissane C, Clark T

Abstract
OBJECTIVE The aim of this study was to investigate the frequency, magnitude, and distribution of head impacts sustained by players in a junior rugby league over a season of matches. METHODS The authors performed a prospective cohort analysis of impact magnitude, frequency, and distribution on data collected with instrumented XPatches worn behind the ear of players in an "under-11" junior rugby league team (players under 11 years old). RESULTS A total of 1977 impacts were recorded. Over the course of the study, players sustained an average of 116 impacts (average of 13 impacts per player per match). The measured linear acceleration ranged from 10g to 123g (mean 22g, median 16g, and 95th percentile 57g). The rotational acceleration ranged from 89 rad/sec(2) to 22,928 rad/sec(2) (mean 4041 rad/sec(2), median 2773 rad/sec(2), and 95th percentile 11,384 rad/sec(2)). CONCLUSIONS The level of impact severity based on the magnitude of impacts for linear and rotational accelerations recorded was similar to the impacts reported in studies of American junior and high school football, collegiate football, and youth ice hockey players, but the players in the rugby league cohort were younger, had less body mass, and played at a slower speed than the American players. Junior rugby league players are required to tackle the player to the ground and use a different tackle technique than that used in American football, likely increasing the rotational accelerations recorded at the head.

PMID: 27791705 [PubMed - as supplied by publisher]

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Impact of intraoperative 3-T MRI with diffusion tensor imaging on hemispherectomy.

Impact of intraoperative 3-T MRI with diffusion tensor imaging on hemispherectomy.

J Neurosurg Pediatr. 2016 Oct 28;:1-7

Authors: Kim GH, Seo JH, Schroff S, Chen PC, Lee KH, Baumgartner J

Abstract
OBJECTIVE Hemispherectomy can produce remarkable seizure control of medically intractable hemispheric epilepsy in children, but some patients continue to have seizures after surgery. A frequent cause of treatment failure is incomplete surgical disconnection of the abnormal hemisphere. This study explores whether intraoperative 3-T MRI with diffusion tensor imaging (DTI) during hemispherectomy can identify areas of incomplete disconnection and allow complete disconnection during a single surgery. METHODS The charts of 32 patients with epilepsy who underwent hemispherectomy between January 2012 and July 2014 at the Florida Hospital for Children were reviewed. Patients were grouped as having had curative or palliative hemispherectomy. To assess the completeness of disconnection when the surgeon considered the operation completed, intraoperative 3-T MRI-DTI was performed. If incomplete disconnection was identified, additional surgery was performed until MRI-DTI sequences confirmed satisfactory disconnection. Seizure outcome data were collected via medical records at last follow-up. RESULTS Of 32 patients who underwent hemispherectomy, 23 had curative hemispherectomy and 9 had palliative hemispherectomy. In 11 of 32 surgeries, the first intraoperative MRI-DTI sequences suggested incomplete disconnection and additional surgery followed by repeat MRI-DTI was performed. Complete disconnection was accomplished in 30 of 32 patients (93.8%). Two of 32 disconnections (6.3%) were incomplete on postoperative imaging. Cross-sectional results showed that 21 of 23 patients (91.3%) who had curative hemispherectomy remained free of seizures (International League Against Epilepsy Class 1) at a median follow-up of 1.7 years (range 0.4-2.9 years). The longitudinal seizure freedom after curative hemispherectomy was 95.2% (SE 0.05) at 6 months, 90.5% (SE 0.06) at 1 year, and 90.5% (SE 0.05) at 2 years. CONCLUSIONS Intraoperative 3-T MRI-DTI sequences can identify incomplete disconnection during hemispherectomy and allow higher rates of complete disconnection in a single surgery. Higher rates of complete disconnection seem to achieve better seizure-free outcome following modified functional hemispherectomy.

PMID: 27791704 [PubMed - as supplied by publisher]

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Reconstruction of a large calvarial traumatic defect using a custom-made porous hydroxyapatite implant covered by a free latissimus dorsi muscle flap in an 11-year-old patient.

Reconstruction of a large calvarial traumatic defect using a custom-made porous hydroxyapatite implant covered by a free latissimus dorsi muscle flap in an 11-year-old patient.

J Neurosurg Pediatr. 2016 Oct 28;:1-5

Authors: Morice A, Kolb F, Picard A, Kadlub N, Puget S

Abstract
Reconstruction of complex skull defects requires collaboration between neurosurgeons and plastic surgeons to choose the most appropriate procedure, especially in growing children. The authors describe herein the reconstruction of an extensive traumatic bone and soft tissue defect of the cranial vault in an 11-year-old boy. The size of the defect, quality of the tissues, and patient's initial condition required a 2-stage approach. Ten months after an initial emergency procedure in which lacerated bone and soft tissue were excised, reconstruction was performed. The bone defect, situated on the left frontoparietal region, was 85 cm(2) and was filled by a custom-made porous hydroxyapatite implant. The quality of the overlying soft tissue did not allow the use of classic local and locoregional coverage techniques. A free latissimus dorsi muscle flap branched on the contralateral superficial temporal pedicle was used and left for secondary healing to take advantage of scar retraction and to minimize alopecia. Stable well-vascularized implant coverage as well as an esthetically pleasing skull shape was achieved. Results in this case suggest that concomitant reconstruction of large calvarial defects by cranioplasty with a custom-made hydroxyapatite implant covered by a free latissimus dorsi muscle flap is a safe and efficient procedure in children, provided that there is no underlying infection of the operative site.

PMID: 27791703 [PubMed - as supplied by publisher]

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Hemispherotomy in children with electrical status epilepticus of sleep.

Hemispherotomy in children with electrical status epilepticus of sleep.

J Neurosurg Pediatr. 2016 Oct 28;:1-7

Authors: Jeong A, Strahle J, Vellimana AK, Limbrick DD, Smyth MD, Bertrand M

Abstract
OBJECTIVE Electrical status epilepticus of sleep (ESES) is a rare electrographic pattern associated with global regression, which is often poorly responsive to traditional epilepsy treatments and can have a devastating and permanent neurocognitive outcome. The authors analyzed clinical, electroencephalographic, and neuropsychological outcomes in 9 patients with refractory ESES treated with functional hemispherotomy to illustrate the wide clinical spectrum associated with the disease and explore the role of hemispherotomy in its treatment. METHODS During the period between 2003 and 2015, 80 patients underwent hemispherotomy at the authors' institution. Video electroencephalography (EEG) reports were reviewed for ESES or continuous spikes and waves during sleep (CSWS). Patients with preoperative ESES (> 85% slow-wave sleep occupied by spike waves), a unilateral structural lesion amenable to surgery, and more than 6 months of follow-up data were included in the analysis. Clinical data, EEG recordings, neuropsychological testing, and parental and clinician reports were retrospectively reviewed. RESULTS Nine patients were eligible for study inclusion. Age at seizure onset ranged from birth to 4.2 years (mean 1.9 years), age at ESES diagnosis ranged from 3.5 to 8.8 years (mean 6.0 years), and age at hemispherotomy ranged from 3.7 to 11.5 years (mean 6.8 years). All patients had drug-resistant epilepsy. The duration of epilepsy prior to hemispherotomy ranged from 2.7 to 8.9 years (mean ± SD, 5.0 ± 2.2 years). Engel Class I seizure outcome was observed in all 9 children, with a mean follow-up of 3.0 years (range 0.5-6.1 years). Hemispherotomy terminated ESES in 6 of 6 patients with available postoperative sleep EEG. All children had preoperative neuropsychological impairments. Developmental regression was halted postoperatively, but none of the children returned to their original pre-ESES baseline. Four children demonstrated academic gains, 2 of whom transitioned to mainstream classes. CONCLUSIONS Children with drug-resistant ESES and a unilateral structural lesion should be evaluated for hemispherotomy as they may experience the cessation of seizures, termination of ESES, and improvement in neuropsychological status.

PMID: 27791702 [PubMed - as supplied by publisher]

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Football fatalities: the first-impact syndrome.

Football fatalities: the first-impact syndrome.

J Neurosurg Pediatr. 2016 Oct 28;:1-6

Authors: Bailes JE, Patel V, Farhat H, Sindelar B, Stone J

PMID: 27791701 [PubMed - as supplied by publisher]

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Does Shear Wave Elastography Provide Additional Value in the Evaluation of Thyroid Nodules That Are Suspicious for Malignancy?

Does Shear Wave Elastography Provide Additional Value in the Evaluation of Thyroid Nodules That Are Suspicious for Malignancy?

J Ultrasound Med. 2016 Nov;35(11):2397-2404

Authors: Wang F, Chang C, Gao Y, Chen YL, Chen M, Feng LQ

Abstract
OBJECTIVES: We aimed to determine whether the integration of shear wave elastography (SWE) with conventional ultrasonography (US) improves diagnostic performance for suspicious thyroid lesions.
METHODS: For 215 thyroid lesions in 185 patients classified as Thyroid Imaging Reporting and Data System category 4 or 5 according to the findings of conventional US, SWE elasticity indices were automatically calculated. A receiver operating characteristic curve analysis was used to determine the threshold. Thyroid Imaging Reporting and Data System categories were upgraded for high-stiffness nodules and unchanged for low- and normal-stiffness nodules. The diagnostic performances were assessed and compared with histologic findings. Intraobserver and interobserver variability of SWE was assessed.
RESULTS: Elasticity indices were significantly higher in malignant versus benign nodules (P≤ .001). The minimum elasticity index (cutoff, 40.7 kPa) of the stiffest part combined with conventional US showed the highest area under the curve (0.774; 95% confidence interval, 0.682-0.866) but was not superior to conventional US (0.791; 95% confidence interval, 0.706-0.876; P = .48). Combined with the standard deviation of the elasticity index for the whole lesion (cutoff, 6.8 kPa), US yielded the highest sensitivity (95.5%; P < .001) and lowest specificity (42.1%; P < .001). Sensitivity increased and specificity decreased by adding any other SWE elasticity index. The intraobserver and interobserver reliability of SWE was fair to excellent according to the interclass correlation coefficients, with correlation coefficients of 0.765 to 0.846 (all P < .001).
CONCLUSIONS: The SWE elasticity indices of malignant thyroid nodules were significantly high. Adding SWE to conventional US did not improve diagnostic performance.

PMID: 27794130 [PubMed - in process]

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Phase I Study of the Pan-PI3K Inhibitor Buparlisib in Adult Chinese Patients with Advanced Solid Tumors.

Phase I Study of the Pan-PI3K Inhibitor Buparlisib in Adult Chinese Patients with Advanced Solid Tumors.

Anticancer Res. 2016 Nov;36(11):6185-6194

Authors: Wu YL, Zhang LI, Trandafir L, Dong T, Duval V, Hazell K, Xu B

Abstract
BACKGROUND/AIM: The phosphatidylinositol-3-kinase (PI3K) signaling pathway is frequently activated in cancer. Buparlisib (BKM120), an oral pan-PI3K inhibitor, inhibits proliferation of human cancer in preclinical models. Studies of buparlisib in Western and Japanese adults with advanced solid tumors established a recommended dose of 100 mg/day and showed an acceptable safety profile and evidence of efficacy. This phase I dose-escalation/expansion study aimed to establish the maximum tolerated dose (MTD) of single-agent, once daily oral buparlisib in Chinese patients with advanced solid tumors.
MATERIALS AND METHODS: Patients (n=32; primary tumor site: lung (n=15), breast (n=10) or head and neck (n=7); ≥2 prior lines of antineoplastic therapy (n=26)) received 80 mg (n=15) or 100 mg (n=17) daily buparlisib.
RESULTS: Five patients experienced dose-limiting toxicities: grade (G)3 depression (n=1), G2 hyperglycemia (n=3) and G3 hyperglycemia (n=1). Most frequent buparlisib-related adverse events were hyperglycemia (n=18; 56%), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increase (n=9; 28%), as well as anxiety (n=6; 19%); most common buparlisib-related G3/4 adverse events: hyperglycemia (n=3; 9%), ALT and AST increase (n=2; 6%), as well as gamma-glutamyltransferase increase (n=2; 6%). Best response was stable disease (SD) in 10 patients (31%).
CONCLUSION: The MTD of buparlisib was declared as 100 mg/day. Safety, efficacy and pharmacokinetic data from this study were similar to those previously reported in Western and Japanese populations.

PMID: 27793950 [PubMed - in process]

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The Behavior and Role of Lipolysis-stimulated Lipoprotein Receptor, a Component of Tricellular Tight Junctions, in Head and Neck Squamous Cell Carcinomas.

The Behavior and Role of Lipolysis-stimulated Lipoprotein Receptor, a Component of Tricellular Tight Junctions, in Head and Neck Squamous Cell Carcinomas.

Anticancer Res. 2016 Nov;36(11):5895-5904

Authors: Takano K, Kakuki T, Obata K, Nomura K, Miyata R, Kondo A, Kurose M, Kakiuchi A, Kaneko Y, Kohno T, Himi T, Kojima T

Abstract
BACKGROUND/AIM: Lipolysis-stimulated lipoprotein receptor (LSR) knockdown has also been reported to increase the motility and invasiveness of certain cancer cells. Here, we describe, for the first time, the behavior and role of LSR in head and neck squamous cell carcinoma (HNSCC) in vivo and in vitro.
MATERIALS AND METHODS: Samples of HNSCC, normal palatine tonsils, the pharynx carcinoma cell line Detroit562 and primary cultured HNSCC were characterized by immunostaining, western blot, real-time polymerase chain reaction (PCR), Matrigel invasion and proliferation assays.
RESULTS: Protein and mRNA of LSR were strongly expressed, as well as claudin-1 in HNSCC tissues than in normal tissues, especially in invasive tissues. Knock-down of LSR and claudin-1 (CLDN-1), but not tricellulin (TRIC) by siRNAs, markedly induced invasiveness of Detroit562 cells and primary cultured HNSCC. LSR inhibited the development and progression of HNSCC.
CONCLUSION: LSR is a potential target for new forms of head and neck cancer therapy.

PMID: 27793914 [PubMed - in process]

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Central odontogenic fibromyxoma of mandible: an aggressive odontogenic pathology.

Central odontogenic fibromyxoma of mandible: an aggressive odontogenic pathology.

BMJ Case Rep. 2016 Oct 28;2016:

Authors: Bahl S, Raju GS, Shah G, Chandarana P

Abstract
Myxoma of the jaws which was first described by Thoma and Goldman in 1947 is a rare neoplasm and its rate of prevalence and incidence is not available. Myxoma term, according to 1992 WHO classification, is used along with odontogenic myxoma (OM) and myxofibroma. There are two forms of myxomas or fibromyxomas that are recognised in head and neck region: one is derived from the facial skeleton and the other is derived from the soft tissue. Most of the OM are located intraosseously, but peripheral ones are also recognised. OM behaves differently from myxomatous tumours of long bones, which recur more often and may transform into malignancy. A majority of these lesions occur between 2nd and 4th decade. In the pathogenesis of OM, dental papilla, dental follicle and periodontal ligament tissues have been implicated as possible 'germ centres'. This case describes an uncommon finding of central odontogenic fibromyxoma, throwing light on its epidemiology, clinical, histopathology, molecular and treatment aspects.

PMID: 27793851 [PubMed - in process]

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Ameloblastoma of the jaws: Management and recurrence rate.

Ameloblastoma of the jaws: Management and recurrence rate.

Eur Ann Otorhinolaryngol Head Neck Dis. 2016 Oct 25;:

Authors: Laborde A, Nicot R, Wojcik T, Ferri J, Raoul G

Abstract
INTRODUCTION: Ameloblastoma is a rare, benign odontogenic tumour associated with a high recurrence rate. It accounts for 1% of all tumours of the jaws. The purpose of this study was to compare the ameloblastoma recurrence rate according to the type of treatment: radical or conservative.
PATIENTS AND METHODS: All patients with a diagnosis of ameloblastoma between 1991 and 2013 were retrospectively identified in order to extract topographic, radiological, and histological data and the type of treatment: conservative (marsupialization, enucleation, curettage) or radical (segmental resection) and to compare the recurrence rate according to the type of treatment.
RESULTS: Twenty-seven patients were included, managed by conservative treatment (CT) in 22 cases and radical treatment (RT) in 14 cases. The recurrence rate was 90.9% in the CT group and 9.1% in the RT group (P=0.025) with a mean follow-up of 56.2 months.
DISCUSSION: The recurrence rate after conservative treatment was higher than that after radical treatment. These results are similar to those reported in the literature. The choice of treatment must be adapted to the macroscopic and histological characteristics of each tumour and to the patient.

PMID: 27793625 [PubMed - as supplied by publisher]

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A panel of four genes accurately differentiates benign from malignant thyroid nodules.

A panel of four genes accurately differentiates benign from malignant thyroid nodules.

J Exp Clin Cancer Res. 2016 Oct 28;35(1):169

Authors: Wang QX, Chen ED, Cai YF, Li Q, Jin YX, Jin WX, Wang YH, Zheng ZC, Xue L, Wang OC, Zhang XH

Abstract
BACKGROUND: Clinicians are confronted with an increasing number of patients with thyroid nodules. Reliable preoperative diagnosis of thyroid nodules remains a challenge because of inconclusive cytological examination of fine-needle aspiration biopsies. Although molecular analysis of thyroid tissue has shown promise as a diagnostic tool in recent years, it has not been successfully applied in routine clinical use, particularly in Chinese patients.
METHODS: Whole-transcriptome sequencing of 19 primary papillary thyroid cancer (PTC) samples and matched adjacent normal thyroid tissue (NT) samples were performed. Bioinformatics analysis was carried out to identify candidate diagnostic genes. Then, RT-qPCR was performed to evaluate these candidate genes, and four genes were finally selected. Based on these four genes, diagnostic algorithm was developed (training set: 100 thyroid cancer (TC) and 65 benign thyroid lesions (BTL)) and validated (independent set: 123 TC and 81 BTL) using the support vector machine (SVM) approach.
RESULTS: We discovered four genes, namely fibronectin 1 (FN1), gamma-aminobutyric acid type A receptor beta 2 subunit (GABRB2), neuronal guanine nucleotide exchange factor (NGEF) and high-mobility group AT-hook 2 (HMGA2). A SVM model with these four genes performed with 97.0 % sensitivity, 93.8 % specificity, 96.0 % positive predictive value (PPV), and 95.3 % negative predictive value (NPV) in training set. For additional independent validation, it also showed good performance (92.7 % sensitivity, 90.1 % specificity, 93.4 % PPV, and 89.0 % NPV).
CONCLUSIONS: Our diagnostic panel can accurately distinguish benign from malignant thyroid nodules using a simple and affordable method, which may have daily clinical application in the near future.

PMID: 27793213 [PubMed - in process]

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Subcellular localisation of pMEK has a different prognosis in locally advanced head and neck cancer treated with concomitant radiochemotherapy.

Subcellular localisation of pMEK has a different prognosis in locally advanced head and neck cancer treated with concomitant radiochemotherapy.

BMC Cancer. 2016 Oct 28;16(1):829

Authors: Gomez-Millan J, Pajares B, Perez-Villa L, Carnero A, Alvarez M, De Luque V, Rivas F, Trigo JM, Toledo MD, Alba E, Medina JA

Abstract
BACKGROUND: MEK1 (MAP2K1) and MEK2 (MAP2K2) are closely related dual-specificity protein kinases which function by phosphorylating both serine/threonine and tyrosine residues of their substrates ERK1 and ERK2, controlling fundamental cellular processes that include cell growth and proliferation. To investigate the prognostic significance of pMEK expression in the nucleus and cytoplasm among patients with locally advanced head and neck cancer treated with concurrent radiochemotherapy.
METHODS: Immunohistochemistry was performed on the retrieved archival tissue of 96 patients to detect pMEK, p53 and Ki-67.
RESULTS: Sixty-six percent of patients were positive for pMEK expression in the nucleus and 41 % in cytoplasm. On univariate analysis, high nuclear pMEK was predictive of worse 5y-DFS and 5y-OS, with a trend to significance (26 % vs. 41 %, p = 0.09; 36 % vs. 47 %, p = 0.07). High cytoplasmic pMEK was predictive of better 5-y OS and 5-y DFS outcomes (61 % vs. 27 %, p = 0.01; 46 % vs. 22 %, p = 0.02). On multivariate analysis, low cytoplasmic pMEK and high nuclear pMEK predicted worse DFS and OS (p = 0.01; p = 0.04 and p = 0.02; p = 0.02 respectively).
CONCLUSIONS: Subcellular localisation of pMEK has different prognosis in locally advanced head and neck cancer treated with radiochemotherapy.

PMID: 27793200 [PubMed - in process]

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Detailed vascular anatomy of the medial femoral condyle and the significance of its use as a free flap.

Detailed vascular anatomy of the medial femoral condyle and the significance of its use as a free flap.

J Plast Reconstr Aesthet Surg. 2016 Oct 5;:

Authors: Weitgasser L, Cotofana S, Winkler M, Buerger H, Jamnig D, Anderhuber F, Gaggl A

Abstract
OBJECTIVE: The aim of this study is to provide detailed information on the arterial variations of the descending geniculate artery (DGA) for the harvest of a cortico-periostal flap from the medial femoral condyle and a fascio-cutaneous perforator flap with its respective pedicles.
MATERIAL AND METHODS: A total of 50 lower limbs from embalmed cadavers were dissected. The distribution pattern, length, and diameter of the DGA, saphenous artery (SA), muscular, periostal, and articular branches, and their concomitant veins were measured and evaluated.
RESULTS: The DGA was present in 98% of the cases. In 80%, a Y-shaped distribution was identified where the SA branched from the DGA. Here, the mean lengths of DGA, SA, and the articular branch of the DGA were 3.2 ± 1.1, 7.18 ± 3.2, and 6.72 ± 2.07 cm, respectively. In 18%, an H-shaped distribution was noted, where the SA emerged directly from the femoral artery with a length of 10.2 ± 1.9 cm, whereas the length of the DGA (and its terminal articular branch) was 7.5 ± 1.5 cm. The mean length of the arterial pedicle for a cortico-periostal flap from the medial condyle was 9.92 cm, whereas for the fascio-cutaneous perforator flap, it was 9.46 cm in Y-shaped distribution and 10.2 cm for the H-shaped distribution.
CONCLUSION: Different arterial distribution patterns increase the need for routine preoperative vascular imaging when planning to harvest a cortico-periostal flap and a fascio-cutaneous perforator flap from the medial femoral condyle, especially when a double-chimeric flap is targeted.
LEVEL OF EVIDENCE: Level 4, case series.

PMID: 27793561 [PubMed - as supplied by publisher]

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A pilot study demonstrating the feasibility of supermicrosurgical end-to-side anastomosis onto large recipient vessels in head and neck reconstruction.

A pilot study demonstrating the feasibility of supermicrosurgical end-to-side anastomosis onto large recipient vessels in head and neck reconstruction.

J Plast Reconstr Aesthet Surg. 2016 Sep 28;:

Authors: Iida T, Yoshimatsu H, Yamamoto T, Koshima I

Abstract
In head and neck reconstruction using free flaps, microvascular anastomosis is commonly performed in an end-to-end fashion to relatively sizable arteries including the superficial temporal, facial, and superior thyroid arteries. With the recent developments of less invasive perforator flaps such as the superficial circumflex iliac artery perforator flap, anastomosis of smaller vessels of less than 0.8 mm diameter has become necessary; however, appropriate recipient arteries for end-to-end anastomosis are often absent. We have introduced supermicrosurgical end-to-side anastomosis to such arteries in 12 cases of head and neck reconstruction. Double-needle, short-thread microsutures were used to facilitate this procedure, and indocyanine green intraoperative angiography was used to confirm patency. All patients, except one with partial necrosis, survived. We believe that our method is a safe and reliable option for cases in which there is a discrepancy between the flap pedicle and recipient arteries.

PMID: 27789210 [PubMed - as supplied by publisher]

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Three-dimensional printing for restoration of the donor face: A new digital technique tested and used in the first facial allotransplantation patient in Finland.

Three-dimensional printing for restoration of the donor face: A new digital technique tested and used in the first facial allotransplantation patient in Finland.

J Plast Reconstr Aesthet Surg. 2016 Oct 5;:

Authors: Mäkitie AA, Salmi M, Lindford A, Tuomi J, Lassus P

Abstract
BACKGROUND AND AIMS: Prosthetic mask restoration of the donor face is essential in current facial transplant protocols. The aim was to develop a new three-dimensional (3D) printing (additive manufacturing; AM) process for the production of a donor face mask that fulfilled the requirements for facial restoration after facial harvest.
MATERIALS AND METHODS: A digital image of a single test person's face was obtained in a standardized setting and subjected to three different image processing techniques. These data were used for the 3D modeling and printing of a donor face mask. The process was also tested in a cadaver setting and ultimately used clinically in a donor patient after facial allograft harvest.
RESULTS: and Conclusions: All the three developed and tested techniques enabled the 3D printing of a custom-made face mask in a timely manner that is almost an exact replica of the donor patient's face. This technique was successfully used in a facial allotransplantation donor patient.

PMID: 27789209 [PubMed - as supplied by publisher]

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Belinostat and Vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma.

Belinostat and Vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma.

Cancer Biol Ther. 2016 Oct 28;:0

Authors: Havas AP, Rodrigues KB, Bhakta A, Demirjian JA, Hahn S, Tran J, Scavello M, Tula-Sanchez AA, Zeng Y, Schmelz M, Smith CL

Abstract
Diffuse Large B-cell lymphoma (DLBCL) is an aggressive malignancy that has a 60 percent five-year survival rate, highlighting a need for new therapeutic approaches. Histone deacetylase inhibitors (HDACi) are novel therapeutics being clinically-evaluated in combination with a variety of other drugs. However, rational selection of companion therapeutics for HDACi is difficult due to their poorly-understood, cell-type specific mechanisms of action. To address this, we developed a pre-clinical model system of sensitivity and resistance to the HDACi belinostat using DLBCL cell lines. In the current study, we demonstrate that cell lines sensitive to the cytotoxic effects of HDACi undergo early mitotic arrest prior to apoptosis. In contrast, HDACi-resistant cell lines complete mitosis after a short delay and arrest in G1. To force mitotic arrest in HDACi-resistant cell lines, we used low dose vincristine or paclitaxel in combination with belinostat and observed synergistic cytotoxicity. Belinostat curtails vincristine-induced mitotic arrest and triggers a strong apoptotic response associated with downregulated MCL-1 expression and upregulated BIM expression. Resistance to microtubule targeting agents (MTAs) has been associated with their propensity to induce polyploidy and thereby increase the probability of genomic instability that enables cancer progression. Co-treatment with belinostat effectively eliminated a vincristine-induced, actively cycling polyploid cell population. Our study demonstrates that vincristine sensitizes DLBCL cells to the cytotoxic effects of belinostat and that belinostat prevents polyploidy that could cause vincristine resistance. Our findings provide a rationale for using low dose MTAs in conjunction with HDACi as a potential therapeutic strategy for treatment of aggressive DLBCL.

PMID: 27791595 [PubMed - as supplied by publisher]

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Blocking NOTCH Pathway can Enhance the Effect of EGFR Inhibitor through Targeting CD133+ Endometrial Cancer Cells.

Blocking NOTCH Pathway can Enhance the Effect of EGFR Inhibitor through Targeting CD133+ Endometrial Cancer Cells.

Cancer Biol Ther. 2016 Oct 28;:0

Authors: Shang C, Lang B, Meng LR

Abstract
ABSTACT Although the molecular therapeutics targeting key biomarkers such as epithelial growth factor receptor (EGFR), PI3K/AKT/mTOR, and vascular endothelial growth factor (VEGF) shows some success in clinical trials, some internally existing challenges in endothelial cancer biology hinder the drug effects. One of the major challenges stems from cancer stem cell-derived drug resistance. CD133 positive cells are well believed as cancer stem cells (CSC) in endometrial cancers and NOTCH pathway plays a critical role in retaining CD133+ cells by promoting CSC self-renewal and chemoresistance. Here, we initiated a therapeutic strategy to improve effects of EGFR inhibition by targeting NOTCH pathway of CD133+ cells in endometrial cancers. We first detected and purified the CD133+ cell fraction in endometrial cancer cell line Ishikawa (IK), and validated activation of NOTCH pathway in the CD133+ cells that have higher proliferation rate and lower apoptosis rate, comparing to CD133- cells. Results of nude mouse xenograft experiments further demonstrated CD133+ cells retain higher tumorigenesis capacity than CD133- cells, indicating their tumor-initiating property. Last, we applied both NOTCH inhibitor DAPT and EGFR inhibitor AG1478 treatment on endometrial cancer lines IK and HEC-1A and the results suggested improvement effects of the combination therapy compared to the treatments of DAPT or AG1478 alone. These findings indicated targeting NOTCH pathway in CD133+ cells, combining with EGFR inhibition, which provides a novel therapeutic strategy for endometrial cancer diseases.

PMID: 27791463 [PubMed - as supplied by publisher]

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Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse.

Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse.

Cancer Biol Ther. 2016 Oct 28;:0

Authors: Nardone V, Botta C, Caraglia M, Martino EC, Ambrosio MR, Carfagno T, Tini P, Semeraro L, Misso G, Grimaldi A, Boccellino M, Facchini G, Berretta M, Vischi G, Rocca BJ, Barone A, Tassone P, Tagliaferri P, Del Vecchio MT, Pirtoli L, Correale P

Abstract
Tumor immunologic microenvironment is strongly involved in tumor progression and the presence of tumor infiltrating lymphocytes (TIL) with different phenotypes has been demonstrated to be of prognostic relevance in different malignancies. We investigated whether TIL infiltration of tumor tissues could also predict the outcome of prostate cancer patients. To this end, we carried out a retrospective analysis correlating the outcome of locally advanced prostate cancer patients undergone salvage radiotherapy upon relapse after radical surgery with the infiltration by different TIL populations. Twenty-two patients with resectable prostate cancer, with a mean age of 67 (+/-3.93) years, who received salvage radiotherapy with a mean of 69.66 (+/- 3.178) Gy in 8 weeks, between June 1999 and January 2009 and with a median follow up of 123 (+/- 55.82) months, were enrolled in this study. We evaluated by immunohistochemistry the intratumoral ((t)) and peripheral stroma ((p)) infiltration by CD45, CD3, CD4, CD8, CCR7, FoxP3, or PD-1-positive cells on tumor samples taken at the diagnosis ((d)) and relapse times ((R)). We correlated these variables with patients' biochemical progression free survival (bPFS), post-radiotherapy progression free survival (PFS), and overall survival (OS). Substantial changes in the rate of TIL subsets were found between the first and the second biopsy with progressive increase in CD4, CCR7, FoxP3, PD-1(+) cells. Our analysis revealed that higher CD8(p,R+) and lower PD-1(R+) TIL scores correlated to a longer bPFS. Higher CD8(p,R+) and CCR7(t,R+) TIL scores and lower CD45(p,R+) and FoxP3(p,R+) TIL scores correlated to a prolonged PFS and OS. These results suggest that the immunological microenvironment of primary tumor is strictly correlated with patient outcome and provide the rationale for immunological treatment of prostate cancer.

PMID: 27791459 [PubMed - as supplied by publisher]

http://ift.tt/2f0ASqj

Chk1 and DNA-PK mediate TPEN-induced DNA damage in a ROS dependent manner in human colon cancer cells.

Chk1 and DNA-PK mediate TPEN-induced DNA damage in a ROS dependent manner in human colon cancer cells.

Cancer Biol Ther. 2016 Oct 3;:1-10

Authors: Rahal ON, Fatfat M, Hankache C, Osman B, Khalife H, Machaca K, Muhtasib HG

Abstract
Recently, we showed that the metal chelator TPEN targets colon cancer cells through redox cycling of copper. Here, we studied the DNA damage potential of TPEN and deciphered the role of Chk1, ATM and DNA-PK in TPEN-induced toxicity in 3 human colon cancer cell lines, HCT116, SW480 and HT29. We also investigated the role of reactive oxygen species (ROS) in TPEN-induced DNA damage. TPEN reduced cell viability in a dose- and time-dependent manner. Cytotoxicity was associated with significant DNA damage and higher expression of γ-H2AX protein and activation of ATM/ATR signaling pathway. Cell death by TPEN was dependent on ROS generation as evidenced by the reversal of cell viability, and DNA damage and the abrogation of γ-H2AX levels in the presence of antioxidants. Treatment with antioxidants, however, failed to reverse cytotoxicity at high TPEN concentrations (10µM). TPEN-induced cell death was also dependent on the redox cycling of copper since the copper chelator neocuproine inhibited DNA damage and reduced pChk1, γ-H2AX, and ATM protein expression. Cell death by low TPEN concentrations, involved ATM/ATR signaling in all 3 cell lines, since pre-incubation with specific inhibitors of ATM and DNA-PK led to the recovery of cells from TPEN-induced DNA damage. In addition, siRNA silencing of Chk1, DNA-PK and ATM abrogated the expression of γ-H2AX and reversed cell death, suggesting that Chk1 and DNA-PK mediate TPEN-induced cytotoxicity in colon cancer cells. This study shows for the first time the involvement of Chk1, DNA-PK and ATM in TPEN-induced DNA damage and confirms our previous findings that ROS generation and the redox cycling of copper in response to TPEN are the main mechanisms by which this compound induces cell death in human colon cancer cells. Inhibition of ATM or DNA-PK did not reverse cytotoxicity at high TPEN concentrations that cause excessive levels of ROS and irreversible cellular damage.

PMID: 27690730 [PubMed - as supplied by publisher]

http://ift.tt/2cPQ2eZ

Investigating the extremes of the continuum of paracrine functions in CD34-/CD31+ CACs across diverse populations.

Investigating the extremes of the continuum of paracrine functions in CD34-/CD31+ CACs across diverse populations.

Am J Physiol Heart Circ Physiol. 2016 Oct 28;:ajpheart.00342.2016

Authors: Landers-Ramos RQ, Sapp RM, VandeWater E, Macko J, Robinson S, Wang Y, Chin ER, Spangenburg EE, Prior SJ, Hagberg JM

Abstract
Paracrine function of circulating angiogenic cells (CACs) is thought to contribute to vascular maintenance. We previously identified S100A8 and S100A9 secreted from physically inactive individuals' CD34-/CD31+ CACs as negative regulators of capillary-like network formation. The purpose of this study was to further investigate the extremes of the continuum of CAC paracrine actions using two distinctly different groups representing "healthy" and "impaired" CAC function. We aimed to determine how capillary-like network formation in human umbilical vein endothelial cells (HUVECs) is affected by S100A8 and S100A9 in concentrations secreted by CACs from different ends of the health spectrum. CD34-/CD31+ CACs were isolated and cultured from 10 "impaired function" individuals defined as older (50-89 yrs) non-ST-elevation myocardial infarction (NSTEMI) patients and 10 "healthy" individuals defined as younger (18-35 yrs), healthy individuals, and conditioned media (CM) was generated. CM from the impaired function groups' CACs significantly diminished network formation compared to CM from healthy group (P<0.05). We identified elevations in S100A8, S100A9, and S100A8/A9 in the CM from the impaired function group (P<0.05). Pretreatment of HUVECs with inhibitors to a known S100A8 and S100A9 receptor, TLR4, but not RAGE, improved HUVEC network formation (P<0.05) compared to CM alone in the impaired function conditions. Exposure of HUVECs to the TLR4 signaling inhibitor also blocked recombinant S100A8 and S100A9-mediated reductions in network formation. Collectively, the results suggest that the mechanisms behind impaired CAC CD34-/CD31+ CM-mediated reductions in capillary-like network formation involve secretion of S100A8 and S100A9 and binding of these proteins to TLR4 receptors on HUVECs.

PMID: 27793853 [PubMed - as supplied by publisher]

http://ift.tt/2f5lMhG

Tumor Necrosis Factor-Alpha and the ERK Pathway Drive Chemerin Expression in Response to Hypoxia in Cultured Human Coronary Artery Endothelial Cells.

Tumor Necrosis Factor-Alpha and the ERK Pathway Drive Chemerin Expression in Response to Hypoxia in Cultured Human Coronary Artery Endothelial Cells.

PLoS One. 2016;11(10):e0165613

Authors: Chua SK, Shyu KG, Lin YF, Lo HM, Wang BW, Chang H, Lien LM

Abstract
BACKGROUND: Chemerin, a novel adipokine, plays a role in the inflammation status of vascular endothelial cells. Hypoxia causes endothelial-cell proliferation, migration, and angiogenesis. This study was aimed at evaluating the protein and mRNA expression of chemerin after exposure of human coronary artery endothelial cells (HCAECs) to hypoxia.
METHODS AND RESULTS: Cultured HCAECs underwent hypoxia for different time points. Chemerin protein levels increased after 4 h of hypoxia at 2.5% O2, with a peak of expression of tumor necrosis factor-alpha (TNF-alpha) at 1 h. Both hypoxia and exogenously added TNF-alpha during normoxia stimulated chemerin expression, whereas an ERK inhibitor (PD98059), ERK small interfering RNA (siRNA), or an anti-TNF-alpha antibody attenuated the chemerin upregulation induced by hypoxia. A gel shift assay indicated that hypoxia induced an increase in DNA-protein binding between the chemerin promoter and transcription factor SP1. A luciferase assay confirmed an increase in transcriptional activity of SP1 on the chemerin promoter during hypoxia. Hypoxia significantly increased the tube formation and migration of HCAECs, whereas PD98059, the anti-TNF-alpha antibody, and chemerin siRNA each attenuated these effects.
CONCLUSION: Hypoxia activates chemerin expression in cultured HCAECs. Hypoxia-induced chemerin expression is mediated by TNF-alpha and at least in part by the ERK pathway. Chemerin increases early processes of angiogenesis by HCAECs after hypoxic treatment.

PMID: 27792771 [PubMed - in process]

http://ift.tt/2eW8DuU

Advances and controversies in the management of medullary thyroid carcinoma.

Advances and controversies in the management of medullary thyroid carcinoma.

Curr Opin Oncol. 2016 Oct 26;

Authors: Maia AL, Wajner SM, Vargas CV

Abstract
PURPOSE OF REVIEW: Medullary thyroid carcinoma (MTC) comprises approximately 4% of all malignant thyroid neoplasms. Although the majority of patients have a good prognosis, a subgroup of patients develops progressive disease and requires systemic therapy. Here, we focused on the current MTC therapeutic approaches and discussed the advantages and disadvantages of molecular targeted therapies.
RECENT FINDINGS: Targeted molecular therapies that inhibit REarranged during Transfection and other tyrosine kinase receptors involved in angiogenesis have been shown to improve progression-free survival in patients with advanced MTC. Two drugs, vandetanib and cabozantinib, have been approved for the treatment of progressive or symptomatic MTC, and several others have exhibited variable efficacy. No tyrosine kinase inhibitor has been shown to improve survival. Although no definitive recommendation can currently be made, cumulative data indicate that knowledge of the tumor mutational profile may facilitate improvements in targeted therapy for MTC.
SUMMARY: Tyrosine kinase inhibitors are effective therapeutic agents for the treatment of progressive MTC. Nevertheless, it is not clear who will benefit the most from therapy, and the decision regarding when and how to initiate the treatment should be made based on the patient's medical history and tumor behavior. Hopefully, in the near future, molecular profiling of MTC can be used to determine the most effective molecular therapeutic target.

PMID: 27792051 [PubMed - as supplied by publisher]

http://ift.tt/2dSsyvj

Experimental and early investigational drugs for angina pectoris.

Experimental and early investigational drugs for angina pectoris.

Expert Opin Investig Drugs. 2016 Oct 28;

Authors: Elgendy IY, Winchester DE, Pepine CJ

Abstract
INTRODUCTION: Ischemic heart disease (IHD) is a major cause of death and disability among Western countries and angina pectoris is the most prevalent symptomatic manifestation. Strategies to improve management of chronic stable angina are a priority. Areas covered: A comprehensive review was conducted using the Medline and Cochrane databases as well as the clinical trial databases in the United States and Europe. Traditional therapies for angina will be discussed. This review particularly emphasizes investigational therapies for angina (including pharmacological agents, cell and gene based therapies, and herbal medications). Expert commentary: There has been renewed interest in older anti-angina agents (e.g., perhexiline, amiodarone, and phosphodiestrase-5 inhibitors). Other anti-inflammatory agents (e.g., allopurinol and febuxostat) are currently undergoing evaluation for angina therapy. Therapeutic angiogenesis continues to face some challenges. Future trials should evaluate the optimum patient population that would benefit from this form of therapy.

PMID: 27791405 [PubMed - as supplied by publisher]

http://ift.tt/2f5lCa1

Resveratrol increases microRNA-130a expression to promote angiogenesis and improve heart functions in mice after myocardial infarction.

Resveratrol increases microRNA-130a expression to promote angiogenesis and improve heart functions in mice after myocardial infarction.

Exp Mol Pathol. 2016 Oct 24;:

Authors: Tang G, Peng L, Qian G, Wang S, Hu H, Zhang X, Song G, Yao M, Zhai C

Abstract
BACKGROUND: Resveratrol, a polyphenol of natural compounds, has beneficial cardiovascular effects. Increased expression of miR-130a has been reported to attenuate cardiac remodeling after myocardial infarction (MI). We hypothesized that resveratrol via an miR-130a-dependent mechanism promotes angiogenesis and improves heart functions in mice after MI.
METHODS: The MI model was established in mice by ligation of left anterior descending coronary artery. The expression of miR-130a was examined by RT-qPCR. Angiogenesis was assessed by immunohistochemistry. Heart function was determined by echocardiography.
RESULTS: Resveratrol increased miR-130a expression, promoted cell proliferations and migrations in HUVECs, which were abolished by miR-130a antagomir or AMPK inhibitor Compound C. In mice following MI, administration of resveratrol significantly increased miR-130a expressional level, promoted angiogenesis, reduced infarct size, and improved heart functions after 14 postoperative days. Importantly, these in vivo effects of resveratrol were ablated by antagonism of miR-130a.
CONCLUSION: Resveratrol via upregulation of miR-130a promotes ischemia-induced angiogenesis and improves heart functions.

PMID: 27789328 [PubMed - as supplied by publisher]

http://ift.tt/2f5jH5s

Liraglutide restores angiogenesis in palmitate-impaired human endothelial cells through PI3K/Akt-Foxo1-GTPCH1 pathway.

http:--linkinghub.elsevier.com-ihub-imag

Liraglutide restores angiogenesis in palmitate-impaired human endothelial cells through PI3K/Akt-Foxo1-GTPCH1 pathway.

Peptides. 2016 Oct 21;86:95-101

Authors: Ke J, Wei R, Yu F, Zhang J, Hong T

Abstract
Glucagon-like peptide-1 (GLP-1) and its analogues have a beneficial role in cardiovascular system. Here, we aimed to investigate whether liraglutide, a GLP-1 analogue, modulated angiogenesis impaired by palmitic acid (PA) in cultured human umbilical vein endothelial cells (HUVECs). Cells were incubated with liraglutide (3-100 nmol/L) in the presence of PA (0.5mmol/L), and endothelial tube formation was observed and quantified. The protein levels of signaling molecules were analyzed and the specific inhibitors were used to identify the signaling pathways through which liraglutide affected angiogenesis. Results showed that liraglutide ameliorated endothelial tube formation impaired by PA in HUVECs in a dose-dependent manner. Meanwhile, liraglutide increased the phosphorylation of Akt and forkhead box O1 (Foxo1), and upregulated the levels of guanosine 5'-triphosphate cyclohydrolase 1 (GTPCH1) and endothelial nitric oxide synthase (eNOS) in PA-impaired HUVECs. Notably, addition of the PI3K inhibitor LY294002, Foxo1 nuclear export inhibitor trifluoperazine dihydrochloride (TFP), GTPCH1 inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP) or NOS inhibitor N-nitro-l-arginine-methyl ester (L-NAME) eliminated the angiogenic effect of liraglutide. Moreover, either LY294002 or TFP abolished the liraglutide-induced upregulation of GTPCH1 and eNOS protein levels. In conclusion, liraglutide restores angiogenesis in PA-impaired HUVECs. The effect is mediated via upregulation of GTPCH1 and eNOS levels in a PI3K/Akt-Foxo1-dependent mechanism.

PMID: 27777063 [PubMed - as supplied by publisher]

http://ift.tt/2f5n3oU

Erythropoietin improves hypoxic-ischemic encephalopathy in neonatal rats after short-term anoxia by enhancing angiogenesis.

Erythropoietin improves hypoxic-ischemic encephalopathy in neonatal rats after short-term anoxia by enhancing angiogenesis.

Brain Res. 2016 Nov 15;1651:104-113

Authors: Yan F, Zhang M, Meng Y, Li H, Yu L, Fu X, Tang Y, Jiang C

Abstract
Erythropoietin (EPO) is important for angiogenesis after hypoxia/ischemia. In this study, we investigated whether recombinant human erythropoietin (rhEPO) can enhance angiogenesis, and promote cognitive function through vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling pathway in a rat model of hypoxic-ischemic encephalopathy (HIE). RhEPO, selective VEGFR2 inhibitor (SU5416) or vehicle was administrated by intraperitoneal injection. The assessment for cognitive function begins on day 60 after anoxia. Vascular density in hippocampus and white matter damage within corpus callosum were examined on day 28 after anoxia. The expression of erythropoietin receptor (EPOR), VEGF, rapidly accelerated fibrosarcoma 1 (Raf1), and extracellular-signal-regulated kinases 1 and 2 (ERK1/2) in hippocampus were evaluated on day 7 after anoxia. RhEPO-treated anoxia rats had better cognitive recovery, higher vascular density, and less white matter damage than in the vehicle anoxia rats. These protective effects associated with increased expression of EPOR, VEGF; and increased phosphorylation of Raf1 and ERK1/2. While this up-regulation, and changes in the histopathologic and functional outcomes were abolished by SU5416. Our data indicate that rhEPO can enhance angiogenesis, reduce white matter damage, and promote cognitive recovery through VEGF/VEGFR2 signaling pathway in anoxia rats.

PMID: 27659964 [PubMed - in process]

http://ift.tt/2eaL9RB

Modulatory effects of 1,25-dihydroxyvitamin D3 on eye disorders: A critical review.

Modulatory effects of 1,25-dihydroxyvitamin D3 on eye disorders: A critical review.

Crit Rev Food Sci Nutr. 2017 Feb 11;57(3):559-565

Authors: Nebbioso M, Buomprisco G, Pascarella A, Pescosolido N

Abstract
Many studies have shown that the presence of 1,25-dihydroxyvitamin D3 in the eye is able to modulate inflammatory responses. In fact, it has been demonstrated that topical administration of vitamin D3 inhibits Langerhans cells migration from the central cornea, corneal neovascularization, and production of cytokines (i.e., interleukin-1-6-8) in experimental animals. Moreover, both in vitro and in vivo studies have demonstrated that vitamin D is a potent inhibitor of retinal neovascularization. It has been shown that calcitriol, the biologically active form of vitamin D, inhibits angiogenesis both in cultured endothelial cells and in retinas from guinea pigs with retinoblastoma or oxygen-induced ischemic retinopathy. In addition, it seems that this compound is able to prevent the progression from early to neovascular age-related macular degeneration (AMD) and, at the same time, to down-regulate the characteristic inflammatory cascade at the retinal pigment epithelium-choroid interface due to its anti-inflammatory and immunomodulatory capabilities. Furthermore, 1,25-dihydroxyvitamin D3 and its analogue, 2-methylene-19-nor-1,25-dihydroxyvitamin D3, are able to modulate intraocular pressure (IOP) through gene expression. Several studies have suggested a role in glaucoma and diabetic retinopathy therapies for vitamin D3. In conclusion, this review summarizes our current knowledge on the potential use of vitamin D3 in the protection and treatment of ocular diseases in ophthalmology.

PMID: 26054653 [PubMed - in process]

http://ift.tt/2f5lqYx

Distinct capacity for differentiation to inner ear cell types by progenitor cells of the cochlea and vestibular organs.

Distinct capacity for differentiation to inner ear cell types by progenitor cells of the cochlea and vestibular organs.

Development. 2016 Oct 27;:

Authors: McLean WJ, McLean DT, Eatock RA, Edge AS

Abstract
Disorders of hearing and balance are most commonly associated with damage to cochlear and vestibular hair cells or neurons. Although these cells are not capable of spontaneous regeneration, progenitor cells in the hearing and balance organs of the neonatal mammalian inner ear have the capacity to generate new hair cells after damage. To investigate whether these cells were restricted in their differentiation capacity, we assessed the phenotypes of differentiated progenitor cells isolated from three compartments of the inner ear - the vestibular and cochlear sensory epithelia and the spiral ganglion - by measuring electrophysiological properties and gene expression. Lgr5+ progenitor cells from the sensory epithelia gave rise to hair cell-like cells, but not neurons or glial cells. Newly created hair cell-like cells had hair bundle proteins, synaptic proteins, and membrane proteins characteristic of the compartment of origin. PLP+ glial cells from the spiral ganglion were identified as neural progenitors, which gave rise to neurons, astrocytes, and oligodendrocytes, but not hair cells. Thus, distinct progenitor populations from the neonatal inner ear differentiate to cell types associated with their organ of origin.

PMID: 27789624 [PubMed - as supplied by publisher]

http://ift.tt/2eIAApO

Hypermethylation of the HIC1 promoter and aberrant expression of HIC1/SIRT1 contribute to the development of thyroid papillary carcinoma.

Hypermethylation of the HIC1 promoter and aberrant expression of HIC1/SIRT1 contribute to the development of thyroid papillary carcinoma.

Oncotarget. 2016 Oct 26;:

Authors: Wu W, Zhang L, Lin J, Huang H, Shi B, Lin X, Huang Z, Wang C, Qiu J, Wei X

Abstract
Hypermethylation leading to the loss of hypermethylated in cancer-1 (HIC1) gene expression occurs in many different types of human cancer. HIC1 is a transcriptional repressor that directly binds to the promoter region of NAD-dependent deacetylase sirtuin-1 (SIRT1). SIRT1 functions in cell growth, is anti-apoptotic, protect neurons, functions in senescence, and regulates energy restriction. Epigenetic modification and dysregulation affecting the HIC1/SIRT1 axis is potentially important for the development of malignancies. However, the importance of HIC1 expression in the development of papillary thyroid carcinoma, especially in Chinese patients, is uncertain. Therefore, we assessed the level of methylation in the HIC1 promoter and the mRNA and protein expression levels of HIC1 and SIRT1 in human thyroid papillary carcinoma and tumor adjacent control tissues. The demethylation reagent 5-aza-2'-deoxyctidine (5-aza-dc) and an HIC1 overexpression plasmid were used to manipulate the HIC1/SIRT1 pathway, and the effects on cell senescence, apoptosis, and cell cycle progression were assessed. Compared to normal thyroid tissue, thyroid tumors had lower expression of HIC1 and higher SIRT1 expression. The level of HIC1 methylation was also higher in thyroid carcinoma tissues than adjacent tissues. HIC1 expression was closely correlated with patient age and tumor progression. Restoration of HIC1 expression through an overexpression plasmid or 5-aza-dC treatment reduced SIRT1 expression and cell proliferation, and led to senescence, cell cycle arrest, and apoptosis. Aberrant expression of HIC1/SIRT1 and hypermethylation of the HIC1 promoter may be critical for the development and progression of papillary thyroid cancer.

PMID: 27793057 [PubMed - as supplied by publisher]

http://ift.tt/2dSquU3

The implication of tumor biomarker CA19-9 in the diagnosis of intracranial epidermoid cyst.

The implication of tumor biomarker CA19-9 in the diagnosis of intracranial epidermoid cyst.

Oncotarget. 2016 Oct 26;:

Authors: Wang Y, Yan W, Wu Q, Chen G, Zhang J

Abstract
OBJECT: The diagnosis of intracranial epidermoid cyst (IEC) relies solely on MRI, which is time and money consuming. The application of tumor biomarkers in IEC has never been systematically studied. Here we screened a group of commonly used tumor biomarkers to assess their diagnostic value in IEC.
RESULTS: Serum tumor biomarkers were assessed in 42 IECs and 42 paired healthy controls. Only serum CA19-9 level was significantly higher in the IEC group (median 20.3U/ml vs. 6.5U/ml, p < 0.001). Area under curve for CA19-9 was 0.806 (95% CI 0.700-0.912), with cutoff value of 13.15 U/ml (sensitivity 71.4%, specificity 97.6%). Tumor size was significantly different between CA19-9 positive and CA19-9 negative groups(64.14 ± 67.91cm3 vs. 19.43 ± 13.76 cm3, p = 0.04) and linear regression analysis revealed a positive correlation. Neither the extent of resection nor recurrence rate showed any significant difference between the two groups.
METHODS: This is a retrospective study of IEC patients treated between 2009 and 2014. We analyzed the expression of common serum tumor biomarkers, including carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen, carbohydrate antigen125 and squamous cell carcinoma in both IEC and healthy control group. Receiver operating characterisitics curves were constructed to evaluate the diagnostic accuracy.
CONCLUSIONS: Our data indicated that for serum CA19-9 level higher than 13.15U/ml, after excluding the possibility of gastrointestinal system tumor, lung cancer, inflammation and other related diseases, the existence of IEC should be considered. Further prospective study is needed to gain more understanding of the value of CA19- 9 in postoperative evaluation and surveillance.

PMID: 27793056 [PubMed - as supplied by publisher]

http://ift.tt/2enFoO8

Personalized anticancer therapy selection using molecular landscape topology and thermodynamics.

Personalized anticancer therapy selection using molecular landscape topology and thermodynamics.

Oncotarget. 2016 Oct 26;:

Authors: Rietman EA, Scott JG, Tuszynski JA, Klement GL

Abstract
Personalized anticancer therapy requires continuous consolidation of emerging bioinformatics data into meaningful and accurate information streams. The use of novel mathematical and physical approaches, namely topology and thermodynamics can enable merging differing data types for improved accuracy in selecting therapeutic targets. We describe a method that uses chemical thermodynamics and two topology measures to link RNA-seq data from individual patients with academically curated protein-protein interaction networks to select clinically relevant targets for treatment of low-grade glioma (LGG). We show that while these three histologically distinct tumor types (astrocytoma, oligoastrocytoma, and oligodendroglioma) may share potential therapeutic targets, the majority of patients would benefit from more individualized therapies. The method involves computing Gibbs free energy of the protein-protein interaction network and applying a topological filtration on the energy landscape to produce a subnetwork known as persistent homology. We then determine the most likely best target for therapeutic intervention using a topological measure of the network known as Betti number. We describe the algorithm and discuss its application to several patients.

PMID: 27793055 [PubMed - as supplied by publisher]

http://ift.tt/2enzM6H

Cranial irradiation induces transient microglia accumulation, followed by long-lasting inflammation and loss of microglia.

Cranial irradiation induces transient microglia accumulation, followed by long-lasting inflammation and loss of microglia.

Oncotarget. 2016 Oct 26;:

Authors: Han W, Umekawa T, Zhou K, Zhang XM, Ohshima M, Dominguez CA, Harris RA, Zhu C, Blomgren K

Abstract
The relative contribution of resident microglia and peripheral monocyte-derived macrophages in neuroinflammation after cranial irradiation is not known. A single dose of 8 Gy was administered to postnatal day 10 (juvenile) or 90 (adult) CX3CR1GFP/+ CCR2RFP/+ mouse brains. Microglia accumulated in the subgranular zone of the hippocampal granule cell layer, where progenitor cell death was prominent. The peak was earlier (6 h vs. 24 h) but less pronounced in adult brains. The increase in juvenile, but not adult, brains was partly attributed to proliferation. Microglia numbers then decreased over time to 39% (juvenile) and 58% (adult) of controls 30 days after irradiation, largely as a result of cell death. CD68 was expressed in 90% of amoeboid microglia in juvenile hippocampi but only in 9% of adult ones. Isolated hippocampal microglia revealed reduced CD206 and increased IL1-beta expression after irradiation, more pronounced in juvenile brains. CCL2 and IL-1 beta increased after irradiation, more in juvenile hippocampi, and remained elevated at all time points. In summary, microglia activation after irradiation was more pronounced, protracted and pro-inflammatory by nature in juvenile than in adult hippocampi. Common to both ages was long-lasting inflammation and the absence of monocyte-derived macrophages.

PMID: 27793054 [PubMed - as supplied by publisher]

http://ift.tt/2enC2KZ

Epigenetic regulation of cancer biology and anti-tumor immunity by EZH2.

Epigenetic regulation of cancer biology and anti-tumor immunity by EZH2.

Oncotarget. 2016 Oct 26;:

Authors: Christofides A, Karantanos T, Bardhan K, Boussiotis VA

Abstract
Polycomb group proteins regulate chromatin structure and have an important regulatory role on gene expression in various cell types. Two polycomb group complexes (Polycomb repressive complex 1 (PRC1) and 2 (PRC2)) have been identified in mammalian cells. Both PRC1 and PRC2 compact chromatin, and also catalyze histone modifications. PRC1 mediates monoubiquitination of histone H2A, whereas PRC2 catalyzes methylation of histone H3 on lysine 27. These alterations of histones can lead to altered gene expression patterns by regulating chromatin structure. Numerous studies have highlighted the role of the PRC2 catalytic component enhancer of zeste homolog 2 (EZH2) in neoplastic development and progression, and EZH2 mutations have been identified in various malignancies. Through modulating the expression of critical genes, EZH2 is actively involved in fundamental cellular processes such as cell cycle progression, cell proliferation, differentiation and apoptosis. In addition to cancer cells, EZH2 also has a decisive role in the differentiation and function of T effector and T regulatory cells. In this review we summarize the recent progress regarding the role of EZH2 in human malignancies, highlight the molecular mechanisms by which EZH2 aberrations promote the pathogenesis of cancer, and discuss the anti-tumor effects of EZH2 targeting via activating direct anti-cancer mechanisms and anti-tumor immunity.

PMID: 27793053 [PubMed - as supplied by publisher]

http://ift.tt/2enzNHN

Andrographolide ameliorates OVA-induced lung injury in mice by suppressing ROS-mediated NF-κB signaling and NLRP3 inflammasome activation.

Andrographolide ameliorates OVA-induced lung injury in mice by suppressing ROS-mediated NF-κB signaling and NLRP3 inflammasome activation.

Oncotarget. 2016 Oct 26;:

Authors: Peng S, Gao J, Liu W, Jiang C, Yang X, Sun Y, Guo W, Xu Q

Abstract
In this study, we attempted to explore the effect and possible mechanism of Andrographolide on OVA-induced asthma. OVA challenge induced significant airway inflammatory cell recruitment and lung histological alterations, which were ameliorated by Andrographolide. The protein levels of cytokines in bron-choalveolar fluid (BALF) and serum were reduced by Andrographolide administration as well as the mRNA levels in lung tissue. Mechanically, Andrographolide markedly hampered the activation of nuclear factor-κB (NF-κB) and NLRP3 inflammasome both in vivo and vitro thus decreased levels of TNF-α and IL-1β. Finally, we confirmed that ROS scavenging was responsible for Andrographolide's inactivation of NF-κB and NLRP3 inflammasome signaling. Our study here revealed the effect and possible mechanism of Andrographolide on asthma, which may represent a new therapeutic approach for treating this disease.

PMID: 27793052 [PubMed - as supplied by publisher]

http://ift.tt/2fjjkct

Alteration of colonic epithelial cell differentiation in mice deficient for glucosaminyl N-deacetylase/N-sulfotransferase 4.

Alteration of colonic epithelial cell differentiation in mice deficient for glucosaminyl N-deacetylase/N-sulfotransferase 4.

Oncotarget. 2016 Oct 26;:

Authors: Jao TM, Li YL, Lin SW, Tzeng ST, Yu IS, Yen SJ, Tsai MH, Yang YC

Abstract
Glucosaminyl N-deacetylase/N-sulfotransferases (NDSTs) are the first enzymes that mediate the initiation of heparan sulfate sulfation. We previously identified NDST4 as a putative tumor suppressor in human colorectal cancer. In the study, we generated an Ndst4 knockout (Ndst4-/-) mouse strain and explored its phenotypic characteristics, particularly in the development of colonic epithelial homeostasis. The Ndst4-deficient mice were viable and fertile, and their life spans were similar to those of wild-type littermates. No gross behavioral or morphological differences were observed between the Ndst4-/- and wild-type mice, and no significant changes were determined in the hematological or serum biochemical parameters of the Ndst4-/- mice. Ndst4 RNA transcripts were expressed in the brain, lung, gastrointestinal tract, pancreas, and ovary. However, Ndst4-null mice exhibited no gross or histological abnormalities in the studied organs, except for the colon. Although no alterations were observed in the crypt length or number of proliferating cells, the Ndst4-/- mice exhibited an increased number of goblet cells and a decreased number of colonocytes in the proximal colon compared with the wild-type mice. Moreover, Ndst4 deficiency increased the basal level of apoptosis in the colonic epithelium. Taken together, we established, for the first time, an Ndst4-/- mouse strain and revealed the involvement of Ndst4 in the development and homeostasis of colonic epithelium. Accordingly, NDST4 in human colon might direct the biosynthesis of specific heparan sulfate proteoglycans that are essential for the maintenance of colonic epithelial homeostasis. Thus, the loss of its function may result in the tumorigenesis and progression of colorectal cancer.

PMID: 27793051 [PubMed - as supplied by publisher]

http://ift.tt/2enC0CO

The laminA/NF-Y protein complex reveals an unknown transcriptional mechanism on cell proliferation.

The laminA/NF-Y protein complex reveals an unknown transcriptional mechanism on cell proliferation.

Oncotarget. 2016 Oct 26;:

Authors: Cicchillitti L, Manni I, Mancone C, Regazzo G, Spagnuolo M, Alonzi T, Carlomosti F, Dell'Anna ML, Dell'Omo G, Picardo M, Ciana P, Capogrossi MC, Tripodi M, Magenta A, Rizzo MG, Gurtner A, Piaggio G

Abstract
Lamin A is a component of the nuclear matrix that also controls proliferation by largely unknown mechanisms. NF-Y is a ubiquitous protein involved in cell proliferation composed of three subunits (-YA -YB -YC) all required for the DNA binding and transactivation activity. To get clues on new NF-Y partner(s) we performed a mass spectrometry screening of proteins that co-precipitate with the regulatory subunit of the complex, NF-YA. By this screening we identified lamin A as a novel putative NF-Y interactor. Co-immunoprecipitation experiments and confocal analysis confirmed the interaction between the two endogenous proteins. Interestingly, this association occurs on euchromatin regions, too. ChIP experiments demonstrate lamin A enrichment in several promoter regions of cell cycle related genes in a NF-Y dependent manner. Gain and loss of function experiments reveal that lamin A counteracts NF-Y transcriptional activity. Taking advantage of a recently generated transgenic reporter mouse, called MITO-Luc, in which an NF-Y-dependent promoter controls luciferase expression, we demonstrate that lamin A counteracts NF-Y transcriptional activity not only in culture cells but also in living animals. Altogether, our data demonstrate the occurrence of lamin A/NF-Y interaction and suggest a possible role of this protein complex in regulation of NF-Y function in cell proliferation.

PMID: 27793050 [PubMed - as supplied by publisher]

http://ift.tt/2enFGod

Ultraviolet radiation-induced differential microRNA expression in the skin of hairless SKH1 mice, a widely used mouse model for dermatology research.

Ultraviolet radiation-induced differential microRNA expression in the skin of hairless SKH1 mice, a widely used mouse model for dermatology research.

Oncotarget. 2016 Oct 26;:

Authors: Singh A, Willems E, Singh A, Ong IM, Verma AK

Abstract
Cutaneous squamous cell carcinoma (cSCC) is the most common type of non-melanoma skin cancer that can metastasize. The major etiological factor associated with cSCC is Ultraviolet radiation (UVR) with a limited understanding of its molecular mechanism. It was hypothesized that there is a direct effect of UVR on modulation of microRNAs (miRNAs), a novel class of short noncoding RNAs which affects translation and stability of mRNAs. To test the hypothesis, the dorsal skin of the SKH1 mice (6-7 week old) was exposed to acute and chronic doses of UVR. In miRNA array profiling, we found differential expression (log fold change>1) of miR-25-5p between untreated and acute UVR treated (4kJ/m2) SKH1 mice skin. However, differential expression (>1 log fold) of miR-144-3p, miR-33-5p, miR-32-5p, miR-1983, miR-136-5p, miR-142-3p, miR-376a-3p, miR-142-5p, miR-3968, and miR-29b-3p was observed between untreated and chronically UVR treated mice skin. Differentially expressed selected miRNAs (miR-32-5p, miR-33-5p, miR-144-3p, and miR-376a-3p) were further validated in real time PCR using miRNA specific primers. Web based data mining, for the prediction of potential miRNA associated gene pathways in miRBase database revealed a link with important pathways (PI3K-Akt, MAPK, Wnt, transcriptional misregulation, and other oncogenic pathway) associated with cSCC. Furthermore, findings of PI3K-Akt pathway genes affected due to chronic UVR were confirmed using cDNA array.

PMID: 27793049 [PubMed - as supplied by publisher]

http://ift.tt/2f1UH0d

Diagnostic and prognostic value of serum MACC1 in breast cancer patients.

Diagnostic and prognostic value of serum MACC1 in breast cancer patients.

Oncotarget. 2016 Oct 25;:

Authors: Tan W, Xie X, Li L, Tang H, Ye X, Chen L, Tang W, Gao J, Pan L, Zhang X, Ye F, Li X, Yang L, Xie X, Zheng W

Abstract
Metastasis-associated in colon cancer-1 (MACC1) promotes colorectal cancer progression and predicts prognosis. The aim of our study was to determine the diagnostic and prognostic value of preoperative serum MACC1 levels in breast cancer patients. Serum MACC1 levels were measured in 378 breast cancer patients, 120 patients with benign breast disease, and 40 healthy volunteers using an ELISA. Serum MACC1 levels were higher in breast cancer patients than patients with benign disease or healthy volunteers. Increased serum MACC1 was associated with breast cancer TNM stage (P < 0.001), tumor size (P < 0.001), lymph node metastasis (P < 0.001), and Ki-67 status (P = 0.014). Serum MACC1 measurement successfully discriminated breast cancer patients from normal and healthy controls (AUC = 0.785, 95% CI: 0.746-0.825) with an optimal cut-off value of 38.35 pg/ml (sensitivity = 0.725, specificity = 0.696). Moreover, serum MACC1 exhibited significant prognostic value in breast cancer (AUC = 0.757, 95% CI: 0.700-0.814), and high MACC1 was associated with poor disease-free survival (HR 5.63, 95% CI: 3.51-9.04; P < 0.001). Our findings demonstrated that circulating MACC1 could serve as a reliable diagnostic and prognostic biomarker for breast cancer.

PMID: 27793048 [PubMed - as supplied by publisher]

http://ift.tt/2enCby7

Attenuation of cancer-initiating cells stemness properties by abrogating S100A4 calcium binding ability in head and neck cancers.

Attenuation of cancer-initiating cells stemness properties by abrogating S100A4 calcium binding ability in head and neck cancers.

Oncotarget. 2016 Oct 26;:

Authors: Cheng LH, Hung KF, Huang TF, Hsieh HP, Wang SY, Huang CY, Lo JF

Abstract
S100A4 is a calcium-binding protein capable of promoting epithelial-mesenchymal transition. Previously, we have demonstrated that S100A4 is required to sustain the head and neck cancer-initiating cells (HN-CICs) subpopulation. In this study, to further investigate the molecular mechanism, we established the head and neck squamous cell carcinoma (HNSCC) cell lines stably expressing mutant S100A4 proteins with defective calcium-binding sites on either N-terminal (NM) or C-terminal (CM), or a deletion of the last 15 amino-acid residues (CD). We showed that the NM, CM and CD harboring sphere cells that were enriched with HN-CICs population exhibited impaired stemness and malignant properties in vitro, as well as reduced tumor growth ability in vivo. Mechanistically, we demonstrated that mutant S100A4 proteins decreased the promoter activity of Nanog, likely through inhibition of p53. Moreover, the biophysical analyses of purified recombinant mutant S100A4 proteins suggest that both NM and CM mutant S100A4 were very similar to the WT S100A4 with subtle difference on the secondary structure, and that the CD mutant protein displayed the unexpected monomeric form in the solution phase.Taken together, our results suggest that both the calcium-binding ability and the C-terminal region of S100A4 are important for HN-CICs to sustain its stemness property and malignancy, and that the mechanism could be mediated by repressing p53 and subsequently activating the Nanog expression.

PMID: 27793047 [PubMed - as supplied by publisher]

http://ift.tt/2enzuwq

A 36-Year-Old Female with Recurrent Left Sided Pleural Effusion: A Rare Case of Mediastinal Lymphangioma.

A 36-Year-Old Female with Recurrent Left Sided Pleural Effusion: A Rare Case of Mediastinal Lymphangioma.

Am J Case Rep. 2016 Oct 28;17:799-804

Authors: Swarnakar RN, Hazarey JD, Dhoble C, Vaghani B, Ainsley AS, Khargie JF, Likaj L

Abstract
BACKGROUND Lymphangioma is an atypical non-malignant, lymphatic lesion that is congenital in origin. Lymphangioma is most frequently observed in the head and neck, but can occur at any location in the body. About 65% of lymphangiomas are apparent at birth, while 80-90% are diagnosed by two years of age. Occurrence in adults is rare, as evidenced by less than 100 cases of adult lymphangiomas reported in the literature. CASE REPORT A 36-year-old Indian woman with a medical history of recurrent pleural effusions presented with chief complaints of dyspnea on exertion for one year and a low-grade fever for one month. A thorax CT revealed left-sided pleural effusion with thin internal septations. Thoracoscopy revealed a large cystic lesion arising from the mediastinum from the hilum surrounding the mediastinal great vessels. The diagnosis of lymphangioma was confirmed via histopathologic examination of the cyst. It was managed with partial cystectomy along with the use of a sclerosing agent (talc). CONCLUSIONS The size and location of lymphangiomas can vary, with some patients presenting with serious problems like respiratory distress, while others may be asymptomatic. Complete cyst resection is the gold standard treatment for mediastinal cystic lymphangioma. Partial cyst resection along with the use of sclerosing agents can be an effective option when complete cystectomy is not possible. Although lymphangioma is a rare patient condition, it should be included in the differentials for patients presenting with pleural effusions. Also, a biopsy should be done at the earliest opportunity to differentiate lymphangioma from other mediastinal malignant tumors.

PMID: 27789902 [PubMed - in process]

http://ift.tt/2dSpYFq

Hippocampal phospho-tau/MAPT neuropathology in the fornix in Alzheimer disease: an immunohistochemical autopsy study.

Hippocampal phospho-tau/MAPT neuropathology in the fornix in Alzheimer disease: an immunohistochemical autopsy study.

Acta Neuropathol Commun. 2016 Oct 28;4(1):114

Authors: Plowey ED, Ziskin JL

Abstract
Whereas early Alzheimer disease (AD) neuropathology and mild cognitive impairment are relatively common in aging, accurate prediction of patients that will progress to dementia requires new biomarkers. Recently, substantial work has focused on phospho-tau/MAPT (p-MAPT) neuropathology since its regional propagation correlates with the degree of cognitive impairment in AD. Recent diffusion tensor imaging studies in AD suggest that increased diffusion in the fornix secondary to p-MAPT-related axonal injury could serve as a predictive biomarker of the risk of disease progression. However, our knowledge of p-MAPT neuropathology in the fornix is limited. To address this gap in knowledge, we examined p-MAPT neuropathology in the fornix and basal forebrain nuclei via AT8 immunohistochemistry in 39 brain autopsies spanning the spectrum of AD neuropathologic changes. We found that the fornix and its precommissural efferent target nuclei (septum and nucleus accumbens) demonstrated neuronal and thread-like p-MAPT neuropathology only in National Institute on Aging/Alzheimer Association (NIA/AA) stages B2 and B3 of neurofibrillary degeneration, consistent with involvement after (and propagation from) the hippocampal formation. Interestingly, although tau astrogliopathy was frequently observed in the mammillary bodies in stage B2, neuronal tauopathy was not observed in the postcommissural targets (mammillary bodies and anterior thalamic nucleus) until stage B3. Tauopathy in the nucleus basalis of Meynert was strongly correlated with p-MAPT-positive axons in the fornix, suggesting that projections to the hippocampus also likely contribute to fornix tauopathy. Our cross-sectional autopsy findings indicate that the fornix is involved by p-MAPT neuropathology secondary to hippocampal involvement by AD neuropathology. Furthermore, our findings are compatible with the goal of in vivo detection of p-MAPT-related axonal pathology in the fornix in AD as a possible biomarker of p-MAPT progression from the hippocampal formation and underscore a need for additional clinical-radiologic-pathologic correlation studies.

PMID: 27793193 [PubMed - in process]

http://ift.tt/2e0K4bC

ALS-associated endoplasmic reticulum proteins in denervated skeletal muscle: Implications for motor neuron disease pathology.

ALS-associated endoplasmic reticulum proteins in denervated skeletal muscle: Implications for motor neuron disease pathology.

Brain Pathol. 2016 Oct 28;:

Authors: Jesse CM, Bushuven E, Tripathi P, Chandrasekar A, Simon CM, Drepper C, Yamoah A, Dreser A, Katona I, Johann S, Beyer C, Wagner S, Grond M, Nikolin S, Anink J, Troost D, Sendtner M, Goswami A, Weis J

Abstract
Alpha-motoneurons and muscle fibers are structurally and functionally interdependent. Both cell types particularly rely on endoplasmic reticulum (ER/SR) functions. Mutations of the ER proteins VAPB, SigR1 and HSP27 lead to hereditary motor neuron diseases (MNDs). Here, we determined the expression profile and localization of these ER proteins/chaperons by immunohistochemistry and immunoblotting in biopsy and autopsy muscle tissue of patients with amyotrophic lateral sclerosis (ALS) and other neurogenic muscular atrophies (NMAs) and compared these patterns to mouse models of neurogenic muscular atrophy. Postsynaptic neuromuscular junction staining for VAPB was intense in normal human and mouse muscle and decreased in denervated Nmd(2J) mouse muscle fibers. In contrast, VAPB levels together with other chaperones and autophagy markers were increased in extrasynaptic regions of denervated muscle fibers of patients with MNDs and other NMAs, especially at sites of focal myofibrillar disintegration (targets). These findings did not differ between NMAs due to ALS and other causes. G93A-SOD1 mouse muscle fibers showed a similar pattern of protein level increases in denervated muscle fibers. In addition, they showed globular VAPB-immunoreactive structures together with misfolded SOD1 protein accumulations, suggesting a primary myopathic change. Our findings indicate that altered expression and localization of these ER proteins and autophagy markers are part of the dynamic response of muscle fibers to denervation. The ER is particularly prominent and vulnerable in both muscle fibers and alpha-motoneurons. Thus, ER pathology could contribute to the selective build-up of degenerative changes in the neuromuscular axis in MNDs. This article is protected by copyright. All rights reserved.

PMID: 27790792 [PubMed - as supplied by publisher]

http://ift.tt/2eIBum6

Health-promoting effects of the citrus flavanone hesperidin.

Health-promoting effects of the citrus flavanone hesperidin.

Crit Rev Food Sci Nutr. 2017 Feb 11;57(3):613-631

Authors: Li C, Schluesener H

Abstract
Hesperidin, a member of the flavanone group of flavonoids, can be isolated in large amounts from the rinds of some citrus species. Considering the wide range of pharmacological activities and widespread application of hesperidin, this paper reviews preclinical and clinical trials of hesperidin and its related compounds, including their occurrence, pharmacokinetics, and some marketed products available. Preclinical studies and clinical trials demonstrated therapeutical effects of hesperidin and its aglycone hesperetin in various diseases, such as neurological disorders, psychiatric disorders, and cardiovascular diseases and others, due to its anti-inflammatory, antioxidant, lipid-lowering, and insulin-sensitizing properties.

PMID: 25675136 [PubMed - in process]

http://ift.tt/2e0I0k5

Effects of long-term non-traumatic noise exposure on the adult central auditory system. Hearing problems without hearing loss.

Effects of long-term non-traumatic noise exposure on the adult central auditory system. Hearing problems without hearing loss.

Hear Res. 2016 Oct 25;:

Authors: Eggermont JJ

Abstract
It is known that hearing loss induces plastic changes in the brain, causing loudness recruitment and hyperacusis, increased spontaneous firing rates and neural synchrony, reorganizations of the cortical tonotopic maps, and tinnitus. Much less in known about the central effects of exposure to sounds that cause a temporary hearing loss, affect the ribbon synapses in the inner hair cells, and cause a loss of high-threshold auditory nerve fibers. In contrast there is a wealth of information about central effects of long-duration sound exposures at levels ≤ 80 dB SPL that do not even cause a temporary hearing loss. The central effects for these moderate level exposures described in this review include changes in central gain, increased spontaneous firing rates and neural synchrony, and reorganization of the cortical tonotopic map. A putative mechanism is outlined, and the effect of the acoustic environment during the recovery process is illustrated. Parallels are drawn with hearing problems in humans with long-duration exposures to occupational noise but with clinical normal hearing.

PMID: 27793584 [PubMed - as supplied by publisher]

http://ift.tt/2fjlcSr

Susac's syndrome: Clinical course and epidemiology in a Central European population.

Susac's syndrome: Clinical course and epidemiology in a Central European population.

Int J Neurosci. 2016 Oct 27;:1-16

Authors: Seifert-Held T, Langner-Wegscheider BJ, Komposch M, Simschitz P, Franta C, Teuchner B, Offenbacher H, Otto F, Sellner J, Rauschka H, Fazekas F

Abstract
OBJECTIVE: Susac's syndrome is characterized by inflammation and occlusion of pre-capillary arterioles with the clinical triad of branch retinal artery occlusion (BRAO), encephalopathy and hearing loss. No epidemiological data is available for the disease.
METHODS: All neurology departments in Austria were addressed to report adult patients who were on immunosuppressive treatment for a diagnosis of Susac's syndrome between 1(st) August 2010 and 1(st) August 2015. Clinical course, treatment regimens, period and point prevalence rates, and annual incidence of Susac's syndrome in Austria in people over 19 years of age are reported.
RESULTS: 10 patients with Susac's syndrome were identified, 8 of them were newly diagnosed within the 5-year timeframe. Minimum 5-year period prevalence of the disease is 0.148/100,000 (95% CI 0.071-0.272), annual incidence is 0.024/100,000 (95% CI 0.010-0.047). Minimum point prevalence rates varied from 0.030/100,000 (95% CI 0.004-0.108) to 0.088/100,000 (95% CI 0.032-0.192). Of all 10 patients, 8 showed typical callosal or internal capsule MRI lesions at first presentation, 7 presented with BRAO, and 5 had hearing loss or tinnitus at the beginning of the disease. Four patients developed the complete clinical triad of Susac's syndrome during the observation period.
CONCLUSIONS: We provide for the first time population based data about the clinical course, prevalence and incidence of Susac's syndrome.

PMID: 27788613 [PubMed - as supplied by publisher]

http://ift.tt/2fjgcNX

Patients' perspectives in the management of psoriasis: The Italian results of the Multinational Assessment of Psoriasis and Psoriatic Arthritis (MAPP) survey.

Patients' perspectives in the management of psoriasis: The Italian results of the Multinational Assessment of Psoriasis and Psoriatic Arthritis (MAPP) survey.

J Dermatolog Treat. 2016 Oct 28;:1-14

Authors: Gisondi P, Girolomoni G

Abstract
PURPOSE: The perspective of patients with psoriasis about medical care treatment goals and strategies is receiving increasing attention. Here, we performed a country-based analysis of the Multinational Assessment of Psoriasis and Psoriatic Arthritis (MAPP) survey, in order to provide specific information on patients' perspective of treatment of psoriasis in Italy.
METHODS: This was a systematic household telephone survey recruiting subjects by random digit dialing. Household members ≥18 years were included if they had ever been diagnosed with psoriasis.
RESULTS: 12,785 households were screened in Italy. 132 patients were ineligible for the analysis including patients with psoriatic arthritis. 359 patients were surveyed. About half of patients had very mild disease with less than 1 palm skin involvement, and 38% had from 1 to 10 palm skin disease. Noteworthy, 48% of patients with widespread disease were not taking any medication. Patients indicated the relief of symptoms, including itching (54.9%), as the main goal for their current therapy, whereas 14.2% reported no specific expectation from their medication. Overall, 70% of patients declared to be satisfied by their therapy, in terms of primary goal reached.
CONCLUSIONS: Our findings suggest that most psoriasis patients have mild/moderate disease in Italy, and that a portion of patients with severe disease does not receive an adequate treatment.

PMID: 27791480 [PubMed - as supplied by publisher]

http://ift.tt/2fjfm3u

Treatment patterns in moderate-to-severe plaque psoriasis: results from a Belgian cross-sectional study (DISCOVER).

Treatment patterns in moderate-to-severe plaque psoriasis: results from a Belgian cross-sectional study (DISCOVER).

J Dermatolog Treat. 2016 Oct 28;:1-26

Authors: Lambert J, Ghislain PD, Lambert J, Cauwe B, Van den Enden M

Abstract
PURPOSE: The present study aimed to evaluate current treatment patterns and achievement of treatment goals in Belgian patients with moderate-to-severe plaque psoriasis.
MATERIALS AND METHODS: This cross-sectional observational study (DISCOVER) was conducted in 2011 - 2012 in Belgian dermatology centers. Patient data were collected during a single visit and included information on psoriasis management and severity (PASI and DLQI). Treatment success was defined according to the current European consensus treatment goal algorithm.
RESULTS: Of the 556 patients included in the study, 38.1% reported no current treatment or only topicals, 34.2% were being treated with traditional systemics and/or phototherapy, and 29.5% with biologics. Methotrexate (11.7%) was the most commonly prescribed traditional systemic and adalimumab (14.2%) the most commonly prescribed biologic at the time of the study. The percentage of patients achieving treatment goals was significantly higher in biologic-treated patients (73.1%) compared to those using traditional systemics (50.6%), phototherapy (41.1%), or no treatment/only topicals (20.9%; p<0.001).
CONCLUSIONS: Nearly 40% of Belgian patients with moderate-to-severe psoriasis in the DISCOVER study were undertreated despite the severity of their disease. Undertreatment of psoriasis remains a problem in Belgium and more effective educational strategies are needed to ensure the best treatment outcome for these patients.

PMID: 27791446 [PubMed - as supplied by publisher]

http://ift.tt/2fjjgcL

A comparative study of pulsed dye laser versus long pulsed Nd:YAG laser treatment in recalcitrant viral warts.

A comparative study of pulsed dye laser versus long pulsed Nd:YAG laser treatment in recalcitrant viral warts.

J Dermatolog Treat. 2016 Oct 28;:1-24

Authors: Shin YS, Cho EB, Park EJ, Kim KH, Kim KJ

Abstract
BACKGROUND: Viral warts are common infectious skin disease induced by human papillomavirus (HPV). But treatment of recalcitrant warts is still challenging.
OBJECTIVE: In this study, we compared the effectiveness of Pulsed dye laser (PDL) and Long pulsed ND:YAG (LPNY) laser in the treatment of recalcitrant viral warts.
METHODS: We retrospectively analyzed the medical records of patients with recalcitrant warts treated with laser therapy between January, 2013 and February, 2016.
RESULTS: 72 patients with recalcitrant warts were evaluated. 39 patients were treated with pulsed dye laser and 33 patients were treated with LPNY laser. The following parameters were used: PDL (spot size, 7mm; pulse duration, 1.5ms; and fluence, 10-14 J/cm(2)), and LPNY (spot size, 5mm; pulse duration, 20ms; and fluence, 240-300 J/cm(2)). Complete clearance of 2 patients (5.1%) in PDL group, and 3 patients (9.1%) in LPNY group were observed without significant side effects. The patients who achieved at least 50% improvement from baseline were 20 (51.3%) in PDL, and 22 (66.7%) in LPNY, respectively.
CONCLUSION: This research is meaningful because we compared the effectiveness of the PDL and LPNY in the recalcitrant warts. Both PDL and LPNY laser could be used as a safe and alternative treatment for recalcitrant warts.

PMID: 27791434 [PubMed - as supplied by publisher]

http://ift.tt/2fjh8So

A consensus on the use of daylight photodynamic therapy in the UK.

A consensus on the use of daylight photodynamic therapy in the UK.

J Dermatolog Treat. 2016 Oct 27;:1-8

Authors: Ibbotson S, Stones R, Bowling J, Campbell S, Kownacki S, Sivaramakrishnan M, Valentine R, Morton CA

Abstract
BACKGROUND: Actinic keratoses (AKs) are a consequence of chronic exposure to ultraviolet radiation. Treatment of chronically photo-damaged skin and AKs is driven by risk of progression to squamous cell carcinoma, as well as for symptomatic relief. Conventional photodynamic therapy (c-PDT) is indicated when AKs are multiple or confluent and if patients respond poorly or are unable to tolerate other therapies. c-PDT is limited by the field size that can be treated in single sessions and can cause significant discomfort.
OBJECTIVE: Recent studies investigated daylight illumination to activate protoporphyrin IX and daylight-PDT (d-PDT) is now licensed in the UK for face and scalp AKs. A group of experts met to discuss application of d-PDT with methyl aminolevulinate (MAL) and develop a UK consensus statement, specific to UK weather conditions.
METHODS: The UK consensus recommendations were reached among eight experts, who reviewed recent studies on d-PDT, assessed UK meteorological data and discussed personal experiences of d-PDT for AKs.
RESULTS: Recommendations from these discussions provide guidance on d-PDT use, specifically regarding patient selection, therapeutic indications, when to treat, skin preparation, MAL application and daylight exposure for patients with AKs.
CONCLUSIONS: This UK expert consensus provides practical guidance for UK application of d-PDT.

PMID: 27788605 [PubMed - as supplied by publisher]

http://ift.tt/2fjfoZi

Increased survival rate by local release of diclofenac in a murine model of recurrent oral carcinoma.

Increased survival rate by local release of diclofenac in a murine model of recurrent oral carcinoma.

Int J Nanomedicine. 2016;11:5311-5321

Authors: Will OM, Purcz N, Chalaris A, Heneweer C, Boretius S, Purcz L, Nikkola L, Ashammakhi N, Kalthoff H, Glüer CC, Wiltfang J, Açil Y, Tiwari S

Abstract
Despite aggressive treatment with radiation and combination chemotherapy following tumor resection, the 5-year survival rate for patients with head and neck cancer is at best only 50%. In this study, we examined the therapeutic potential of localized release of diclofenac from electrospun nanofibers generated from poly(D,L-lactide-co-glycolide) polymer. Diclofenac was chosen since anti-inflammatory agents that inhibit cyclooxygenase have shown great potential in their ability to directly inhibit tumor growth as well as suppress inflammation-mediated tumor growth. A mouse resection model of oral carcinoma was developed by establishing tumor growth in the oral cavity by ultrasound-guided injection of 1 million SCC-9 cells in the floor of the mouth. Following resection, mice were allocated into four groups with the following treatment: 1) no treatment, 2) implanted scaffolds without diclofenac, 3) implanted scaffolds loaded with diclofenac, and 4) diclofenac given orally. Small animal ultrasound and magnetic resonance imaging were utilized for longitudinal determination of tumor recurrence. At the end of 7 weeks following tumor resection, 33% of mice with diclofenac-loaded scaffolds had a recurrent tumor, in comparison to 90%-100% of the mice in the other three groups. At this time point, mice with diclofenac-releasing scaffolds showed 89% survival rate, while the other groups showed survival rates of 10%-25%. Immunohistochemical staining of recurrent tumors revealed a near 10-fold decrease in the proliferation marker Ki-67 in the tumors derived from mice with diclofenac-releasing scaffolds. In summary, the local application of diclofenac in an orthotopic mouse tumor resection model of oral cancer reduced tumor recurrence with significant improvement in survival over a 7-week study period following tumor resection. Local drug release of anti-inflammatory agents should be investigated as a therapeutic option in the prevention of tumor recurrence in oral squamous carcinoma.

PMID: 27789944 [PubMed - in process]

http://ift.tt/2fjgcxr

Αρχειοθήκη ιστολογίου

! # Ola via Alexandros G.Sfakianakis on Inoreader

Η λίστα ιστολογίων μου

Κυριακή 30 Οκτωβρίου 2016

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