Management of paratracheal lymph nodes in laryngeal cancer with subglottic involvement.

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Management of paratracheal lymph nodes in laryngeal cancer with subglottic involvement.

Head Neck. 2017 Sep 27;:

Authors: Lucioni M, D'Ascanio L, De Nardi E, Lionello M, Bertolin A, Rizzotto G

Abstract
BACKGROUND: The purpose of this study was to present our findings on the involvement of paratracheal lymph nodes in laryngeal squamous cell carcinoma (SCC) with subglottis extension, which is controversial.
METHODS: We assessed 196 patients with laryngeal SCC involving the subglottis, treated with open laryngeal surgery with or without paratracheal neck dissection (PTND). The relationship of the paratracheal lymph node metastatic pattern with laterocervical nodal status and tumor location within different subglottic subsites was analyzed. The influence of PTND on regional disease control was assessed.
RESULTS: Paratracheal lymph nodes were affected in 12.2% of cases. An increased frequency (P = .064) of paratracheal metastasis was noticed in case of anterior subglottis extension with respect to other subsites. A correlation (P < .001) between paratracheal lymph node and laterocervical node involvement was found among subjects with posterior subglottic extension.
CONCLUSIONS: Prophylactic PTND is indicated in laryngeal SCC with anterior subglottic extension and/or posterior subglottis involvement with clinically apparent laterocervical node metastases.

PMID: 28960661 [PubMed - as supplied by publisher]

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Does the quality of life impact of tonsillitis correlate with SIGN guideline compliance? An assessment of range and normality.

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Does the quality of life impact of tonsillitis correlate with SIGN guideline compliance? An assessment of range and normality.

Clin Otolaryngol. 2016 Oct;41(5):481-6

Authors: Roplekar R, Van M, Hussain SS

Abstract
OBJECTIVES: To assess the scores of those who are eligible to be listed for tonsillectomy through compliance with the SIGN guidelines for any trends or range.
DESIGN: A prospective study of all patients (aged 16 or above) listed for elective tonsillectomy from a nurse led tonsil clinic. Patients were given a TOI-14 questionnaire to complete after they had been added to the waiting list for surgery, but before undergoing tonsillectomy. Scores were assessed using SPSS.
SETTING: Outpatient clinic.
PARTICIPANTS: Patients aged over 16 listed for Tonsillectomy via SIGN Guideline 117.
MAIN OUTCOME MEASURE: Scores from TOI-14, completed pre-operatively.
RESULTS: 155 patients were listed from the nurse led clinic from October 2012 to August 2014; 5 questionnaires were excluded for being incomplete. The score range was 55 (15-70), with a calculated mean score of 45.62 and standard deviation of 9.701. Over 95% of results were within 2 standard deviations of the mean. A calculated negative skew also confirms that most patients who have clinical indications for tonsillectomy compliant with the SIGN guidelines show a higher score on the TOI-14.
CONCLUSION: This analysis indicates a trend of pre-intervention scores on the TOI-14 questionnaire for those patients who have a SIGN guideline compliant clinical indication for a tonsillectomy. We therefore propose that this suggests correlation between 'clinically strong' indication for tonsillitis and patient perceived Quality of Life impact.

PMID: 26506401 [PubMed - indexed for MEDLINE]

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Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii; +18 new citations

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii

These pubmed results were generated on 2017/10/03

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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A Genomic and Protein-Protein Interaction Analyses of Nonsyndromic Hearing Impairment in Cameroon Using Targeted Genomic Enrichment and Massively Parallel Sequencing.

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A Genomic and Protein-Protein Interaction Analyses of Nonsyndromic Hearing Impairment in Cameroon Using Targeted Genomic Enrichment and Massively Parallel Sequencing.

OMICS. 2017 Feb;21(2):90-99

Authors: Lebeko K, Manyisa N, Chimusa ER, Mulder N, Dandara C, Wonkam A

Abstract
Hearing impairment (HI) is one of the leading causes of disability in the world, impacting the social, economic, and psychological well-being of the affected individual. This is particularly true in sub-Saharan Africa, which carries one of the highest burdens of this condition. Despite this, there are limited data on the most prevalent genes or mutations that cause HI among sub-Saharan Africans. Next-generation technologies, such as targeted genomic enrichment and massively parallel sequencing, offer new promise in this context. This study reports, for the first time to the best of our knowledge, on the prevalence of novel mutations identified through a platform of 116 HI genes (OtoSCOPE(®)), among 82 African probands with HI. Only variants OTOF NM_194248.2:c.766-2A>G and MYO7A NM_000260.3:c.1996C>T, p.Arg666Stop were found in 3 (3.7%) and 5 (6.1%) patients, respectively. In addition and uniquely, the analysis of protein-protein interactions (PPI), through interrogation of gene subnetworks, using a custom script and two databases (Enrichr and PANTHER), and an algorithm in the igraph package of R, identified the enrichment of sensory perception and mechanical stimulus biological processes, and the most significant molecular functions of these variants pertained to binding or structural activity. Furthermore, 10 genes (MYO7A, MYO6, KCTD3, NUMA1, MYH9, KCNQ1, UBC, DIAPH1, PSMC2, and RDX) were identified as significant hubs within the subnetworks. Results reveal that the novel variants identified among familial cases of HI in Cameroon are not common, and PPI analysis has highlighted the role of 10 genes, potentially important in understanding HI genomics among Africans.

PMID: 28075205 [PubMed - indexed for MEDLINE]

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Descending necrotizing mediastinitis after a trigger point injection.

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Descending necrotizing mediastinitis after a trigger point injection.

Clin Exp Emerg Med. 2017 Sep;4(3):182-185

Authors: Choe JY, Kim JK, Lee DE, Seo KS, Park JB, Lee MJ, Ryoo HW, Ahn JY, Moon S

Abstract
Descending necrotizing mediastinitis (DNM) is a rare form of mediastinal infection. Most cases are associated with esophageal rupture. DNM after a trigger point injection in the upper trapezius has not been described previously. We present a case of DNM after a trigger point injection in the upper trapezius. A 70-year-old man visited the emergency department with chest discomfort and fever after a trigger point injection in the left upper trapezius. Chest computed tomography showed evidence of DNM, and antibiotic therapy was immediately administered intravenously. Because of the risk of sudden death, poor prognosis due to underlying disease, and his age, he declined surgical treatment and died of septic shock. Although trigger point injections are generally considered safe, caution should be used in patients with an underlying disease or in the elderly. Early diagnosis, broad-spectrum antibiotics, and aggressive surgical management are essential to improve the prognosis.

PMID: 29026893 [PubMed]

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Pathologic significance of a novel oncoprotein in thyroid cancer progression.

Pathologic significance of a novel oncoprotein in thyroid cancer progression.

Head Neck. 2017 Oct 11;:

Authors: Firek AA, Perez MC, Gonda A, Lei L, Munir I, Simental AA, Carr FE, Becerra BJ, De Leon M, Khan S

Abstract
BACKGROUND: The incidence of thyroid cancer is increasing worldwide, and there is an emerging need to develop accurate tools for diagnosis. Fine needle aspiration biopsy has greatly improved evaluation of thyroid nodules, but challenges with indeterminate lesions remain in up to 25% of biopsies. Novel tissue biomarkers may assist in improved nodule characterization. Microcalcifications occurring in thyroid cancers suggest proteins involved in bone formation may play a role in thyroid carcinogenesis. We evaluated the expression of the known osteogenic protein, Enigma, in thyroid cancer as a candidate oncoprotein and role in carcinogenesis based on association with other known oncoproteins such as bone morphogenetic protein-1 (BMP-1).
METHODS: The expression of both Enigma and BMP-1 were evaluated by immunohistochemistry (IHC) in an equal number of benign (n = 120) and different histological subtypes of malignant (n = 120) human archival thyroid nodules with and without calcification. The colocalization of Enigma with BMP-1 was evaluated by confocal microscopy using the BZ analyzer.
RESULTS: Enigma was strongly expressed in thyroid cancer tissue with a higher immunoreactive score in advanced thyroid cancer compared to less advanced and benign nodules. Enigma was localized either in cytoplasm or nucleus depending on the histological subtypes. Higher expression of Enigma was associated with the tumor size and lymph node involvement. There was clear and strong colocalization signal of Enigma and that of BMP-1. Expression of Enigma occurred without regard to calcification in cancer tissue.
CONCLUSION: Enigma may serve as an oncoprotein marker, identifying benign from malignant thyroid tissue on FNA. Enigma may have a role in carcinogenesis of thyroid cancer independent of tissue calcification, possibly in relation to interaction with BMP-1.

PMID: 29024261 [PubMed - as supplied by publisher]

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Chimeric thoracoacromial artery perforator flap for one-staged reconstruction of complex pharyngoesophageal defects: A single unit experience.

Chimeric thoracoacromial artery perforator flap for one-staged reconstruction of complex pharyngoesophageal defects: A single unit experience.

Head Neck. 2017 Oct 11;:

Authors: Song D, Pafitanis G, Pont LEP, Yang P, Koshima I, Zhang Y, Iida T, Zhou X, Li Z

Abstract
BACKGROUND: Circumferential hypopharyngeal defects with anterior neck skin loss often require double-stacked or chimeric flaps to achieve good surgical outcomes. The thoracoacromial artery perforator (TAAP) flap is a simple and reliable method for hypopharyngeal defect reconstruction.
METHODS: From March 2012 to February 2015, 19 male patients with an average age of 62 years (range 42-81 years) underwent complex pharyngoesophageal defect reconstruction with chimeric TAAP flaps.
RESULTS: All 19 male patients who underwent reconstruction with TAAP flaps achieved optimal functional outcomes. All donor sites were closed primarily. The average length of hospital stay was 12.5 days (range 10-19 days). All patients returned back to normal nutrition after 8 weeks postoperatively. The average follow-up period was 19.3 months (range 14-48 months).
CONCLUSION: The chimeric TAAP flap is an innovative local alternative solution for reconstruction of complex circumferential hypopharyngeal defects when free tissue transfer is contraindicated or neck vessels are depleted.

PMID: 29024231 [PubMed - as supplied by publisher]

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Snail-mediated cancer stem cell-like phenotype in human CNE2 nasopharyngeal carcinoma cell.

Snail-mediated cancer stem cell-like phenotype in human CNE2 nasopharyngeal carcinoma cell.

Head Neck. 2017 Oct 12;:

Authors: Peng S, Wu C, Sun W, Liu D, Luo M, Su B, Zhang L, Mei Q, Hu G

Abstract
BACKGROUND: Cancer stem cell (CSC)-like phenotype, which has been proven to play a critical role in invasion and metastasis of many kinds of cancers, has also been reported to be associated with epithelial-mesenchymal transition. Snail, a potent repressor of E-cadherin expression, was found to have a function to regulate the aforementioned processes.
METHODS: In the current study, expression of putative CSCs biomarkers and the ratio of CSC-like CNE2 (cancer cell line) in total CNE2 were measured, and CSC-like characteristics were analyzed with tumor-sphere self-renewal and colony-forming assays. Migration and invasion properties were determined by using transwell and wound healing assays. Xenograft tumor assays in vivo were done to evaluate the function of Snail and radiation in the tumor forming ability.
RESULTS: In human nasopharyngeal carcinoma (NPC) cells, overexpression of Snail mediates a CSC-like phenotype, which enhances the initiation, invasion, and migration ability of cancer cells.
CONCLUSION: Thus, Snail is a potential therapeutic target in NPC.

PMID: 29024225 [PubMed - as supplied by publisher]

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Familial clustering of oropharyngeal squamous cell carcinoma in the Utah population.

Familial clustering of oropharyngeal squamous cell carcinoma in the Utah population.

Head Neck. 2017 Oct 11;:

Authors: Monroe MM, Hashibe M, Orb Q, Alt J, Buchmann L, Hunt J, Cannon-Albright LA

Abstract
BACKGROUND: The main purpose of the current study was to define the familial aggregation of oropharyngeal squamous cell carcinoma (SCC) and risk to relatives of patients with oropharyngeal SCC.
METHODS: We conducted a retrospective study utilizing linked population-based genealogy and state cancer registry databases between 1966 and 2012. Relative risks for oropharyngeal SCC and other malignancies among patients with oropharyngeal SCC and their relatives were estimated.
RESULTS: Significant excess pairwise relatedness was observed for oropharyngeal SCC diagnosed before age 65 years. Significant excess risk for oropharyngeal SCC was observed for first-degree relatives of patients. Relatives of oropharyngeal SCC patients also demonstrated elevated rates of multiple other malignancies, including both lung and cervical cancers.
CONCLUSION: Relatives of patients with oropharyngeal SCC display elevated risks of oropharyngeal, lung, and cervical cancers among others, suggesting a possible shared genetic etiology involving tobacco-related and human papillomavirus (HPV)-related malignancies.

PMID: 29024178 [PubMed - as supplied by publisher]

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Intrathyroidal carotid artery and nonrecurring right recurrent laryngeal nerve: A case report.

Intrathyroidal carotid artery and nonrecurring right recurrent laryngeal nerve: A case report.

Head Neck. 2017 Oct 11;:

Authors: Baker A, Cottrill EE, Munizza O, McGillen K, McKinnon T, Goldenberg D

Abstract
BACKGROUND: When performing thyroidectomy, knowledge of normal anatomy and variants is vital to avoid injuring nearby structures. Typically, the bilateral carotids course posterolateral to the thyroid gland. We describe a rare variant of an intrathyroidal carotid artery, not previously described in the literature.
METHODS: A 23-year-old woman with a strong family history of thyroid cancer presented with a left thyroid nodule, and a fine-needle aspiration biopsy revealing papillary thyroid carcinoma. She underwent total thyroidectomy.
RESULTS: Intraoperatively, the carotid was found coursing centrally through the right lobe parenchyma, associated with an ipsilateral nonrecurrent recurrent laryngeal nerve (NRLN) entering the cricothyroid joint superolaterally.
CONCLUSION: This is, to our knowledge, the first report of such an anatomic variant in the medical literature. Aberrant carotid artery anatomy may potentially cause life-threatening surgical complications and should be considered preoperatively. Furthermore, recognition of concurrent recurrent laryngeal nerve (RLN) anomalies with vascular variations allows identification of nonrecurrent nerves.

PMID: 29024099 [PubMed - as supplied by publisher]

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Attitudes, Risk Behavior, and Noise Exposure among Young Adults with Hearing Problems: Identifying a Typology.

Related Articles

Attitudes, Risk Behavior, and Noise Exposure among Young Adults with Hearing Problems: Identifying a Typology.

Semin Hear. 2017 Nov;38(4):332-347

Authors: Hunter A

Abstract
This study explored attitudes toward leisure noise, use of hearing protection, and perceived susceptibility to leisure-noise damage in young adults with hearing problems. Twelve participants aged between 18 and 35 years took part in a semistructured interview. Data were analyzed using framework analysis. The results showed that a positive attitude to noise, a passion for loud music, a lack of knowledge of the consequences of noise damage, and perceived low risk of hearing problems were associated with people not using earplugs. The aesthetics, comfort, perceived effects on music quality and attitude of others were all barriers to earplug use. Of those who had used earplugs, previous hearing-related symptoms and concern about future hearing damage were the main motivators for use. Four types of people were identified to describe the variation in attitudes and behaviors: those who had no change in behavior or concern about damage; those who were concerned and used earplugs; those who were concerned and avoided loud venues; and those who were concerned about communication difficulties only. Considering the wide variability, it may be more effective to shift attention from trying to change individual attitudes and behaviors to considering systemic changes to protect hearing, through ensuring the music industry and relevant authorities take greater responsibility.

PMID: 29026265 [PubMed]

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"Ear Nose Throat J"[jour]; +17 new citations

17 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Ear Nose Throat J"[jour]

These pubmed results were generated on 2017/09/23

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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Leiomyosarcoma of maxilla: a case report with review of literature.

Related Articles

Leiomyosarcoma of maxilla: a case report with review of literature.

J Exp Ther Oncol. 2017 Sep;11(2):147-153

Authors: Gupta R, Astekar M, Dandriyal R, Bs M

Abstract
OBJECTIVE: One challenging feature of head and neck pathology is that a dizzying array of spindle cell lesions occurs here which ranges all the way from reactive, very aggressive forms to malignant lesions. Leiomyosarcoma is one such malignant tumour of mesenchymal origin exhibiting smooth muscle differentiation; presenting generally nonspecific signs and symptoms. Here we present a case of leiomyosarcoma in a 21 year old female patient associated with single reddish pink swelling present in the posterior right maxillary tuberosity region with moderate facial asymmetry. On histopathological analysis, all the classic features were noted and diagnosis of a spindle cell neoplasm was made without any obscurity. There are many lesions like rhabdomyosarcoma, fibrosarcoma, liposarcoma, multiple peripheral nerve sheath tumour, angiosarcomas, melanomas, kaposi sarcoma, solitary fibrous tumors, etc., which mimic leiomyosarcoma clinically and histopathologically and therefore immunohistochemical staining with specific markers plays a vital role in arriving at a conclusive diagnosis.

PMID: 28976138 [PubMed - in process]

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Auditory and cognitive development in a partially deaf child with bilateral electro-acoustic stimulation: a case study.

Related Articles

Auditory and cognitive development in a partially deaf child with bilateral electro-acoustic stimulation: a case study.

Int J Audiol. 2017 Oct 12;:1-6

Authors: Seebacher J, Muigg F, Fischer N, Weichbold V, Stephan K, Zorowka P, Bliem HR, Schmutzhard J

Abstract
OBJECTIVE: To study the long-term evolution of speech and intelligence in a child with partial deafness and normal hearing in the low frequencies after sequentially receiving cochlear implants in both ears.
DESIGN: Retrospective chart review.
STUDY SAMPLE: Male child aged 6 years was followed over a time period of four years.
RESULTS: The paediatric patient had normal hearing up to 1 kHz and profound hearing loss at all higher frequencies symmetrical in both ears. Deprivation of high-frequency sounds resulted in retarded development of speech, language and cognitive skills. The choice for rehabilitation was cochlear implantation with the aim of preserving a considerable amount of low-frequency hearing. With natural hearing at low frequencies and electrical stimulation at high frequencies, the child was able to compensate most of his developmental deficits. Moreover, spatial hearing was almost normal.
CONCLUSIONS: Electro-natural stimulation without amplification of the low frequencies (electro-natural hearing) provides access to the whole audible frequency range for children, who suffer from partial deafness in the high frequencies and are normal hearing at low frequencies. Such provision allows for regular speech development and favours the development of spatial hearing. The case report also demonstrates a strong impact on intellectual performance.

PMID: 29025322 [PubMed - as supplied by publisher]

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Approach to recurrent fever in childhood.

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Approach to recurrent fever in childhood.

Can Fam Physician. 2017 Oct;63(10):756-762

Authors: Soon GS, Laxer RM

Abstract
OBJECTIVE: To provide an approach to recurrent fever in childhood, explain when infections, malignancies, and immunodeficiencies can be excluded, and describe the features of periodic fever and other autoinflammatory syndromes.
SOURCES OF INFORMATION: PubMed was searched for relevant articles regarding the pathogenesis, clinical findings, diagnosis, prognosis, and treatment of periodic fever and autoinflammatory syndromes.
MAIN MESSAGE: Fever is a common sign of illness in children and is most frequently due to infection. However, when acute and chronic infections have been excluded and when the fever pattern becomes recurrent or periodic, the expanding spectrum of autoinflammatory diseases, including periodic fever syndromes, should be considered. Familial Mediterranean fever is the most common inherited monogenic autoinflammatory syndrome, and early recognition and treatment can prevent its life-threatening complication, systemic amyloidosis. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome is the most common periodic fever syndrome in childhood; however, its underlying genetic basis remains unknown.
CONCLUSION: Periodic fever syndromes and other autoinflammatory diseases are increasingly recognized in children and adults, especially as causes of recurrent fevers. Individually they are rare, but a thorough history and physical examination can lead to their early recognition, diagnosis, and appropriate treatment.

PMID: 29025800 [PubMed - in process]

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Open peroral endoscopic myotomy for achalasia with sigmoid-shaped esophagus.

Open peroral endoscopic myotomy for achalasia with sigmoid-shaped esophagus.

Endoscopy. 2017 Oct 09;:

Authors: Liu W, Liu L, Chen HL, Zeng HZ, Wu CC, Ye LS, Hu B

PMID: 28992639 [PubMed - as supplied by publisher]

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Implementation of an extended scope of practice speech-language pathology allied health practitioner service: an evaluation of service impacts and outcomes.

Related Articles

Implementation of an extended scope of practice speech-language pathology allied health practitioner service: an evaluation of service impacts and outcomes.

Int J Speech Lang Pathol. 2017 Sep 27;:1-10

Authors: Seabrook M, Schwarz M, Ward EC, Whitfield B

Abstract
PURPOSE: Extended scope of practice roles can address health service challenges and enhance patient services; however there has been limited research of extended scope roles in the discipline of speech-language pathology (SLP). The aim of this study was to examine the clinical outcomes and service impacts of a Speech-Language Pathology Allied Health Practitioner (SLP AHP) led dysphagia and dysphonia service within an Integrated Specialist Ear Nose and Throat (ENT) Service.
METHOD: Low risk referrals were triaged by ENT from the waiting list into the SLP AHP dysphagia and dysphonia clinic. Outcomes from an initial 6-month pilot phase (n = 43) and 6-month implementation phase (n = 158) were evaluated.
RESULT: Approximately 70% of patients managed in the SLP AHP clinic in both phases were discharged without requiring separate ENT appointments. There were no adverse events. In the pilot phase, only 4.3% of medium priority and 10% of low priority referrals were seen within clinically recommended time frames. This improved to 90% in the final three months of the implementation phase.
CONCLUSION: With appropriate governance and risk management, an extended scope SLP AHP service for low risk dysphagia and dysphonia can achieve safe, effective and beneficial changes to ENT service delivery.

PMID: 28952361 [PubMed - as supplied by publisher]

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Reference values of maximum performance tests of speech production.

Related Articles

Reference values of maximum performance tests of speech production.

Int J Speech Lang Pathol. 2017 Sep 26;:1-9

Authors: Knuijt S, Kalf J, Van Engelen B, Geurts A, de Swart B

Abstract
PURPOSE: Maximum performance tests examine upper limits of speech motor performance, as used by speech-language pathologists in dysarthria assessment protocols. The Radboud Dysarthria Assessment includes maximum repetition rate, maximum phonation time, fundamental frequency range and maximum phonation volume to assist in detecting pathological performance. This study aims to obtain reference values for each of these tests.
METHOD: A group of 224 healthy Dutch adults aged 18-80 years performed the maximum performance tests. Age, sex, body height, smoking habit, and profession were registered. Using multivariable linear regression, a wide range of models was tested to examine the relationship between these person characteristics and speech performance. The likelihood ratio was used to test the goodness of fit to the data.
RESULT: Above 60 years of age, maximum repetition rate, fundamental frequency range and maximum phonation volume were all negatively affected by age. Below 60 years, only women showed effects of age on fundamental frequency range (increase) and maximum phonation volume (decrease). Maximum phonation time was primarily related to body height (increase).
CONCLUSION: This study presents reference values of four maximum performance tests for comparing the performance of dysarthric patients with non-pathological performance. Age was identified as most important factor influencing maximum speech performance.

PMID: 28949263 [PubMed - as supplied by publisher]

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Core vocabulary in the narratives of bilingual children with and without language impairment.

Related Articles

Core vocabulary in the narratives of bilingual children with and without language impairment.

Int J Speech Lang Pathol. 2017 Sep 22;:1-12

Authors: Shivabasappa P, Peña ED, Bedore LM

Abstract
PURPOSE: Children with primary language impairment (PLI) demonstrate deficits in morphosyntax and vocabulary. We studied how these deficits may manifest in the core vocabulary use of bilingual children with PLI.
METHOD: Thirty bilingual children with and without PLI who were matched pairwise (experimental group) narrated two Spanish and two English stories in kindergarten and first grade. Core vocabulary was derived from the 30 most frequently used words in the stories of 65 and 37 typically developing (TD) first graders (normative group) for Spanish and English, respectively. The number of words each child in the experimental group produced out of the 30 identified core vocabulary words and frequency of each of the core words produced each year were analysed.
RESULT: Children with PLI produced fewer core vocabulary words compared to their TD peers after controlling for total words produced. This difference was more pronounced in first grade. They produced core vocabulary words less frequently in kindergarten than their TD peers. Both groups produced core vocabulary words more frequently in English than Spanish.
CONCLUSIONS: Bilingual children with PLI demonstrate a less productive core vocabulary use compared to their TD peers in both their languages illustrating the nature of their grammatical and lexical-semantic deficits.

PMID: 28937305 [PubMed - as supplied by publisher]

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Hearing crosstalk: the molecular conversation orchestrating inner ear dorsoventral patterning.

Hearing crosstalk: the molecular conversation orchestrating inner ear dorsoventral patterning.

Wiley Interdiscip Rev Dev Biol. 2017 Oct 11;:

Authors: Ohta S, Schoenwolf GC

Abstract
The inner ear is a structurally and functionally complex organ that functions in balance and hearing. It originates during neurulation as a localized thickened region of rostral ectoderm termed the otic placode, which lies adjacent to the developing caudal hindbrain. Shortly after the otic placode forms, it invaginates to delineate the otic cup, which quickly pinches off of the surface ectoderm to form a hollow spherical vesicle called the otocyst; the latter gives rise dorsally to inner ear vestibular components and ventrally to its auditory component. Morphogenesis of the otocyst is regulated by secreted proteins, such as WNTs, BMPs, and SHH, which determine its dorsoventral polarity to define vestibular and cochlear structures and sensory and nonsensory cell fates. In this review, we focus on the crosstalk that occurs among three families of secreted molecules to progressively polarize and pattern the developing otocyst. For further resources related to this article, please visit the WIREs website.

PMID: 29024472 [PubMed - as supplied by publisher]

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Adamantinoma-like Ewing sarcoma of the parotid gland: Cytopathologic findings and differential diagnosis

Adamantinoma-like Ewing sarcoma (AES) is a rare variant of Ewing sarcoma family of tumors (EFTs), primarily affecting bone and soft tissue. AES has mixed features of Ewing sarcoma (ES)/primitive neuroectodermal tumor (PNET) and adamantinoma with a complex immunoprofile and EWSR1 gene rearrangements. Herein, we report a 72-year-old male who presented with left parotid mass, right neck mass and thyroid nodules. Fine needle aspiration of the left parotid mass displayed nests of monotonous epithelioid cells with basaloid features in a background of small round blue cells and lymphocytes. AES can involve head and neck region and is characterized by groups of primitive small round blue cells admixed with groups of epithelioid cells with amphophilic cytoplasm and focal squamous differentiation. The proportion of these components can be variable, creating diagnostic challenges, particularly in unusual anatomic sites such as the parotid gland. However, when additional material is available, CD99 and/or FLI1 immunostains need to be included for diagnostic confirmation.

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Useful aspects of diagnosis of imprint cytology in intraoperative consultation of ovarian tumors: comparison between imprint cytology and frozen sections

Background

In the intraoperative consultation of ovarian tumors, the histological diagnosis of frozen sections (FS) of large tumors is frequently difficult because of the limited number of tumor samples. The application of imprint cytology (IC), in which samples are obtained from wide areas of the tumors, is useful for intraoperative consultation. However, the useful aspects of IC have not been clearly defined. The present study is a detailed comparison of IC and FS that clearly defines the useful aspects of IC.

Methods

Fifty-five cases of ovarian tumors that were examined using both IC and FS were evaluated. The histological diagnoses consisted of benign (16), borderline (6), and malignancy (33). All of the malignant tumors consisted of various types of carcinoma.

Results

Benignity and malignancy were accurately diagnosed by both IC and FS. In the borderline group, the diagnostic accuracy of IC was very low (1/6: 16.6%) compared with FS (4/6: 66.6%). The diagnostic accuracy including benign, borderline, and malignant groups was 90.9% (50/55) for IC and 96.3% (53/55) for FS. Concerning the diagnosis of the types of carcinoma, the overall diagnostic accuracy of IC (25/31: 80.6%) was greater than that of FS (21/31: 67.7%), especially for the diagnosis of clear cell carcinoma (IC, 100%; FS, 80%) and mixed carcinoma (IC, 66.6%; FS, 16.6%).

Conclusion

The useful aspects of IC in the intraoperative consultation are the diagnosis of benignity or malignancy and the accuracy of diagnosing clear cell carcinoma and mixed carcinoma.

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Auditory sequential accumulation of spectral information

Publication date: Available online 11 October 2017
Source:Hearing Research
Author(s): Yi Shen
In many listening situations, information about the spectral content of a target sound may be distributed over time, and estimating the target spectrum requires efficient sequential processing. Listeners' ability to estimate the spectrum of a random-frequency, six-tone complex was investigated and the spectral content of the complex was revealed using a sequence of bursts. Whether each of the six tones was presented within each burst was determined at random according to a presentation probability. In separate conditions, the presentation probabilities (p) ranged from 0.2 to 1, the total number of bursts varied from 1 to 16, and the inter-burst interval was either 0 or 200 ms. To evaluate the information acquired by the listener, the burst sequence was followed, after a 500-ms silent interval, by the six-tone complex acting as an informational masker and the listener was required to detect a pure-tone target presented simultaneously with the masker. Greater performance in this task indicates more accurate estimation of the spectrum of the complex by the listener. Evidence for integration of information across bursts was observed, and the integration process did not significantly depend on inter-burst interval.



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Effects of surgical lesions on choline acetyltransferase activity in the cat cochlea

Publication date: Available online 10 October 2017
Source:Hearing Research
Author(s): Mark Frilling, Gregory J. Wiet, Donald A. Godfrey, Judy A. Parli, Jon D. Dunn, C. David Ross
Although it is well established that the choline acetyltransferase (ChAT, the enzyme for acetylcholine synthesis) in the mammalian cochlea is associated with its olivocochlear innervation, the distribution of this innervation in the cochlea varies somewhat among mammalian species. The quantitative distribution of ChAT activity in the cochlea has been reported for guinea pigs and rats. The present study reports the distribution of ChAT activity within the organ of Corti among the three turns of the cat cochlea and the effects of removing olivocochlear innervation either by a lateral cut aimed to totally transect the left olivocochlear bundle or a more medial cut additionally damaging the superior olivary complex on the same side. Similarly to results for guinea pig and rat, the distribution of ChAT activity in the cat outer hair cell region showed a decrease from base to apex, but, unlike in the guinea pig and rat, the cat inner hair cell region did not. As in the rat, little ChAT activity was measured in the outer supporting cell region. As previously reported for whole cat cochlea and for rat cochlear regions, transection of the olivocochlear bundle resulted in almost total loss of ChAT activity in the hair cell regions of the cat cochlea. Lesions of the superior olivary complex resulted in loss of ChAT activity in the inner hair cell region of all cochlear turns only on the lesion side but bilateral losses in the outer hair cell region of all turns. The results are consistent with previous evidence that virtually all cholinergic synapses in the mammalian cochlea are associated with its olivocochlear innervation, that the olivocochlear innervation to the inner hair cell region is predominantly ipsilateral, and that the olivocochlear innervation to the outer hair cells is bilateral.



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An operating principle of the turtle utricle to detect wide dynamic range

Publication date: Available online 9 October 2017
Source:Hearing Research
Author(s): Jong-Hoon Nam
The utricle encodes both static information such as head orientation, and dynamic information such as vibrations. It is not well understood how the utricle can encode both static and dynamic information for a wide dynamic range (from <0.05 to >2 times the gravitational acceleration; from DC to > 1000 Hz vibrations). Using computational models of the hair cells in the turtle utricle, this study presents an explanation on how the turtle utricle encodes stimulations over such a wide dynamic range. Two hair bundles were modeled using the finite element method—one representing the striolar hair cell (Cell S), and the other representing the medial extrastriolar hair cell (Cell E). A mechano-transduction (MET) channel model was incorporated to compute MET current (iMET) due to hair bundle deflection. A macro-mechanical model of the utricle was used to compute otoconial motions from head accelerations (aHead). According to known anatomical data, Cell E has a long kinocilium that is embedded into the stiff otoconial layer. Unlike Cell E, the hair bundle of Cell S falls short of the otoconial layer. Considering such difference in the mechanical connectivity between the hair cell bundle and the otoconial layer, three cases were simulated: Cell E displacement-clamped, Cell S viscously-coupled, and Cell S displacement-clamped. Head accelerations at different amplitude levels and different frequencies were simulated for the three cases. When a realistic head motion was simulated, Cell E was responsive to head orientation, while the viscously-coupled Cell S was responsive to fast head motion imitating the feeding strike of a turtle.



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Tinnitus-related fear: Mediating the effects of a cognitive behavioural specialised tinnitus treatment

Publication date: Available online 12 October 2017
Source:Hearing Research
Author(s): Rilana F.F. Cima, Gerard van Breukelen, Johan W.S. Vlaeyen
ObjectiveCognitive behavioural treatment (CBT) for the reduction of tinnitus complaints have been shown to be effective; however the specific mechanisms of change are yet to be unveiled. Reductions in tinnitus-related fear have been indicated to be an important factor in alleviating tinnitus suffering. The role of tinnitus-related fear has been proposed as a mediator explaining the cognitive behavioural treatment effects on tinnitus severity, tinnitus-related impairment and general quality of life of tinnitus patients.MethodsA two-group, single-centre RCT was carried out with adult tinnitus patients (n=492), with 3 follow-up assessments up to 12 months after randomization. Patients were randomly assigned to Usual Care (UC) or Specialised cognitive behavioral stepped Care (SC). A repeated-measures design, with group as a between subjects factor, and time as the within-subject factor, was used in an intention-to-treat analysis. Mixed regressions for assessing mediation effects were performed with general health, tinnitus distress, tinnitus related impairment as the dependent variables and tinnitus related fear as the mediator variable.ResultsTinnitus-related fear appears to mediate part of the treatment benefits of specialized care, as compared to usual care, with respect to increased quality of life ratings, and decreased tinnitus severity and tinnitus related impairments.ConclusionsThe effectiveness of cognitive behavioural treatment approaches might be partly explained by significant reductions in tinnitus-related fear. These results are relevant in that currently, though CBT approaches in tinnitus management have been proven to lead to decreased suffering of tinnitus patients, the psychological mechanisms causing these benefits are still to be discovered.



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Corrigendum to “Place dependent stimulation rates improve pitch perception in cochlear implantees with single-sided deafness” [Hear. Res. 339 (2016) 94–103]

Publication date: October 2017
Source:Hearing Research, Volume 354
Author(s): Tobias Rader, Julia Döge, Youssef Adel, Tobias Weissgerber, Uwe Baumann




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Tonotopic organisation of the auditory cortex in sloping sensorineural hearing loss

Publication date: Available online 28 September 2017
Source:Hearing Research
Author(s): Tomasz Wolak, Katarzyna Cieśla, Artur Lorens, Krzysztof Kochanek, Monika Lewandowska, Mateusz Rusiniak, Agnieszka Pluta, Joanna Wójcik, Henryk Skarżyński
Although the tonotopic organisation of the human primary auditory cortex (PAC) has already been studied, the question how its responses are affected in sensorineural hearing loss remains open. Twenty six patients (aged 38.1 ± 9.1 years; 12 men) with symmetrical sloping sensorineural hearing loss (SNHL) and 32 age- and gender-matched controls (NH) participated in an fMRI study using a sparse protocol. The stimuli were binaural 8s complex tones with central frequencies of 400 HzCF, 800 HzCF, 1600 HzCF, 3200 HzCF, or 6400 HzCF, presented at 80 dB(C). In NH responses to all frequency ranges were found in bilateral auditory cortices. The outcomes of a winnermap approach, showing a relative arrangement of active frequency-specific areas, was in line with the existing literature and revealed a V-shape high-frequency gradient surrounding areas that responded to low frequencies in the auditory cortex. In SNHL frequency-specific auditory cortex responses were observed only for sounds from 400 HzCF to 1600 HzCF, due to the severe or profound hearing loss in higher frequency ranges. Using a stringent statistical threshold (p < 0.05; FWE) significant differences between NH and SNHL were only revealed for mid and high-frequency sounds. At a more lenient statistical threshold (p < 0.001, FDRc), however, the size of activation induced by 400 HzCF in PAC was found statistically larger in patients with a prelingual, as compared to a postlingual onset of hearing loss. In addition, this low-frequency range was more extensively represented in the auditory cortex when outcomes obtained in all patients were contrasted with those revealed in normal hearing individuals (although statistically significant only for the secondary auditory cortex). The outcomes of the study suggest preserved patterns of large-scale tonotopic organisation in SNHL which can be further refined following auditory experience, especially when the hearing loss occurs prelingually. SNHL can induce both enlargement and reduction of the extent of responses in the topically organized auditory cortex.



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A nonsynonymous mutation in the WFS1 gene in a Finnish family with age-related hearing impairment

Publication date: Available online 28 September 2017
Source:Hearing Research
Author(s): Laura Kytövuori, Samuli Hannula, Elina Mäki-Torkko, Martti Sorri, Kari Majamaa
Wolfram syndrome (WS) is caused by recessive mutations in the Wolfram syndrome 1 (WFS1) gene. Sensorineural hearing impairment (HI) is a frequent feature in WS and, furthermore, certain mutations in WFS1 cause nonsyndromic dominantly inherited low-frequency sensorineural HI. These two phenotypes are clinically distinct indicating that WFS1 is a reasonable candidate for genetic studies in patients with other phenotypes of HI. Here we have investigated, whether the variation in WFS1 has a pathogenic role in age-related hearing impairment (ARHI). WFS1 gene was investigated in a population sample of 518 Finnish adults born in 1938–1949 and representing variable hearing phenotypes. Identified variants were evaluated with respect to pathogenic potential. A rare mutation predicted to be pathogenic was found in a family with many members with impaired hearing. Twenty members were recruited to a segregation study and a detailed clinical examination. Heterozygous p.Tyr528His variant segregated completely with late-onset HI in which hearing deteriorated first at high frequencies and progressed to mid and low frequencies later in life. We report the first mutation in the WFS1 gene causing late-onset HI with audiogram configurations typical for ARHI. Monogenic forms of ARHI are rare and our results add WFS1 to the short list of such genes.



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Sound wave propagation on the human skull surface with bone conduction stimulation

Publication date: Available online 23 September 2017
Source:Hearing Research
Author(s): Ivo Dobrev, Jae Hoon Sim, Stefan Stenfelt, Sebastian Ihrle, Rahel Gerig, Flurin Pfiffner, Albrecht Eiber, Alexander M. Huber, Christof Röösli
BackgroundBone conduction (BC) is an alternative to air conduction to stimulate the inner ear. In general, the stimulation for BC occurs on a specific location directly on the skull bone or through the skin covering the skull bone. The stimulation propagates to the ipsilateral and contralateral cochlea, mainly via the skull bone and possibly via other skull contents. This study aims to investigate the wave propagation on the surface of the skull bone during BC stimulation at the forehead and at ipsilateral mastoid.MethodsMeasurements were performed in five human cadaveric whole heads. The electro-magnetic transducer from a BCHA (bone conducting hearing aid), a Baha^® Cordelle II transducer in particular, was attached to a percutaneously implanted screw or positioned with a 5-Newton steel headband at the mastoid and forehead. The Baha transducer was driven directly with single tone signals in the frequency range of 0.25–8 kHz, while skull bone vibrations were measured at multiple points on the skull using a scanning laser Doppler vibrometer (SLDV) system and a 3D LDV system. The 3D velocity components, defined by the 3D LDV measurement coordinate system, have been transformed into tangent (in-plane) and normal (out-of-plane) components in a local intrinsic coordinate system at each measurement point, which is based on the cadaver head's shape, estimated by the spatial locations of all measurement points.ResultsRigid-body-like motion was dominant at low frequencies below 1 kHz, and clear transverse traveling waves were observed at high frequencies above 2 kHz for both measurement systems. The surface waves propagation speeds were approximately 450 m/s at 8 kHz, corresponding trans-cranial time interval of 0.4 ms. The 3D velocity measurements confirmed the complex space and frequency dependent response of the cadaver heads indicated by the 1D data from the SLDV system. Comparison between the tangent and normal motion components, extracted by transforming the 3D velocity components into a local coordinate system, indicates that the normal component, with spatially varying phase, is dominant above 2 kHz, consistent with local bending vibration modes and traveling surface waves.ConclusionBoth SLDV and 3D LDV data indicate that sound transmission in the skull bone causes rigid-body-like motion at low frequencies whereas transverse deformations and travelling waves were observed above 2 kHz, with propagation speeds of approximately of 450 m/s at 8 kHz.



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The heterospecific calling song can improve conspecific signal detection in a bushcricket species

Publication date: Available online 21 September 2017
Source:Hearing Research
Author(s): Zainab A.S. Abdelatti, Manfred Hartbauer
In forest clearings of the Malaysian rainforest, chirping and trilling Mecopoda species often live in sympatry. We investigated whether a phenomenon known as stochastic resonance (SR) improved the ability of individuals to detect a low-frequent signal component typical of chirps when members of the heterospecific trilling species were simultaneously active. This phenomenon may explain the fact that the chirping species upholds entrainment to the conspecific song in the presence of the trill. Therefore, we evaluated the response probability of an ascending auditory neuron (TN-1) in individuals of the chirping Mecopoda species to triple-pulsed 2, 8 and 20 kHz signals that were broadcast 1 dB below the hearing threshold while increasing the intensity of either white noise or a typical triller song.Our results demonstrate the existence of SR over a rather broad range of signal-to-noise ratios (SNRs) of input signals when periodic 2 kHz and 20 kHz signals were presented at the same time as white noise. Using the chirp-specific 2 kHz signal as a stimulus, the maximum TN-1 response probability frequently exceeded the 50% threshold if the trill was broadcast simultaneously. Playback of an 8 kHz signal, a common frequency band component of the trill, yielded a similar result. Nevertheless, using the trill as a masker, the signal-related TN-1 spiking probability was rather variable. The variability on an individual level resulted from correlations between the phase relationship of the signal and syllables of the trill. For the first time, these results demonstrate the existence of SR in acoustically-communicating insects and suggest that the calling song of heterospecifics may facilitate the detection of a subthreshold signal component in certain situations. The results of the simulation of sound propagation in a computer model suggest a wide range of sender-receiver distances in which the triller can help to improve the detection of subthreshold signals in the chirping species.



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Diversity of bilateral synaptic assemblies for binaural computation in midbrain single neurons

Publication date: Available online 18 September 2017
Source:Hearing Research
Author(s): Na He, Lingzhi Kong, Tao Lin, Shaohui Wang, Xiuping Liu, Jiyao Qi, Jun Yan
Binaural hearing confers many beneficial functions but our understanding of its underlying neural substrates is limited. This study examines the bilateral synaptic assemblies and binaural computation (or integration) in the central nucleus of the inferior colliculus (ICc) of the auditory midbrain, a key convergent center. Using in-vivo whole-cell patch-clamp, the excitatory and inhibitory postsynaptic potentials (EPSPs/IPSPs) of single ICc neurons to contralateral, ipsilateral and bilateral stimulation were recorded. According to the contralateral and ipsilateral EPSP/IPSP, 7 types of bilateral synaptic assemblies were identified. These include EPSP-EPSP (EE), E-IPSP (EI), E-no response (EO), II, IE, IO and complex-mode (CM) neurons. The CM neurons showed frequency- and/or amplitude-dependent EPSPs/IPSPs to contralateral or ipsilateral stimulation. Bilateral stimulation induced EPSPs/IPSPs that could be larger than (facilitation), similar to (ineffectiveness) or smaller than (suppression) those induced by contralateral stimulation. Our findings have allowed our group to characterize novel neural circuitry for binaural computation in the midbrain.

Graphical abstract

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Standard-interval size affects interval-discrimination thresholds for pure-tone melodic pitch intervals

Publication date: Available online 17 September 2017
Source:Hearing Research
Author(s): Carolyn M. McClaskey
Our ability to discriminate between pitch intervals of different sizes is not only an important aspect of speech and music perception, but also a useful means of evaluating higher-level pitch perception. The current study examined how pitch-interval discrimination was affected by the size of the intervals being compared, and by musical training. Using an adaptive procedure, pitch-interval discrimination thresholds were measured for sequentially presented pure-tone intervals with standard intervals of 1 semitone (minor second), 6 semitones (the tri-tone), and 7 semitones (perfect fifth). Listeners were classified into three groups based on musical experience: non-musicians had less than 3 years of informal musical experience, amateur musicians had at least 10 years of experience but no formal music theory training, and expert musicians had at least 12 years of experience with 1 year of formal ear training, and were either currently pursuing or had earned a Bachelor's degree as either a music major or music minor. Consistent with previous studies, discrimination thresholds obtained from expert musicians were significantly lower than those from other listeners. Thresholds also significantly varied with the magnitude of the reference interval and were higher for conditions with a 6- or 7-semitone standard than a 1-semitone standard. These data show that interval-discrimination thresholds are strongly affected by the size of the standard interval.



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Fascial Graft Repair of Wide Bilateral Cleft Lip Deformity.

Wide bilateral cleft lip deformity reconstruction represents a special difficulty as it affects the lip, nose, and maxillary segments making single-stage reconstruction sometimes unobtainable. Many surgical and nonsurgical techniques have been prescribed to facilitate the definitive repair. Although some of these techniques proved to be useful, they have their inherent limitations and add another treatment step with all its possible complications and costs. The authors present a new method to address muscle layer repair in 1-stage procedure. It entails using fascial graft obtained from the temporalis muscle fascia or fascia lata, to reconstruct orbicularis oris lip muscle. Seven patients of wide bilateral cleft lip deformity (mean 17 mm) with a mean age of 4.4 months were subjected to single-stage lip reconstruction. After measuring the defect between both lateral muscle segments in front of the premaxilla intraoperatively ensuring that direct muscle repair could not be obtained, a fascial graft was harvested and sutured to both muscle edges. The authors found that, regardless the defect size or premaxilla protrusion, all wide clefts could be reconstructed satisfactorily in 1 stage procedure. No serious postoperative complications have been encountered in the lip or donor areas. Early follow-up reporting of the patients revealed stable repair. However more follow-up is still needed to assess late sequelae. In conclusion, fascial graft muscle repair of wide bilateral cleft lip deformity enables early 1-stage lip reconstruction without tension. The added donor morbidity is minimal and well tolerated. (C) 2017 by Mutaz B. Habal, MD.

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Long-Term Follow-Up of Osseointegrated Orbital Prosthetic Reconstruction.

Background: Osseointegrated implants have been used for craniofacial prosthetic reconstruction since 1979. The authors sought to review long-term outcomes of osseointegrated orbital reconstruction at the Institute for Reconstructive Sciences in Medicine (iRSM). Methods: Twenty-six patients have undergone osseointegrated orbital prosthetic (OOP) reconstruction at iRSM since 1991. A retrospective chart review was performed and patient satisfaction assessed through a questionnaire used in previous osseointegration studies. Multivariate binary logistic regression analysis was performed to assess the relationship between smoking, age, sex, and previous radiation treatment with the occurrence of skin reactions and implant failures. A [chi]2 test was used to assess the relationship between implant position within the orbit and development of a skin reaction or implant failure. Results: Patients received an average of 5.8 implants during the course of treatment. Follow-up ranged from 6 months to 24 years (mean = 10.6 years). A statistically significant correlation was found between skin reaction and age (P = 0.022), with younger patients more likely to develop a reaction. No variables in our model were significant for predicting implant failure. Overall, there were 39 failures of 155 osseointegrated implants, for a success rate of 74.8%. There was no relationship between skin reaction and implant failure compared to implant position within the orbit. Survey responses were received from 11 of 19 patients (58% response rate). Ninety-one percent of patients were overall satisfied with their prosthesis. Conclusions: There are minimal contraindications for consideration of OOP reconstruction. Patients find their prosthesis comfortable, report increased self-confidence, and are happy to have undergone reconstruction. (C) 2017 by Mutaz B. Habal, MD.

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Craniocervical Pseudomeningocele Following Cerebellar Meningioma Resection: Demonstration of Neck of Pseudomeningocele With Three-Dimensional Isotropic T2-Weighted SPACE Sequence at 3 Tesla (3T) Magnetic Resonance Imaging.

Postoperative pseudomeningocele is an uncommon complication of craniospinal surgery. Diagnosis is reached on a postoperative computed tomography and magnetic resonance (MR) imaging. Demonstration of the location and dimension of the dural defect before surgical therapy is a very important. T1- and T2-weighted MR images revealed a significant pseudomeningocele extending from left cervicooccipital region. Magnitude and phase-contrast-MR images showed a cerebrospinal fluid (CSF) flow into pseudomeningocele, but they no revealed dural defect. Three-dimensional isotropic T2-weighted SPACE sequence revealed a signal void indicating CSF flow into pseudomeningocele and location and exact size of dural tear. Three-dimensional isotropic T2-weighted SPACE sequence is certainly the noninvasive and optimal method for demonstrating postoperative pseudomeningocele sacs. It demonstrates a pseudomeningocele regardless of an existing communication with the dural membrane. (C) 2017 by Mutaz B. Habal, MD.

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Silicone Facial Prosthesis: A Preliminary Report on Silicone Adhesion to Magnet.

Although a silicone facial prosthesis has many advantages, silicone's limited cementation with resin or metal has caused many maxillofacial reconstructive surgeons and prosthodontists concern regarding the use of silicone-based facial prostheses. This study demonstrates 1 representative silicone facial prosthesis patient with magnet cementation to silicone using plastic clay, which will be applied to various maxillofacial prosthesis strategies in the near future. (C) 2017 by Mutaz B. Habal, MD.

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Form, Function, and Esthetics in Prosthetically Rehabilitated Maxillary Defects.

Purpose: Patients with maxillofacial defects secondary to the removal of benign and malignant pathologies of midface have a profound impact on quality of life. The aim of this study was to collect and analyze the data pertaining to 4 designs of obturator by assessment of the patient with obturator functioning scale (OFS) Materials and Methods: This retrospective analysis included all the patients who underwent prosthetic rehabilitation of maxillary defects using 4 different types (conventional, cast partial, hollow bulb, and magnet retained) of obturators from 2009 to 2016 with minimum 1 year of follow up. Demographics, number, size, location, type of pathology, postmorbid dentition, and the treatment rendered were recorded. Obturator functioning scale was used to subjectively assess the patient satisfaction. Results: The mean score on OFS was 5.67 (standard deviation: 1.8). There was a fair and statistical improvement in chewing/eating, speech clarity in public/on phone, swallowing of foods and liquids, pronunciation of words, and social interaction (P

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Cleft Lip and Palate: Demographic Patterns and the Associated Communication Disorders.

Purpose: This study investigated demographical characteristics, health status, and associated communication disorders in patients with orofacial clefts (OFCs) in Northern Jordan. Methods: A retrospective study of 226 cleft patients and their families was carried out between March 2012 and September 2016 at the Speech and Hearing Clinic and the Maxillofacial Center at King Abdullah University Hospital. Data were collected by interviewing patients and caregivers, having patients or caregiver to complete a questionnaire and reviewing the patient's medical records. The frequencies of OFC type, demographic, health status, and communication disorders variables were calculated. [chi]2 analysis was used to test for significance of associated demographic and communication disorders variables with OFC type. Results: Results revealed higher percentage of males compared with female patients. The majority of OFC patients were born to families who lived in urban areas, obtained high school diploma or lower educational level, lived below poverty cutoff, and showed nonconsanguineous marriages. Most mothers took the prescribed pregnancy supplements. Only one-third of the families received health education and reported other incidences of OFCs. Twenty percent of the patients had other congenital anomalies, 80% experienced dysphagia prior to the cleft repair, dropped to 14% after the repair. Higher percentage of patients with isolated cleft palate and cleft lip and palate exhibited hearing loss, hypernasality, articulation and phonological disorders, and dysphagia compared with those with cleft lip only. None of the demographic variables was associated with OFC type. Conclusions: Data suggested that families who had children with OFCs displayed poor socioeconomic status and low educational level which may impede the delivery of health education by health practitioners. Increased risk of comorbid communication disorders and malformations in OFC patients must be emphasized and disseminated to health professionals involved in the management of patients with OFC. (C) 2017 by Mutaz B. Habal, MD.

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Forehead Sparganosis.

No abstract available

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Craniofacial Surgery in Chile.

No abstract available

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Use of Pedicled Buccal Fat Pad for Midface Augmentation.

The pedicled buccal fat pad has occasionally been used for the closure of oroantral and oronasal fistulae. However, this versatile and convenient technique has not been used widely in the field of esthetic surgery. The main cosmetic interest in the buccal fat pads was to surgically extract them to reduce cheek prominence. Here, the authors introduce a novel operative technique using the pedicled buccal fat pad for midface augmentation in patients with deficient soft-tissue volume, particularly in the anterior malar or paranasal region. This rather simple surgical method can be performed either individually or concomitantly with reduction malarplasty. The surgical outcomes include a natural appearance with reliable long-term stability. (C) 2017 by Mutaz B. Habal, MD.

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Scaling of the ankle extensor muscle-tendon units and the biomechanical implications for bipedal hopping locomotion in the post-pouch kangaroo Macropus fuliginosus

Abstract

Bipedal hopping is used by macropods, including rat-kangaroos, wallabies and kangaroos (superfamily Macropodoidea). Interspecific scaling of the ankle extensor muscle-tendon units in the lower hindlimbs of these hopping bipeds shows that peak tendon stress increases disproportionately with body size. Consequently, large kangaroos store and recover more strain energy in their tendons, making hopping more efficient, but their tendons are at greater risk of rupture. This is the first intraspecific scaling analysis on the functional morphology of the ankle extensor muscle-tendon units (gastrocnemius, plantaris and flexor digitorum longus) in one of the largest extant species of hopping mammal, the western grey kangaroo Macropus fuliginosus (5.8–70.5 kg post-pouch body mass). The effective mechanical advantage of the ankle extensors does not vary with post-pouch body mass, scaling with an exponent not significantly different from 0.0. Therefore, larger kangaroos balance rotational moments around the ankle by generating muscle forces proportional to weight-related gravitational forces. Maximum force is dependent upon the physiological cross-sectional area of the muscle, which we found scales geometrically with a mean exponent of only 0.67, rather than 1.0. Therefore, larger kangaroos are limited in their capacity to oppose large external forces around the ankle, potentially compromising fast or accelerative hopping. The strain energy return capacity of the ankle extensor tendons increases with a mean exponent of ~1.0, which is much shallower than the exponent derived from interspecific analyses of hopping mammals (~1.4–1.9). Tendon safety factor (ratio of rupture stress to estimated peak hopping stress) is lowest in the gastrocnemius (< 2), and it decreases with body mass with an exponent of −0.15, extrapolating to a predicted rupture at 160 kg. Extinct giant kangaroos weighing 250 kg could therefore not have engaged in fast hopping using 'scaled-up' lower hindlimb morphology of extant western grey kangaroos.

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Structurally Novel Antiestrogens Elicit Differential Responses from Constitutively Active Mutant Estrogen Receptors in Breast Cancer Cells and Tumors

Many estrogen receptor α (ERα)–positive breast cancers develop resistance to endocrine therapy via mutation of ERs whose constitutive activation is associated with shorter patient survival. Because there is now a clinical need for new antiestrogens (AE) against these mutant ERs, we describe here our development and characterization of three chemically novel AEs that effectively suppress proliferation of breast cancer cells and tumors. Our AEs are effective against wild-type and Y537S and D538G ERs, the two most commonly occurring constitutively active ERs. The three new AEs suppressed proliferation and estrogen target gene expression in WT and mutant ER-containing cells and were more effective in D538G than in Y537S cells and tumors. Compared with WT ER, mutants exhibited approximately 10- to 20-fold lower binding affinity for AE and a reduced ability to be blocked in coactivator interaction, likely contributing to their relative resistance to inhibition by AE. Comparisons between mutant ER–containing MCF7 and T47D cells revealed that AE responses were compound, cell-type, and ERα-mutant dependent. These new ligands have favorable pharmacokinetic properties and effectively suppressed growth of WT and mutant ER–expressing tumor xenografts in NOD/SCID-γ mice after oral or subcutaneous administration; D538G tumors were more potently inhibited by AE than Y537S tumors. These studies highlight the differential responsiveness of the mutant ERs to different AEs and make clear the value of having a toolkit of AEs for treatment of endocrine therapy–resistant tumors driven by different constitutively active ERs. Cancer Res; 77(20); 5602–13. ©2017 AACR.

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Cancer Self-Defense: An Immune Stealth

The hurdles in realizing successful cancer immunotherapy stem from the fact that cancer patients are either refractory to immune response and/or develop resistance. Here, we propose that these phenomena are due, in part, to the deployment/secretion of a "decoy flare," for example, anomalous cancer-associated antigens by the tumor cells. The cancer secretome, which resembles the parent cell make-up, is composed of soluble macromolecules (proteins, glycans, lipids, DNAs, RNAs, etc.) and insoluble vesicles (exosomes), thus hindering cancer detection/recognition by immunotherapeutic agents, resulting in a "cancer-stealth" effect. Immunotherapy, or any treatment that relies on antigens' expression/function, could be improved by the understanding of the properties of the cancer secretome, as its clinical evaluation may change the therapeutic landscape. Cancer Res; 77(20); 5441–4. ©2017 AACR.

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Highlights from Recent Cancer Literature

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The Rac GTPase in Cancer: From Old Concepts to New Paradigms

Rho family GTPases are critical regulators of cellular functions that play important roles in cancer progression. Aberrant activity of Rho small G-proteins, particularly Rac1 and their regulators, is a hallmark of cancer and contributes to the tumorigenic and metastatic phenotypes of cancer cells. This review examines the multiple mechanisms leading to Rac1 hyperactivation, particularly focusing on emerging paradigms that involve gain-of-function mutations in Rac and guanine nucleotide exchange factors, defects in Rac1 degradation, and mislocalization of Rac signaling components. The unexpected pro-oncogenic functions of Rac GTPase-activating proteins also challenged the dogma that these negative Rac regulators solely act as tumor suppressors. The potential contribution of Rac hyperactivation to resistance to anticancer agents, including targeted therapies, as well as to the suppression of antitumor immune response, highlights the critical need to develop therapeutic strategies to target the Rac pathway in a clinical setting. Cancer Res; 77(20); 5445–51. ©2017 AACR.

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CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy

Expression of the ectonucleotidase CD73 by tumor cells, stromal cells, and immune cells is associated in cancer with immune suppression. In this study, we investigated the role of CD73 on the activity of the anti-HER2/ErbB2 monoclonal antibody (mAb) trastuzumab. In a prospective, randomized phase III clinical trial evaluating the activity of trastuzumab, high levels of CD73 gene expression were associated significantly with poor clinical outcome. In contrast, high levels of PD-1 and PD-L1 were associated with improved clinical outcome. In immunocompetent mouse models of HER2/ErbB2–driven breast cancer, CD73 expression by tumor cells and host cells significantly suppressed immune-mediated responses mediated by anti-ErbB2 mAb. Furthermore, anti-CD73 mAb therapy enhanced the activity of anti-ErbB2 mAb to treat engrafted or spontaneous tumors as well as lung metastases. Gene ontology enrichment analysis from gene-expression data revealed a positive association of CD73 expression with extracellular matrix organization, TGFβ genes, epithelial-to-mesenchymal transition (EMT) transcription factors and hypoxia-inducible-factor (HIF)-1 gene signature. Human mammary cells treated with TGFβ or undergoing EMT upregulated CD73 cell-surface expression, confirming roles for these pathways. In conclusion, our findings establish CD73 in mediating resistance to trastuzumab and provide new insights into how CD73 is regulated in breast cancer. Cancer Res; 77(20); 5652–63. ©2017 AACR.

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HIF-2{alpha} Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1

Disease progression and relapse in multiple myeloma is dependent on the ability of the multiple myeloma plasma cells (PC) to reenter the circulation and disseminate throughout the bone marrow. Increased bone marrow hypoxia is associated with increased recirculation of multiple myeloma PCs. Accordingly, we hypothesized that during chronic hypoxia, activation of HIF-2α may overcome the bone marrow retention signal provided by stromal-derived CXCL12, thereby enabling dissemination of multiple myeloma PCs. Here we demonstrate that HIF-2α upregulates multiple myeloma PC CXCL12 expression, decreasing migration toward CXCL12 and reducing adhesion to mesenchymal stromal cells in vitro. We also found that HIF-2α strongly induced expression of the chemokine receptor CCR1 in multiple myeloma PCs. CCR1 activation potently induces multiple myeloma PC migration toward CCL3 while abrogating the multiple myeloma PC migratory response to CXCL12. In addition, increased CCR1 expression by multiple myeloma PCs conferred poor prognosis in newly diagnosed multiple myeloma patients and was associated with an increase in circulating multiple myeloma PCs in these patients. Taken together, our results suggest a role for hypoxia-mediated CCR1 upregulation in driving the egress of multiple myeloma PCs from the bone marrow. Targeting CCR1 may represent a novel strategy to prevent dissemination and overt relapse in multiple myeloma. Cancer Res; 77(20); 5452–63. ©2017 AACR.

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ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage

Pancreatic ductal adenocarcinomas (PDAC) harbor recurrent functional mutations of the master DNA damage response kinase ATM, which has been shown to accelerate tumorigenesis and epithelial–mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional Atm deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements, and deregulated DNA integrity checkpoints, reminiscent of human PDAC. We hypothesized that altered genome integrity might allow synthetic lethality-based options for targeted therapeutic intervention. Supporting this possibility, we found that the PARP inhibitor olaparib or ATR inhibitors reduced the viability of PDAC cells in vitro and in vivo associated with a genotype-selective increase in apoptosis. Overall, our results offered a preclinical mechanistic rationale for the use of PARP and ATR inhibitors to improve treatment of ATM-mutant PDAC. Cancer Res; 77(20); 5576–90. ©2017 AACR.

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STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway

NOTCH signaling exerts essential roles in normal and malignant intestinal physiology and the homeostasis of cancer stem-like cells (CSC), but the basis for this latter role remains obscure. The signaling scaffold protein STRAP is upregulated in several cancers, where it promotes tumorigenicity and metastasis. Here we report a novel oncogenic function for STRAP in maintaining CSC subpopulations in a heterogeneous mixture by antagonizing formation of the chromatin modifier PRC2 and by epigenetically activating NOTCH signals in human colorectal cancer. Silencing STRAP sensitized colorectal cancer cells to chemotherapeutic drugs in vitro and in vivo. STRAP depletion also contributed to a reduced stem-like phenotype of colorectal cancer cells, as indicated by reduced expression of the CSC signature and NOTCH signaling regulators in vitro and by diminished tumorigenesis in vivo. Genes encoding some upstream activators of NOTCH were highly enriched for H3K27me3, which forms repressive chromatin domains upon STRAP silencing. Mechanistically, STRAP competitively disrupted association of the PRC2 subunits EZH2 and SUZ12, thereby inhibiting PRC2 assembly. Restoring the NOTCH pathway by lentiviral expression of NICD1 or HES1 in STRAP-depleted tumor cells reversed the CSC phenotype. In 90 colorectal cancer clinical specimens, a significant positive correlation was documented between the expression of STRAP and HES1. Overall, our findings illuminated a novel STRAP–NOTCH1–HES1 molecular axis as a CSC regulator in colorectal cancer, with potential implications to improve treatment of this disease. Cancer Res; 77(20); 5464–78. ©2017 AACR.

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Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance

Myeloid-derived suppressor cells (MDSC) are a major obstacle to promising forms of cancer immunotherapy, but tools to broadly limit their immunoregulatory effects remain lacking. In this study, we assessed the therapeutic effect of the humanized anti–Jagged1/2-blocking antibody CTX014 on MDSC-mediated T-cell suppression in tumor-bearing mice. CTX014 decreased tumor growth, affected the accumulation and tolerogenic activity of MDSCs in tumors, and inhibited the expression of immunosuppressive factors arginase I and iNOS. Consequently, anti-Jagged therapy overcame tumor-induced T-cell tolerance, increased the infiltration of reactive CD8+ T cells into tumors, and enhanced the efficacy of T-cell–based immunotherapy. Depletion of MDSC-like cells restored tumor growth in mice treated with anti-Jagged, whereas coinjection of MDSC-like cells from anti–Jagged-treated mice with cancer cells delayed tumor growth. Jagged1/2 was induced in MDSCs by tumor-derived factors via NFkB-p65 signaling, and conditional deletion of NFkB-p65 blocked MDSC function. Collectively, our results offer a preclinical proof of concept for the use of anti-Jagged1/2 to reprogram MDSC-mediated T-cell suppression in tumors, with implications to broadly improve the efficacy of cancer therapy. Cancer Res; 77(20); 5628–38. ©2017 AACR.

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LSD1-Mediated Epigenetic Reprogramming Drives CENPE Expression and Prostate Cancer Progression

Androgen receptor (AR) signaling is a key driver of prostate cancer, and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant prostate cancer (CRPC). Here, we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell-cycle genes, including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decreases tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease. Cancer Res; 77(20); 5479–90. ©2017 AACR.

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T Cells Deficient in Diacylglycerol Kinase {zeta} Are Resistant to PD-1 Inhibition and Help Create Persistent Host Immunity to Leukemia

Efforts to improve the efficacy of adoptive T-cell therapies and immune checkpoint therapies in myelogenous leukemia are desired. In this study, we evaluated the antileukemia activity of adoptively transferred polyclonal cancer antigen-reactive T cells deficient in the regulator diacylglycerol kinase zeta (DGKζ) with or without PD-1/PD-L1 blockade. In the C1498 mouse model of myeloid leukemia, we showed that leukemia was eradicated more effectively in DGKζ-deficient (DGKζ−/−) mice than wild-type mice. T cells transferred from DGKζ-deficient mice to wild-type tumor-bearing recipients conferred this benefit. Leukemia clearance was similar to mice treated with anti-PD-L1. Strikingly, we found that the activity of adoptively transferred DGKζ−/− T cells relied partly on induction of sustainable host T-cell immunity. Transferring DGKζ-deficient T cells increased the levels of IFNγ and other cytokines in recipient mice, especially with coadministration of anti-PD-L1. Overall, our results offered evidence that targeting DGKζ may leverage the efficacy of adoptive T-cell and immune checkpoint therapies in leukemia treatment. Furthermore, they suggest that DGKζ targeting might decrease risks of antigen escape or resistance to immune checkpoint blockade. Cancer Res; 77(20); 5676–86. ©2017 AACR.

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Human Pluripotent Stem Cell-Derived TSC2-Haploinsufficient Smooth Muscle Cells Recapitulate Features of Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a progressive destructive neoplasm of the lung associated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes. Cell or animal models that accurately reflect the pathology of LAM have been challenging to develop. Here, we generated a robust human cell model of LAM by reprogramming TSC2 mutation–bearing fibroblasts from a patient with both tuberous sclerosis complex (TSC) and LAM (TSC-LAM) into induced pluripotent stem cells (iPSC), followed by selection of cells that resemble those found in LAM tumors by unbiased in vivo differentiation. We established expandable cell lines under smooth muscle cell (SMC) growth conditions that retained a patient-specific genomic TSC2+/− mutation and recapitulated the molecular and functional characteristics of pulmonary LAM cells. These include multiple indicators of hyperactive mTORC1 signaling, presence of specific neural crest and SMC markers, expression of VEGF-D and female sex hormone receptors, reduced autophagy, and metabolic reprogramming. Intriguingly, the LAM-like features of these cells suggest that haploinsufficiency at the TSC2 locus contributes to LAM pathology, and demonstrated that iPSC reprogramming and SMC lineage differentiation of somatic patient cells with germline mutations was a viable approach to generate LAM-like cells. The patient-derived SMC lines we have developed thus represent a novel cellular model of LAM that can advance our understanding of disease pathogenesis and develop therapeutic strategies against LAM. Cancer Res; 77(20); 5491–502. ©2017 AACR.

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Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Resistance invariably develops to antiandrogen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, we report that the transcriptional coactivator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth in vitro and in vivo. Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptional activity of the androgen receptor and its target gene expression. Our findings offer a preclinical proof of concept for small-molecule therapies to target the CBP/p300 bromodomain as a strategy to treat castration-resistant prostate cancer. Cancer Res; 77(20); 5564–75. ©2017 AACR.

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De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer

Pancreatic adenocarcinoma is moderately responsive to gemcitabine-based chemotherapy, the most widely used single-agent therapy for pancreatic cancer. Although the prognosis in pancreatic cancer remains grim in part due to poor response to therapy, previous attempts at identifying and targeting the resistance mechanisms have not been very successful. By leveraging The Cancer Genome Atlas dataset, we identified lipid metabolism as the metabolic pathway that most significantly correlated with poor gemcitabine response in pancreatic cancer patients. Furthermore, we investigated the relationship between alterations in lipogenesis pathway and gemcitabine resistance by utilizing tissues from the genetically engineered mouse model and human pancreatic cancer patients. We observed a significant increase in fatty acid synthase (FASN) expression with increasing disease progression in spontaneous pancreatic cancer mouse model, and a correlation of high FASN expression with poor survival in patients and poor gemcitabine responsiveness in cell lines. We observed a synergistic effect of FASN inhibitors with gemcitabine in pancreatic cancer cells in culture and orthotopic implantation models. Combination of gemcitabine and the FASN inhibitor orlistat significantly diminished stemness, in part due to induction of endoplasmic reticulum (ER) stress that resulted in apoptosis. Moreover, direct induction of ER stress with thapsigargin caused a similar decrease in stemness and showed synergistic activity with gemcitabine. Our in vivo studies with orthotopic implantation models demonstrated a robust increase in gemcitabine responsiveness upon inhibition of fatty acid biosynthesis with orlistat. Altogether, we demonstrate that fatty acid biosynthesis pathway manipulation can help overcome the gemcitabine resistance in pancreatic cancer by regulating ER stress and stemness. Cancer Res; 77(20); 5503–17. ©2017 AACR.

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Monocarboxylate Transporter MCT1 Promotes Tumor Metastasis Independently of Its Activity as a Lactate Transporter

Extracellular acidosis resulting from intense metabolic activities in tumors promotes cancer cell migration, invasion, and metastasis. Although host cells die at low extracellular pH, cancer cells resist, as they are well equipped with transporters and enzymes to regulate intracellular pH homeostasis. A low extracellular pH further activates proteolytic enzymes that remodel the extracellular matrix to facilitate cell migration and invasion. Monocarboxylate transporter MCT1 is a passive transporter of lactic acid that has attracted interest as a target for small-molecule drugs to prevent metastasis. In this study, we present evidence of a function for MCT1 in metastasis beyond its role as a transporter of lactic acid. MCT1 activates transcription factor NF-κB to promote cancer cell migration independently of MCT1 transporter activity. Although pharmacologic MCT1 inhibition did not modulate MCT1-dependent cancer cell migration, silencing or genetic deletion of MCT1 in vivo inhibited migration, invasion, and spontaneous metastasis. Our findings raise the possibility that pharmacologic inhibitors of MCT1-mediated lactic acid transport may not effectively prevent metastatic dissemination of cancer cells. Cancer Res; 77(20); 5591–601. ©2017 AACR.

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Sensitivity to BUB1B Inhibition Defines an Alternative Classification of Glioblastoma

Glioblastoma multiforme (GBM) remains a mainly incurable disease in desperate need of more effective treatments. In this study, we develop evidence that the mitotic spindle checkpoint molecule BUB1B may offer a predictive marker for aggressiveness and effective drug response. A subset of GBM tumor isolates requires BUB1B to suppress lethal kinetochore–microtubule attachment defects. Using gene expression data from GBM stem-like cells, astrocytes, and neural progenitor cells that are sensitive or resistant to BUB1B inhibition, we created a computational framework to predict sensitivity to BUB1B inhibition. Applying this framework to tumor expression data from patients, we stratified tumors into BUB1B-sensitive (BUB1BS) or BUB1B-resistant (BUB1BR) subtypes. Through this effort, we found that BUB1BS patients have a significantly worse prognosis regardless of tumor development subtype (i.e., classical, mesenchymal, neural, proneural). Functional genomic profiling of BUB1BR versus BUB1BS isolates revealed a differential reliance of genes enriched in the BUB1BS classifier, including those involved in mitotic cell cycle, microtubule organization, and chromosome segregation. By comparing drug sensitivity profiles, we predicted BUB1BS cells to be more sensitive to type I and II topoisomerase inhibitors, Raf inhibitors, and other drugs, and experimentally validated some of these predictions. Taken together, the results show that our BUB1BR/S classification of GBM tumors can predict clinical course and sensitivity to drug treatment. Cancer Res; 77(20); 5518–29. ©2017 AACR.

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Therapeutic Effects of XPO1 Inhibition in Thymic Epithelial Tumors

Exportin 1 (XPO1) mediates nuclear export of many cellular factors known to play critical roles in malignant processes, and selinexor (KPT-330) is the first XPO1-selective inhibitor of nuclear export compound in advanced clinical development phase for cancer treatment. We demonstrated here that inhibition of XPO1 drives nuclear accumulation of important cargo tumor suppressor proteins, including transcription factor FOXO3a and p53 in thymic epithelial tumor (TET) cells, and induces p53-dependent and -independent antitumor activity in vitro. Selinexor suppressed the growth of TET xenograft tumors in athymic nude mice via inhibition of cell proliferation and induction of apoptosis. Loss of p53 activity or amplification of XPO1 may contribute to resistance to XPO1 inhibitor in TET. Using mass spectrometry–based proteomics analysis, we identified a number of proteins whose abundances in the nucleus and cytoplasm shifted significantly following selinexor treatment in the TET cells. Furthermore, we found that XPO1 was highly expressed in aggressive histotypes and advanced stages of human TET, and high XPO1 expression was associated with poorer patient survival. These results underscore an important role of XPO1 in the pathogenesis of TET and support clinical development of the XPO1 inhibitor for the treatment of patients with this type of tumors. Cancer Res; 77(20); 5614–27. ©2017 AACR.

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Loss of Tumor Suppressor STAG2 Promotes Telomere Recombination and Extends the Replicative Lifespan of Normal Human Cells

Sister chromatids are held together by cohesin, a tripartite ring with a peripheral SA1/2 subunit, where SA1 is required for telomere cohesion and SA2 for centromere cohesion. The STAG2 gene encoding SA2 is often inactivated in human cancer, but not in in a manner associated with aneuploidy. Thus, how these tumors maintain chromosomal cohesion and how STAG2 loss contributes to tumorigenesis remain open questions. Here we show that, despite a loss in centromere cohesion, sister chromatids in STAG2 mutant tumor cells maintain cohesion in mitosis at chromosome arms and telomeres. Telomere maintenance in STAG2 mutant tumor cells occurred by either telomere recombination or telomerase activation mechanisms. Notably, these cells were refractory to telomerase inhibitors, indicating recombination can provide an alternative means of telomere maintenance. STAG2 silencing in normal human cells that lack telomerase led to increased recombination at telomeres, delayed telomere shortening, and postponed senescence onset. Insofar as telomere shortening and replicative senescence prevent genomic instability and cancer by limiting the number of cell divisions, our findings suggest that extending the lifespan of normal human cells due to inactivation of STAG2 could promote tumorigenesis by extending the period during which tumor-driving mutations occur. Cancer Res; 77(20); 5530–42. ©2017 AACR.

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{beta}-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy

The immune context of tumors has significant prognostic value and is predictive of responsiveness to several forms of therapy, including immunotherapy. We report here that CD8+ T-cell frequency and functional orientation within the tumor microenvironment is regulated by β2-adrenergic receptor (β-AR) signaling in host immune cells. We used three strategies—physiologic (manipulation of ambient thermal environment), pharmacologic (β-blockers), and genetic (β2-AR knockout mice) to reduce adrenergic stress signaling in two widely studied preclinical mouse tumor models. Reducing β-AR signaling facilitated conversion of tumors to an immunologically active tumor microenvironment with increased intratumoral frequency of CD8+ T cells with an effector phenotype and decreased expression of programmed death receptor-1 (PD-1), in addition to an elevated effector CD8+ T-cell to CD4+ regulatory T-cell ratio (IFNγ+CD8+:Treg). Moreover, this conversion significantly increased the efficacy of anti-PD-1 checkpoint blockade. These data highlight the potential of adrenergic stress and norepinephrine-driven β-AR signaling to regulate the immune status of the tumor microenvironment and support the strategic use of clinically available β-blockers in patients to improve responses to immunotherapy. Cancer Res; 77(20); 5639–51. ©2017 AACR.

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Shrimp miR-S8 Suppresses the Stemness of Human Melanoma Stem-like Cells by Targeting the Transcription Factor YB-1

Cross-species regulation of gene expression by microRNA is a possible untapped opportunity for miRNA-based therapy. In this study, we report a novel approach to ablate melanoma stem-like cells by targeting the transcription factor YB-1, which is significantly and selectively upregulated in these cells in melanoma. Silencing YB-1 expression was sufficient to significantly inhibit the stemness of melanoma stem-like cells. In exploring YB-1 targeting, we discovered that the shrimp microRNA miR-S8 could suppress human YB-1 expression in melanoma stem-like cells. Mechanistic investigations revealed that miR-S8 recognized the 3′UTR of YB-1 mRNA and mediated its degradation. In tumor cell and xenograft experiments, miR-S8 suppressed the tumorigenic capacity of melanoma stem-like cells by targeting human YB-1. Overall, our results illuminated a novel aspect of miRNA-mediated cross-species gene expression and its use in regulating cancer stem-like cells. Cancer Res; 77(20); 5543–53. ©2017 AACR.

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Timeframe of socket cortication after tooth extraction: A retrospective radiographic study

Abstract

Objectives

To assess the timeframe between tooth extraction and radiographically detectable socket cortication in humans.

Methods

Two hundred and fifty patients with a CT scan ≤36 months after tooth extraction were included. First, three orthoradial multiplanar reconstruction slices, representing the major part of the extraction socket, were scored regarding the degree of bone healing as (i) healed, that is, complete/continuous cortication of the socket entrance, or (ii) non-healed. Thereafter, based on the results of all three slices, the stage of cortication of the extraction socket, as one unit, was classified as (i) non-corticated, that is, all three slices judged as non-healed, (ii) partially corticated, that is, 1 or 2 slices judged as non-healed, or (iii) completely corticated, that is, all three slices judged as healed. The possible effect of several independent parameters, that is, age, gender, timeframe between tooth extraction and CT scan, tooth type, extent of radiographic bone loss of the extracted tooth, tooth-gap type, smoking status, presence of any systemic disease, and medication intake, on cortication status was statistically evaluated.

Results

Three to 6 months after tooth extraction, 27% of the sockets were judged as non-corticated and 53% were judged as partially corticated. After 9–12 months, >80% of the sockets were corticated, while some incompletely corticated sockets were detected up to 15 months after extraction. Each additional month after tooth extraction contributed significantly to a higher likelihood of a more advanced stage of cortication, while radiographic bone loss ≥75% significantly prolonged cortication time; no other independent variable had a significant effect.

Conclusions

The results indicate a considerably long timeframe until complete cortication of an extraction socket, that is, 3–6 months after tooth extraction 3 of 4 sockets were still not completely corticated, and only after 9–12 months, complete cortication was observed in about 80% of the sockets.

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The Activity Demands and Physiological Responses Encountered During Basketball Match-Play: A Systematic Review

Abstract

Background

Basketball is a popular, court-based team sport that has been extensively studied over the last decade.

Objective

The purpose of this article was to provide a systematic review regarding the activity demands and physiological responses experienced during basketball match-play according to playing period, playing position, playing level, geographical location, and sex.

Methods

An electronic database search of relevant articles published prior to 30 September 2016 was performed with PubMed, MEDLINE, ERIC, Google Scholar, SCIndex, and ScienceDirect. Studies that measured activity demands and/or physiological responses during basketball match-play were included.

Results

Following screening, 25 articles remained for review. During live playing time across 40-min matches, male and female basketball players travel 5–6 km at average physiological intensities above lactate threshold and 85% of maximal heart rate (HR). Temporal comparisons show a reduction in vigorous activities in the fourth quarter, likely contributing to lower blood lactate concentrations and HR responses evident towards the end of matches. Guards tend to perform a higher percentage of live playing time sprinting and performing high-intensity shuffling compared with forwards and centers. Guards also perform less standing and walking during match-play compared with forwards and centers. Variations in activity demands likely account for the higher blood lactate concentrations and HR responses observed for guards compared with forwards and centers. Furthermore, higher-level players perform a greater intermittent workload than lower-level players. Moreover, geographical differences may exist in the activity demands (distance and frequency) and physiological responses between Australian, African, and European basketball players, whereby Australian players sustain greater workloads. While activity demands and physiological data vary across playing positions, playing levels, and geographical locations, male and female players competing at the same level experience similar demands.

Conclusion

The current results provide a detailed description of the specific requirements placed on basketball players during match-play according to playing period, playing level, playing position, geographical location, and sex, which may be useful in the development of individualized basketball training drills.

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