Comparative Efficacy of Once-Daily Umeclidinium/Vilanterol and Tiotropium/Olodaterol Therapy in Symptomatic Chronic Obstructive Pulmonary Disease: A Randomized Study

Abstract

Introduction

We report the results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting β₂-agonist (LAMA/LABA) combinations umeclidinium/vilanterol (UMEC/VI) and tiotropium/olodaterol (TIO/OLO) in patients with COPD.

Methods

This was a randomized, two-period crossover open-label study in symptomatic patients with COPD [age 40 years or older, postbronchodilator forced expiratory volume in 1 s (FEV₁) of 70% or less and 50% or more of predicted normal values, and modified Medical Research Council Dyspnoea Scale score of 2 or greater] not receiving inhaled corticosteroid therapy. Patients were randomized to receive UMEC/VI (62.5/25 µg once daily) via a multidose dry powder inhaler (ELLIPTA) followed by TIO/OLO (5/5 µg once daily) via a soft mist inhaler (Respimat), each for 8 weeks with an interim 3-week washout or vice versa. The primary end point was the change from baseline in trough FEV₁ at week 8 with a noninferiority margin of − 50 mL in the per-protocol (PP) population. The incidence of adverse events was also assessed.

Results

In total, 236 patients (mean age 64.4 years, 60% male) were included in the intent-to-treat population and 227 were included in the PP population. UMEC/VI treatment was noninferior in the PP population and superior in the intent-to-treat population to TIO/OLO treatment with regard to trough FEV₁ at week 8 [FEV₁ change from baseline 180 mL vs 128 mL; difference 52 mL (95% confidence interval 28–77 mL); p < 0.001]. Patients receiving UMEC/VI had twofold increased odds of experiencing a clinically meaningful increase (100 mL or more) from baseline in trough FEV₁ at week 8 compared with patients receiving TIO/OLO (odds ratio 2.05; 95% confidence interval 1.34–3.14). Adverse events occurred in 25% of patients in the UMEC/VI group and in 31% of patients in the TIO/OLO group.

Conclusion

In this first direct comparison of two once-daily fixed-dose LAMA/LABA combinations, superiority was observed for the primary end point of trough FEV₁ at week 8 with UMEC/VI compared with TIO/OLO in patients with symptomatic COPD. Both treatments had similar safety profiles. These findings confirm the results of previous indirect LAMA/LABA comparisons, and show that an efficacy gradient exists within the LAMA/LABA class.

Trial Registration

ClinicalTrials.gov identifier NCT02799784.

Funding

GlaxoSmithKline.

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The first postoperative-stimulated serum thyroglobulin is a prognostic factor for thyroid microcarcinomas

Publication date: Available online 31 October 2017
Source:Brazilian Journal of Otorhinolaryngology
Author(s): Isabela de Oliveira Amui, José Vicente Tagliarini, Emanuel C. Castilho, Mariângela de Alencar Marques, Yoshio Kiy, José Eduardo Corrente, Gláucia M.F.S. Mazeto
IntroductionEndogenous thyroid-stimulating hormone-stimulated thyroglobulin collected after total thyroidectomy is a useful predictor of better prognosis in patients with differentiated thyroid carcinomas in general, but studies with microcarcinomas are scarce.ObjectiveTo assess whether the first postoperative stimulated thyroglobulin measurement is a prognostic factor in patients with microcarcinoma.MethodsThe medical data of 150 differentiated thyroid carcinoma patients were studied retrospectively, and 54 (36%) cases with microcarcinoma were selected. The first postoperative stimulated thyroglobulin (1st stimulated thyroglobulin), measured after thyroidectomy, initial presentation data, and microcarcinomas treatment were assessed regarding outcome. Worse prognosis was defined as neoplasm persistence/recurrence.ResultsPersistence/recurrence occurred in 27.6% of the cases. These patients were identified according to the following parameters: receiving more than one ¹³¹iodine dose (100% vs. 0%; p<0.0001); accumulated ¹³¹iodine dose (232.14±99.09 vs. 144±33.61mCi; p<0.0001); presented active disease in the last assessment (53.3% vs. 0%; p<0.0001); follow-up time (103.07±61.27 vs. 66.85±70.14 months; p=0.019); and 1st stimulated thyroglobulin (19.01±44.18 vs. 2.19±2.54ng/dL; p<0.0001). After multivariate logistic regression, only the 1stSTg [odds ratio=1.242; 95% confidence interval: 1.022–1.509; p=0.029] and follow-up time (odds ratio=1.027; 95% confidence interval: 1.007–1.048; p=0.007) were independent predictors of risk of persistence/recurrence. The cutoff point of 1.6ng/dL for the 1st stimulated thyroglobulin was significantly associated with disease persistence/recurrence [area under the curve=0.713 (p=0.019)].ConclusionThe first stimulated thyroglobulin predicted disease persistence/recurrence in patients with microcarcinoma.



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Downregulation of Notch4 – a prognostic marker in distinguishing oral verrucous carcinoma from oral squamous cell carcinoma

Publication date: Available online 31 October 2017
Source:Brazilian Journal of Otorhinolaryngology
Author(s): M.K. Harishankar, A. Mathan Mohan, A. Vinod Krishnan, Devi Arikketh
IntroductionOral verrucous carcinoma is a special form of well-differentiated squamous cell carcinoma which possesses specific clinical, morphologic and cytokinetic features that differ from other types of oral cancers and hence diagnosis requires immense experience in histopathology. Hence it is certainly important to distinguish such a lesion from other oral tumors as treatment strategies vary widely between them.ObjectiveIn search of a critical diagnostic marker in distinguishing oral verrucous carcinoma from oral squamous cell carcinoma, Notch4 receptor, one of the key regulatory molecules of the Notch signaling family has been aberrantly activated in the progression of several types of tumors. However its function in oral verrucous carcinoma remains unexplored. Thus the present study aims in determining the differential expression pattern of Notch4 in oral verrucous carcinoma and oral squamous cell carcinoma.MethodsTen patients reported positive for oral cancer (5 patients with oral verrucous carcinoma and 5 patients with oral squamous cell carcinoma). Five normal tissue samples were also obtained and evaluated for clinicopathological parameters and immunohistochemistry, western blotting and RT-PCR for Notch4 expression.ResultsOur results reveal that the expression of Notch4 was considerably high in oral squamous cell carcinoma lesions compared to normal tissue, whereas in oral verrucous carcinoma, irrespective of the clinicopathological features, complete regulação descendente of Notch4 was observed.ConclusionsThese preliminary findings strongly support the fact that Notch4 is downregulated in oral verrucous carcinoma and could be considered as a suitable prognostic marker in distinguishing oral verrucous carcinoma from oral squamous cell carcinoma. This distinguishing marker can help in improving therapeutic options in patients diagnosed with oral verrucous carcinoma.



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Editorial on Special Issue: Animal models of Tourette syndrome

Publication date: 1 December 2017
Source:Journal of Neuroscience Methods, Volume 292
Author(s): Marco Bortolato, Giuseppe Di Giovanni




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Genetic Hearing Loss: A Comprehensive Review

Hearing loss can be attributed to a variety of inherited and environmental noises (medications, infections, etc.). In recent decades, our improved understanding of genetics, molecular biology, and audiologic pathways has led to the discovery of a variety of Hereditary Hearing Impairments (HHI). HHI can be categorized as syndromic HL and non-syndromic HL, in which HL is associated with other pathophysiological manifestations. Currently, greater than 300 syndromic HLs are recognized, while more than 100 chromosomal loci and 40 genes are attributed for non-syndromic HLs. Improved understanding of the genes impaired in HL, including their structure and function, will soon lead to improvements in screening and possibly treatments. The following is a review of genetic HL where we discuss the definition, classifications, etiology, epidemiology, recognized syndromes, genetics, diagnostics, and screening methods of HL.

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Ménière's Disease: Current and Potential New Objective Measures Using Electrocochleography

The characteristic manifestations of Ménière's disease (MD) are mainly subjective, making MD difficult for physicians to diagnose without objective confirmation. A classic electrophysiologic technique for objective diagnosis of MD is electrocochleography (ECochG) to slow stimulus rates. This review will provide information regarding the sensitivity, specificity, and limitations of the conventional click and frequency specific ECochG measures. In addition, the paper will discuss two novel, promising techniques: fast click ECochG with the use of continuous loop averaging deconvolution (CLAD) and the auditory nerve overlapped waveform (ANOW). These new techniques may offer a new way in diagnosing MD through assessing neural adaptation and function of the apical half of the cochlear spiral.

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Coordinator's Column

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A Review of Human Immunodeficiency Virus on the Auditory System

There are an increasing number of large-scale studies on the association between human immunodeficiency virus (HIV) and hearing loss; these studies include both HIV-infected adults from horizontal disease transmission to HIV-infected children from vertical disease transmission in utero. With advances in HIV treatment approaches, this disease has become a chronic health condition rather than a terminal health condition. Based on recent data in this area, mechanisms within the auditory system are at risk based on HIV status. HIV-infected children have poorer hearing compared to perinatally exposed to HIV, but uninfected children. HIV-infected children also have poorer hearing compared to HIV-unexposed, uninfected children. HIV-infected adults also have poorer hearing compared with HIV-uninfected adults. Individuals with greater HIV disease severity had poorer hearing than HIV-infected individuals with lesser HIV disease severity. Auditory brainstem response data demonstrate poor waveform morphology, lower peak amplitude, increased peak and interpeak latencies in HIV-infected individuals. Conversely, distortion product otoacoustic emission data are similar for HIV-infected and HIV-uninfected individuals status. Taken together, differences in hearing sensitivity based on HIV status may be a result of auditory neural function, although large-scale studies are currently ongoing to further examine these risk factors of HIV on the auditory system.

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SIG 6 Perspectives Vol. 19, No. 2, November 2015: Earn 0.15 CEUs

Download the CE Questions PDF from the toolbar, above. Use the questions to guide your Perspectives reading. When you're ready, purchase the activity from the ASHA Store and follow the instructions to take the exam in ASHA's Learning Center. Available until October 29, 2018.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://article/19/2/C1/2475847/SIG-6-Perspectives-Vol-19-No-2-November-2015Earn

Intelligibility of Synthetic Speech for Normal-Hearing and Hearing-Impaired Listeners

This study examined the perceived intelligibility of synthetic speech. Participants were adults aged 49–69, one group with normal hearing and one group with acquired sensorineural hearing impairment. Word lists were presented in two speech types: DECtalk (a high-quality speech synthesizer) and a natural male speaker. Results revealed differences between groups, with normal-hearing listeners scoring higher than hearing-impaired listeners, and between speech types, with higher scores for natural speech than for synthesized speech. There was no significant interaction of hearing level and speech type.

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Who shall be Called Language Disordered? Some Reflections and One Perspective

This paper discusses some issues involved in identifying children who have language problems. The perspective taken is that (a) the goal of identification must be clearly distinguished from other goals of assessment; (b) identification of children with language disorders is better based on language performance than on inferences about the language knowledge that underlies this performance; (c) language performance must be sampled in more than one context, including, for purposes of identification, contexts that stress the language system; (d) the standards of expectations for comparing performance and determining differences must be explicit; (e) standards used to determine differences are better based on the performance of chronological-age peers than on the performance of children with similar mental abilities; and (f) children who do not evidence poor language performance but are considered at risk for language-related problems should be distinguished from children who demonstrate poor language skills.

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Comments on "Concomitant Speech and Language Disorders in Stuttering Children: A Critique of the Literature"

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Effects of Repair Strategies on Visual Identification of Sentences

This investigation determined whether information elicited by repair strategies enhances an individual's ability to lipread a misperceived sentence. Five groups of subjects were each assigned one of five repair strategies: (a) asking the talker to repeat a sentence, (b) simplify it, (c) rephrase it, (d) say an important keyword, and (e) speak two sentences. Subjects viewed sentences spoken by six different talkers. When a subject did not recite a sentence verbatim, the talker performed the assigned repair strategy and then repeated the original sentence. A control group of subjects saw only the original sentence repeated twice. All five test groups demonstrated a significantly greater improvement for the second presentation score (referenced to the first presentation score) than the control group. The benefits provided by the repair strategies were independent of the talker, and benefits did not differ significantly among the groups.

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The Iowa Articulation Norms Project and its Nebraska Replication

The purpose of the Iowa Articulation Norms Project and its Nebraska replication was to provide normative information about speech sound acquisition in these two states. An assessment instrument consisting of photographs and a checklist form for narrow phonetic transcription was administered by school-based speech-language pathologists to stratified samples of children in the age range 3–9 years. The resulting data were not influenced by the demographic variables of population density (rural/urban), SES (based on parental education), or state of residence (Iowa/Nebraska); however, sex of the child exerted a significant influence in some of the preschool age groups. The criteria used to determine acceptability of a production appeared to influence outcomes for some speech sounds. Acquisition curves were plotted for individual phoneme targets or groups of targets. These curves were used to develop recommended ages of acquisition for the tested speech sounds, with recommendations based generally on a 90% level of acquisition. Special considerations were required for the phonemes /n s z/.

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Spoken and Written English Errors of Postsecondary Students with Severe Hearing Impairment

This investigation compared the spoken and written English errors of 20 hearing-impaired postsecondary students with intelligible speech and poor English language. Error categories used to assess the language samples were function, content, and structure. Spoken and written performances were distinguished only by a greater number of function word errors in writing samples. A trend toward greater complexity in writing was also found. Implications for instruction are discussed.

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Taxonomies in Biology, Phonetics, Phonology, and Speech Motor Control

This article begins with a review explaining the different purposes of biological taxonomies. Taxonomic units are often dependent on the purpose for which the taxonomy has been constructed. Biological taxonomies provide an analogy that we use to emphasize some of the distinctions among the units of phonetic transcription systems, competence phonologies, and performance phonologies. The units of both phonology and phonetic transcription are considered as possible units of the speech motor system, and some of the difficulties of this assumption are explained. Although phonemic units, like units of phonetic transcription, are useful for many purposes, it is not theoretically necessary to use units derived as part of competence phonologies in systems attempting to explain phonological performance or speech motor performance. In this regard, we challenge the concept of coarticulation, because it is based on assumptions about the role of phonological or phonetic units in speech motor control. We offer an integrated perspective that has implications for research in speech motor control and deficits of the speech motor system. We see speech motor deficits as distinct from, yet possibly interacting with, phonological deficits.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://article/55/4/596/1775637/Taxonomies-in-Biology-Phonetics-Phonology-and

Tabletop Versus Microcomputer-Assisted Speech Management: Response Evocation Phase

This is the third in a series of studies on the use of microcomputers with speech-delayed children. Two repeated-measures designs (n=15) and five case studies were completed to compare tabletop management at early and late stages of the response development phase with two comparable, computer-assisted drill-and-practice activities. Discrimination of correct articulatory responses was mediated by the clinician in all modes, rather than by speech recognition hardware, but all contingent reinforcement in the computer modes was presented by animation graphics. The two computer modes were identical except for the addition of fantasy involvement in one of the modes. Findings indicated that the three modes of intervention were equally effective, efficient, and engaging. Subject-level analyses suggested that microcomputer software has excellent potential to engage children in drill-and-practice for late-phase response evocation, when the target sound is stimulable, but limited usefulness with young children at early-phase response evocation, when specific articulatory behaviors need to be cued. Discussion considers learning, child, and hardware/software factors in microcomputer-assisted speech management.

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Fast Mapping of Words in Event Contexts by Children with Down Syndrome

Fast mapping of novel words for objects was compared in 48 children and adolescents with Down syndrome (ages 5:6-20:6), who were delayed in expressive language acquisition compared to mental age, and 48 normally developing children matched for mental age (chronological ages 2:0-6:0). Normal and Down syndrome groups did not differ in their ability to infer a connection between the novel word and referent (100% vs. 100%), to comprehend the novel word after a single exposure (83% vs. 73%), and to recall the location in which they hid the novel referent (83% vs. 75%). Nor did they differ in their ability to produce the novel word correctly (at least two out of three phonemes in order: 48% vs. 40%). When retested after an hour of other activity, only the production task showed a significant, and comparable, decrement. Comparing youngest and oldest quarters of each group showed improved memory for location in both, improved comprehension in the Down syndrome group, and improved production in the control group. Adults (n=12), in contrast, performed perfectly on all tasks except the delayed word production. Neither intelligibility differences nor use of real word labels accounts for the failure to find a difference between groups. Fast mapping skills were unrelated to expressive language deficit in these children with Down syndrome.

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The Relationship between Communication Problems and Psychological Difficulties in Persons with Profound Acquired Hearing Loss

Communication strategies, accommodations to deafness, and perceptions of the communication environment by profoundly deaf subjects were correlated with indices of psychosocial adjustment to determine whether accommodations to deafness could play a role in the presence of psychological difficulties among deaf persons. Persons with postlingually acquired profound deafness were administered the Communication Profile for the Hearing Impaired (CPHI) and several standardized tests of psychological functioning and adjustment. Inadequate communication strategies and poor accommodations to deafness reported on the CPHI were associated with depression, social introversion, loneliness, and social anxiety. Limited communication performance at home and with friends was related to both social introversion and the experience of loneliness; perceived attitudes and behaviors of others correlated with depression as well as loneliness. In general, the pattern of correlations obtained suggests that specific communication strategies and accommodations to deafness, rather than deafness per se, may contribute to the presence of some psychological difficulties in individuals.

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Response to Hamre

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Generalized Learning of Receptive and Expressive Action-Object Responses by Language-Delayed Preschoolers

This study examined the effectiveness of matrix-training procedures in teaching action + object utterances in both the receptive and expressive language modalities. The subjects were 4 developmentally delayed preschool boys who failed to produce spontaneous, functional two-word utterances. A multiple baseline design across responses with a multiple probe technique was employed. Subjects were taught 4–6 of 48 receptive and 48 expressive responses. Acquisition of a word combination rule was facilitated by the use of familiar lexical items, whereas subsequent acquisition of new lexical knowledge was enhanced by couching training in a previously trained word combination pattern. Although receptive knowledge was not sufficient for the demonstration of corresponding expressive performance for most of the children, only minimal expressive training was required to achieve this objective. For most matrix items, subjects responded receptively before they did so expressively. For 2 subjects, when complete receptive recombinative generalization had not been achieved, expressive training facilitated receptive responding. The results of this study elucidate benefits to training one linguistic aspect (lexical item, word combination pattern) at a time to maximize generalization in developmentally delayed preschoolers.

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Comment on "Methodological Variables Affecting Phonational Frequency Range in Adults"

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Partner Sensitivity to Communication Behavior of Young Children with Developmental Disabilities

Aspects of partner sensitivity to communication behaviors of 24 presymbolic children with developmental disabilities were examined. The children were grouped according to their movement abilities (normal vs. abnormal patterns) and communication status (intentional vs. preintentional). Participating communication partners were those with whom the children interacted on a regular basis and included their mothers, early childhood special educators, and speech-language pathologists. Procedures were developed whereby the partners served as informants in order to provide information regarding (a) recognition of the children's communicative cues and (b) consistency of cue recognition and descriptions across partners. Results indicated wide individual variability in the partners' basic recognition abilities as well as their consistency with each other. Further, the observed variations could not be attributed to the children's movement and communication abilities. It was concluded that sensitivity, as measured in the present investigation, was highly partner-child specific, with some children likely to be exposed to more optimal interactions than others.

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Patient Compliance with Cleft Palate Team Regimens

A cleft palate team's prescribed regimen requires prompt and continued compliance in order to meet the management objectives and to justify the large investment of professional time. The purposes of this clinical investigation were to determine the rate of compliance with the recommendations made by a cleft palate team for its patients and to identify variables associated with compliance. A subject was defined as the person(s) who could best respond to questions concerning the management of the team's patient. Each subject was interviewed using a questionnaire. The mean patient compliance rate was 64.4%, and noncompliance with specific recommendations ranged from 12.5% to 100%. Using Jones and Caldwell's (1981) classification, 17.1% of the patients were classified as compliers, 78% as partial compliers, and 4.9% as noncompliers. The best predictor of compliance was a set of nine variables.

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Numb-/low Enriches a Castration-Resistant Prostate Cancer Cell Subpopulation Associated with Enhanced Notch and Hedgehog Signaling

Purpose: To elucidate the role and molecular mechanism of Numb in prostate cancer and the functional contribution of Numb^–/low prostate cancer cells in castration resistance.

Experimental Design: The expression of Numb was assessed using multiple Oncomine datasets and prostate cancer tissues from both humans and mice. The biological effects of the overexpression and knockdown of Numb in human prostate cancer cell lines were investigated in vitro and in vivo. In addition, we developed a reliable approach to distinguish between prostate cancer cell populations with a high or low endogenous expression of Numb protein using a Numb promoter–based lentiviral reporter system. The difference between Numb^–/low and Numb^high prostate cancer cells in the response to androgen-deprivation therapy (ADT) was then tested. The likely downstream factors of Numb were analyzed using luciferase reporter assays, immunoblotting, and quantitative real-time PCR.

Results: We show here that Numb was downregulated and negatively correlated with prostate cancer advancement. Functionally, Numb played an inhibitory role in xenograft prostate tumor growth and castration-resistant prostate cancer development by suppressing Notch and Hedgehog signaling. Using a Numb promoter–based lentiviral reporter system, we were able to distinguish Numb^–/low prostate cancer cells from Numb^high cells. Numb^–/low prostate cancer cells were smaller and quiescent, preferentially expressed Notch and Hedgehog downstream and stem-cell–associated genes, and associated with a greater resistance to ADT. The inhibition of the Notch and Hedgehog signaling pathways significantly increased apoptosis in Numb^–/low cells in response to ADT.

Conclusions: Numb^–/low enriches a castration-resistant prostate cancer cell subpopulation that is associated with unregulated Notch and Hedgehog signaling. Clin Cancer Res; 23(21); 6744–56. ©2017 AACR.

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Biochemical, Molecular, and Clinical Characterization of Succinate Dehydrogenase Subunit A Variants of Unknown Significance

Purpose: Patients who inherit a pathogenic loss-of-function genetic variant involving one of the four succinate dehydrogenase (SDH) subunit genes have up to an 86% chance of developing one or more cancers by the age of 50. If tumors are identified and removed early in these high-risk patients, they have a higher potential for cure. Unfortunately, many alterations identified in these genes are variants of unknown significance (VUS), confounding the identification of high-risk patients. If we could identify misclassified SDH VUS as benign or pathogenic SDH mutations, we could better select patients for cancer screening procedures and remove tumors at earlier stages.

Experimental Design: In this study, we combine data from clinical observations, a functional yeast model, and a computational model to determine the pathogenicity of 22 SDHA VUS. We gathered SDHA VUS from two primary sources: The OHSU Knight Diagnostics Laboratory and the literature. We used a yeast model to identify the functional effect of a VUS on mitochondrial function with a variety of biochemical assays. The computational model was used to visualize variants' effect on protein structure.

Results: We were able to draw conclusions on functional effects of variants using our three-prong approach to understanding VUS. We determined that 16 (73%) of the alterations are actually pathogenic, causing loss of SDH function, and six (27%) have no effect upon SDH function.

Conclusions: We thus report the reclassification of the majority of the VUS tested as pathogenic, and highlight the need for more thorough functional assessment of inherited SDH variants. Clin Cancer Res; 23(21); 6733–43. ©2017 AACR.

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The Future of Surveillance in the Context of Cancer Predisposition: Through the Murky Looking Glass

At least 10% of children with cancer harbor a disease-associated pathogenic variant in a known cancer predisposition gene. It is widely accepted that pathogenic variants affecting other genes, epigenetic factors, or abnormalities in additional gene products may contribute to the etiology of many more childhood cancers. Effective preventive measures exist for only a few cancer types associated with predisposing conditions, but the development and implementation of surveillance protocols aimed at reducing morbidity and mortality in at-risk children through the early detection of cancer has emerged as an important clinical tool. The articles in this Clinical Cancer Research series present international consensus generated recommendations for surveillance for a wide spectrum of cancer predisposition syndromes affecting children. In this article, we explore the challenges and opportunities for researchers and practitioners in the many fields affiliated with pediatric cancer, and we offer insights into what the future might hold as we continue our efforts to mitigate the impact of cancer susceptibility on children, their families and society. Clin Cancer Res; 23(21); e133–e7. ©2017 AACR.

See all articles in the online-only CCR Pediatric Oncology Series.

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Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer

Purpose: Resistance to platinum-based chemotherapy or PARP inhibition in germline BRCA1 or BRCA2 mutation carriers may occur through somatic reversion mutations or intragenic deletions that restore BRCA1 or BRCA2 function. We assessed whether BRCA1/2 reversion mutations could be identified in circulating cell-free DNA (cfDNA) of patients with ovarian or breast cancer previously treated with platinum and/or PARP inhibitors.

Experimental Design: cfDNA from 24 prospectively accrued patients with germline BRCA1 or BRCA2 mutations, including 19 patients with platinum-resistant/refractory ovarian cancer and five patients with platinum and/or PARP inhibitor pretreated metastatic breast cancer, was subjected to massively parallel sequencing targeting all exons of 141 genes and all exons and introns of BRCA1 and BRCA2. Functional studies were performed to assess the impact of the putative BRCA1/2 reversion mutations on BRCA1/2 function.

Results: Diverse and often polyclonal putative BRCA1 or BRCA2 reversion mutations were identified in cfDNA from four patients with ovarian cancer (21%) and from two patients with breast cancer (40%). BRCA2 reversion mutations were detected in cfDNA prior to PARP inhibitor treatment in a patient with breast cancer who did not respond to treatment and were enriched in plasma samples after PARP inhibitor therapy. Foci formation and immunoprecipitation assays suggest that a subset of the putative reversion mutations restored BRCA1/2 function.

Conclusions: Putative BRCA1/2 reversion mutations can be detected by cfDNA sequencing analysis in patients with ovarian and breast cancer. Our findings warrant further investigation of cfDNA sequencing to identify putative BRCA1/2 reversion mutations and to aid the selection of patients for PARP inhibition therapy. Clin Cancer Res; 23(21); 6708–20. ©2017 AACR.

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Dasatinib Reversibly Disrupts Endothelial Vascular Integrity by Increasing Non-Muscle Myosin II Contractility in a ROCK-Dependent Manner

Purpose: Dasatinib is a short-acting dual ABL/SRC family tyrosine kinase inhibitor (TKI), which is frequently used to treat chronic myeloid leukemia. Although very effective, patients taking dasatinib often display severe adverse effects, including pleural effusions and increased risk of bleeding primarily in the gastrointestinal tract. The actual causes of these side effects are currently undetermined. We hypothesize that endothelial cells (ECs) that line the inner walls of blood vessels and control the traffic to the underlying tissues might be involved.

Experimental Design: The effects of TKIs on ECs were studied by various assays, such as real-time cell impedance measurements, live-cell microscopy, wound healing, Western blot, and an in vivo model.

Results: Dasatinib uniquely causes a profound, dose-dependent disorganization of the EC monolayers. Dasatinib promoted the disassembly of cell–cell contacts, altered cell–matrix contacts, and further altered the wound healing. A key observation is that this effect is fully reversible after drug washout. In line with these in vitro observations, intraperitoneal administration of dasatinib to mice caused significant vascular leakage in the intestine. The underlying molecular mechanism of dasatinib-induced reorganization of the actin involves ROCK activation, which increases the amount of the phosphorylation of myosin light chain and consequently activates the non-muscle myosin II.

Conclusions: Our data are consistent with a scenario in which dasatinib triggers a transient increase in vascular leakage that probably contributes to adverse effects such as bleeding diathesis and pleural effusions. Clin Cancer Res; 23(21); 6697–707. ©2017 AACR.

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Burden and Profile of Somatic Mutation in Duodenal Adenomas from Patients with Familial Adenomatous- and MUTYH-associated Polyposis

Purpose: Duodenal polyposis and cancer are important causes of morbidity and mortality in familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). This study aimed to comprehensively characterize somatic genetic changes in FAP and MAP duodenal adenomas to better understand duodenal tumorigenesis in these disorders.

Experimental Design: Sixty-nine adenomas were biopsied during endoscopy in 16 FAP and 10 MAP patients with duodenal polyposis. Ten FAP and 10 MAP adenomas and matched blood DNA samples were exome sequenced, 42 further adenomas underwent targeted sequencing, and 47 were studied by array comparative genomic hybridization. Findings in FAP and MAP duodenal adenomas were compared with each other and to the reported mutational landscape in FAP and MAP colorectal adenomas.

Results: MAP duodenal adenomas had significantly more protein-changing somatic mutations (P = 0.018), truncating mutations (P = 0.006), and copy number variants (P = 0.005) than FAP duodenal adenomas, even though MAP patients had lower Spigelman stage duodenal polyposis. Fifteen genes were significantly recurrently mutated. Targeted sequencing of APC, KRAS, PTCHD2, and PLCL1 identified further mutations in each of these genes in additional duodenal adenomas. In contrast to MAP and FAP colorectal adenomas, neither exome nor targeted sequencing identified WTX mutations (P = 0.0017).

Conclusions: The mutational landscapes in FAP and MAP duodenal adenomas overlapped with, but had significant differences to those reported in colorectal adenomas. The significantly higher burden of somatic mutations in MAP than FAP duodenal adenomas despite lower Spigelman stage disease could increase cancer risk in the context of apparently less severe benign disease. Clin Cancer Res; 23(21); 6721–32. ©2017 AACR.

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The KMT1A-GATA3-STAT3 Circuit Is a Novel Self-Renewal Signaling of Human Bladder Cancer Stem Cells

Purpose: Bladder cancer is one of the most common urinary malignancies worldwide characterized by a high rate of recurrence and no targeted therapy method. Bladder cancer stem cells (BCSCs) play a crucial role in tumor initiation, metastasis, and drug resistance. However, the regulatory signaling and self-renewal mechanisms of BCSCs remain largely unknown. Here, we identified a novel signal, the KMT1A-GATA3-STAT3 circuit, which promoted the self-renewal and tumorigenicity of human BCSCs.

Experimental Design: In a discovery step, human BCSCs and bladder cancer non-stem cells (BCNSCs) isolated from primary bladder cancer samples #1 and #2, and the bladder cancer cell line EJ were analyzed by transcriptome microarray. In a validation step, 10 paired bladder cancer and normal tissues, different tumor cell lines, the public microarray datasets of human bladder cancer, and The Cancer Genome Atlas database were applied for the verification of gene expression.

Results: KMT1A was highly expressed and responsible for the increase of tri-methylating lysine 9 of histone H3 (H3K9me3) modification in BCSCs compared with either BCNSCs or normal bladder tissue. GATA3 bound to the -1710~-1530 region of STAT3 promoter and repressed its transcription. H3K9me3 modification on the -1351~-1172bp region of the GATA3 promoter mediated by KMT1A repressed the transcription of GATA3 and upregulated the expression of STAT3. In addition, the activated STAT3 triggered self-renewal of BCSCs. Furthermore, depletion of KMT1A or STAT3 abrogated the formation of BCSC tumorspheres and xenograft tumors.

Conclusions: KMT1A positively regulated the self-renewal and tumorigenicity of human BCSCs via KMT1A-GATA3-STAT3 circuit, in which KMT1A could be a promising target for bladder cancer therapy. Clin Cancer Res; 23(21); 6673–85. ©2017 AACR.

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Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models

Purpose: MET exon 14 deletion (METex14 del) mutations represent a novel class of non–small cell lung cancer (NSCLC) driver mutations. We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in METex14 del–positive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET inhibitors.

Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials.

Results: Glesatinib inhibited MET signaling, demonstrated marked regression of METex14 del-driven patient-derived xenografts, and demonstrated a durable RECIST partial response in a METex14 del mutation-positive patient enrolled on a glesatinib clinical trial. Prolonged treatment of nonclinical models with selected MET inhibitors resulted in differences in resistance kinetics and mutations within the MET activation loop (i.e., D1228N, Y1230C/H) that conferred resistance to type I MET inhibitors, but remained sensitive to glesatinib. In vivo models exhibiting METex14 del/A-loop double mutations and resistance to type I inhibitors exhibited a marked response to glesatinib. Finally, a METex14 del mutation-positive NSCLC patient who responded to crizotinib but later relapsed, demonstrated a mixed response to glesatinib including reduction in size of a MET Y1230H mutation-positive liver metastasis and concurrent loss of detection of this mutation in plasma DNA.

Conclusions: Together, these data demonstrate that glesatinib exhibits a distinct mechanism of target inhibition and can overcome resistance to type I MET inhibitors. Clin Cancer Res; 23(21); 6661–72. ©2017 AACR.

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Sarcomatoid Renal Cell Carcinoma Has a Distinct Molecular Pathogenesis, Driver Mutation Profile, and Transcriptional Landscape

Purpose: Sarcomatoid renal cell carcinoma (SRCC) ranks among the most aggressive clinicopathologic phenotypes of RCC. However, the paucity of high-quality, genome-wide molecular examinations of SRCC has hindered our understanding of this entity.

Experimental Design: We interrogated the mutational, copy number, and transcriptional characteristics of SRCC and compared these data with those of nonsarcomatoid RCC (RCC). We evaluated whole-exome sequencing, single-nucleotide polymorphism, and RNA sequencing data from patients with SRCC (n = 65) and RCC (n = 598) across different parent RCC subtypes, including clear-cell RCC, papillary RCC, and chromophobe RCC subtypes.

Results: SRCC was molecularly discrete from RCC and clustered according to its parent RCC subtype, though with upregulation of TGFβ signaling across all subtypes. The epithelioid (E-) and spindled (S-) histologic components of SRCC did not show differences in mutational load among cancer-related genes despite a higher mutational burden in S-. Notably, sarcomatoid clear-cell RCC (SccRCC) showed significantly fewer deletions at 3p21-25, a lower rate of two-hit loss for VHL and PBRM1, and more mutations in PTEN, TP53, and RELN compared with ccRCC. A two-hit loss involving VHL predicted for ccRCC and a better prognosis, whereas mutations in PTEN, TP53, or RELN predicted for SccRCC and worse prognosis.

Conclusions: SRCC segregates by parent subtype, and SccRCC has a fundamentally different early molecular pathogenesis, usually lacking the classic 3p21-25 deletion and showing distinctive mutational and transcriptional profiles. These features prompt a more precise molecular classification of RCC, with diagnostic, prognostic, and therapeutic implications. Clin Cancer Res; 23(21); 6686–96. ©2017 AACR.

See related commentary by Bergerot et al., p. 6381

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Cyclophilin A Maintains Glioma-Initiating Cell Stemness by Regulating Wnt/{beta}-Catenin Signaling

Purpose: Glioma-initiating cells (GIC) are glioma stem–like cells that contribute to glioblastoma (GBM) development, recurrence, and resistance to chemotherapy and radiotherapy. They have recently become the focus of novel treatment strategies. Cyclophilin A (CypA) is a cytosolic protein that belongs to the peptidyl–prolyl isomerase (PPIase) family and the major intracellular target of the immunosuppressive drug cyclosporin A (CsA). In this study, we investigate the functions of CypA and its mechanism of action in GICs' development.

Experimental Design: We analyzed differences in CypA expression between primary tumors and neurospheres from the GDS database, both before and after GIC differentiation. A series of experiments was conducted to investigate the role of CypA in GIC stemness, self-renewal, proliferation, radiotherapy resistance, and mechanism. We then designed glutathione S-transferase (GST) pulldown and coimmunoprecipitation assays to detect signaling activity.

Results: In this study, we demonstrated that CypA promotes GIC stemness, self-renewal, proliferation, and radiotherapy resistance. Mechanistically, we found that CypA binds β-catenin and is recruited to Wnt target gene promoters. By increasing the interaction between β-catenin and TCF4, CypA enhances transcriptional activity.

Conclusions: Our results demonstrate that CypA enhances GIC stemness, self-renewal, and radioresistance through Wnt/β-catenin signaling. Due to its promotive effects on GICs, CypA is a potential target for future glioma therapy. Clin Cancer Res; 23(21); 6640–9. ©2017 AACR.

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p53 Nongenotoxic Activation and mTORC1 Inhibition Lead to Effective Combination for Neuroblastoma Therapy

Purpose: mTORC1 inhibitors are promising agents for neuroblastoma therapy; however, they have shown limited clinical activity as monotherapy, thus rational drug combinations need to be explored to improve efficacy. Importantly, neuroblastoma maintains both an active p53 and an aberrant mTOR signaling.

Experimental Design: Using an orthotopic xenograft model and modulating p53 levels, we investigated the antitumor effects of the mTORC1 inhibitor temsirolimus in neuroblastoma expressing normal, decreased, or mutant p53, both as single agent and in combination with first- and second-generation MDM2 inhibitors to reactivate p53.

Results: Nongenotoxic p53 activation suppresses mTOR activity. Moreover, p53 reactivation via RG7388, a second-generation MDM2 inhibitor, strongly enhances the in vivo antitumor activity of temsirolimus. Single-agent temsirolimus does not elicit apoptosis, and tumors rapidly regrow after treatment suspension. In contrast, our combination therapy triggers a potent apoptotic response in wild-type p53 xenografts and efficiently blocks tumor regrowth after treatment completion. We also found that this combination uniquely led to p53-dependent suppression of survivin whose ectopic expression is sufficient to rescue the apoptosis induced by our combination.

Conclusions: Our study supports a novel highly effective strategy that combines RG7388 and temsirolimus in wild-type p53 neuroblastoma, which warrants testing in early-phase clinical trials. Clin Cancer Res; 23(21); 6629–39. ©2017 AACR.

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Infiltrating T Cells Increase IDO1 Expression in Glioblastoma and Contribute to Decreased Patient Survival

Purpose: Indoleamine 2,3 dioxygenase 1 (IDO1) mediates potent immunosuppression in multiple preclinical models of cancer. However, the basis for elevated IDO1 expression in human cancer, including the most common primary malignant brain tumor in adults, glioblastoma (GBM), is poorly understood. The major objective of this study is to address this gap in our understanding of how IDO1 expression contributes to the biology of GBM, and whether its level of expression is a determinant of GBM patient outcome.

Experimental Design: Patient-resected GBM, The Cancer Genome Atlas, human T-cell:GBM cocultures, as well as nu/nu, NOD-scid, and humanized (NSG-SGM3-BLT) mice-engrafted human GBM form the basis of our investigation.

Results: In situ hybridization for IDO1 revealed transcript expression throughout patient-resected GBM, whereas immunohistochemical IDO1 positivity was highly variable. Multivariate statistical analysis revealed that higher levels of IDO1 transcript predict a poor patient prognosis (P = 0.0076). GBM IDO1 mRNA levels positively correlated with increased gene expression for markers of cytolytic and regulatory T cells, in addition to decreased patient survival. Humanized mice intracranially engrafted human GBM revealed an IFN-associated T-cell–mediated increase of intratumoral IDO1.

Conclusions: Our data demonstrate that high intratumoral IDO1 mRNA levels correlate with a poor GBM patient prognosis. It also confirms the positive correlation between increased GBM IDO1 levels and human-infiltrating T cells. Collectively, this study suggests that future efforts aimed at increasing T-cell–mediated effects against GBM should consider combinatorial approaches that coinhibit potential T-cell–mediated IDO1 enhancement during therapy. Clin Cancer Res; 23(21); 6650–60. ©2017 AACR.

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Amiloride, An Old Diuretic Drug, Is a Potential Therapeutic Agent for Multiple Myeloma

Purpose: The search for new drugs that control the continuous relapses of multiple myeloma is still required. Here, we report for the first time the potent antimyeloma activity of amiloride, an old potassium-sparing diuretic approved for the treatment of hypertension and edema due to heart failure.

Experimental Design: Myeloma cell lines and primary samples were used to evaluate cytotoxicity of amiloride. In vivo studies were carried out in a xenograft mouse model. The mechanisms of action were investigated using RNA-Seq experiments, qRT-PCR, immunoblotting, and immunofluorescence assays.

Results: Amiloride-induced apoptosis was observed in a broad panel of multiple myeloma cell lines and in a xenograft mouse model. Moreover, amiloride also had a synergistic effect when combined with dexamethasone, melphalan, lenalidomide, and pomalidomide. RNA-Seq experiments showed that amiloride not only significantly altered the level of transcript isoforms and alternative splicing events, but also deregulated the spliceosomal machinery. In addition, disruption of the splicing machinery in immunofluorescence studies was associated with the inhibition of myeloma cell viability after amiloride exposure. Although amiloride was able to induce apoptosis in myeloma cells lacking p53 expression, activation of p53 signaling was observed in wild-type and mutated TP53 cells after amiloride exposure. On the other hand, we did not find a significant systemic toxicity in mice treated with amiloride.

Conclusions: Overall, our results demonstrate the antimyeloma activity of amiloride and provide a mechanistic rationale for its use as an alternative treatment option for relapsed multiple myeloma patients, especially those with 17p deletion or TP53 mutations that are resistant to current therapies. Clin Cancer Res; 23(21); 6602–15. ©2017 AACR.

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Preclinical Evaluation of Intravesical Cisplatin Nanoparticles for Non-Muscle-Invasive Bladder Cancer

Purpose: Prior clinical trials evaluating cisplatin for non–muscle-invasive bladder cancer (NMIBC) were stopped due to local and systemic toxicity. Currently, there is still a need for improved intravesical therapies, and nanoparticle-based CDDP may be efficacious without the toxicity of free cisplatin observed in the past.

Experimental Design: Cisplatin nanoparticles (CDDP NPs) were developed using biocompatible poly(l-aspartic acid sodium salt; PAA), both with and without low and high grafting density of methoxy-polyethylene glycol (PEG). In vitro cytotoxicity studies confirmed activity of CDDP NPs and CDDP solution against a papillary bladder cancer cell line. Local toxicity was assessed by three weekly intravesical administrations of CDDP formulations. CDDP NPs and CDDP solution were evaluated for bladder absorption in murine models 1 and 4 hours after intravesical administration. In vivo efficacy was evaluated in an immunocompetent carcinogen model of NMIBC.

Results: CDDP NPs showed decreased local toxicity, as assessed by bladder weight, compared with CDDP solution. Furthermore, >2 μg/mL of platinum was observed in mouse serum after intravesical administration of CDDP solution, whereas serum platinum was below the limit of quantification after intravesical administration of CDDP NPs. CDDP NPs provided significantly increased (P < 0.05) drug levels in murine bladders compared with CDDP solution for at least 4 hours after intravesical administration. In vivo, CDDP NPs reduced cancer cell proliferation compared with untreated controls, and was the only treatment group without evidence of invasive carcinoma.

Conclusions: Cisplatin-loaded PAA NPs have the potential to improve intravesical treatment of NMIBC while reducing local and systemic side effects. Clin Cancer Res; 23(21); 6592–601. ©2017 AACR.

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131I-labeled Anti-HER2 Camelid sdAb as a Theranostic Tool in Cancer Treatment

Purpose: Camelid single-domain antibody-fragments (sdAb) have beneficial pharmacokinetic properties, and those targeted to HER2 can be used for imaging of HER2-overexpressing cancer. Labeled with a therapeutic radionuclide, they may be used for HER2-targeted therapy. Here, we describe the generation of a ¹³¹I-labeled sdAb as a theranostic drug to treat HER2-overexpressing cancer.

Experimental Design: Anti-HER2 sdAb 2Rs15d was labeled with ¹³¹I using [¹³¹I]SGMIB and evaluated in vitro. Biodistribution was evaluated in two HER2⁺ murine xenograft models by micro-SPECT/CT imaging and at necropsy, and under challenge with trastuzumab and pertuzumab. The therapeutic potential of [¹³¹I]SGMIB-2Rs15d was investigated in two HER2⁺ tumor mouse models. A single-dose toxicity study was performed in mice using unlabeled [¹²⁷I]SGMIB-sdAb at 1.4 mg/kg. The structure of the 2Rs15d–HER2 complex was determined by X-ray crystallography.

Results: [¹³¹I]SGMIB-2Rs15d bound specifically to HER2⁺ cells (K_d = 4.74 ± 0.39 nmol/L). High and specific tumor uptake was observed in both BT474/M1 and SKOV-3 tumor xenografted mice and surpassed kidney levels by 3 hours. Extremely low uptake values were observed in other normal tissues at all time points. The crystal structure revealed that 2Rs15d recognizes HER2 Domain 1, consistent with the lack of competition with trastuzumab and pertuzumab observed in vivo. [¹³¹I]SGMIB-2Rs15d alone, or in combination with trastuzumab, extended median survival significantly. No toxicity was observed after injecting [¹²⁷I]SGMIB-2Rs15d.

Conclusions: These findings demonstrate the theranostic potential of [¹³¹I]SGMIB-2Rs15d. An initial scan using low radioactive [*I]SGMIB-2Rs15d allows patient selection and dosimetry calculations for subsequent therapeutic [¹³¹I]SGMIB-2Rs15d and could thereby impact therapy outcome on HER2⁺ breast cancer patients. Clin Cancer Res; 23(21); 6616–28. ©2017 AACR.

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Overcoming Acquired Resistance to AZD9291, A Third-Generation EGFR Inhibitor, through Modulation of MEK/ERK-Dependent Bim and Mcl-1 Degradation

Purpose: The mechanisms accounting for anticancer activity of AZD9291 (osimertinib or TAGRISSO), an approved third-generation EGFR inhibitor, in EGFR-mutant non–small cell lung cancer (NSCLC) cells and particularly for the subsequent development of acquired resistance are unclear and thus are the focus of this study.

Experimental Design: AZD9219-resistant cell lines were established by exposing sensitive cell lines to AZD9291. Protein alterations were detected with Western blotting. Apoptosis was measured with annexin V/flow cytometry. Growth-inhibitory effects of tested drugs were evaluated in vitro with cell number estimation and colony formation assay and in vivo with mouse xenograft models. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. Gene knockdown were achieved with siRNA or shRNA.

Results: AZD9291 potently induced apoptosis in EGFR-mutant NSCLC cell lines, in which ERK phosphorylation was suppressed accompanied with Bim elevation and Mcl-1 reduction likely due to enhanced Mcl-1 degradation and increased Bim stability. Blocking Bim elevation by gene knockdown or enforcing Mcl-1 expression attenuated or abolished AZD9291-induced apoptosis. Moreover, AZD9291 lost its ability to modulate Bim and Mcl-1 levels in AZD9291-resistant cell lines. The combination of a MEK inhibitor with AZD9291 restores the sensitivity of AZD9291-resistant cells including those with C797S mutation to undergo apoptosis and growth regression in vitro and in vivo.

Conclusions: Modulation of MEK/ERK-dependent Bim and Mcl-1 degradation critically mediates sensitivity and resistance of EGFR-mutant NSCLC cells to AZD9291 and hence is an effective strategy to overcome acquired resistance to AZD9291. Clin Cancer Res; 23(21); 6567–79. ©2017 AACR.

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The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer

Purpose: Activation of the PI3K pathway occurs in over 40% of bladder urothelial cancers. The aim of this study is to determine the therapeutic potential, the underlying action, and the resistance mechanisms of drugs targeting the PI3K pathway.

Experimental Design: Urothelial cancer cell lines and patient-derived xenografts (PDXs) were analyzed for alterations of the PI3K pathway and for their sensitivity to the small-molecule inhibitor pictilisib alone and in combination with cisplatin and/or gemcitabine. Potential predictive biomarkers for pictilisib were evaluated, and RNA sequencing was performed to explore drug resistance mechanisms.

Results: The bladder cancer cell line TCCSUP, which harbors a PIK3CA E545K mutation, was sensitive to pictilisib compared to cell lines with wild-type PIK3CA. Pictilisib exhibited stronger antitumor activity in bladder cancer PDX models with PI3KCA H1047R mutation or amplification than the control PDX model. Pictilisib synergized with cisplatin and/or gemcitabine in vitro, significantly delayed tumor growth, and prolonged survival compared with single-drug treatment in the PDX models. The phosphorylation of ribosomal protein S6 correlated with response to pictilisib both in vitro and in vivo, and could potentially serve as a biomarker to predict response to pictilisib. Pictilisib activated the compensatory MEK/ERK pathway that likely contributed to pictilisib resistance, which was reversed by cotreatment with the RAF inhibitor sorafenib. RNA sequencing of tumors resistant to treatment suggested that LSP1 downregulation correlated with drug resistance.

Conclusions: These preclinical results provide new insights into the therapeutic potential of targeting the PI3K pathway for the treatment of bladder cancer. Clin Cancer Res; 23(21); 6580–91. ©2017 AACR.

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Replication Stress Leading to Apoptosis within the S-phase Contributes to Synergism between Vorinostat and AZD1775 in HNSCC Harboring High-Risk TP53 Mutation

Purpose: The cure rate for patients with advanced head and neck squamous cell carcinoma (HNSCC) remains poor due to resistance to standard therapy primarily consisting of chemoradiation. As mutation of TP53 in HNSCC occurs in 60% to 80% of non–HPV-associated cases and is in turn associated with resistance to these treatments, more effective therapies are needed. In this study, we evaluated the efficacy of a regimen combining vorinostat and AZD1775 in HNSCC cells with a variety of p53 mutations.

Experimental Design: Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine the in vitro and in vivo sensitivity of high-risk mutant p53 HNSCC cell lines to vorinostat in combination with AZD1775. Cell cycle, replication stress, homologous recombination (HR), live cell imaging, RNA sequencing, and apoptosis analyses were performed to dissect molecular mechanisms.

Results: We found that vorinostat synergizes with AZD1775 in vitro to inhibit growth of HNSCC cells harboring high-risk mutp53. These drugs interact synergistically to induce DNA damage, replication stress associated with impaired Rad51-mediated HR through activation of CDK1, and inhibition of Chk1 phosphorylation, culminating in an early apoptotic cell death during the S-phase of the cell cycle. The combination of vorinostat and AZD1775 inhibits tumor growth and angiogenesis in vivo in an orthotopic mouse model of oral cancer and prolongs animal survival.

Conclusions: Vorinostat synergizes with AZD1775 in HNSCC cells with mutant p53 in vitro and in vivo. A strategy combining HDAC and WEE1 inhibition deserves further clinical investigation in patients with advanced HNSCC. Clin Cancer Res; 23(21); 6541–54. ©2017 AACR.

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Complementary Value of Contralateral Parenchymal Enhancement on DCE-MRI to Prognostic Models and Molecular Assays in High-risk ER+/HER2- Breast Cancer

Purpose: To determine whether markers of healthy breast stroma are able to select a subgroup of patients at low risk of death or metastasis from patients considered at high risk according to routine markers of the tumor.

Experimental Design: Patients with ER⁺/HER2^– breast cancer were consecutively included for retrospective analysis. The contralateral parenchyma was segmented automatically on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), where upon the average of the top-10% late enhancement was calculated. This contralateral parenchymal enhancement (CPE) was analyzed with respect to routine prognostic models and molecular assays (Nottingham Prognostic Index, Dutch clinical chemotherapy-selection guidelines, 70-gene signature, and 21-gene recurrence score). CPE was split in tertiles and tested for overall and distant disease-free survival. CPE was adjusted for patient and tumor characteristics, as well as systemic therapy, using inverse probability weighting (IPW). Subanalyses were performed in patients at high risk according to prognostic models and molecular assays.

Results: Four-hundred-and-fifteen patients were included, constituting the same group in which the association between CPE and survival was discovered. Median follow-up was 85 months, 34/415(8%) patients succumbed. After IPW-adjustment for patient and tumor characteristics, patients with high CPE had significantly better overall survival than those with low CPE in groups at high risk according to the Nottingham Prognostic Index [HR (95% CI): 0.08 (0.00–0.40), P < 0.001]; Dutch clinical guidelines [HR (95% CI): 0.22 (0.00–0.81), P = 0.021]; and 21-gene recurrence score [HR (95% CI): 0.14 (0.00–0.84), P = 0.030]. One group showed a trend [70-gene signature: HR (95% CI): 0.25 (0.00–1.02), P = 0.054].

Conclusions: In patients at high risk based on the tumor, subgroups at relatively low risk were identified using pretreatment enhancement of the stroma on breast DCE-MRI. Clin Cancer Res; 23(21); 6505–15. ©2017 AACR.

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An Integrative Scoring System for Survival Prediction Following Umbilical Cord Blood Transplantation in Acute Leukemia

Purpose: Survival of acute leukemia (AL) patients following umbilical cord blood transplantation (UCBT) is dependent on an array of individual features. Integrative models for risk assessment are lacking. We sought to develop a scoring system for prediction of overall survival (OS) and leukemia-free survival (LFS) at 2 years following UCBT in AL patients.

Experimental Design: The study cohort included 3,140 pediatric and adult AL UCBT patients from the European Society of Blood and Marrow Transplantation and Eurocord registries. Patients received single or double cord blood units. The dataset was geographically split into a derivation (n = 2,362, 65%) and validation set (n = 778, 35%). Top predictors of OS were identified using the Random Survival Forest algorithm and introduced into a Cox regression model, which served for the construction of the UCBT risk score.

Results: The score includes nine variables: disease status, diagnosis, cell dose, age, center experience, cytomegalovirus serostatus, degree of HLA mismatch, previous autograft, and anti-thymocyte globulin administration. Over the validation set an increasing score was associated with decreasing probabilities for 2 years OS and LFS, ranging from 70.21% [68.89–70.71, 95% confidence interval (CI)] and 64.76% (64.33–65.86, 95% CI) to 14.78% (10.91–17.41) and 18.11% (14.40–22.30), respectively. It stratified patients into six distinct risk groups. The score's discrimination (AUC) over multiple imputations of the validation set was 68.76 (68.19–69.04, range) and 65.78 (65.20–66.28) for 2 years OS and LFS, respectively.

Conclusions: The UCBT score is a simple tool for risk stratification of AL patients undergoing UCBT. Widespread application of the score will require further independent validation. Clin Cancer Res; 23(21); 6478–86. ©2017 AACR.

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Fracture behavior, marginal gap width, and marginal quality of vented or pre-cemented CAD/CAM all-ceramic crowns luted on Y-TZP implants

Abstract

Objectives

To investigate the fracture behavior and marginal gap region of CAD/CAM fabricated lithium disilicate (L) and zirconium dioxide (Z) crowns using palatal venting (PV), pre-cementation with custom analogs (CA), or conventional cementation technique (SP) with adhesive cement (A) or resin-modified glass ionomer cement (B).

Material and methods

Twelve groups (n = 6) were set according to material (L, Z), cement (A, B), and technique (PV, CA, SP). Specimens were thermo-mechanical aged (TML), loaded until fracture (LF) and fracture patterns recorded. Marginal gap width and quality were assessed and compared to replicas obtained before and after TML.

Results

Crown material significantly influenced LF with a mean of 1037.6 ± 282.4 N in L and 5356.3 ± 1207.0 N in Z groups (p < .001). Neither cement material nor cementation method affected the outcome. Fractures occurred along the mesial-distal central fissure in both materials. Gap width before TML was 22.04 ± 13.42 μm for L and 19.98 ± 12.72 μm for Z specimens, with overall no influence of crown material, cement type, or method. Marginal cleanliness just below the polished implant shoulder reached 66.7%–88.9% with A, and 91.7%–100% with B, and tended to increase in all groups during TML indicating a decrease in excess cement. Implant-crown junctions were cleaner with B compared to A (p ≤ .001) and along Z crown surfaces compared to L (p ≤ .007).

Conclusions

Crown venting of lithium disilicate and zirconium dioxide crowns did not affect the fracture load and patterns. Complete cement removal was rare, and the observed particle ablation requires further clinical attention, particularly with submucosal margins.

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Cross-Cancer Analysis Reveals Novel Pleiotropic Associations—Letter

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Lysyl Oxidase-like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer

The lysyl oxidase–like protein LOXL2 has been suggested to contribute to tumor progression and metastasis, but in vivo evidence has been lacking. Here we provide functional evidence that LOXL2 is a key driver of breast cancer metastasis in two conditional transgenic mouse models of PyMT-induced breast cancer. LOXL2 ablation in mammary tumor cells dramatically decreased lung metastasis, whereas LOXL2 overexpression promoted metastatic tumor growth. LOXL2 depletion or overexpression in tumor cells does not affect extracellular matrix stiffness or organization in primary and metastatic tumors, implying a function for LOXL2 independent of its conventional role in extracellular matrix remodeling. In support of this likelihood, cellular and molecular analyses revealed an association of LOXL2 action with elevated levels of the EMT regulatory transcription factor Snail1 and expression of several cytokines that promote premetastatic niche formation. Taken together, our findings established a pathophysiologic role and new function for LOXL2 in breast cancer metastasis. Cancer Res; 77(21); 5846–59. ©2017 AACR.

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The Cancer Genomics Cloud: Collaborative, Reproducible, and Democratized—A New Paradigm in Large-Scale Computational Research

The Seven Bridges Cancer Genomics Cloud (CGC; http://ift.tt/1NbKD2N) enables researchers to rapidly access and collaborate on massive public cancer genomic datasets, including The Cancer Genome Atlas. It provides secure on-demand access to data, analysis tools, and computing resources. Researchers from diverse backgrounds can easily visualize, query, and explore cancer genomic datasets visually or programmatically. Data of interest can be immediately analyzed in the cloud using more than 200 preinstalled, curated bioinformatics tools and workflows. Researchers can also extend the functionality of the platform by adding their own data and tools via an intuitive software development kit. By colocalizing these resources in the cloud, the CGC enables scalable, reproducible analyses. Researchers worldwide can use the CGC to investigate key questions in cancer genomics. Cancer Res; 77(21); e3–6. ©2017 AACR.

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Upregulation of Cystathionine-{beta}-Synthase in Colonic Epithelia Reprograms Metabolism and Promotes Carcinogenesis

The trans-sulfuration enzyme cystathionine-β-synthase (CBS) and its product hydrogen sulfide (H2S) are aberrantly upregulated in colorectal cancers, where they contribute to tumor growth and progression by both autocrine and paracrine mechanisms. However, it is unknown whether the CBS/H2S axis plays a role in colorectal carcinogenesis. Here, we report upregulation of CBS in human biopsies of precancerous adenomatous polyps and show that forced upregulation of CBS in an adenoma-like colonic epithelial cell line is sufficient to induce metabolic and gene expression profiles characteristic of colorectal cancer cells. Differentially expressed metabolites (65 increased and 20 decreased) clustered into the glycolytic pathway, nucleotide sugars, intermediates of the pentose phosphate pathway, and lipogenesis, including primarily phospholipids, sphingolipids, and bile acids. CBS upregulation induced broad changes in the NCM356 cell transcriptome with over 350 differentially expressed genes. These genes overlapped significantly with gene sets related to glycolysis, hypoxia, and a colon cancer cell phenotype, including genes regulated by NF-κB, KRAS, p53, and Wnt signaling, genes downregulated after E-cadherin knockdown, and genes related to increased extracellular matrix, cell adhesion, and epithelial-to-mesenchymal transition. The CBS-induced switch to an anabolic metabolism was associated with increased NCM356 cell bioenergetics, proliferation, invasion through Matrigel, resistance to anoikis, and CBS-dependent tumorigenesis in immunocompromised mice. Genetic ablation of CBS in CBS heterozygous mice (CBS+/−) reduced the number of mutagen-induced aberrant colonic crypt foci. Taken together, these results establish that activation of the CBS/H2S axis promotes colon carcinogenesis. Cancer Res; 77(21); 5741–54. ©2017 AACR.

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The ISB Cancer Genomics Cloud: A Flexible Cloud-Based Platform for Cancer Genomics Research

The ISB Cancer Genomics Cloud (ISB-CGC) is one of three pilot projects funded by the National Cancer Institute to explore new approaches to computing on large cancer datasets in a cloud environment. With a focus on Data as a Service, the ISB-CGC offers multiple avenues for accessing and analyzing The Cancer Genome Atlas, TARGET, and other important references such as GENCODE and COSMIC using the Google Cloud Platform. The open approach allows researchers to choose approaches best suited to the task at hand: from analyzing terabytes of data using complex workflows to developing new analysis methods in common languages such as Python, R, and SQL; to using an interactive web application to create synthetic patient cohorts and to explore the wealth of available genomic data. Links to resources and documentation can be found at www.isb-cgc.org. Cancer Res; 77(21); e7–10. ©2017 AACR.

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Gemcitabine-Induced TIMP1 Attenuates Therapy Response and Promotes Tumor Growth and Liver Metastasis in Pancreatic Cancer

Gemcitabine constitutes one of the backbones for chemotherapy treatment in pancreatic ductal adenocarcinoma (PDAC), but patients often respond poorly to this agent. Molecular markers downstream of gemcitabine treatment in preclinical models may provide an insight into resistance mechanisms. Using cytokine arrays, we identified potential secretory biomarkers of gemcitabine resistance (response) in the transgenic KRasG12D; Trp53R172H; Pdx-1 Cre (KPC) mouse model of PDAC. We verified the oncogenic role of the cytokine tissue inhibitor of matrix metalloproteinases 1 (TIMP1) in primary pancreatic tumors and metastases using both in vitro techniques and animal models. We identified potential pathways affected downstream of TIMP1 using the Illumina Human H12 array. Our findings were validated in both primary and metastatic models of pancreatic cancer. Gemcitabine increased inflammatory cytokines including TIMP1 in the KPC mouse model. TIMP1 was upregulated in patients with pancreatic intraepithelial neoplasias grade 3 and PDAC lesions relative to matched normal pancreatic tissue. In addition, TIMP1 played a role in tumor clonogenic survival and vascular density, while TIMP1 inhibition resensitized tumors to gemcitabine and radiotherapy. We observed a linear relationship between TIMP-1 expression, liver metastatic burden, and infiltration by CD11b+Gr1+ myeloid cells and CD4+CD25+FOXP3+ Tregs, whereas the presence of tumor cells was required for immune cell infiltration. Overall, our results identify TIMP1 upregulation as a resistance mechanism to gemcitabine and provide a rationale for combining chemo/radiotherapy with TIMP1 inhibitors in PDAC. Cancer Res; 77(21); 5952–62. ©2017 AACR.

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WebMeV: A Cloud Platform for Analyzing and Visualizing Cancer Genomic Data

Although large, complex genomic datasets are increasingly easy to generate, and the number of publicly available datasets in cancer and other diseases is rapidly growing, the lack of intuitive, easy-to-use analysis tools has remained a barrier to the effective use of such data. WebMeV (http://mev.tm4.org) is an open-source, web-based tool that gives users access to sophisticated tools for analysis of RNA-Seq and other data in an interface designed to democratize data access. WebMeV combines cloud-based technologies with a simple user interface to allow users to access large public datasets, such as that from The Cancer Genome Atlas or to upload their own. The interface allows users to visualize data and to apply advanced data mining analysis methods to explore the data and draw biologically meaningful conclusions. We provide an overview of WebMeV and demonstrate two simple use cases that illustrate the value of putting data analysis in the hands of those looking to explore the underlying biology of the systems being studied. Cancer Res; 77(21); e11–14. ©2017 AACR.

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Meiosis-like Functions in Oncogenesis: A New View of Cancer

Cancer cells have many abnormal characteristics enabling tumors to grow, spread, and avoid immunologic and therapeutic destruction. Central to this is the innate ability of populations of cancer cells to rapidly evolve. One feature of many cancers is that they activate genes that are normally associated with distinct developmental states, including germ cell–specific genes. This has historically led to the proposal that tumors take on embryonal characteristics, the so called embryonal theory of cancer. However, one group of germline genes, not directly associated with embryonic somatic tissue genesis, is the one that encodes the specific factors to drive the unique reductional chromosome segregation of meiosis I, which also results in chromosomal exchanges. Here, we propose that meiosis I–specific modulators of reductional segregation can contribute to oncogenic chromosome dynamics and that the embryonal theory for cancer cell growth/proliferation is overly simplistic, as meiotic factors are not a feature of most embryonic tissue development. We postulate that some meiotic chromosome-regulatory functions contribute to a soma-to-germline model for cancer, in which activation of germline (including meiosis) functions drive oncogenesis, and we extend this to propose that meiotic factors could be powerful sources of targets for therapeutics and biomonitoring in oncology. Cancer Res; 77(21); 5712–6. ©2017 AACR.

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Developing Cancer Informatics Applications and Tools Using the NCI Genomic Data Commons API

The NCI Genomic Data Commons (GDC) was launched in 2016 and makes available over 4 petabytes (PB) of cancer genomic and associated clinical data to the research community. This dataset continues to grow and currently includes over 14,500 patients. The GDC is an example of a biomedical data commons, which collocates biomedical data with storage and computing infrastructure and commonly used web services, software applications, and tools to create a secure, interoperable, and extensible resource for researchers. The GDC is (i) a data repository for downloading data that have been submitted to it, and also a system that (ii) applies a common set of bioinformatics pipelines to submitted data; (iii) reanalyzes existing data when new pipelines are developed; and (iv) allows users to build their own applications and systems that interoperate with the GDC using the GDC Application Programming Interface (API). We describe the GDC API and how it has been used both by the GDC itself and by third parties. Cancer Res; 77(21); e15–18. ©2017 AACR.

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Genetic Dissociation of Glycolysis and the TCA Cycle Affects Neither Normal nor Neoplastic Proliferation

Rapidly proliferating cells increase glycolysis at the expense of oxidative phosphorylation (oxphos) to generate sufficient levels of glycolytic intermediates for use as anabolic substrates. The pyruvate dehydrogenase complex (PDC) is a critical mitochondrial enzyme that catalyzes pyruvate's conversion to acetyl coenzyme A (AcCoA), thereby connecting these two pathways in response to complex energetic, enzymatic, and metabolic cues. Here we utilized a mouse model of hepatocyte-specific PDC inactivation to determine the need for this metabolic link during normal hepatocyte regeneration and malignant transformation. In PDC "knockout" (KO) animals, the long-term regenerative potential of hepatocytes was unimpaired, and growth of aggressive experimental hepatoblastomas was only modestly slowed in the face of 80%–90% reductions in AcCoA and significant alterations in the levels of key tricarboxylic acid (TCA) cycle intermediates and amino acids. Overall, oxphos activity in KO livers and hepatoblastoma was comparable with that of control counterparts, with evidence that metabolic substrate abnormalities were compensated for by increased mitochondrial mass. These findings demonstrate that the biochemical link between glycolysis and the TCA cycle can be completely severed without affecting normal or neoplastic proliferation, even under the most demanding circumstances. Cancer Res; 77(21); 5795–807. ©2017 AACR.

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Cistrome Cancer: A Web Resource for Integrative Gene Regulation Modeling in Cancer

Cancer results from a breakdown of normal gene expression control, so the study of gene regulation is critical to cancer research. To gain insight into the transcriptional and epigenetic factors regulating abnormal gene expression patterns in cancers, we developed the Cistrome Cancer web resource (http://ift.tt/2humGIv). We conducted the systematic integration and modeling of over 10,000 tumor molecular profiles from The Cancer Genome Atlas (TCGA) with over 23,000 ChIP-seq and chromatin accessibility profiles from our Cistrome collection. The results include reconstruction of functional enhancer profiles, "super-enhancer" target genes, as well as predictions of active transcription factors and their target genes for each TCGA cancer type. Cistrome Cancer reveals novel insights from integrative analyses combining chromatin profiles with tumor molecular profiles and will be a useful resource to the cancer gene regulation community. Cancer Res; 77(21); e19–22. ©2017 AACR.

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KDM4 Inhibition Targets Breast Cancer Stem-like Cells

Traditional treatments for breast cancer fail to address therapy-resistant cancer stem–like cells that have been characterized by changes in epigenetic regulators such as the lysine demethylase KDM4. Here, we describe an orally available, selective and potent KDM4 inhibitor (QC6352) with unique preclinical characteristics. To assess the antitumor properties of QC6352, we established a method to isolate and propagate breast cancer stem–like cells (BCSC) from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy. Limiting-dilution orthotopic xenografts of these BCSCs regenerated original patient tumor histology and gene expression. QC6352 blocked BCSC proliferation, sphere formation, and xenograft tumor formation. QC6352 also abrogated expression of EGFR, which drives the growth of therapy-resistant triple-negative breast cancer cells. Our findings validate a unique BCSC culture system for drug screening and offer preclinical proof of concept for KDM4 inhibition as a new strategy to treat triple-negative breast cancer. Cancer Res; 77(21); 5900–12. ©2017 AACR.

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A Galaxy Implementation of Next-Generation Clustered Heatmaps for Interactive Exploration of Molecular Profiling Data

Clustered heatmaps are the most frequently used graphics for visualization of molecular profiling data in biology. However, they are generally rendered as static, or only modestly interactive, images. We have now used recent advances in web technologies to produce interactive "next-generation" clustered heatmaps (NG-CHM) that enable extreme zooming and navigation without loss of resolution. NG-CHMs also provide link-outs to additional information sources and include other features that facilitate deep exploration of the biology behind the image. Here, we describe an implementation of the NG-CHM system in the Galaxy bioinformatics platform. We illustrate the algorithm and available computational tool using RNA-seq data from The Cancer Genome Atlas program's Kidney Clear Cell Carcinoma project. Cancer Res; 77(21); e23–26. ©2017 AACR.

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Transplantation of iPS-Derived Tumor Cells with a Homozygous MHC Haplotype Induces GRP94 Antibody Production in MHC-Matched Macaques

Immune surveillance is a critical component of the antitumor response in vivo, yet the specific components of the immune system involved in this regulatory response remain unclear. In this study, we demonstrate that autoantibodies can mitigate tumor growth in vitro and in vivo. We generated two cancer cell lines, embryonal carcinoma and glioblastoma cell lines, from monkey-induced pluripotent stem cells (iPSC) carrying a homozygous haplotype of major histocompatibility complex (MHC, Mafa in Macaca fascicularis). To establish a monkey cancer model, we transplanted these cells into monkeys carrying the matched Mafa haplotype in one of the chromosomes. Neither Mafa-homozygous cancer cell line grew in monkeys carrying the matched Mafa haplotype heterozygously. We detected in the plasma of these monkeys an IgG autoantibody against GRP94, a heat shock protein. Injection of the plasma prevented growth of the tumor cells in immunodeficient mice, whereas plasma IgG depleted of GRP94 IgG exhibited reduced killing activity against cancer cells in vitro. These results indicate that humoral immunity, including autoantibodies against GRP94, plays a role in cancer immune surveillance. Cancer Res; 77(21); 6001–10. ©2017 AACR.

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Integrating DNA Methylation and Hydroxymethylation Data with the Mint Pipeline

DNA methylation (5mC) plays important roles in mammalian development, oncogenesis, treatment response, and responses to the environment. DNA hydroxymethylation (5hmC) is also an informative epigenetic mark with distinct roles in regulation and cancer. Gold-standard, widely used technologies (bisulfite conversion, followed by deep sequencing) cannot distinguish between 5mC and 5hmC. Therefore, additional experiments are required to differentiate the two marks, and in silico methods are needed to analyze, integrate, and interpret these data. We developed the Methylation INTegration (mint) pipeline to support the comprehensive analysis of bisulfite conversion and immunoprecipitation-based methylation and hydroxymethylation assays, with additional steps toward integration, visualization, and interpretation. The pipeline is available as both a command line and a Galaxy graphical user interface tool. Both implementations require minimal configuration while remaining flexible to experiment specific needs. Cancer Res; 77(21); e27–30. ©2017 AACR.

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Cancer Informatics: New Tools for a Data-Driven Age in Cancer Research

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Variant Review with the Integrative Genomics Viewer

Manual review of aligned reads for confirmation and interpretation of variant calls is an important step in many variant calling pipelines for next-generation sequencing (NGS) data. Visual inspection can greatly increase the confidence in calls, reduce the risk of false positives, and help characterize complex events. The Integrative Genomics Viewer (IGV) was one of the first tools to provide NGS data visualization, and it currently provides a rich set of tools for inspection, validation, and interpretation of NGS datasets, as well as other types of genomic data. Here, we present a short overview of IGV's variant review features for both single-nucleotide variants and structural variants, with examples from both cancer and germline datasets. IGV is freely available at https://www.igv.org. Cancer Res; 77(21); e31–34. ©2017 AACR.

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Discovery of Human-Similar Gene Fusions in Canine Cancers

Canine cancers represent a tremendous natural resource due to their incidence and striking similarities to human cancers, sharing similar clinical and pathologic features as well as oncogenic events, including identical somatic mutations. Considering the importance of gene fusions as driver alterations, we explored their relevance in canine cancers. We focused on three distinct human-comparable canine cancers representing different tissues and embryonic origins. Through RNA-Seq, we discovered similar gene fusions as those found in their human counterparts: IGK-CCND3 in B-cell lymphoma, MPB-BRAF in glioma, and COL3A1-PDGFB in dermatofibrosarcoma protuberans-like. We showed not only similar partner genes but also identical breakpoints leading to oncogene overexpression. This study demonstrates similar gene fusion partners and mechanisms in human–dog corresponding tumors and allows for selection of targeted therapies in preclinical and clinical trials with pet dogs prior to human trials, within the framework of personalized medicine. Cancer Res; 77(21); 5721–7. ©2017 AACR.

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CRAVAT 4: Cancer-Related Analysis of Variants Toolkit

Cancer sequencing studies are increasingly comprehensive and well powered, returning long lists of somatic mutations that can be difficult to sort and interpret. Diligent analysis and quality control can require multiple computational tools of distinct utility and producing disparate output, creating additional challenges for the investigator. The Cancer-Related Analysis of Variants Toolkit (CRAVAT) is an evolving suite of informatics tools for mutation interpretation that includes mutation mapping and quality control, impact prediction and extensive annotation, gene- and mutation-level interpretation, including joint prioritization of all nonsilent mutation consequence types, and structural and mechanistic visualization. Results from CRAVAT submissions are explored in an interactive, user-friendly web environment with dynamic filtering and sorting designed to highlight the most informative mutations, even in the context of very large studies. CRAVAT can be run on a public web portal, in the cloud, or downloaded for local use, and is easily integrated with other methods for cancer omics analysis. Cancer Res; 77(21); e35–38. ©2017 AACR.

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YAP Suppresses Lung Squamous Cell Carcinoma Progression via Deregulation of the DNp63-GPX2 Axis and ROS Accumulation

Lung squamous cell carcinoma (SCC), accounting for approximately 30% of non–small cell lung cancer, is often refractory to therapy. Screening a small-molecule library, we identified digitoxin as a high potency compound for suppressing human lung SCC growth in vitro and in vivo. Mechanistic investigations revealed that digitoxin attenuated YAP phosphorylation and promoted YAP nuclear sequestration. YAP activation led to excessive accumulation of reactive oxygen species (ROS) by downregulating the antioxidant enzyme GPX2 in a manner related to p63 blockade. In patient-derived xenograft models, digitoxin treatment efficiently inhibited lung SCC progression in correlation with reduced expression of YAP. Collectively, our results highlight a novel tumor-suppressor function of YAP via downregulation of GPX2 and ROS accumulation, with potential implications to improve precision medicine of human lung SCC. Cancer Res; 77(21); 5769–81. ©2017 AACR.

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Molecular alterations in a new cell line (KU-Lu-MPPt3) established from a human lung adenocarcinoma with a micropapillary pattern

Abstract

Purpose

Lung adenocarcinomas with a micropapillary pattern (MPP) are characterized by more frequent and pronounced vascular invasion, higher incidence and more advanced lymph node involvement and poorer prognosis than papillary adenocarcinomas without an MPP. Here we established a new lung cancer cell line featuring micropapillary structure.

Methods

A 73-year-old never-smoker Japanese female, presenting with an abnormal chest shadow, was diagnosed with a clinical T2aN0M0 Stage IB lung adenocarcinoma and underwent left upper lobectomy with mediastinal lymph node dissection. Pathological study demonstrated a T2aN2M0 Stage IIIA micropapillary adenocarcinoma. Tumor cells were obtained from freshly resected lung material and used to establish the KU-Lu-MPPt3 cell line.

Results

The KU-Lu-MPPt3 cells featured adherent monolayers, adherent tufts, and suspended tufts without adhesion under the same culture conditions. The cells were positive for cytokeratin, epithelial cell-adhesion molecules, E-cadherin, mucin-1, thyroid transcription factor-1, vimentin, and anti-programmed death ligand 1. Xenograft tumors clearly demonstrated micropapillary structures. Sequencing and fragment analysis of the epidermal growth factor receptor in the primary tumor tissue and KU-Lu-MPPt3 cells revealed an in-frame deletion E746-A750 in exon 19.

Conclusions

This cell line represents a new model system for molecular studies of lung adenocarcinoma which may be suitable for investigation of cancer spread and also for development of molecular-targeting and immunotherapies, both in vitro and in vivo.

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Feasibility of deep brain stimulation for controlling the lower urinary tract functions: An animal study

Publication date: December 2017
Source:Clinical Neurophysiology, Volume 128, Issue 12
Author(s): Shih-Ching Chen, Pei-Yi Chu, Tsung-Hsun Hsieh, Yu-Ting Li, Chih-Wei Peng
ObjectiveTo evaluate the feasibility of deep brain stimulation (DBS) and compare the potential of four DBS targets in rats for regulating bladder activity: the periaqueductal gray (PAG), locus coeruleus (LC), rostral pontine reticular nucleus (PnO), and pedunculopontine tegmental nucleus (PPTg).MethodsA bipolar stimulating electrode was implanted. The effects of DBS on the inhibition and activation of micturition reflexes were investigated by using isovolumetric intravesical pressure recordings.ResultsPAG DBS at 2–2.5 V, PnO DBS at 2–2.5 V, and PPTg DBS at 1.75–2.5 V nearly completely inhibited reflexive isovolumetric bladder contractions. By contrast, LC DBS at 1.75 and 2 V slightly augmented reflexive isovolumetric bladder contractions in rats. DBSs on PnO and PPTg at higher intensities (2.5–5 V) demonstrated a higher success rate and larger contraction area evocation in activating bladder contractions in a partially filled bladder. DBS targeting the PPTg was most efficient in suppressing reflexive isovolumetric bladder contractions.ConclusionPPTg DBS demonstrated stable results and high potency for controlling bladder contractions. PPTg might be a promising DBS target for developing new neuromodulatory approaches for the treatment of bladder dysfunctions.SignificanceDBS could be a potential approach to manage bladder function under various conditions.



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Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer

Background: KRAS mutations occur in approximately 25% of patients with non-small cell lung cancer (NSCLC).  Despite the uniform presence of KRAS mutations, patients with KRAS-mutant NSCLC can have a heterogeneous clinical course. Since the pattern of co-occurring mutations may describe different biological subsets of patients with KRAS-mutant lung adenocarcinoma, we explored the effects of co-occurring mutations on patient outcomes and response to therapy. Methods: We identified patients with advanced KRAS-mutant NSCLC and evaluated the most common co-occurring genomic alterations. Multivariate analyses were performed incorporating the most frequent co-mutations and clinical characteristics to evaluate association with overall survival as well as response to platinum-pemetrexed chemotherapy and immune checkpoint inhibitors. Results: Among 330 patients with advanced KRAS-mutant lung cancers, the most frequent comutations were found in TP53 (42%), STK11 (29%), and KEAP1/NFE2L2 (27%). In a multivariate analysis, there was a significantly shorter survival in patients with co-mutations in KEAP1/NFE2L2 (HR 1.96, 95%CI 1.33-2.92, p=<0.001). STK11 (HR1.3, p=0.22) and TP53 (HR 1.11, p= 0.58) co-mutation status were not associated with survival. Co-mutation in KEAP1/NFE2L2 was also associated with shorter duration of initial chemotherapy (HR 1.64, 95% CI 1.04-2.59, p=0.03) and shorter overall survival from initiation of immune therapy (HR 3.54, 95% CI 1.55-8.11, p=0.003). Conclusions: Among people with KRAS-mutant advanced NSCLC, TP53, STK11, and KEAP1/NFE2L2 are the most commonly co-occurring somatic genomic alterations. Comutation of KRAS and KEAP1/ NFE2L2 is an independent prognostic factor, predicting shorter survival, duration of response to initial platinum based chemotherapy, and survival from start of immune therapy.

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Selected highlights in clinical anesthesia research

To review research highlights of manuscripts published in 2016 that pertain to all aspects of the clinical practice of anesthesiology.

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Oncocytic carcinoma of the salivary glands: A Danish national study

To present a Danish national series of oncocytic carcinoma (OC) patients, including data on treatment, recurrence and survival.

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Factors affecting the effect of physical rehabilitation therapy for synkinesis as a sequela to facial nerve palsy

To investigate factors affecting the effect of physical rehabilitation therapy for synkinesis as a sequela to facial nerve palsy.

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Central mucoepidermoid carcinoma: an up-to-date analysis of 147 cases and review of prognostic factors

To integrate the available data published on central mucoepidermoid carcinoma (CMC) into a comprehensive analysis of its clinical aspects, histology, treatment, and prognostic factors.

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The localization and risk factors of squamous cell carcinoma in the oral cavity: A study of 1501 cases

Head and neck cancer is the tenth leading cause of cancer mortality. Ninety percent of tumours in the oral cavity are squamous cell carcinomas. Information about the exact localisation of OSCC is missing in the literature. In the present study, we retrospectively analysed a total of 1501 OSCC patients, who were treated between 1975 and 2009. The purpose of this study was to examine the localisation of OSCC tumours and to analyse the influence of various parameters on tumour localisation. 71.5% of these patients were male and 28.5% were female.

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Three-dimensional changes of scleral show after surgical treatment of endocrine orbitopathy

Surgery in endocrine orbitopathy should address exophthalmos and adjunct stigmata such as increased lid aperture and scleral show. Secondary to decompression, rehabilitative surgical treatment such as blepharoplasty is routinely used to achieve this goal. Until now, however, there has been no investigation to measure the effect of decompression surgery on scleral show and lid aperture 3-dimensionally.

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Donor site morbidity after vascularized fibula free flap: gait analysis during prolonged walk conditions

The aim of this study was to determine the effect of vascularized fibula free flap (VFFF) harvest on gait variables during the six-minute walk test (6MWT). Eleven patients who had undergone VFFF harvest and 11 healthy peers participated in this case–control study. The main evaluation consisted of the collection of gait variables using the GAITRite system during three periods of the 6MWT: beginning (0–1min), middle (2:30–3:30min), and end (5–6min). The 6MWT was significantly shorter in the VFFF group than in the reference group (−31%, P<0.001).

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Psychometric Properties of Voice Activity Participation Profile—Persian Version (VAPPP)

Individuals with voice disorders may experience limits in activity and restricted participation in daily activities. The aim of this study was to investigate the psychometric properties of the Voice Activity Participation Profile—Persian Version (VAPPP), a questionnaire which specifically investigates activity limitation and participation restriction in Persian-speaking individuals with voice disorders.

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