Risk factors of pediatric tinnitus: Systematic review and meta-analysis

Objectives/Hypothesis

Medications for pediatric tinnitus are not widely used due to a lack of evidence-based information. The modification of risk factors is essential in pediatric tinnitus; however, there is a lack of systematic reviews despite several reports on risk factors. This study performed a systematic review and meta-analysis of available literature to evaluate risk factors of pediatric tinnitus.

Methods

Studies reporting the risk factors of pediatric tinnitus were systematically reviewed by searching the MEDLINE, PubMed, and Embase databases for studies published from database inception to 2016. The selected articles included clinical or epidemiological studies conducted with at least 50 subjects and at least one risk factor, including age, gender, hearing loss, noise exposure, or smoking.

Results

Eleven studies involving a total of 28,358 individuals were identified. Increased age was not a significant risk factor with a standardized median difference of 0.16 (95% confidence interval [CI]: −0.01 to 0.33). However, there was a significant correlation between increased age and tinnitus in the adolescent population. The odds ratio (OR) was 1.37 for female gender (95% CI: 1.17 to 1.60), 2.39 for hearing loss (95% CI: 1.48 to 3.87), and 11.35 for noise exposure (95% CI: 1.87 to 68.77). Two studies in adolescents showed statistical significance for smoking as a risk factor in developing tinnitus (OR: 6.05, 95% CI: 1.81 to 20.21).

Conclusions

Older-aged adolescents, as well as those who are females and those with hearing loss may have a higher risk of tinnitus. Noise exposure in the general pediatric population and smoking in adolescents may represent especially important risk factors in pediatric tinnitus. Laryngoscope, 2017

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Adult normative data for phonatory aerodynamics in connected speech

Objectives/Hypothesis

To establish normative values for phonatory aerodynamic measurements in connected speech across adult ages and gender.

Study Design

Prospective data collection across group design.

Methods

One hundred fifty adults aged >18 years without voice complaints were stratified into three equal-age groups (group 1 [ages 18–39 years]; group 2 [ages 40–59 years], and group 3 [ages 60 + years]) and two equal-gender groups (male and female) resulting in 25 participants in each category. Participants read the first four sentences of the Rainbow Passage at comfortable pitch and loudness to obtain a connected speech sample. The following dependent variables were analyzed: breath number, reading passage duration, mean phonatory airflow, inspiratory airflow duration, and expiratory airflow duration.

Results

A gender effect was found for mean phonatory airflow, with males showing significantly greater phonatory airflow than females during connected speech (P < .001). Number of breaths was significantly greater for group 3 than group 2 (P < .001) and group 1 (P < .001). Duration, and inspiratory and expiratory airflow durations were all significantly greater for group 3 (P < .001) than group 2 (P < .001) than group 1 (P < .001).

Conclusions

This study provides normative data for phonatory aerodynamics in adult connected speech. Significant age and gender effects were observed. Laryngoscope, 2017

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Thirty-five years of single surgeon experience in the reconstruction of esophagus and voice with free ileocolon flap following total pharyngolaryngectomy

Background

Several surgical options exist for the reconstruction of total pharyngolaryngectomy defect. The purpose of this report is to present our experience with ileocolon flap for simultaneous reconstruction of both esophagus and voice.

Methods

Demographic data, clinical information, and outcomes of 205 patients who underwent the ileocolon flap procedure over the last 35 years were examined. Preoperative evaluation, intraoperative details, and postoperative management were analyzed. The types of additional procedures performed to improve outcomes were explored.

Results

Of the 205 patients, 191 had a free ileocolon flap and the remaining 14 a pedicled flap. Ninety-seven percent of the flaps were successful with a fistula rate of 5.4%. Seven patients required reexploration and six flaps failed. Seventy-eight percent of the patients reported their swallowing function to be very good to excellent. Speech function was rated as good in 64% of patients and moderate in 21%. Three patients develop bowel obstruction, two of which required enterolysis. Five patients had postoperative diarrhea that responded to conservative measures.

Conclusion

Reconstruction of pharyngoesophageal defects with ileocolon flap permits resumption of swallowing and production of speech without the need for voice prosthesis and with minimal complications.

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Anorectal dysfunction after laparoscopic low anterior rectal resection for rectal cancer with and without radiotherapy (manometry study)

Background and Objectives

The aim was to evaluate the impact of radiotherapy (RT) on anorectal function of patients with low rectal cancer undergoing low anterior resection (LAR).

Methods

Prospective clinical cohort study conducted to assess the functional outcome by means of high-resolution anorectal manometry and LARS score.

Results

In total, 65 patients were enrolled in the study (27 patients underwent LAR without RT, 38 patients underwent RT and LAR). There were no statistically significant differences between study subgroups regarding demographic and clinical data; postoperative morbidity was significantly higher in irradiated patients. One year after the surgery, mean LARS score was significantly higher in patients who underwent RT and surgery. Major LARS was detected in 37.0% of irradiated patients and in 14.8% of patients after surgery alone. Anorectal manometry revealed significantly lower resting pressures in patients after RT and LAR; the squeeze pressures were similar. Rectal compliance and all volumes describing rectal sensitivity (first sensation, urge to defecate, and discomfort volume) were significantly lower in irradiated patients.

Conclusions

RT significantly deteriorates the functional outcome of patients after LAR. Manometry revealed internal sphincter dysfunction, reduced capacity, and compliance of neorectum, which seem to have a significant correlation with LARS presence/seriousness.

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Prognostic significance of the distribution of lymph node metastasis in rectal cancer after neoadjuvant chemoradiation

Background

This study aimed to evaluate the prognostic significance of lymph node distribution (LND) in rectal cancer after neoadjuvant chemoradiation.

Methods

A total of 519 patients with primary rectal cancer who underwent curative resection after neoadjuvant chemoradiation were included. LND was classified into four groups: LND0, no lymph node metastasis (368/519, 70.9%); LNDp, lymph node metastasis along the inferior mesenteric artery (proximal) (15/519, 2.9%); LNDm, lymph node metastasis at the mesorectum (109/519, 21.0%); and LNDpm, lymph node metastasis at both the proximal and mesorectal areas (27/519, 5.2%). Clinicopathologic characteristics were analyzed to identify independent prognostic factors.

Results

In patients with positive lymph nodes, LND showed superior discrimination for 3-year DFS (LNDp 67.7%, LNDm 48.9%, and LNDpm 26.8%, P = 0.003) and 3-year LRFS (LNDp 93.3%, LNDm 81.4%, and LNDpm 60.5%, P = 0.009) compared to ypN stage (3-year DFS, N1 47.8%, N2 40.0%, P = 0.184; 3-year LRFS, N1 79.4%, N2 75.2%, P = 0.527). On multivariate survival analysis, LND was an independent prognostic factor for LRFS (P = 0.030) in patients with positive lymph nodes.

Conclusions

LND may improve the prognostic value of the ypTNM staging system for patients with node-positive rectal cancer after neoadjuvant chemoradiation, particularly in terms of local recurrence.

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mGluR2/3 activation of the SIRT1 axis preserves mitochondrial function in diabetic neuropathy

Abstract

Objectives

There is a critical need to develop effective treatments for diabetic neuropathy. This study determined if a selective mGluR2/3 receptor agonist prevented or treated experimental diabetic peripheral neuropathy (DPN) through glutamate recycling and improved mitochondrial function.

Methods

Adult male streptozotocin treated Sprague-Dawley rats with features of type 1 diabetes mellitus (T1DM) or Low Capacity Running (LCR) rats with insulin resistance or glucose intolerance were treated with 3 or 10 mg/kg/day LY379268. Neuropathy end points included mechanical allodynia, nerve conduction velocities (NCV), and intraepidermal nerve fiber density (IENFD). Markers of oxidative stress, antioxidant response, glutamate recycling pathways, and mitochondrial oxidative phosphorylation (OXPHOS) associated proteins were measured in dorsal root ganglia (DRG).

Results

In diabetic rats, NCV and IENFD were decreased. Diabetic rats treated with an mGluR2/3 agonist did not develop neuropathy despite remaining diabetic. Diabetic DRG showed increased levels of oxidized proteins, decreased levels of glutathione, decreased levels of mitochondrial DNA (mtDNA) and OXPHOS proteins. In addition, there was a 20-fold increase in levels of glial fibrillary acidic protein (GFAP) and the levels of glutamine synthetase and glutamate transporter proteins were decreased. When treated with a specific mGluR2/3 agonist, levels of glutathione, GFAP and oxidized proteins were normalized and levels of superoxide dismutase 2 (SOD2), SIRT1, PGC-1α, TFAM, glutamate transporter proteins, and glutamine synthetase were increased in DRG neurons.

Interpretation

Activation of glutamate recycling pathways protects diabetic DRG and this is associated with activation of the SIRT1-PGC-1α–TFAM axis and preservation of mitochondrial OXPHOS function.

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Additive naftopidil treatment synergizes docetaxel-induced apoptosis in human prostate cancer cells

Abstract

Purpose

Docetaxel (DTX) is a standard chemotherapeutic drug for castration-resistant prostate cancer (CRPC), although adverse events are common. To overcome this problem, researchers have evaluated the efficacy of DTX treatment in combination with other drugs. Naftopidil is a tubulin-binding drug with fewer adverse events, implying the usefulness of this drug in clinical applications when combined with DTX. Here, we investigated the efficacy of additive naftopidil treatment in combination with DTX on prostate cancer (PCa) cells.

Methods

The effects of combination treatment with DTX plus naftopidil were analyzed using two animal models of LNCaP cells plus PrSC xenografts (sub-renal capsule grafting) and PC-3 xenografts (intratibial injection).

Results

Combination treatment with DTX plus naftopidil significantly inhibited cell growth in LNCaP cells compared with DTX alone. Analysis of the cooperativity index (CI) showed that combination treatment exhibited additive effects on DTX-induced growth inhibition in LNCaP cells. In contrast, combination treatment showed more than an additive (synergistic) effect on DTX-induced apoptosis in LNCaP and PC-3 cells. In LNCaP cells plus PrSC xenografts, combination treatment showed synergistic effects on DTX-induced apoptosis. The synergistic effects of naftopidil on DTX-induced apoptosis were also observed in PC-3 xenografts.

Conclusions

Our results demonstrated that additive naftopidil treatment in combination with DTX increased the efficacy of DTX for the treatment of LNCaP and PC-3 tumors in vivo. Thus, additive naftopidil treatment showed a synergistic effect on DTX-induced apoptosis in PCa cells in vitro and in vivo, suggesting that this treatment approach may yield improved clinical benefits compared with DTX alone.

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Geographic Disparity in Liver Allocation: Time to Act or Have Others Act for us

No abstract available

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International Data Base Populated by Anonymous Social Networking to Study Transplant Tourism

No abstract available

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A Metabolic Therapy for Malignant Glioma Requires a Clinical Measure

Abstract

Cancers are "reprogrammed" to use a much higher rate of glycolysis (GLY) relative to oxidative phosphorylation (OXPHOS), even in the presence of adequate amounts of oxygenation. Originally identified by Nobel Laureate Otto Warburg, this hallmark of cancer has recently been termed metabolic reprogramming and represents a way for the cancer tissue to divert carbon skeletons to produce biomass. Understanding the mechanisms that underlie this metabolic shift should lead to better strategies for cancer treatments. Malignant gliomas, cancers that are very resistant to conventional treatments, are highly glycolytic and seem particularly suited to approaches that can subvert this phenotype.

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Characteristics and outcome of Prostate cancer patients with overall biopsy Gleason score 3+4=7 and highest Gleason score 3+4=7 or > 3+4=7

Abstract

Aim

Prostate cancer heterogeneity and multifocality might result in different Gleason scores (GS) at individual biopsy cores. According to WHO/ISUP guidelines, the GS in each biopsy core should be recorded with optional reporting of overall GS for the entire case. We aimed to compare the clinicopathologic characteristics and outcome of men with overall biopsy GS 3+4=7 with highest GS 3+4=7 (HI=OV) to those with highest GS > 3+4=7 (HI>OV).

Methods and results

Prostate cancer biopsies from the European Randomized Study of Screening for Prostate Cancer (ERSPC) were revised according to WHO/ISUP 2014 guidelines (n=1031). In total 370 patients had overall GS 3+4=7, of whom 60 (16%) had at least one biopsy core with GS 4+3=7 or 4+4=8. Men with higher GS than 3+4 (HI>OV) in any of the cores had higher age, Prostate Specific Antigen (PSA) level, number of positive biopsies, percentage tumour involvement, percentage Gleason grade 4 and cribriform or intraductal growth (all P<.05) than those with GS 3+4=7 at highest (HI=OV). In multivariable Cox regression analysis including PSA, percentage positive biopsies and percentage tumour involvement, biochemical recurrence-free survival after radical prostatectomy (P=.52) or radiotherapy (P=.35) was not statistically different between both groups.

Conclusion

Among patients with overall GS 3+4=7, those with highest GS >3+4=7 had worse clinicopathologic features, but clinical outcome was not statistically significant. Therefore use of overall GS instead of highest GS for clinical decision-making is justified, potentially preventing overtreatment in prostate cancer patients.

This article is protected by copyright. All rights reserved.

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Acute and Residual Soccer Match-Related Fatigue: A Systematic Review and Meta-analysis

Abstract

Background

Understanding soccer players' match-related fatigue and recovery profiles likely helps with developing conditioning programs that increase team performance and reduce injuries and illnesses. In order to improve match recovery (the return-to-play process and ergogenic interventions) it is also pivotal to determine if match simulation protocols and actual match-play lead to similar responses.

Objectives

(1) To thoroughly describe the development of fatigue during actual soccer match play and its recovery time course in terms of physiological, neuromuscular, technical, biochemical and perceptual responses, and (2) to determine similarities of recovery responses between actual competition (11 vs. 11) and match simulations.

Methods

A first screening phase consisted of a systematic search on PubMed (MEDLINE) and SportDiscus databases until March 2016. Inclusion criteria were: longitudinal study with soccer players; match or validated protocol; duration > 45 min; and published in English.

Results

A total of 77 eligible studies (n = 1105) were used to compute 1196 effect sizes (ES). Half-time assessments revealed small to large alterations in immunological parameters (e.g. leukocytes, ES = 1.9), a moderate decrement in insulin concentration (ES = − 0.9) and a small to moderate impairment in lower-limb muscle function (ES = − 0.5 to − 0.7) and physical performance measures (e.g. linear sprint, ES = − 0.3 to − 1.0). All the systematically analyzed fatigue-related markers were substantially altered at post-match. Hamstrings force production capacity (ES = − 0.7), physical performance (2–4%, ES = 0.3−0.5), creatine kinase (CK, ES = 0.4), well-being (ES = 0.2−0.4) and delayed onset muscle soreness (DOMS, ES = 0.6–1.3) remained substantially impaired at G + 72 h. Compared to simulation protocols, 11 vs. 11 match format (CK, ES = 1.8) induced a greater magnitude of change in muscle damage (i.e. CK, ES = 1.8 vs. 0.7), inflammatory (IL-6, ES = 2.6 vs. 1.1) and immunological markers and DOMS (ES = 1.5 vs. 0.7) than simulation protocols at post-assessments. Neuromuscular performances at post-match did not differ between protocols.

Conclusion

While some parameters are fully recovered (e.g. hormonal and technical), our systematic review shows that a period of 72 h post-match play is not long enough to completely restore homeostatic balance (e.g. muscle damage, physical and well-being status). The extent of the recovery period post-soccer game cannot consist of a 'one size fits all approach'. Additionally, the 'real match' (11 vs. 11 format) likely induces greater magnitudes of perceptual (DOMS) and biochemical alterations (e.g. muscle damage), while neuromuscular alterations were essentially similar. Overall, coaches must adjust the structure and content of the training sessions during the 72-h post-match intervention to effectively manage the training load within this time-frame.

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Post-exercise Ingestion of Carbohydrate, Protein and Water: A Systematic Review and Meta-analysis for Effects on Subsequent Athletic Performance

Abstract

Background

Athletes may complete consecutive exercise sessions with limited recovery time between bouts (e.g. ≤ 4 h). Nutritional strategies that optimise post-exercise recovery in these situations are therefore important.

Objective

This two-part review investigated the effect of consuming carbohydrate (CHO) and protein with water (W) following exercise on subsequent athletic (endurance/anaerobic exercise) performance.

Data Sources

Studies were identified by searching the online databases SPORTDiscus, PubMed, Web of Science and Scopus.

Study Eligibility Criteria and Interventions

Investigations that measured endurance performance (≥ 5 min duration) ≤ 4 h after a standardised exercise bout (any type) under the following control vs. intervention conditions were included: Part 1: W vs. CHO ingested with an equal volume of W (CHO + W); and, Part 2: CHO + W vs. protein (PRO) ingested with CHO and an equal volume of W (PRO + CHO + W), where CHO or energy intake was matched.

Study Appraisal and Synthesis Methods

Publications were examined for bias using the Rosendal scale. Random-effects meta-analyses and meta-regression analyses were conducted to evaluate intervention efficacy.

Results

The quality assessment yielded a Rosendal score of 63 ± 9% (mean ± standard deviation). Part 1: 45 trials (n = 486) were reviewed. Ingesting CHO + W (102 ± 50 g CHO; 0.8 ± 0.6 g CHO kg⁻¹ h⁻¹) improved exercise performance compared with W (1.6 ± 0.7 L); %_Δ mean power output = 4.0, 95% confidence interval 3.2–4.7 (I ² = 43.9). Improvement was attenuated when participants were 'Fed' (a meal 2–4 h prior to the initial bout) as opposed to 'Fasted' (p = 0.012). Part 2: 13 trials (n = 125) were reviewed. Ingesting PRO + CHO + W (35 ± 26 g PRO; 0.5 ± 0.4 g PRO kg⁻¹) did not affect exercise performance compared with CHO + W (115 ± 61 g CHO; 0.6 ± 0.3 g CHO·kg body mass⁻¹ h⁻¹; 1.2 ± 0.6 L); %_Δ mean power output = 0.5, 95% confidence interval − 0.5 to 1.6 (I ² = 72.9).

Conclusions

Athletes with limited time for recovery between consecutive exercise sessions should prioritise CHO and fluid ingestion to enhance subsequent athletic performance.

PROSPERO Registration Number

CRD42016046807.

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Interleukin-33 promotes the inflammatory reaction in chronic rhinosinusitis with nasal polyps by NF-κB signaling pathway

OBJECTIVE: Interleukin (IL)-33 promotes T helper (Th2) immune response and may be involved in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). Using murine and human specimens, we evaluated the role of IL-33 in CRSwNP.

MATERIALS AND METHODS: To establish CRSwNP, Balb/c mice were sensitized with house dust mite, followed up by intranasal exposure to Staphylococcus aureus to stimulate the inflammatory response of nasal mucosa. The hematoxylin-eosin staining and total serum IgE were used to the successful construction of CRSwNP model. For mechanistic studies, we blocked mice with IL-33 and the Th2 cells counts in tissue were detected. Th2 cytokine expression of IL-4, IL-5, IL-13, IL-22, CCL-11, and CCL-24 in control group, CRSwNP group and IL-33 blockade group at 12 weeks after CRSwNP model establishment, were analyzed by qRT-PCR. Meanwhile, the relative mRNA and protein expression levels of NF-κB, MyD88 and TLR7 were detected after IL-33 blockade. To document the inflammatory response in patients with CRSwNP, The relative mRNA expression of IL-4, IL-5, IL-13, IL-22, CCL-11, and CCL-24 in control individuals and patients with CRSwNP (chronic rhinosinusitis with nasal polyps) were analyzed by qRT-PCR.

RESULTS: The CRSwNP model was successfully constructed. After IL-33 blocked, the relative expression of IL-33 and Th2 cells counts were reduced significantly. CRSwNP mice showed overproduction of IL-4, IL-5, IL-13, IL-22, CCL-11, and CCL-24 and IL-33 blockade inhibited the expression of IL-4, IL-5, IL-13, IL-22, CCL-11, and CCL-24. Furthermore, IL-33 blockade decreased the mRNA levels of NF-κB, MyD88 and TLR7, and also restrained the protein expression of them. On the other hand, patients' specimens with CRSwNP showed high levels of Th2 cytokines including IL-33, IL-4, IL-5, IL-13, IL-22, CCL-11, and CCL-24.

CONCLUSIONS: CRSwNP is associated with overexpression of IL-33, with subsequent activation of Th2 immune response by NF-κB signaling pathway.

L'articolo Interleukin-33 promotes the inflammatory reaction in chronic rhinosinusitis with nasal polyps by NF-κB signaling pathway sembra essere il primo su European Review.

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Restorative Strategies in Movement Disorders: the Contribution of Imaging

Abstract

Purpose of Review

The purpose of this review was to review the imaging, particularly positron emission tomography (PET), findings in neurorestoration studies in movement disorders, with specific focus on neural transplantation in Parkinson's disease (PD) and Huntington's disease (HD).

Recent Findings

PET findings in PD transplantation studies have shown that graft survival as reflected by increases in dopaminergic PET markers does not necessarily correlate with clinical improvement. PD patients with more denervated ventral striatum and more imbalanced serotonin-to-dopamine ratio in the grafted neurons tended to have worse outcome. In HD transplantation studies, variable graft survival and clinical responses may be related to host inflammatory/immune responses to the grafts.

Summary

Information gleaned from imaging findings in previous neural transplantation studies has been used to refine study protocol and patient selection in future trials. This includes identifying suitable candidates for transplantation using imaging markers, employing multiple and/or novel PET tracers to better assess graft functions and inflammatory responses to grafts.

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Improving Gene-Expression Studies from Sputum: A Multistep Optimization of RNA Isolation and qPCR Protocols

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page 626-628, November 2017.


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November Highlights/Papers by Junior Investigators/NIH News

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page v-v, November 2017.


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Unbiased Quantitation of Alveolar Type II to Alveolar Type I Cell Transdifferentiation during Repair after Lung Injury in Mice

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page 519-526, November 2017.


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Preexisting Type 2 Immune Activation Protects against the Development of Sepsis

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page 628-630, November 2017.


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Obstructive Sleep Apnea and Atherosclerosis: Both the Gut Microbiome and Hypercapnia Matter

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page 501-503, November 2017.


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Epithelial Deletion of Sulf2 Exacerbates Bleomycin-Induced Lung Injury, Inflammation, and Mortality

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page 560-569, November 2017.


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Pharmacological Inhibition of mTOR Kinase Reverses Right Ventricle Remodeling and Improves Right Ventricle Structure and Function in Rats

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page 615-625, November 2017.


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Is p38 MAPK a Dark Force in Right Ventricular Hypertrophy and Failure in Pulmonary Arterial Hypertension?

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page 506-508, November 2017.


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Hypoxia Modulates Epithelial Permeability via Regulation of Vascular Endothelial Growth Factor in Airway Epithelia

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page 527-535, November 2017.


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Hypercapnia Accelerates Adipogenesis: A Novel Role of High CO2 in Exacerbating Obesity

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page 570-580, November 2017.


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Cardiomyocytes of the Heart and Pulmonary Veins: Novel Contributors to Asthma?

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page 512-518, November 2017.


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mTOR: A Key to Both Pulmonary Vessel Remodeling and Right Ventricular Function in Pulmonary Arterial Hypertension?

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page 509-511, November 2017.


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An Emerging Role for Megalin as a Regulator of Protein Leak in Acute Lung Injury

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page 504-505, November 2017.


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p38 MAPK Inhibition Improves Heart Function in Pressure-Loaded Right Ventricular Hypertrophy

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page 603-614, November 2017.


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Critical Role of IRAK-M in Regulating Antigen-Induced Airway Inflammation

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page 547-559, November 2017.


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CO2 as a Potential Obesogen: A Gas That Will Stick to Your Ribs

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page 499-500, November 2017.


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Intermittent Hypoxia and Hypercapnia Accelerate Atherosclerosis, Partially via Trimethylamine-Oxide

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page 581-588, November 2017.


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Restoration of Megalin-Mediated Clearance of Alveolar Protein as a Novel Therapeutic Approach for Acute Lung Injury

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page 589-602, November 2017.


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Human CD8+ T Cells Damage Noninfected Epithelial Cells during Influenza Virus Infection In Vitro

American Journal of Respiratory Cell and Molecular Biology, Volume 57, Issue 5, Page 536-546, November 2017.


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Fatty-Acid Catabolism Promotes T-cell Revitalization in Melanoma [Immunology]

A hypoxic and hypoglycemic tumor microenvironment induces the metabolic reprogramming of CD8⁺ TILs.

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FDA OKs Abemaciclib for ER+, HER2- Breast Cancer [News in Brief]

The FDA has approved abemaciclib for women with advanced or metastatic ER-positive, HER2-negative breast cancer whose disease has progressed on endocrine therapy. This is the third CDK4/6 inhibitor to get the agency's go-ahead in 2.5 years.

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Targeting Angiogenesis in Bladder Cancer [News in Brief]

Findings from the phase III RANGE study indicate that adding ramucirumab to docetaxel may improve progression-free survival for patients with advanced or metastatic urothelial carcinoma whose disease is refractory to platinum chemotherapy.

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Tissue Force Programs Cell Fate and Tumor Aggression [Review]

Biomechanical and biochemical cues within a tissue collaborate across length scales to direct cell fate during development and are critical for the maintenance of tissue homeostasis. Loss of tensional homeostasis in a tissue not only accompanies malignancy but may also contribute to oncogenic transformation. High mechanical stress in solid tumors can impede drug delivery and may additionally drive tumor progression and promote metastasis. Mechanistically, biomechanical forces can drive tumor aggression by inducing a mesenchymal-like switch in transformed cells so that they attain tumor-initiating or stem-like cell properties. Given that cancer stem cells have been linked to metastasis and treatment resistance, this raises the intriguing possibility that the elevated tissue mechanics in tumors could promote their aggression by programming their phenotype toward that exhibited by a stem-like cell.

Significance: Recent findings argue that mechanical stress and elevated mechanosignaling foster malignant transformation and metastasis. Prolonged corruption of tissue tension may drive tumor aggression by altering cell fate specification. Thus, strategies that could reduce tumor mechanics might comprise effective approaches to prevent the emergence of treatment-resilient metastatic cancers. Cancer Discov; 7(11); 1224–37. ©2017 AACR.

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Nivolumab Approved for Liver Cancer [News in Brief]

The FDA granted accelerated approval to nivolumab for second-line treatment of advanced hepatocellular carcinoma, making it just the third drug on the market for the disease. The PD-1 inhibitor is approved for patients who cannot tolerate sorafenib and those whose disease progressed despite treatment with the multikinase inhibitor.

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Talimogene Laherparepvec Enhances the Efficacy of PD-1 Blockade [Melanoma]

Talimogene laherparepvec plus pembrolizumab achieved response in 62% of patients with melanoma.

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Durvalumab Promising for NSCLC [News in Brief]

The PD-L1 inhibitor durvalumab increases progression-free survival and objective response rate in patients with inoperable and locally advanced stage III non–small cell lung cancer, according to interim results of a phase III trial. The benefit was great enough that the drug could become the standard of care in the United States for these patients.

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Inhibition of p300/CBP Suppresses Castration-Resistant Prostate Cancer [Drug Discovery]

A virtual ligand screen led to generation of A-485, a potent selective p300/CBP catalytic inhibitor.

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Checkpoint Inhibitor Combo Effective for RCC [News in Brief]

In a phase III trial, the combination of nivolumab and ipilimumab yielded more and longer responses than sunitinib in patients with renal cell carcinoma at intermediate or high risk of progression. More than 41% of patients who received the immunotherapy combination responded, compared with 26.5% of patients who received sunitinib. Patients receiving the combination also experienced longer progression-free survival and fewer side effects.

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VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma [Research Articles]

Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel–Lindau (VHL) tumor suppressor. Roles for noncoding cis-regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profiles, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specific aspects of malignancy. Superenhancer profiling identified ZNF395 as a ccRCC-specific and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivo. VHL loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α–HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter–enhancer interactions. Subtype-specific driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression.

Significance: Comprehensive epigenomic profiling of ccRCC establishes a compendium of somatically altered cis-regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL, a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specific promoter–enhancer complexes. Cancer Discov; 7(11); 1284–305. ©2017 AACR.

See related commentary by Ricketts and Linehan, p. 1221.

This article is highlighted in the In This Issue feature, p. 1201

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First-Line Abemaciclib Effective in ER+ Breast Cancer [News in Brief]

Interim data from the MONARCH3 study indicate that abemaciclib is an effective first-line therapy for advanced ER-positive, HER2-negative breast cancer. Adding the investigational CDK4/6 inhibitor to letrozole significantly improved patients' progression-free survival, compared with those given a placebo alongside endocrine therapy.

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Checkpoint Inhibitors Spur Changes in Trial Design [News in Depth]

Given the success of checkpoint inhibitors and the desire to test them in combination with other immunotherapies and targeted therapies, hundreds of clinical trials have been launched. To most efficiently study these agents, researchers and the FDA are exploring the use of novel endpoints, the use of new preclinical models, and adaptive trial designs. However, the cost and demands associated with the conduct of increasingly sophisticated early-phase clinical trials are putting smaller companies and some academic medical centers at a disadvantage.

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Melanoma Drugs Effective as Adjuvants [News in Brief]

BRAF-targeted strategies and PD-1–blocking immunotherapy are more effective adjuvant therapies than currently approved options for patients with high-risk resectable melanoma. However, choosing the best agent for patients with BRAF-mutated disease remains a challenge.

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Tigecycline May Selectively Target Leukemic Stem Cells in CML [Leukemia]

Tigecycline inhibits mitochondrial oxidative phosphorylation to target leukemic stem cells (LSC).

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PPARG-Activated Bladder Cancer Cells Exhibit a PPARG Dependency [Bladder Cancer]

PPARG-selective inverse agonists can suppress proliferation in PPARG-activated bladder cancer cells.

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ASF1A Facilitates DNA Double-Strand Break Repair by NHEJ [DNA Repair]

ASF1A promotes NHEJ over homologous recombination for DNA double-strand break (DSB) repair.

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The Splicing Regulator PRMT5 Is Critical for Glioblastoma Proliferation [Brain Tumors]

PRMT5 regulates the splicing of detained introns in proliferation-associated genes in GBM.

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Targeting the Lysosome for Cancer Therapy [In the Spotlight]

Summary: Lysosomes are the recycling centers of the cell where organelles and proteins are degraded during autophagy and macropinocytosis; they also serve as signaling hubs that control the activity of mTORC1. In this issue, Rebecca and colleagues report the development of a new type of lysosomal inhibitor for cancer therapy that can inhibit multiple lysosomal activities that are needed for tumor cell survival and growth. Cancer Discov; 7(11); 1218–20. ©2017 AACR.

See related article by Rebecca et al., p. 1266.

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WNT and SHH Drive the Tumorigenesis of a Rare Embryonal Brain Tumor [Brain Tumors]

Coexpression of Wnt and Shh in Sox2⁺/Pax6⁺ apical radial glia in the VZ drives ETMR formation in vivo.

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Recurrent Tumor Cell-Intrinsic and -Extrinsic Alterations during MAPKi-Induced Melanoma Regression and Early Adaptation [Research Articles]

Treatment of advanced BRAF^V600-mutant melanoma using a BRAF inhibitor or its combination with a MEK inhibitor typically elicits partial responses. We compared the transcriptomes of patient-derived tumors regressing on MAPK inhibitor (MAPKi) therapy against MAPKi-induced temporal transcriptomic states in human melanoma cell lines or murine melanoma in immune-competent mice. Despite heterogeneous dynamics of clinical tumor regression, residual tumors displayed highly recurrent transcriptomic alterations and enriched processes, which were also observed in MAPKi-selected cell lines (implying tumor cell–intrinsic reprogramming) or in bulk mouse tumors (and the CD45-negative or CD45-positive fractions, implying tumor cell–intrinsic or stromal/immune alterations, respectively). Tumor cell–intrinsic reprogramming attenuated MAPK dependency, while enhancing mesenchymal, angiogenic, and IFN-inflammatory features and growth/survival dependence on multi-RTKs and PD-L2. In the immune compartment, PD-L2 upregulation in CD11c⁺ immunocytes drove the loss of T-cell inflammation and promoted BRAFi resistance. Thus, residual melanoma early on MAPKi therapy already displays potentially exploitable adaptive transcriptomic, epigenomic, immune-regulomic alterations.

Significance: Incomplete MAPKi-induced melanoma regression results in transcriptome/methylome-wide reprogramming and MAPK-redundant escape. Although regressing/residual melanoma is highly T cell–inflamed, stromal adaptations, many of which are tumor cell–driven, could suppress/eliminate intratumoral T cells, reversing tumor regression. This catalog of recurrent alterations helps identify adaptations such as PD-L2 operative tumor cell intrinsically and/or extrinsically early on therapy. Cancer Discov; 7(11); 1248–65. ©2017 AACR.

See related commentary by Haq, p. 1216.

This article is highlighted in the In This Issue feature, p. 1201

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Phase I trial of bortezomib daily dose: safety, pharmacokinetic profile, biological effects and early clinical evaluation in patients with advanced solid tumors

Summary

Purpose This phase I study investigated bortezomib in solid tumors used as a daily subcutaneous regimen. Previous regimens showed only modest activity in solid tumors which was potentially related to sub-optimal tumor penetration. We aimed at exploring if daily low dose administration of bortezomib may allow a greater and tolerable pharmacokinetic exposure which might be required for antitumor activity in solid tumors. Patients and methods This 3 + 3 design, dose escalation, monocentric study aimed at defining the maximum tolerated dose of daily low dose schedule of bortezomib. Tolerability, pharmacokinetics, pharmacodynamics, antitumor activity, biomarkers for proteasome inhibition, pre- and post-treatment tumor biopsies were also evaluated. Results A total of eighteen patients were dosed in 3 bortezomib cohorts (0.5, 0.6 and 0.7 mg/m2), with 3, 11 and 4 patients respectively. Three patients experienced dose-limiting toxicities: Grade (G) 3 Sweet's syndrome (at 0.6 mg/m2), G3 asthenia and anorexia or ataxia (2 patients at 0.7 mg/m2). The most common study drug-related adverse events (all grades) were thrombocytopenia (72%), fatigue (56%), neuropathy (50%), anorexia (44%) and rash (39%). Dose 0.6 mg/m2 of bortezomib was considered as the recommended phase II dose. A significant tumor shrinkage (−36% according to WHO criteria) was observed in one patient with heavily pre-treated GIST, and 2 minor responses (−20%) were recorded in two patients with melanoma and mesothelioma. Conclusion This daily subcutaneous regimen of bortezomib showed a dose dependent plasma exposure, evidence of target inhibition and preliminary signs of clinical activity. However, cumulative neurological toxicity of this dose-dense daily regimen might preclude its further clinical development.

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Wilms Tumor NCAM-Expressing Cancer Stem Cells as Potential Therapeutic Target for Polymeric Nanomedicine

Cancer stem cells (CSC) form a specific population within the tumor that has been shown to have self-renewal and differentiation properties, increased ability to migrate and form metastases, and increased resistance to chemotherapy. Consequently, even a small number of cells remaining after therapy can repopulate the tumor and cause recurrence of the disease. CSCs in Wilms tumor, a pediatric renal cancer, were previously shown to be characterized by neural cell adhesion molecule (NCAM) expression. Therefore, NCAM provides a specific biomarker through which the CSC population in this tumor can be targeted. We have recently developed an NCAM-targeted nanosized conjugate of paclitaxel bound to a biodegradable polyglutamic acid polymer. In this work, we examined the ability of the conjugate to inhibit Wilms tumor by targeting the NCAM-expressing CSCs. Results show that the conjugate selectively depleted the CSC population of the tumors and effectively inhibited tumor growth without causing toxicity. We propose that the NCAM-targeted conjugate could be an effective therapeutic for Wilms tumor. Mol Cancer Ther; 16(11); 2462–72. ©2017 AACR.

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Inhibition of Discoidin Domain Receptor 1 Reduces Collagen-mediated Tumorigenicity in Pancreatic Ductal Adenocarcinoma

The extracellular matrix (ECM), a principal component of pancreatic ductal adenocarcinoma (PDA), is rich in fibrillar collagens that facilitate tumor cell survival and chemoresistance. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that specifically binds fibrillar collagens and has been implicated in promoting cell proliferation, migration, adhesion, ECM remodeling, and response to growth factors. We found that collagen-induced activation of DDR1 stimulated protumorigenic signaling through protein tyrosine kinase 2 (PYK2) and pseudopodium-enriched atypical kinase 1 (PEAK1) in pancreatic cancer cells. Pharmacologic inhibition of DDR1 with an ATP-competitive orally available small-molecule kinase inhibitor (7rh) abrogated collagen-induced DDR1 signaling in pancreatic tumor cells and consequently reduced colony formation and migration. Furthermore, the inhibition of DDR1 with 7rh showed striking efficacy in combination with chemotherapy in orthotopic xenografts and autochthonous pancreatic tumors where it significantly reduced DDR1 activation and downstream signaling, reduced primary tumor burden, and improved chemoresponse. These data demonstrate that targeting collagen signaling in conjunction with conventional cytotoxic chemotherapy has the potential to improve outcome for pancreatic cancer patients. Mol Cancer Ther; 16(11); 2473–85. ©2017 AACR.

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Estrogen Receptor {beta} Is a Novel Target in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a devastating disease characterized by poor patient outcome and suboptimal chemotherapeutics. Here, a high-throughput screen identified diosmetin, a citrus flavonoid, with anti-AML activity. Diosmetin imparted selective toxicity against leukemia and leukemia stem cells in vitro and in vivo with no effect on normal hematopoietic stem cells. Mechanistically, we demonstrated that diosmetin targets estrogen receptor (ER) β. ERβ expression conferred cell sensitivity, as patient-derived AML cells with high levels of ERβ were sensitive, whereas cells with low ERβ were insensitive to diosmetin. Knockdown of ERβ confirmed resistance, whereas overexpression enhanced sensitivity to diosmetin, which was demonstrated to be mediated by reactive oxygen species signaling. In summary, these studies highlight targeting of ERβ with diosmetin as a potential novel therapeutic strategy for the treatment of AML. Mol Cancer Ther; 16(11); 2618–26. ©2017 AACR.

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TTK Inhibitors as a Targeted Therapy for CTNNB1 ({beta}-catenin) Mutant Cancers

The spindle assembly checkpoint kinase TTK (Mps1) is a key regulator of chromosome segregation and is the subject of novel targeted therapy approaches by small-molecule inhibitors. Although the first TTK inhibitors have entered phase I dose escalating studies in combination with taxane chemotherapy, a patient stratification strategy is still missing. With the aim to identify a genomic biomarker to predict the response of tumor cells to TTK inhibitor therapy, we profiled a set of preclinical and clinical TTK inhibitors from different chemical series on a panel of 66 genetically characterized cell lines derived from different tumors (Oncolines). Cell lines harboring activating mutations in the CTNNB1 gene, encoding the Wnt pathway signaling regulator β-catenin, were on average up to five times more sensitive to TTK inhibitors than cell lines wild-type for CTNNB1. The association of CTNNB1-mutant status and increased cancer cell line sensitivity to TTK inhibition was confirmed with isogenic cell line pairs harboring either mutant or wild-type CTNNB1. Treatment of a xenograft model of a CTNNB1-mutant cell line with the TTK inhibitor NTRC 0066-0 resulted in complete inhibition of tumor growth. Mutations in CTNNB1 occur at relatively high frequency in endometrial cancer and hepatocellular carcinoma, which are known to express high TTK levels. We propose mutant CTNNB1 as a prognostic drug response biomarker, enabling the selection of patients most likely to respond to TTK inhibitor therapy in proof-of-concept clinical trials. Mol Cancer Ther; 16(11); 2609–17. ©2017 AACR.

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Oncolytic Reactivation of KSHV as a Therapeutic Approach for Primary Effusion Lymphoma

Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Currently, treatment options for patients with PEL are limited. Oncolytic viruses have been engineered as anticancer agents and have recently shown increased therapeutic promise. Similarly, lytic activation of endogenous viruses from latently infected tumor cells can also be applied as a cancer therapy. In theory, such a therapeutic strategy would induce oncolysis by viral replication, while simultaneously stimulating an immune response to viral lytic cycle antigens. We examined the combination of the FDA-approved drug ingenol-3-angelate (PEP005) with epigenetic drugs as a rational therapeutic approach for KSHV-mediated malignancies. JQ1, a bromodomain and extra terminal (BET) protein inhibitor, in combination with PEP005, not only robustly induced KSHV lytic replication, but also inhibited IL6 production from PEL cells. Using the dosages of these agents that were found to be effective in reactivating HIV (as a means to clear latent virus with highly active antiretroviral therapy), we were able to inhibit PEL growth in vitro and delay tumor growth in a PEL xenograft tumor model. KSHV reactivation was mediated by activation of the NF-B pathway by PEP005, which led to increased occupancy of RNA polymerase II onto the KSHV genome. RNA-sequencing analysis further revealed cellular targets of PEP005, JQ1, and the synergistic effects of both. Thus, combination of PEP005 with a BET inhibitor may be considered as a rational therapeutic approach for the treatment of PEL. Mol Cancer Ther; 16(11); 2627–38. ©2017 AACR.

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EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

The EZH2 small-molecule inhibitor tazemetostat (EPZ-6438) is currently being evaluated in phase II clinical trials for the treatment of non-Hodgkin lymphoma (NHL). We have previously shown that EZH2 inhibitors display an antiproliferative effect in multiple preclinical models of NHL, and that models bearing gain-of-function mutations in EZH2 were consistently more sensitive to EZH2 inhibition than lymphomas with wild-type (WT) EZH2. Here, we demonstrate that cell lines bearing EZH2 mutations show a cytotoxic response, while cell lines with WT-EZH2 show a cytostatic response and only tumor growth inhibition without regression in a xenograft model. Previous work has demonstrated that cotreatment with tazemetostat and glucocorticoid receptor agonists lead to a synergistic antiproliferative effect in both mutant and wild-type backgrounds, which may provide clues to the mechanism of action of EZH2 inhibition in WT-EZH2 models. Multiple agents that inhibit the B-cell receptor pathway (e.g., ibrutinib) were found to have synergistic benefit when combined with tazemetostat in both mutant and WT-EZH2 backgrounds of diffuse large B-cell lymphomas (DLBCL). The relationship between B-cell activation and EZH2 inhibition is consistent with the proposed role of EZH2 in B-cell maturation. To further support this, we observe that cell lines treated with tazemetostat show an increase in the B-cell maturation regulator, PRDM1/BLIMP1, and gene signatures corresponding to more advanced stages of maturation. These findings suggest that EZH2 inhibition in both mutant and wild-type backgrounds leads to increased B-cell maturation and a greater dependence on B-cell activation signaling. Mol Cancer Ther; 16(11); 2586–97. ©2017 AACR.

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Characterization of In Vivo Resistance to Osimertinib and JNJ-61186372, an EGFR/Met Bispecific Antibody, Reveals Unique and Consensus Mechanisms of Resistance

Approximately 10% of non–small cell lung cancer (NSCLC) patients in the United States and 40% of NSCLC patients in Asia have activating epidermal growth factor receptor (EGFR) mutations and are eligible to receive targeted anti-EGFR therapy. Despite an extension of life expectancy associated with this treatment, resistance to EGFR tyrosine kinase inhibitors and anti-EGFR antibodies is almost inevitable. To identify additional signaling routes that can be cotargeted to overcome resistance, we quantified tumor-specific molecular changes that govern resistant cancer cell growth and survival. Mass spectrometry–based quantitative proteomics was used to profile in vivo signaling changes in 41 therapy-resistant tumors from four xenograft NSCLC models. We identified unique and tumor-specific tyrosine phosphorylation rewiring in tumors resistant to treatment with the irreversible third-generation EGFR-inhibitor, osimertinib, or the novel dual-targeting EGFR/Met antibody, JNJ-61186372. Tumor-specific increases in tyrosine-phosphorylated peptides from EGFR family members, Shc1 and Gab1 or Src family kinase (SFK) substrates were observed, underscoring a differential ability of tumors to uniquely escape EGFR inhibition. Although most resistant tumors within each treatment group displayed a marked inhibition of EGFR as well as SFK signaling, the combination of EGFR inhibition (osimertinib) and SFK inhibition (saracatinib or dasatinib) led to further decrease in cell growth in vitro. This result suggests that residual SFK signaling mediates therapeutic resistance and that elimination of this signal through combination therapy may delay onset of resistance. Overall, analysis of individual resistant tumors captured unique in vivo signaling rewiring that would have been masked by analysis of in vitro cell population averages. Mol Cancer Ther; 16(11); 2572–85. ©2017 AACR.

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Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers

Immunotherapy induces durable responses in a subset of patients with cancer. High tumor mutational burden (TMB) may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non–small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free survival (PFS), and overall survival (OS). Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥20 mutations/mb) versus low to intermediate TMB was 22/38 (58%) versus 23/113 (20%; P = 0.0001); median PFS, 12.8 months vs. 3.3 months (P ≤ 0.0001); median OS, not reached versus 16.3 months (P = 0.0036). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders versus nonresponders treated with anti-PD-1/PD-L1 monotherapy was 18.0 versus 5.0 mutations/mb (P < 0.0001). Interestingly, anti-CTLA4/anti-PD-1/PD-L1 combinations versus anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%; P = 0.004) and PFS (P = 0.024). Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB. Mol Cancer Ther; 16(11); 2598–608. ©2017 AACR.

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Synthetic Lethality Interaction Between Aurora Kinases and CHEK1 Inhibitors in Ovarian Cancer

Ovarian cancer is characterized by frequent mutations at TP53. These tumors also harbor germline mutations at homologous recombination repair genes, so they rely on DNA-damage checkpoint proteins, like the checkpoint kinase 1 (CHEK1) to induce G₂ arrest. In our study, by using an in silico approach, we identified a synthetic lethality interaction between CHEK1 and mitotic aurora kinase A (AURKA) inhibitors. Gene expression analyses were used for the identification of relevant biological functions. OVCAR3, OVCAR8, IGROV1, and SKOV3 were used for proliferation studies. Alisertib was tested as AURKA inhibitor and LY2603618 as CHEK1 inhibitor. Analyses of cell cycle and intracellular mediators were performed by flow cytometry and Western blot analysis. Impact on stem cell properties was evaluated by flow cytometry analysis of surface markers and sphere formation assays. Gene expression analyses followed by functional annotation identified a series of deregulated genes that belonged to cell cycle, including AURKA/B, TTK kinase, and CHEK1. AURKA and CHEK1 were amplified in 8.7% and 3.9% of ovarian cancers, respectively. AURKA and CHEK1 inhibitors showed a synergistic interaction in different cellular models. Combination of alisertib and LY2603618 triggered apoptosis, reduced the stem cell population, and increased the effect of taxanes and platinum compounds. Finally, expression of AURKA and CHEK1 was linked with detrimental outcome in patients. Our data describe a synthetic lethality interaction between CHEK1 and AURKA inhibitors with potential translation to the clinical setting. Mol Cancer Ther; 16(11); 2552–62. ©2017 AACR.

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TDP1 is Critical for the Repair of DNA Breaks Induced by Sapacitabine, a Nucleoside also Targeting ATM- and BRCA-Deficient Tumors

2'-C-cyano-2'-deoxy-1-β-d-arabino-pentofuranosylcytosine (CNDAC) is the active metabolite of the anticancer drug, sapacitabine. CNDAC is incorporated into the genome during DNA replication and subsequently undergoes β-elimination that generates single-strand breaks with abnormal 3'-ends. Because tyrosyl-DNA phosphodiesterase 1 (TDP1) selectively hydrolyzes nonphosphorylated 3'-blocking ends, we tested its role in the repair of CNDAC-induced DNA damage. We show that cells lacking TDP1 (avian TDP1^–/– DT40 cells and human TDP1 KO TSCER2 and HCT116 cells) exhibit marked hypersensitivity to CNDAC. We also identified BRCA1, FANCD2, and PCNA in the DNA repair pathways to CNDAC. Comparing CNDAC with the chemically related arabinosyl nucleoside analog, cytosine arabinoside (cytarabine, AraC) and the topoisomerase I inhibitor camptothecin (CPT), which both generate 3'-end blocking DNA lesions that are also repaired by TDP1, we found that inactivation of BRCA2 renders cells hypersensitive to CNDAC and CPT but not to AraC. By contrast, cells lacking PARP1 were only hypersensitive to CPT but not to CNDAC or AraC. Examination of TDP1 expression in the cancer cell line databases (CCLE, GDSC, NCI-60) and human cancers (TCGA) revealed a broad range of expression of TDP1, which was correlated with PARP1 expression, TDP1 gene copy number and promoter methylation. Thus, this study identifies the importance of TDP1 as a novel determinant of response to CNDAC across various cancer types (especially non–small cell lung cancers), and demonstrates the differential involvement of BRCA2, PARP1, and TDP1 in the cellular responses to CNDAC, AraC, and CPT. Mol Cancer Ther; 16(11); 2543–51. ©2017 AACR.

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Vessel-Targeted Chemophototherapy with Cationic Porphyrin-Phospholipid Liposomes

Cationic liposomes have been used for targeted drug delivery to tumor blood vessels, via mechanisms that are not fully elucidated. Doxorubicin (Dox)-loaded liposomes were prepared that incorporate a cationic lipid; 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), along with a small amount of porphyrin-phospholipid (PoP). Near-infrared (NIR) light caused release of entrapped Dox via PoP-mediated DOTAP photo-oxidation. The formulation was optimized to enable extremely rapid NIR light-triggered Dox release (i.e., in 15 seconds), while retaining reasonable serum stability. In vitro, cationic PoP liposomes readily bound to both MIA PaCa-2 human pancreatic cancer cells and human vascular endothelial cells. When administered intravenously, cationic PoP liposomes were cleared from circulation within minutes, with most accumulation in the liver and spleen. Fluorescence imaging revealed that some cationic PoP liposomes also localized at the tumor blood vessels. Compared with analogous neutral liposomes, strong tumor photoablation was induced with a single treatment of cationic PoP liposomes and laser irradiation (5 mg/kg Dox and 100 J/cm² NIR light). Unexpectedly, empty cationic PoP liposomes (lacking Dox) induced equally potent antitumor phototherapeutic effects as the drug loaded ones. A more balanced chemo- and phototherapeutic response was subsequently achieved when antitumor studies were repeated using higher drug dosing (7 mg/kg Dox) and a low fluence phototreatment (20 J/cm² NIR light). These results demonstrate the feasibility of vessel-targeted chemophototherapy using cationic PoP liposomes and also illustrate synergistic considerations. Mol Cancer Ther; 16(11); 2452–61. ©2017 AACR.

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Potency-matched Dual Cytokine-Antibody Fusion Proteins for Cancer Therapy

A novel biopharmaceutical, consisting of the F8 mAb (specific to a splice isoform of fibronectin) simultaneously fused to both TNF and IL2, was found to react with the majority of solid tumors and hematologic malignancies in mouse and man, but not with healthy adult tissues. The product selectively localized to neoplastic lesions in vivo, as evidenced by quantitative biodistribution studies using radioiodinated protein preparations. When the potency of the cytokine payloads was matched by a single-point mutation, the resulting fusion protein (IL2-F8-TNF^mut) eradicated soft-tissue sarcomas in immunocompetent mice, which did not respond to individual antibody–cytokine fusion proteins or by standard doxorubicin treatment. Durable complete responses were also observed in mice bearing CT26, C1498, and F9 tumors. The simultaneous delivery of multiple proinflammatory payloads to the cancer site conferred protective immunity against subsequent tumor challenges. A fully human homolog of IL2-F8-TNF^mut, which retained selectivity similar to its murine counterpart when tested on human material, may open new clinical applications for the immunotherapy of cancer. Mol Cancer Ther; 16(11); 2442–51. ©2017 AACR.

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T790M-Selective EGFR-TKI Combined with Dasatinib as an Optimal Strategy for Overcoming EGFR-TKI Resistance in T790M-Positive Non-Small Cell Lung Cancer

T790M mutation–selective EGFR tyrosine kinase inhibitors (EGFR-TKI) have demonstrated clinical benefits in non–small cell lung cancer (NSCLC) patients harboring T790M mutation, which is the major cause of resistance to EGFR-TKI. However, their efficacy is limited, possibly due to the emergence of apoptosis resistance in T790M-positive NSCLC. We previously identified Src family kinases as cooncogenic drivers along with T790M and found that the Src inhibitor dasatinib combined with an irreversible or a preclinical T790M-selective EGFR-TKI enhanced antitumor activity in T790M-positive cells. In the current study, we evaluated the efficacy of dasatinib combined with the clinically relevant T790M-selective EGFR-TKI ASP8273 or osimertinib in EGFR mutation–positive NSCLC with or without T790M mutation. A cell viability assay revealed that dasatinib had synergistic effects with these TKIs in T790M-positive cells and simultaneously inhibited Src, Akt, and Erk, which remained activated upon single-agent treatment. Dasatinib also increased the rate of apoptosis in T790M-positive cells induced by T790M-selective EGFR-TKIs, as determined by the Annexin-V binding assay; this was associated with downregulation of the antiapoptotic Bcl-2 family member Bcl-xL, a finding that was confirmed in mice bearing T790M-positive xenografts. Our results suggest that Bcl-xL plays a key role in the apoptosis resistance of T790M-positive NSCLC, and that dasatinib combined with clinically relevant T790M-selective EGFR-TKIs is potentially effective in overcoming resistance to first-generation EGFR-TKIs in NSCLC patients with acquired T790M. Mol Cancer Ther; 16(11); 2563–71. ©2017 AACR.

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The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors

Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation, and metastasis, which can offset the effects of chemotherapy, radiation, and antiangiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and protumoral Tie2-expressing macrophages in mouse models of metastatic cancer. Rebastinib reduces tumor growth and metastasis in an orthotopic mouse model of metastatic mammary carcinoma through reduction of Tie2⁺ myeloid cell infiltration, antiangiogenic effects, and blockade of tumor cell intravasation mediated by perivascular Tie2^Hi/Vegf-A^Hi macrophages in the tumor microenvironment of metastasis (TMEM). The antitumor effects of rebastinib enhance the efficacy of microtubule inhibiting chemotherapeutic agents, either eribulin or paclitaxel, by reducing tumor volume, metastasis, and improving overall survival. Rebastinib inhibition of angiopoietin/Tie2 signaling impairs multiple pathways in tumor progression mediated by protumoral Tie2⁺ macrophages, including TMEM-dependent dissemination and angiopoietin/Tie2-dependent angiogenesis. Rebastinib is a promising therapy for achieving Tie2 inhibition in cancer patients. Mol Cancer Ther; 16(11); 2486–501. ©2017 AACR.

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Autophagy Inhibition Improves Sunitinib Efficacy in Pancreatic Neuroendocrine Tumors via a Lysosome-dependent Mechanism

Increasing the efficacy of approved systemic treatments in metastasized pancreatic neuroendocrine tumors (PanNET) is an unmet medical need. The antiangiogenic tyrosine kinase inhibitor sunitinib is approved for PanNET treatment. In addition, sunitinib is a lysosomotropic drug and such drugs can induce lysosomal membrane permeabilization as well as autophagy. We investigated sunitinib-induced autophagy as a possible mechanism of PanNET therapy resistance. Sunitinib accumulated in lysosomes and induced autophagy in PanNET cell lines. Adding the autophagy inhibitor chloroquine reduced cell viability in cell lines and in primary cells isolated from PanNET patients. The same treatment combination reduced tumor burden in the Rip1Tag2 transgenic PanNET mouse model. The combination of sunitinib and chloroquine reduced recovery and induced apoptosis in vitro, whereas single treatments did not. Knockdown of key autophagy proteins in combination with sunitinib showed similar effect as chloroquine. Sunitinib also induced lysosomal membrane permeabilization, which further increased in the presence of chloroquine or knockdown of lysosome-associated membrane protein (LAMP2). Both combinations led to cell death. Our data indicate that chloroquine increases sunitinib efficacy in PanNET treatment via autophagy inhibition and lysosomal membrane permeabilization. We suggest that adding chloroquine to sunitinib treatment will increase efficacy of PanNET treatment and that such patients should be included in respective ongoing clinical trials. Mol Cancer Ther; 16(11); 2502–15. ©2017 AACR.

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Sphingosine-1-Phosphate Receptor-1 Promotes Environment-Mediated and Acquired Chemoresistance

Drug resistance is a major barrier for the development of effective and durable cancer therapies. Overcoming this challenge requires further defining the cellular and molecular mechanisms underlying drug resistance, both acquired and environment-mediated drug resistance (EMDR). Here, using neuroblastoma (NB), a childhood cancer with high incidence of recurrence due to resistance to chemotherapy, as a model we show that human bone marrow–mesenchymal stromal cells induce tumor expression of sphingosine-1-phosphate receptor-1 (S1PR1), leading to their resistance to chemotherapy. Targeting S1PR1 by shRNA markedly enhances etoposide-induced apoptosis in NB cells and abrogates EMDR, while overexpression of S1PR1 significantly protects NB cells from multidrug-induced apoptosis via activating JAK–STAT3 signaling. Elevated S1PR1 expression and STAT3 activation are also observed in human NB cells with acquired resistance to etoposide. We show in vitro and in human NB xenograft models that treatment with FTY720, an FDA-approved drug and antagonist of S1PR1, dramatically sensitizes drug-resistant cells to etoposide. In summary, we identify S1PR1 as a critical target for reducing both EMDR and acquired chemoresistance in NB. Mol Cancer Ther; 16(11); 2516–27. ©2017 AACR.

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PPAR{gamma} Ligand-induced Annexin A1 Expression Determines Chemotherapy Response via Deubiquitination of Death Domain Kinase RIP in Triple-negative Breast Cancers

Metastatic breast cancer is still incurable so far; new specifically targeted and more effective therapies for triple-negative breast cancer (TNBC) are required in the clinic. In this study, our clinical data have established that basal and claudin-low subtypes of breast cancer (TNBC types) express significantly higher levels of Annexin A1 (ANXA1) with poor survival outcomes. Using human cancer cell lines that model the TNBC subtype, we observed a strong positive correlation between expression of ANXA1 and PPAR. A similar correlation between these two markers was also established in our clinical breast cancer patients' specimens. To establish a link between these two markers in TNBC, we show de novo expression of ANXA1 is induced by activation of PPAR both in vitro and in vivo and it has a predictive value in determining chemosensitivity to PPAR ligands. Mechanistically, we show for the first time PPAR-induced ANXA1 protein directly interacts with receptor interacting protein-1 (RIP1), promoting its deubiquitination and thereby activating the caspase-8–dependent death pathway. We further identified this underlying mechanism also involved a PPAR-induced ANXA1-dependent autoubiquitination of cIAP1, the direct E3 ligase of RIP1, shifting cIAP1 toward proteosomal degradation. Collectively, our study provides first insight for the suitability of using drug-induced expression of ANXA1 as a new player in RIP1-induced death machinery in TNBCs, presenting itself both as an inclusion criterion for patient selection and surrogate marker for drug response in future PPAR chemotherapy trials. Mol Cancer Ther; 16(11); 2528–42. ©2017 AACR.

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Targeting Phosphatidylinositol 3-Kinase Signaling Pathway for Therapeutic Enhancement of Vascular-Targeted Photodynamic Therapy

Vascular-targeted photodynamic therapy (PDT) selectively disrupts vascular function by inducing oxidative damages to the vasculature, particularly endothelial cells. Although effective tumor eradication and excellent safety profile are well demonstrated in both preclinical and clinical studies, incomplete vascular shutdown and angiogenesis are known to cause tumor recurrence after vascular-targeted PDT. We have explored therapeutic enhancement of vascular-targeted PDT with PI3K signaling pathway inhibitors because the activation of PI3K pathway was involved in promoting endothelial cell survival and proliferation after PDT. Here, three clinically relevant small-molecule inhibitors (BYL719, BKM120, and BEZ235) of the PI3K pathway were evaluated in combination with verteporfin-PDT. Although all three inhibitors were able to synergistically enhance PDT response in endothelial cells, PDT combined with dual PI3K/mTOR inhibitor BEZ235 exhibited the strongest synergism, followed in order by combinations with pan-PI3K inhibitor BKM120 and p110α isoform-selective inhibitor BYL719. Combination treatments of PDT and BEZ235 exhibited a cooperative inhibition of antiapoptotic Bcl-2 family protein Mcl-1 and induced more cell apoptosis than each treatment alone. In addition to increasing treatment lethality, BEZ235 combined with PDT effectively inhibited PI3K pathway activation and consequent endothelial cell proliferation after PDT alone, leading to a sustained growth inhibition. In the PC-3 prostate tumor model, combination treatments improved treatment outcomes by turning a temporary tumor regrowth delay induced by PDT alone to a more long-lasting treatment response. Our study strongly supports the combination of vascular-targeted PDT and PI3K pathway inhibitors, particularly mTOR inhibitors, for therapeutic enhancement. Mol Cancer Ther; 16(11); 2422–31. ©2017 AACR.

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mTOR Kinase Inhibition Effectively Decreases Progression of a Subset of Neuroendocrine Tumors that Progress on Rapalog Therapy and Delays Cardiac Impairment

Inhibition of mTOR signaling using the rapalog everolimus is an FDA-approved targeted therapy for patients with lung and gastroenteropancreatic neuroendocrine tumors (NET). However, patients eventually progress on treatment, highlighting the need for additional therapies. We focused on pancreatic NETs (pNET) and reasoned that treatment of these tumors upon progression on rapalog therapy, with an mTOR kinase inhibitor (mTORKi), such as CC-223, could overcome a number of resistance mechanisms in tumors and delay cardiac carcinoid disease. We performed preclinical studies using human pNET cells in vitro and injected them subcutaneously or orthotopically to determine tumor progression and cardiac function in mice treated with either rapamycin alone or switched to CC-223 upon progression. Detailed signaling and RNA sequencing analyses were performed on tumors that were sensitive or progressed on mTOR treatment. Approximately 57% of mice bearing pNET tumors that progressed on rapalog therapy showed a significant decrease in tumor volume upon a switch to CC-223. Moreover, mice treated with an mTORKi exhibited decreased cardiac dilation and thickening of heart valves than those treated with placebo or rapamycin alone. In conclusion, in the majority of pNETs that progress on rapalogs, it is possible to reduce disease progression using an mTORKi, such as CC-223. Moreover, CC-223 had an additional transient cardiac benefit on valvular fibrosis compared with placebo- or rapalog-treated mice. These results provide the preclinical rationale to further develop mTORKi clinically upon progression on rapalog therapy and to further test their long-term cardioprotective benefit in those NET patients prone to carcinoid syndrome. Mol Cancer Ther; 16(11); 2432–41. ©2017 AACR.

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Combination Therapy with c-Met and Src Inhibitors Induces Caspase-Dependent Apoptosis of Merlin-Deficient Schwann Cells and Suppresses Growth of Schwannoma Cells

Neurofibromatosis type 2 (NF2) is a nervous system tumor disorder caused by inactivation of the merlin tumor suppressor encoded by the NF2 gene. Bilateral vestibular schwannomas are a diagnostic hallmark of NF2. Mainstream treatment options for NF2-associated tumors have been limited to surgery and radiotherapy; however, off-label uses of targeted molecular therapies are becoming increasingly common. Here, we investigated drugs targeting two kinases activated in NF2-associated schwannomas, c-Met and Src. We demonstrated that merlin-deficient mouse Schwann cells (MD-MSC) treated with the c-Met inhibitor, cabozantinib, or the Src kinase inhibitors, dasatinib and saracatinib, underwent a G₁ cell-cycle arrest. However, when MD-MSCs were treated with a combination of cabozantinib and saracatinib, they exhibited caspase-dependent apoptosis. The combination therapy also significantly reduced growth of MD-MSCs in an orthotopic allograft mouse model by greater than 80% of vehicle. Moreover, human vestibular schwannoma cells with NF2 mutations had a 40% decrease in cell viability when treated with cabozantinib and saracatinib together compared with the vehicle control. This study demonstrates that simultaneous inhibition of c-Met and Src signaling in MD-MSCs triggers apoptosis and reveals vulnerable pathways that could be exploited to develop NF2 therapies. Mol Cancer Ther; 16(11); 2387–98. ©2017 AACR.

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Personality biomarkers of pathological gambling: A machine learning study

Publication date: 15 January 2018
Source:Journal of Neuroscience Methods, Volume 294
Author(s): Antonio Cerasa, Danilo Lofaro, Paolo Cavedini, Iolanda Martino, Antonella Bruni, Alessia Sarica, Domenico Mauro, Giuseppe Merante, Ilaria Rossomanno, Maria Rizzuto, Antonio Palmacci, Benedetta Aquino, Pasquale De Fazio, Giampaolo R. Perna, Elena Vanni, Giuseppe Olivadese, Domenico Conforti, Gennarina Arabia, Aldo Quattrone
BackgroundThe application of artificial intelligence to extract predictors of Gambling disorder (GD) is a new field of study. A plethora of studies have suggested that maladaptive personality dispositions may serve as risk factors for GD.New methodHere, we used Classification and Regression Trees algorithm to identify multivariate predictive patterns of personality profiles that could identify GD patients from healthy controls at an individual level.Forty psychiatric patients, recruited from specialized gambling clinics, without any additional comorbidity and 160 matched healthy controls completed the Five-Factor model of personality as measured by the NEO-PI-R, which were used to build the classification model.ResultsClassification algorithm was able to discriminate individuals with GD from controls with an AUC of 77.3% (95% CI 0.65–0.88, p<0.0001). A multidimensional construct of traits including sub-facets of openness, neuroticism and conscientiousness was employed by algorithm for classification detection.Comparison with existing method(s)To the best of our knowledge, this is the first study that combines behavioral data with machine learning approach useful to extract multidimensional features characterizing GD realm.ConclusionOur study provides a proof-of-concept demonstrating the potential of the proposed approach for GD diagnosis. The multivariate combination of personality facets characterizing individuals with GD can potentially be used to assess subjects' vulnerability in clinical setting.



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Shear Wave Elastography in Thyroid Nodules with Indeterminate Cytology: Results of a Prospective Bicentric Study

Thyroid Nov 2017, Vol. 27, No. 11: 1441-1449.


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Low Malignancy Rates in Fine-Needle Aspiration Cytologies in a Primary Care Setting in Germany

Thyroid Nov 2017, Vol. 27, No. 11: 1385-1392.


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The 2017 Bethesda System for Reporting Thyroid Cytopathology

Thyroid Nov 2017, Vol. 27, No. 11: 1341-1346.


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Future Meetings

Thyroid Nov 2017, Vol. 27, No. 11: 1461-1461.


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Contribution of 3D printing to mandibular reconstruction after cancer

Publication date: Available online 1 November 2017
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): A. Dupret-Bories, S. Vergez, T. Meresse, F. Brouillet, G. Bertrand
Three-dimensional (3D) printing is booming in the medical field. This technology increases the possibilities of personalized treatment for patients, while lowering manufacturing costs. To facilitate mandibular reconstruction with fibula free flap, some companies propose cutting guides obtained by CT-guided moulding. However, these guides are prohibitively expensive (€2,000 to €6,000). Based on a partnership with the CNRS, engineering students and a biomedical company, the authors have developed cutting guides and 3D-printed mandible templates, deliverable in 7days and at a lower cost. The novelty of this project is the speed of product development at a significantly lower price. In this technical note, the authors describe the logistic chain of production of mandible templates and cutting guides, as well as the results obtained. The goal is to allow access to this technology to all patients in the near future.



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Prognostic factors for parotid metastasis of cutaneous squamous cell carcinoma of the head and neck

Publication date: Available online 1 November 2017
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): C. Bobin, P. Ingrand, B. Dréno, E. Rio, O. Malard, F. Espitalier
BackgroundCutaneous squamous cell carcinoma (CSCC) develops on the head in 80% of cases. Parotid metastasis (PM) is rare, but treatment, which associates surgery and radiation therapy, is heavy and prognosis poor.Material and methodsAll cases of parotidectomy for PM of CSCC of the head and neck between 2005 and 2015 were studied retrospectively. Epidemiologic, oncologic and therapeutic data were analyzed. Overall and specific survival were calculated following Kaplan-Meier. Log-rank and Cox models were used to identify prognostic factors for PM.ObjectivesThe principal study objective was to identify factors for survival in PM from CSCC of the head and neck.ResultsThirty-five patients were included. Mean time to onset of PM was 13months. Overall 1-, 2- and 5-year survival was respectively 70, 66 and 59%. Independent prognostic factors comprised immunodepression, age at treatment, positive CSCC margins, macroscopic facial nerve involvement, and metastatic cervical adenopathies.ConclusionThe study confirmed an association of several independent prognostic factors at the stage of parotid lymph-node metastasis, related to patient, primary CSCC and PM. Complete primary resection is essential to reduce the risk of PM. Intensified radiologic and clinical surveillance should enable early diagnosis.



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In This Issue

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Issue Information

Cover of this issue. Cenp-r contribution to proliferation of skin papilloma. See also Okumura et al. (pp. 2142-2148 of this issue).

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A chinese case of prevotella intermedia and streptococcus constellatus intracranial mixed infection

Abstract

Streptococcal Species is increasingly recognized as a potentially preventable emerging infection in human's brain with high prevalence around the world. Streptococcus constellatus is one of the most common pathogens. Meanwhile, anaerobic bacteria are the rare causes for intracranial infection. To date, intracranial mixed infection caused by Prevotella intermedia and Streptococcus constellatus has not been reported. We reported a Chinese case to raise the global awareness of severity of the intracranial mixed infection. Here, we illustrated the epidemiological risk factors, clinical manifestations and outcomes of the patient. For patients who suffer from exacerbated brain infection with fetid cerebrospinal fluid, early repeated imaging is urgently needed and empiric antibiotic therapy should consider anaerobic and aerobic bacteria in these situations.

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Activating Transcription Factor-6α Deletion Modulates the Endoplasmic Reticulum Stress Response after Spinal Cord Injury but Does Not Affect Locomotor Recovery

Journal of Neurotrauma , Vol. 0, No. 0.


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Plasminogen Activator Inhibitor Type 1: A Possible Novel Biomarker of Late Pituitary Dysfunction after Mild Traumatic Brain Injury

Journal of Neurotrauma , Vol. 0, No. 0.


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Traumatic Brain Injury in hTau Model Mice: Enhanced Acute Macrophage Response and Altered Long-Term Recovery

Journal of Neurotrauma , Vol. 0, No. 0.


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Activating Transcription Factor-6α Deletion Modulates the Endoplasmic Reticulum Stress Response after Spinal Cord Injury but Does Not Affect Locomotor Recovery

Journal of Neurotrauma , Vol. 0, No. 0.


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Plasminogen Activator Inhibitor Type 1: A Possible Novel Biomarker of Late Pituitary Dysfunction after Mild Traumatic Brain Injury

Journal of Neurotrauma , Vol. 0, No. 0.


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Traumatic Brain Injury in hTau Model Mice: Enhanced Acute Macrophage Response and Altered Long-Term Recovery

Journal of Neurotrauma , Vol. 0, No. 0.


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Effect of dietary palmitic and stearic acids on sucrose motivation and hypothalamic and striatal cell signals in the rat

e have reported that motivation for sucrose is increased in rats fed a moderate (31%) mixed-fat diet for 4-6 weeks. In this study, rats were fed diets containing 32% stearic (STEAR) or palmitic (PALM) acid, and behavior, metabolic profile, and cell signals were compared with those of rats fed a matched low fat (11% fat [LF]) diet. Rats fed STEAR or PALM increased sucrose motivation relative to LF rats (one-way ANOVA for lever presses, p=.03). Diet did not change fasting glucose, insulin, total cholesterol, triglycerides, intravenous glucose tolerance test glucose profile, percent body fat, or total kcal, although kcal as fat were increased (ANOVA p<0.05). Cell signals were assessed in rats ranked from high to low sucrose motivation. Diet did not alter Thr- and Ser-phosphorylation of Akt in the medial hypothalamus (HYP) and striatum (STR). However, Ser-phosphorylation of GSK3B was decreased in HYP and STR from both High- and Low-Performer tertiles of STEAR and PALM rats (ANOVA within each brain region, p<0.05). Two Histone 3 (H3) modifications were also assessed. Whereas there was no effect of diet on the transcription-repressive H3 modification, H3K27me3, the transcription-permissive H3 modification, H3K4me3, was significantly decreased in the HYP of High-Performers fed PALM or STEAR (ANOVA p=.013). There was no effect of diet on H3K4me3 levels in HYP of Low-Performers, or in STR. Our findings suggest signal-specific and brain region-specific effects of PALM or STEAR diets, and may link downstream signaling effects of GSK3B activity and H3 modifications with enhanced motivational behavior.

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Editorial Team Changes in the New Year

None

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Chronic Maternal Hypercortisolemia in Late Gestation Alters Fetal Cardiac Function at Birth

Studies in our laboratory have shown that modest chronic increases in maternal cortisol concentrations over the last 0.20 of gestation impair maternal glucose metabolism and increase the incidence of perinatal stillbirth. Previous studies had found an increase in maternal cortisol concentrations from 115 to 130d gestation in sheep increased both proliferation in fetal cardiomyocytes and apoptosis in the fetal cardiac Purkinje Fibers. We hypothesized that the adverse effects of excess cortisol may result in defects in cardiac conduction during labor and delivery. In the current study, we infused cortisol (1 mg·kg^-1·day^-1) into late gestation pregnant ewes and continuously monitored fetal aortic pressure and ECG through labor and delivery. We found that although the fetuses of cortisol infused ewes had normal late gestation patterns of arterial pressure and heart rate, there was a significant decrease in fetal aortic pressure and heart rate on the day of birth, specifically in the final hour before delivery. Significant changes in the fetal ECG were also apparent on the day of birth, including prolongation of the P wave and PR interval. We speculate that chronic exposure to glucocorticoids alters cardiac metabolism /or ion homeostasis, contributing to cardiac dysfunction, precipitated by active labor and delivery.

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Exercise training reverses inflammation and muscle wasting after tobacco smoke exposure

Long term cigarette smoking induces inflammatory processes in the pulmonary system which are suggested to "spill over" into systemic inflammation. Regular exercise has been shown to have anti-inflammatory properties. The aim of the study was to investigate the effects of therapeutic exercise on inflammation and muscle wasting in smoke-exposed mice. C57BL/6J-mice (n = 30) were separated into three groups to receive either: (1) controls with no specific treatment (Con group), (2) 8 months exposure to cigarette smoke (smoke-exposed (SE) group), (3) 8 months of cigarette smoke combined with exercise training during the last 2 months (SEex group). The inflammatory status was analyzed by quantifying levels of various plasma proteins using multiplex ELISA and detection of lymphocyte surface markers by flow cytometry. Muscle tissue was analyzed by histological techniques and measurements of RNA/protein expression. SE was lead to decreased VO_2max and V_max, which was reversed by exercise (p<0.05). Expression of ICAM-1, VCAM-1, and CD62L on T cells increased and was reversed by exercise (p<0.05). Similarly, SE induced an increase of various inflammatory cytokines, which were down-regulated by exercise. In muscle, exercise improved the structure, oxidative capacity, and metabolism by reducing UPS activation, stimulating IGF-1 expression and the SE-induced inhibition of mTOR signaling pathway (p<0.05). Exercise training reverses smoke-induced decline in exercise capacity, systemic inflammation and muscle wasting, by addressing immune regulating, anabolic, and metabolic pathways.

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Urinary Bladder Hypertrophy is Susceptible in Male but Protected in Female ROMK Bartter's Mouse

The renal outer medullary potassium channel (ROMK; K_ir1.1) plays an important role in Na⁺ and K⁺ homeostasis. ROMK knockout mice (KO) show a similar phenotype to Bartter's syndrome of salt wasting and dehydration due to reduced Na-2Cl-K-cotransporter activity but not in ROMK1 KO. ROMK KO mice also show hydronephrosis; however, the mechanism of this phenotype has not been understood. We have previously demonstrated a gender-sex difference in hydronephrosis and PGE2 production in ROMK KO mouse. In this study we compared the gender-sex difference in bladder hypertrophy and hydronephrosis in ROMK KO mice. The bladder weight, bladder capacity and the thickness of urothelium in male ROMK KO showed average increased 2~4 fold greater than WT but there was no difference in either female or ROMK1 KO. The thickness of the urothelium was 648.8±33.2 vs. 302.7±16.5 (p<0.001) and the detrusor muscle 1940.7±98.9 vs. 1308.2±102.1 (p=0.013) respectively in 12-month males ROMK KO compared with the same-age WT mice. Western blotting detected ROMK expression at 45~48 kDa, and both ROMK1 and ROMK2 mRNA were detected by Q-PCR in the bladder. Immunofluorescence staining showed ROMK stained in the bladder, ureter and urethra in WT but not in KO. In addition, there was a correlation between the severity of hydronephrosis and the bladder weight in male but not in female ROMK KO mice. In conclusion, ROMK expressed in the urinary tract at both protein and mRNA levels; significant enlargement and hypertrophy of the bladder may contribute to hydronephrosis in male ROMK KO mice.

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Safety, efficacy, and drug survival of biologics and biosimilars for moderate-to-severe plaque psoriasis

Abstract

Background

Real-life data on newer biologic and biosimilar agents for moderate-to-severe psoriasis are lacking.

Objectives

To examine safety, efficacy, and time to discontinuation (drug survival) of biologics (adalimumab, etanercept, infliximab, secukinumab, and ustekinumab) and compare originators with biosimilars (i.e. Enbrel with Benepali, and Remicade with Remsima).

Methods

The DERMBIO registry contains data on all Danish patients with moderate-to-severe plaque psoriasis treated with biologics. We examined patients treated between January 1^st, 2007 and March 31^st, 2017. We used Kaplan-Meier survival curves and Cox-regression to examine drug survival patterns.

Results

A total of 3495 treatment series (2161 patients) were included (adalimumab n=1332, etanercept n=579, infliximab n=333, ustekinumab n=1055, and secukinumab n=196). Secukinumab had the highest number of PASI100 respondants, but also the lowest drug survival among all biologics. Ustekinumab had the highest drug survival overall. There were no significant differences in discontinuation risk between originator and biosimilar versions of infliximab or etanercept. Treatment with higher-than-approved dosages was frequent for all drugs except for adalimumab and secukinumab. Adverse events (predominantly infections) were most frequent for secukinumab and showed an increased (albeit low) incidence of cardiovascular events compared with the other agents.

Conclusions

Ustekinumab was associated with the highest drug survival, and secukinumab with the lowest, albeit that most patients on secukinumab were non-naïve. Switching from originator to biosimilar had no significant impact on drug survival, and the safety profiles were comparable. Adverse events occurred most frequently with secukinumab. Future studies are warranted to assess the long-term safety of novel biologics for psoriasis.

This article is protected by copyright. All rights reserved.

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Population-based Clinical Practice Research Datalink study using algorithm modelling to identify the true burden of hidradenitis suppurativa

Summary

Background

Epidemiology data regarding hidradenitis suppurativa (HS) are conflicting and prevalence estimates vary 80-fold, from 0.05% in a population-based study, to 4%.

Objectives

To assess the hypothesis that previous population-based studies under-estimated true HS prevalence by missing undiagnosed cases.

Methods

We performed a population-based observational and case-control study using the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics data. Physician-diagnosed cases in CPRD were identified from specific Read codes. Algorithms identified unrecognised 'proxy' cases, with at least five Read code records for boils in flexural skin sites. Validation of proxy cases was undertaken with General Practitioner questionnaires to confirm criteria-diagnosed cases. A case-control study assessed disease associations.

Results

On 30 June 2013, 23,353 physician-diagnosed HS cases were documented in 4,364,308 research-standard records. 68,890 proxy cases were identified, reduced to 10,146 criteria-diagnosed cases after validation, extrapolated from 107 completed questionnaires (61% return rate). Overall point prevalence was 0.77% (95% CI 0.76% to 0.78%). An additional 18,417 cases had a history of 1-4 flexural skin boils.

In physician-diagnosed cases, ORs for current smoker and obesity (BMI>30) were 3.61 (95% CI 3.44 to 3.79) and 3.29 (95% CI 3.14 to 3.45). HS was associated with type 2 diabetes, Crohn's disease, hyperlipidaemia, acne and depression and not associated with ulcerative colitis or polycystic ovary syndrome.

Conclusions

Contrary to results of previous population-based studies, HS is relatively common, with a UK prevalence of 0.77%, one-third being unrecognised, criteria-diagnosed cases using the most stringent disease definition. If probable cases are included, HS prevalence rises to 1.19%.

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Interleukin-27 Exerts Its Antitumor Effects by Promoting Differentiation of Hematopoietic Stem Cells to M1 Macrophages

The interleukin (IL)-27 promotes expansion and differentiation of hematopoietic stem cells into myeloid progenitor cells. Many tumor-infiltrating myeloid cells exert immunosuppressive effects but we hypothesized that the myeloid cells induced by IL-27 would have antitumor activity. In this study we corroborated this hypothesis as investigated in two distinct mouse transplantable tumor models. Malignant mouse cells engineered to express IL-27 exhibited reduced tumor growth in vivo. Correlated with this effect was a significant increase in the number of tumor-infiltrating CD11b+ myeloid cells exhibiting a reduced immunosuppressive activity. Notably, these CD11b+ cells were characterized by an activated M1 macrophage phenotype, on the basis of increased expression of inducible nitric oxide synthase and other M1 biomarkers. Notably, in vivo depletion of these cells by administering anti-Gr-1 eradicated the antitumor effects of IL-27. When admixed with parental tumors, CD11b+ cells inhibited tumor growth and directly killed the tumor in a nitric oxide-dependent manner. Mechanstically, IL-27 expanded Lineage−Sca-1+c-Kit+ cells in bone marrow. Transplant experiments in Ly5.1/5.2 congenic mice revealed that IL-27 directly acted on these cells and promoted their differentiation into M1 macrophages which mobilized into tumors. Overall, our results illustrated how IL-27 exerts antitumor activity by enhancing the generation of myeloid progenitor cells that can differentiate into antitumorigenic M1 macrophages.

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Rapid Intraoperative Diagnosis of Pediatric Brain Tumors Using Stimulated Raman Histology

Accurate histopathologic diagnosis is essential for providing optimal surgical management of pediatric brain tumors. Current methods for intraoperative histology are time- and labor-intensive and often introduce artifacts that limit interpretation. Stimulated Raman histology (SRH) is a novel label-free imaging technique that provides intraoperative histologic images of fresh, unprocessed surgical specimens. Here we evaluate the capacity of SRH for use in the intraoperative diagnosis of pediatric type brain tumors. SRH revealed key diagnostic features in fresh tissue specimens collected from 33 prospectively enrolled pediatric type brain tumor patients, preserving tumor cytology and histoarchitecture in all specimens. We simulated an intraoperative consultation for 25 patients with specimens imaged using both SRH and standard hematoxylin and eosin histology. SRH-based diagnoses achieved near-perfect diagnostic concordance (Cohen's kappa, κ > 0.90) and an accuracy of 92-96%. We then developed a quantitative histologic method using SRH images based on rapid image feature extraction. Nuclear density, tumor-associated macrophage infiltration, and nuclear morphology parameters from 3337 SRH fields of view were used to develop and validate a decision-tree machine-learning model. Using SRH image features, our model correctly classified 25 fresh pediatric type surgical specimens into normal versus lesional tissue and low-grade versus high-grade tumors with 100% accuracy. Our results provide insight into how SRH can deliver rapid diagnostic histologic data that could inform the surgical management of pediatric brain tumors.

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