PET Molecular Imaging Research of Levodopa-Induced Dyskinesias in Parkinson’s Disease

Abstract

Purpose of Review

To review the current status of positron emission tomography (PET) molecular imaging research of levodopa-induced dyskinesias (LIDs) in Parkinson's disease (PD).

Recent Findings

Recent PET studies have provided robust evidence that LIDs in PD are associated with elevated and fluctuating striatal dopamine synaptic levels, which is a consequence of the imbalance between dopaminergic and serotonergic terminals, with the latter playing a key role in mishandling presynaptic dopamine release. Long-term exposure to levodopa is no longer believed to solely induce LIDs, as studies have highlighted that PD patients who go on to develop LIDs exhibit elevated putaminal dopamine release before the initiation of levodopa treatment, suggesting the involvement of other mechanisms, including altered neuronal firing and abnormal levels of phosphodiesterase 10A.

Summary

Dopaminergic, serotonergic, glutamatergic, adenosinergic and opioid systems and phosphodiesterase 10A levels have been shown to be implicated in the development of LIDs in PD. However, no system may be considered sufficient on its own for the development of LIDs, and the mechanisms underlying LIDs in PD may have a multisystem origin. In line with this notion, future studies should use multimodal PET molecular imaging in the same individuals to shed further light on the different mechanisms underlying the development of LIDs in PD.

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Henry’s retirement blues

Late in his career, 'our Henry' has established a glowing reputation on the international stage both as a riveting storyteller with Do No Harm and as an eloquent performer on YouTube and TV (Your Life in their Hands and The English Surgeon). Both Ian McEwan and The Economist ventured that neurosurgery had found its Boswell. In his new book Admissions, Henry is in reflective mode as he struggles with retirement, loss of professional identity, lost opportunities to put matters right and post-retirement blues. The book starts with his suicide kit and ends with his ambition not to wait for the end, but to be ready to leave, booted and spurred, when it comes. In between, there is a compelling mix of poignant patient vignettes interspersed with laments about his own clinical failings, the state of medicine at home and abroad, and fleeting observations on consciousness and the hereafter.

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Pharmacological targeting of apelin impairs glioblastoma growth

Abstract

Glioblastoma are highly aggressive brain tumours that are associated with an extremely poor prognosis. Within these tumours exists a subpopulation of highly plastic self-renewing cancer cells that retain the ability to expand ex vivo as tumourspheres, induce tumour growth in mice, and have been implicated in radio- and chemo-resistance. Although their identity and fate are regulated by external cues emanating from endothelial cells, the nature of such signals remains unknown. Here, we used a mass spectrometry proteomic approach to characterize the factors released by brain endothelial cells. We report the identification of the vasoactive peptide apelin as a central regulator for endothelial-mediated maintenance of glioblastoma patient-derived cells with stem-like properties. Genetic and pharmacological targeting of apelin cognate receptor abrogates apelin- and endothelial-mediated expansion of glioblastoma patient-derived cells with stem-like properties in vitro and suppresses tumour growth in vivo. Functionally, selective competitive antagonists of apelin receptor were shown to be safe and effective in reducing tumour expansion and lengthening the survival of intracranially xenografted mice. Therefore, the apelin/apelin receptor signalling nexus may operate as a paracrine signal that sustains tumour cell expansion and progression, suggesting that apelin is a druggable factor in glioblastoma.

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Intraoperative naloxone reduces remifentanil-induced postoperative hyperalgesia but not pain: a randomized controlled trial

Abstract

Background

Intraoperative use of a high-dose remifentanil may induce postoperative hyperalgesia. Low-dose naloxone can selectively reverse some adverse effects of opioids without compromising analgesia. We thus hypothesized that the intraoperative use of a high-dose remifentanil combined with a low-dose naloxone infusion reduces postoperative hyperalgesia compared with the use of remifentanil alone.

Methods

Patients undergoing elective thyroid surgery were randomly assigned into one of three groups, depending on the intraoperative effect-site concentration of remifentanil, with or without a continuous infusion of naloxone: 4 ng ml⁻¹ remifentanil with 0.05 μg kg⁻¹ h⁻¹ naloxone in the high-remifentanil with naloxone group, and 4 or 1 ng ml⁻¹ remifentanil with a placebo in the high- or low-remifentanil groups, respectively. We measured the pain thresholds (primary outcome) to mechanical stimuli using von Frey filaments and incidence of hyperalgesia on the peri-incisional area 24 h after surgery. We also measured pain intensity, analgesic consumptions and adverse events up to 48 h after surgery.

Results

The pain threshold presented as von Frey numbers [median (interquartile range)] was significantly lower in the high-remifentanil group (n=31) than in the high-remifentanil with naloxone (n=30) and the low-remifentanil (n=30) groups [3.63 (3.22–3.84) vs 3.84 (3.76–4.00) vs 3.80 (3.69–4.08), P=0.011]. The incidence of hyperalgesia was also higher in the high-remifentanil group than in the other groups [21/31 vs 10/30 vs 9/30, P=0.005]. Postoperative pain intensity, analgesic consumptions and adverse events were similar between groups.

Conclusions

The intraoperative use of low-dose naloxone combined with high-dose remifentanil reduced postoperative hyperalgesia but not pain.

Clinical trial registration

NCT02856087.

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Veliparib With Temozolomide or Carboplatin/Paclitaxel Versus Placebo With Carboplatin/Paclitaxel in Patients With BRCA1/2 Locally Recurrent/Metastatic Breast Cancer: Randomized Phase II Study

Abstract

Background

Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, which interfere with DNA damage repair. Veliparib, a potent PARP inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer.

Patients and methods

Eligible patients ≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1:1:1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and overall response rate (ORR).

Results

Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively (hazard ratio [HR], 0.789; 95% CI, 0.536–1.162; P=0.227), interim median OS 28.3 and 25.9 months (HR, 0.750; 95% CI, 0.503–1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR, 1.858; 95% CI, 1.278–2.702; P=0.001), interim median OS 19.1 months (HR, 1.483; 95% CI, 1.032–2.131; P=0.032), and ORR 28.6% (P<0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP.

Conclusion

Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared to PCP. The addition of veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with veliparib/placebo if chemotherapy is discontinued without progression, in this patient population.Clinical trial information: NCT01506609.

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Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer)

Abstract

Background

Chemotherapy remains a viable option for the management of advanced non-small-cell lung cancer (NSCLC) despite recent advances in molecular targeted therapy and immunotherapy. We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with standard docetaxel therapy in patients with advanced NSCLC.

Patients and methods

Patients with advanced NSCLC previously treated with ≥1 platinum-based therapy were randomized 1:1 to docetaxel (60 mg/m² in Japan, 75mg/m² at all other study sites; day 1 in a 3-week cycle) or S-1 (80–120 mg/day, depending on body surface area; days 1–28 in a 6-week cycle). The primary endpoint was overall survival. The non-inferiority margin was a hazard ratio (HR) of 1.2.

Results

A total of 1154 patients (577 in each arm) were enrolled, with balanced patient characteristics between the two arms. Median overall survival was 12.75 and 12.52 months in the S-1 and docetaxel arms, respectively (HR 0.945; 95% confidence interval [CI] 0.833–1.073; P=0.3818). The upper limit of 95% CI of HR fell below 1.2, confirming non-inferiority of S-1 to docetaxel. Difference in progression-free survival between treatments was not significant (HR 1.033; 95% CI 0.913–1.168; P=0.6080). Response rate was 8.3% and 9.9% in the S-1 and docetaxel arms, respectively. Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm. The most common adverse drug reactions were decreased appetite (50.4%), nausea (36.4%), and diarrhea (35.9%) in the S-1 arm, and neutropenia (54.8%), leukocytopenia (43.9%), and alopecia (46.6%) in the docetaxel arm.

Conclusion

S-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC.

Clinical trial number

Japan Pharmaceutical Information Center, JapicCTI-101155

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Surgery for patients with ‘lower grade’ glioma: putting assumptions, beliefs and convictions into perspective

Annals of Oncology 2017:00:1-2. doi:10.1093/annonc/mdx295

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TMPRSS2-ERG Alters the cis-Regulatory Landscape and Activates NOTCH [Prostate Cancer]

In TMPRSS2–ERG-positive prostate tumors, ERG establishes new clusters of regulatory elements (CORE).

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Equipping NK Cells with CARs [News in Brief]

Adding a chimeric antigen receptor (CAR) to natural killer (NK) cells is garnering interest as a therapeutic strategy because this immune cell type doesn't cause graft-versus-host disease, making its widespread, off-the-shelf use feasible. Based on promising preclinical data, a phase I/II trial of one such CAR NK-cell therapy is under way, targeting CD19 in hematologic malignancies.

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Superenhancer Analysis Defines Novel Epigenomic Subtypes of Non-APL AML, Including an RAR{alpha} Dependency Targetable by SY-1425, a Potent and Selective RAR{alpha} Agonist [Research Articles]

We characterized the enhancer landscape of 66 patients with acute myeloid leukemia (AML), identifying 6 novel subgroups and their associated regulatory loci. These subgroups are defined by their superenhancer (SE) maps, orthogonal to somatic mutations, and are associated with distinct leukemic cell states. Examination of transcriptional drivers for these epigenomic subtypes uncovers a subset of patients with a particularly strong SE at the retinoic acid receptor alpha (RARA) gene locus. The presence of a RARA SE and concomitant high levels of RARA mRNA predisposes cell lines and ex vivo models to exquisite sensitivity to a selective agonist of RARα, SY-1425 (tamibarotene). Furthermore, only AML patient-derived xenograft (PDX) models with high RARA mRNA were found to respond to SY-1425. Mechanistically, we show that the response to SY-1425 in RARA-high AML cells is similar to that of acute promyelocytic leukemia treated with retinoids, characterized by the induction of known retinoic acid response genes, increased differentiation, and loss of proliferation.

Significance: We use the SE landscape of primary human AML to elucidate transcriptional circuitry and identify novel cancer vulnerabilities. A subset of patients were found to have an SE at RARA, which is predictive for response to SY-1425, a potent and selective RARα agonist, in preclinical models, forming the rationale for its clinical investigation in biomarker-selected patients. Cancer Discov; 7(10); 1136–53. ©2017 AACR.

See related commentary by Wang and Aifantis, p. 1065..

This article is highlighted in the In This Issue feature, p. 1047

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Mapping Out Cancer Dependencies [News in Brief]

Through large-scale RNAi screens, two groups of researchers have documented, in depth, the molecular players essential for tumor cell viability. Their cancer "dependency maps," which are publicly accessible, should aid drug discovery efforts by pinpointing therapeutic targets that merit developmental focus.

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CMTM6 Regulates PD-L1 Expression and Antitumor Immunity [Immunotherapy]

CMTM6 binds to PD-L1 on the plasma membrane to promote its stability and inhibitory activity.

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Enasidenib Approved for AML, but Best Uses Unclear [News in Brief]

The FDA approved the targeted therapy enasidenib for patients with refractory or relapsed acute myeloid leukemia with mutant IDH2. The drug produces remissions in some patients and may reduce the need for blood transfusions, although researchers acknowledge that the FDA's approval came with less supporting evidence than usual.

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Gilead Buying Kite for $11.9 Billion [News in Brief]

Gilead Sciences will buy Kite Pharma—and its autologous CAR T-cell technology—for $11.9 billion. The acquisition will help Gilead build its oncology portfolio and boost its revenues.

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$10M Gift Supports "Data Recycling" at UCSF [News in Brief]

The University of California, San Francisco's Institute for Computational Health Sciences has received a $10 million gift to support "data recycling" investigations. The approach to medical research involves mining existing data to potentially uncover new uses for existing drugs and help improve clinical care.

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Ascorbate Depletion Reduces TET2 Activity to Accelerate Leukemogenesis [Leukemia]

Elevated ascorbate levels maintain TET2 activity in HSCs and decline with differentiation.

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CAR T Cells Drive CLL Remissions [News in Brief]

A new study shows that chimeric antigen receptor T cells produce objective responses in 71% of patients with chronic lymphocytic leukemia whose disease progressed despite receiving ibrutinib or who are unable to tolerate the drug. Cancer cells were undetectable in the bone marrow in 81% of tested patients, and 64% of tested patients showed complete lymph node responses. Most patients experienced adverse effects, however.

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How Ribosomes Translate Cancer [Review]

A wealth of novel findings, including congenital ribosomal mutations in ribosomopathies and somatic ribosomal mutations in various cancers, have significantly increased our understanding of the relevance of ribosomes in oncogenesis. Here, we explore the growing list of mechanisms by which the ribosome is involved in carcinogenesis—from the hijacking of ribosomes by oncogenic factors and dysregulated translational control, to the effects of mutations in ribosomal components on cellular metabolism. Of clinical importance, the recent success of RNA polymerase inhibitors highlights the dependence on "onco-ribosomes" as an Achilles' heel of cancer cells and a promising target for further therapeutic intervention.

Significance: The recent discovery of somatic mutations in ribosomal proteins in several cancers has strengthened the link between ribosome defects and cancer progression, while also raising the question of which cellular mechanisms such defects exploit. Here, we discuss the emerging molecular mechanisms by which ribosomes support oncogenesis, and how this understanding is driving the design of novel therapeutic strategies. Cancer Discov; 7(10); 1069–87. ©2017 AACR.

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Trastuzumab Biosimilar on Track for Approval [News in Brief]

An FDA expert panel recommended approval of Mylan's MYL-14010, a biosimilar candidate for Genentech's trastuzumab, putting it on track to become the first approved biosimilar for cancer. Experts predict that biosimilars will lead to lower drug prices, but caution that the savings won't be as dramatic as that seen with generics.

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First-Ever CAR T-cell Therapy Approved in U.S. [News in Brief]

The first chimeric antigen receptor T-cell therapy, tisagenlecleucel, received FDA approval for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia who haven't responded to standard therapy or who have relapsed at least twice.

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Z-endoxifen Is Active in Endocrine-Refractory Metastatic Breast Cancer [Clinical Trials]

The tamoxifen metabolite Z-endoxifen has acceptable tolerability and antitumor activity.

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Noted [News in Brief]

A collection of recently published news items.

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VEGFR Inhibitor-Resistant Thyroid Cancer Responds to Cabozantinib [Clinical Trials]

Cabozantinib achieved partial responses in 40% of patients with differentiated thyroid cancer (DTC).

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PON2 Promotes Glucose Uptake to Support PDAC Growth and Metastasis [Pancreatic Cancer]

PON2 promotes GLUT1-mediated glucose transport, is upregulated in PDAC, and is required for PDAC growth.

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Yield-scaled N2O emissions were effectively reduced by biochar amendment of sandy loam soil under maize - wheat rotation in the North China Plain

Publication date: December 2017
Source:Atmospheric Environment, Volume 170
Author(s): Yuhui Niu, Zengming Chen, Christoph Müller, Monhammad M. Zaman, Donggill Kim, Hongyan Yu, Weixin Ding
It is increasingly recognized that the addition of biochar to soil has potential to mitigate climate change and increase soil fertility by enhancing carbon (C) storage. However, the effect of biochar on yield and nitrous oxide (N2O) emissions from upland fields remains unclear. In this study, a one-year field experiment was conducted in an area of calcareous fluvo-aquic soil to assess and quantify the effect of maize straw biochar in reducing N2O loss during 2014–2015 in the North China Plain. Eight treatments were designed as follows: no nitrogen (N) fertilizer (control, CK); biochar application at rates of 3 (B3), 6 (B6) and 12 (B12) t ha⁻¹; chemical fertilizer (NPK) application at 200 kg N ha⁻¹ (F); and fertilizer plus biochar application at rates of 3 (FB3), 6 (FB6) and 12 (FB12) t ha⁻¹. Crop yield, N2O fluxes, soil mineral N concentrations, and soil auxiliary parameters were measured following the application of treatments during each season. During the maize growing season, N2O emission was 0.57 kg N2O-N ha⁻¹ under CK treatment, and increased to 0.88, 0.93 and 1.10 kg N2O-N ha⁻¹ under B3, B6 and B12, respectively. In contrast, N2O emissions were significantly reduced by 31.4–39.9% (P < 0.05) under FB treatments compared with F, and the N2O emission factor of the applied N was reduced from 1.36% under F to 0.71–0.85% under FB. There was also a significant interaction effect of fertilizer and biochar on N2O emissions (P < 0.01). During the wheat growing season, biochar had no effect on N2O emissions regardless of the fertilizer regime. Biochar application did not affect maize yield; however, a significant increase in wheat yield of 16.6–25.9% (P < 0.05) was observed without N fertilization. Nevertheless, a reduction in wheat yield was measured at a biochar rate of 12 t ha⁻¹ with fertilization. Overall, under maize cropping, N2O emissions per unit yield of grain, biomass, grain N and biomass N (yield-scaled N2O emissions) were significantly reduced by 32.4–39.9% under FB compared with F treatment, regardless of the biochar application rate. Biochar did not affect yield-scaled N2O emissions in wheat. Decreased soil bulk density with biochar is suggested to reduce the denitrification potential and N2O emissions; while increased retention capacity of fertilizer N in biochar-added soil decreased wheat growth and yield. These findings suggest that N fertilization plus biochar application at 3 t ha⁻¹ is a practical strategy for reducing yield-scaled N2O emissions from maize fields in the North China Plain.

Graphical abstract

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Carbon dioxide emissions from lakes and reservoirs of China: A regional estimate based on the calculated pCO2

Publication date: December 2017
Source:Atmospheric Environment, Volume 170
Author(s): Zhidan Wen, Kaishan Song, Yingxin Shang, Chong Fang, Lin Li, Lili Lv, Xianguo Lv, Lijiang Chen
The role of inland water in CO2 exchange with the atmosphere was evaluated on the basis of calculated partial pressure of CO2 (pCO2) from sampling of 207 lakes and 84 reservoirs across China in late summer. The results suggested that almost 60% of these water bodies were supersaturated with CO2 with respect to atmosphere, and the collected reservoirs samples exhibited higher mean pCO2 than lakes. The mean pCO2 in fresh water lakes was about 3.5 times of the value in saline lakes. The lakes and reservoirs were divided into five groups (Inner Mongolia -Xinjiang plateau region, Tibetan Plateau region, Northeastern plain and mountainous region, Yunnan- Guizhou Plateau region, and Eastern plain region). The Yunnan- Guizhou Plateau region showed the highest pCO2 compared with other regions, most likely due to the typical karst landforms, karst processes may promote aqueous CO2 concentration, and karstification has a significant effect on the capture of atmospheric CO2. Inner Mongolia-Xinjiang plateau and Tibetan Plateau region reserviors showed negative CO2 flux to atmosphere, other waters in this study all supersaturated with CO2 with respect to the atmosphere. A which We analyzed the relationship between pCO2 and environmental variables, and results showed that some indicators had correlations with pCO2 in individual region such as total phosphorus, dissolved organic matter, and total suspended solids, but the relationship could not be observed with all surveyed waters. This indicated that it might be much more effective in a smaller regional scale than the broadened scale when the environmental factors were used as the predictor of pCO2 in lakes. Therefore, the common algorithm that extrapolates CO2 concentration or emission flux from the study region to a wider scale might not be accurate because of the changes in the environmental and water quality conditions.



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Assessment of long-term and large-scale even-odd license plate controlled plan effects on urban air quality and its implication

Publication date: December 2017
Source:Atmospheric Environment, Volume 170
Author(s): Suping Zhao, Ye Yu, Dahe Qin, Daiying Yin, Jianjun He
To solve traffic congestion and to improve urban air quality, long-lasting and large-scale even-odd license plate controlled plan was implemented by local government during 20 November to 26 December 2016 in urban Lanzhou, a semi-arid valley city of northwest China. The traffic control measures provided an invaluable opportunity to evaluate its effects on urban air quality in less developed cities of northwest China. Based on measured simultaneously air pollutants and meteorological parameters, the abatement of traffic-related pollutants induced by the implemented control measures such as CO, PM2.5 and PM10 (the particulate matter with diameter less than 2.5 μm and 10 μm) concentrations were firstly quantified by comparing the air quality data in urban areas with those in rural areas (uncontrolled zones). The concentrations of CO, NO2 from motor vehicles and fine particulate matter (PM2.5) were shown to have significant decreases of 15%–23% during traffic control period from those measured before control period with hourly maximum CO, PM2.5, and NO2/SO2 reduction of 43%, 35% and 141.4%, respectively. The influence of the control measures on AQI (air quality index) and ozone was less as compared to its effect on other air pollutants. Therefore, to alleviate serious winter haze pollution in China and to protect human health, the stringent long-term and large-scale even-odd license plate controlled plan should be implemented aperiodically in urban areas, especially for the periods with poor diffusion conditions.



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Wnt Signaling Inhibition Promotes Apoptosis in Sarcomas--Response

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Wnt Signaling Inhibition Promotes Apoptosis in Sarcomas--Letter

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Retraction: EGFR-Mediated Reactivation of MAPK Signaling Induces Acquired Resistance to GSK2118436 in BRAF V600E-Mutant NSCLC Cell Lines

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Modulation of Plasma Metabolite Biomarkers of the MAPK Pathway with MEK Inhibitor RO4987655: Pharmacodynamic and Predictive Potential in Metastatic Melanoma

MAPK pathway activation is frequently observed in human malignancies, including melanoma, and is associated with sensitivity to MEK inhibition and changes in cellular metabolism. Using quantitative mass spectrometry–based metabolomics, we identified in preclinical models 21 plasma metabolites including amino acids, propionylcarnitine, phosphatidylcholines, and sphingomyelins that were significantly altered in two B-RAF–mutant melanoma xenografts and that were reversed following a single dose of the potent and selective MEK inhibitor RO4987655. Treatment of non–tumor-bearing animals and mice bearing the PTEN-null U87MG human glioblastoma xenograft elicited plasma changes only in amino acids and propionylcarnitine. In patients with advanced melanoma treated with RO4987655, on-treatment changes of amino acids were observed in patients with disease progression and not in responders. In contrast, changes in phosphatidylcholines and sphingomyelins were observed in responders. Furthermore, pretreatment levels of seven lipids identified in the preclinical screen were statistically significantly able to predict objective responses to RO4987655. The RO4987655 treatment–related changes were greater than baseline physiological variability in nontreated individuals. This study provides evidence of a translational exo-metabolomic plasma readout predictive of clinical efficacy together with pharmacodynamic utility following treatment with a signal transduction inhibitor. Mol Cancer Ther; 16(10); 2315–23. ©2017 AACR.

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The IGF1R/INSR Inhibitor BI 885578 Selectively Inhibits Growth of IGF2-Overexpressing Colorectal Cancer Tumors and Potentiates the Efficacy of Anti-VEGF Therapy

Clinical studies of pharmacologic agents targeting the insulin-like growth factor (IGF) pathway in unselected cancer patients have so far demonstrated modest efficacy outcomes, with objective responses being rare. As such, the identification of selection biomarkers for enrichment of potential responders represents a high priority for future trials of these agents. Several reports have described high IGF2 expression in a subset of colorectal cancers, with focal IGF2 amplification being responsible for some of these cases. We defined a novel cut-off value for IGF2 overexpression based on differential expression between colorectal tumors and normal tissue samples. Analysis of two independent colorectal cancer datasets revealed IGF2 to be overexpressed at a frequency of 13% to 22%. An in vitro screen of 34 colorectal cancer cell lines revealed IGF2 expression to significantly correlate with sensitivity to the IGF1R/INSR inhibitor BI 885578. Furthermore, autocrine IGF2 constitutively activated IGF1R and Akt phosphorylation, which was inhibited by BI 885578 treatment. BI 885578 significantly delayed the growth of IGF2-high colorectal cancer xenograft tumors in mice, while combination with a VEGF-A antibody increased efficacy and induced tumor regression. Besides colorectal cancer, IGF2 overexpression was detected in more than 10% of bladder carcinoma, hepatocellular carcinoma and non-small cell lung cancer patient samples. Meanwhile, IGF2-high non-colorectal cancer cells lines displayed constitutive IGF1R phosphorylation and were sensitive to BI 885578. Our findings suggest that IGF2 may represent an attractive patient selection biomarker for IGF pathway inhibitors and that combination with VEGF-targeting agents may further improve clinical outcomes. Mol Cancer Ther; 16(10); 2223–33. ©2017 AACR.

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Disruption of Aneuploidy and Senescence Induced by Aurora Inhibition Promotes Intrinsic Apoptosis in Double Hit or Double Expressor Diffuse Large B-cell Lymphomas

Double hit (DH) or double expressor (DE) diffuse large B-cell lymphomas (DLBCL) are aggressive non-Hodgkin's lymphomas (NHL) with translocations and/or overexpressions of MYC and BCL-2, which are difficult to treat. Aurora kinase (AK) inhibition with alisertib in DH/DE-DLBCL induces cell death in ~30%, while ~70% are aneuploid and senescent cells (AASC), a mitotic escape mechanism contributing to drug resistance. These AASCs elaborated a high metabolic rate by increased AKT/mTOR and ERK/MAPK activity via BTK signaling through the chronic active B-cell receptor (BCR) pathway. Combinations of alisertib + ibrutinib or alisertib + ibrutinib + rituximab significantly reduced AASCs with enhanced intrinsic cell death. Inhibition of AK + BTK reduced phosphorylation of AKT/mTOR and ERK-1/2, upregulated phospho-H2A-X and Chk-2 (DNA damage), reduced Bcl-6, and decreased Bcl-2 and Bcl-xL and induced apoptosis by PARP cleavage. In a DE-DLBCL SCID mouse xenograft model, ibrutinib alone was inactive, while alisertib + ibrutinib was additive with a tumor growth inhibition (TGI) rate of ~25%. However, TGI for ibrutinib + rituximab was ~50% to 60%. In contrast, triple therapy showed a TGI rate of >90%. Kaplan–Meier survival analysis showed that 67% of mice were alive at day 89 with triple therapy versus 20% with ibrutinib + rituximab. All treatments were well tolerated with no changes in body weights. A novel triple therapy consisting of alisertib + ibrutinib + rituximab inhibits AASCs induced by AK inhibition in DH/DE-DLBCL leading to a significant antiproliferative signal, enhanced intrinsic apoptosis and may be of therapeutic potential in these lymphomas. Mol Cancer Ther; 16(10); 2083–93. ©2017 AACR.

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Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic {beta}-catenin Signaling and EMT Progression

Ormeloxifene is a clinically approved selective estrogen receptor modulator, which has also shown excellent anticancer activity, thus it can be an ideal repurposing pharmacophore. Herein, we report therapeutic effects of ormeloxifene on prostate cancer and elucidate a novel molecular mechanism of its anticancer activity. Ormeloxifene treatment inhibited epithelial-to-mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, vimentin, MMPs (MMP2 and MMP3), β-catenin/TCF-4 transcriptional activity, and induced the expression of pGSK3β. In molecular docking analysis, ormeloxifene showed proficient docking with β-catenin and GSK3β. In addition, ormeloxifene induced apoptosis, inhibited growth and metastatic potential of prostate cancer cells and arrested cell cycle in G₀–G₁ phase via modulation of cell-cycle regulatory proteins (inhibition of Mcl-1, cyclin D1, and CDK4 and induction of p21 and p27). In functional assays, ormeloxifene remarkably reduced tumorigenic, migratory, and invasive potential of prostate cancer cells. In addition, ormeloxifene treatment significantly (P < 0.01) regressed the prostate tumor growth in the xenograft mouse model while administered through intraperitoneal route (250 μg/mouse, three times a week). These molecular effects of ormeloxifene were also observed in excised tumor tissues as shown by immunohistochemistry analysis. Our results, for the first time, demonstrate repurposing potential of ormeloxifene as an anticancer drug for the treatment of advanced stage metastatic prostate cancer through a novel molecular mechanism involving β-catenin and EMT pathway. Mol Cancer Ther; 16(10); 2267–80. ©2017 AACR.

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MiR-125b Increases Nasopharyngeal Carcinoma Radioresistance by Targeting A20/NF-{kappa}B Signaling Pathway

Radioresistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment, but little is known about how miRNA regulates this phenomenon. In this study, we investigated the function and mechanism of miR-125b in NPC radioresistance, one of upregulated miRNAs in the radioresistant NPC cells identified by our previous microarray analysis. We observed that miR-125b was frequently upregulated in the radioresistant NPCs, and its increment was significantly correlated with NPC radioresistance, and was an independent predictor for poor patient survival. In vitro radioresponse assays showed that miR-125b inhibitor decreased, whereas miR-125b mimic increased NPC cell radioresistance. In a mouse model, therapeutic administration of miR-125b antagomir dramatically sensitized NPC xenografts to irradiation. Mechanistically, we confirmed that A20 was a direct target of miR-125b and found that miR-125b regulated NPC cell radioresponse by targeting A20/NF-B signaling. With a combination of loss-of-function and gain-of-function approaches, we further showed that A20 overexpression decreased while A20 knockdown increased NPC cell radioresistance both in vitro and in vivo. Moreover, A20 was significantly downregulated while p-p65 (RelA) significantly upregulated in the radioresistant NPCs relative to radiosensitive NPCs, and miR-125b expression level was negatively associated with A20 expression level, whereas positively associated with p-p65 (RelA) level. Our data demonstrate that miR-125b and A20 are critical regulators of NPC radioresponse, and high miR-125b expression enhances NPC radioresistance through targeting A20 and then activating the NF-B signaling pathway, highlighting the therapeutic potential of the miR-125b/A20/NF-B axis in clinical NPC radiosensitization. Mol Cancer Ther; 16(10); 2094–106. ©2017 AACR.

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Epidermal Growth Factor Receptor (EGFR)-targeted Photoimmunotherapy (PIT) for the Treatment of EGFR-expressing Bladder Cancer

The use of light as a means of therapy for bladder cancer has a long history but has been hampered by a lack of tumor specificity and therefore, damage to the normal bladder mucosa. Here, we describe a targeted form of phototherapy called photoimmunotherapy (PIT), which targets EGFR-expressing bladder cancer. Anti-EGFR antibody panitumumab was labeled with the photoabsorber (PA), IRDye 700Dx (IR700), to create a panitumumab-IR700 antibody–PA conjugate that is activated by near-infrared radiation (NIR). Bladder cancer tissue microarray (TMA) and bladder cancer cell lines were analyzed for expression of EGFR. Mechanism of PIT-induced cell death was studied using proliferation assays, transmission electron microscopy (TEM), and production of reactive oxygen species. Finally, the in vivo effect was studied in xenografts. EGFR staining of TMAs showed that while most bladder cancers have expression of EGFR to a varying degree, squamous cell carcinomas (SCC) have the highest expression of EGFR. Panitumumab-IR700 activated by NIR light rapidly killed UMUC-5 cells, a bladder SCC line. Panitumumab alone, panitumumab-IR700 without NIR, or NIR alone had no effect on cells. TEM demonstrated that cell death is due to necrosis. Singlet oxygen species contributed toward cell death. NIR-PIT with panitumumab-IR700 reduced growth compared with only panitumumab-IR700–treated UMUC-5 xenograft tumors. PIT is a new targeted treatment for bladder cancer. Panitumumab-IR700–induced PIT selectively kills EGFR-expressing bladder cancer cells in vitro and in vivo and therefore warrants further therapeutic studies in orthotopic xenografts of bladder cancer and ultimately in patients. Mol Cancer Ther; 16(10); 2201–14. ©2017 AACR.

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The MET/AXL/FGFR Inhibitor S49076 Impairs Aurora B Activity and Improves the Antitumor Efficacy of Radiotherapy

Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non–small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation, and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL, and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefitinib in NSCLC patients whose tumors show resistance to EGFR inhibitors. Here, we studied the impact of S49076 on MET signaling, cell proliferation, and clonogenic survival in MET-dependent (GTL16 and U87-MG) and MET-independent (H441, H460, and A549) cells. Our data show that S49076 exerts its cytotoxic activity at low doses on MET-dependent cells through MET inhibition, whereas it inhibits growth of MET-independent cells at higher but clinically relevant doses by targeting Aurora B. Furthermore, we found that S49076 improves the antitumor efficacy of radiotherapy in both MET-dependent and MET-independent cell lines in vitro and in subcutaneous and orthotopic tumor models in vivo. In conclusion, our study demonstrates that S49076 has dual antitumor activity and can be used in combination with radiotherapy for the treatment of both MET-dependent and MET-independent tumors. These results support the evaluation of combined treatment of S49076 with radiation in clinical trials without patient selection based on the tumor MET dependency status. Mol Cancer Ther; 16(10); 2107–19. ©2017 AACR.

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The Tumor-Suppressor Protein OPCML Potentiates Anti-EGFR- and Anti-HER2-Targeted Therapy in HER2-Positive Ovarian and Breast Cancer

Opioid-binding protein/cell adhesion molecule-like (OPCML) is a tumor-suppressor gene that is frequently inactivated in ovarian cancer and many other cancers by somatic methylation. We have previously shown that OPCML exerts its suppressor function by negatively regulating a spectrum of receptor tyrosine kinases (RTK), such as ErbB2/HER2, FGFR1, and EphA2, thus attenuating their related downstream signaling. The physical interaction of OPCML with this defined group of RTKs is a prerequisite for their downregulation. Overexpression/gene amplification of EGFR and HER2 is a frequent event in multiple cancers, including ovarian and breast cancers. Molecular therapeutics against EGFR/HER2 or EGFR only, such as lapatinib and erlotinib, respectively, were developed to target these receptors, but resistance often occurs in relapsing cancers. Here we show that, though OPCML interacts only with HER2 and not with EGFR, the interaction of OPCML with HER2 disrupts the formation of the HER2-EGFR heterodimer, and this translates into a better response to both lapatinib and erlotinib in HER2-expressing ovarian and breast cancer cell lines. Also, we show that high OPCML expression is associated with better response to lapatinib therapy in breast cancer patients and better survival in HER2-overexpressing ovarian cancer patients, suggesting that OPCML co-therapy could be a valuable sensitizing approach to RTK inhibitors. Mol Cancer Ther; 16(10); 2246–56. ©2017 AACR.

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Inhibition of Androgen Receptor Nuclear Localization and Castration-Resistant Prostate Tumor Growth by Pyrroloimidazole-based Small Molecules

The androgen receptor (AR) is a ligand-dependent transcription factor that controls the expression of androgen-responsive genes. A key step in androgen action, which is amplified in castration-resistant prostate cancer (CRPC), is AR nuclear translocation. Small molecules capable of inhibiting AR nuclear localization could be developed as novel therapeutics for CRPC. We developed a high-throughput screen and identified two structurally-related pyrroloimidazoles that could block AR nuclear localization in CRPC cells. We show that these two small molecules, 3-(4-ethoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (EPPI) and 3-(4-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (CPPI) can inhibit the nuclear localization and transcriptional activity of AR and reduce the proliferation of AR-positive but not AR-negative prostate cancer cell lines. EPPI and CPPI did not inhibit nuclear localization of the glucocorticoid receptor or the estrogen receptor, suggesting they selectively target AR. In LNCaP tumor xenografts, CPPI inhibited the proliferation of relapsed LNCaP tumors. These findings suggest that EPPI and CPPI could serve as lead structures for the development of therapeutic agents for CRPC. Mol Cancer Ther; 16(10); 2120–9. ©2017 AACR.

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Inactivation of the Kinase Domain of CDK10 Prevents Tumor Growth in a Preclinical Model of Colorectal Cancer, and Is Accompanied by Downregulation of Bcl-2

Cyclin-dependent kinase 10 (CDK10), a CDC2-related kinase, is highly expressed in colorectal cancer. Its role in the pathogenesis of colorectal cancer is unknown. This study examines the function of CDK10 in colorectal cancer, and demonstrates its role in suppressing apoptosis and in promoting tumor growth in vitro and in vivo. Modulation of CDK10 expression in colorectal cancer cell lines demonstrates that CDK10 promotes cell growth, reduces chemosensitivity and inhibits apoptosis by upregulating the expression of Bcl-2. This effect appears to depend on its kinase activity, as kinase-defective mutant colorectal cancer cell lines have an exaggerated apoptotic response and reduced proliferative capacity. In vivo, inhibiting CDK10 in colorectal cancer following intratumoral injections of lentivirus-mediated CDK10 siRNA in a patient-derived xenograft mouse model demonstrated its efficacy in suppressing tumor growth. Furthermore, using a tissue microarray of human colorectal cancer tissues, the potential for CDK10 to be a prognostic biomarker in colorectal cancer was explored. In tumors of individuals with colorectal cancer, high expression of CDK10 correlates with earlier relapse and shorter overall survival. The findings of this study indicate that CDK10 plays a role in the pathogenesis in colorectal cancer and may be a potential therapeutic target for treatment. Mol Cancer Ther; 16(10); 2292–303. ©2017 AACR.

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Mechanisms of Resistance to NTRK Inhibitors and Therapeutic Strategies in NTRK1-Rearranged Cancers

Neurotrophic receptor tyrosine kinase 1 (NTRK1) gene rearrangement leads to constitutive activation of NTRK1, which induces high-transforming ability. NTRK-rearranged cancers have been identified in several cancer types, such as glioblastoma, non–small cell lung cancer, and colorectal cancer. Although there are currently no clinically approved inhibitors that target NTRK1, several tyrosine kinase inhibitors (TKI), such as entrectinib and LOXO-101, are in clinical trials. The purpose of this study was to identify potential mechanisms of resistance to NTRK inhibitors and find potential therapeutic strategies to overcome the resistance. We examined the sensitivity of TPM3-NTRK1-transformed Ba/F3 cells and TPM3-NTRK1-harboring KM12 cells to multiple NTRK inhibitors. Acquired NTRK inhibitor-resistant mutations were screened by N-ethyl-N-nitrosourea mutagenesis with Ba/F3-TPM3-NTRK1 cells or by the establishment of NTRK-TKI-resistant cells from KM12 cells continuously treated with NTRK-TKIs. We identified multiple novel NTRK-TKI resistance mutations in the NTRK1 kinase domain, including G595R, and insulin growth factor receptor type 1 (IGF1R) bypass pathway-mediated resistance. After identifying the resistance mechanisms, we performed drug screening with small-molecule inhibitors to overcome the resistance. As a result, we found that ponatinib and nintedanib effectively inhibited the survival of TPM3-NTRK1-G667C but not G595R mutants, both of which showed resistance to entrectinib or larotrectinib (LOXO-101). Furthermore, cabozantinib with an IGF1R inhibitor such as OSI-906 could overcome bypass pathway-mediated resistance. We developed a comprehensive model of acquired resistance to NTRK inhibitors in cancer with NTRK1 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance. Mol Cancer Ther; 16(10); 2130–43. ©2017 AACR.

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Dual Inhibition of NOX2 and Receptor Tyrosine Kinase by BJ-1301 Enhances Anticancer Therapy Efficacy via Suppression of Autocrine-Stimulatory Factors in Lung Cancer

NADPH oxidase–derived reactive oxygen species (ROS) potentiate receptor tyrosine kinase (RTK) signaling, resulting in enhanced angiogenesis and tumor growth. In this study, we report that BJ-1301, a hybrid of pyridinol and alpha-tocopherol, exerts anticancer effects by dual inhibition of NADPH oxidase and RTK activities in endothelial and lung cancer cells. BJ-1301 suppresses ROS production by blocking translocation of NADPH oxidase cytosolic subunits to the cell membrane, thereby inhibiting activation. The potency of RTK inhibition by BJ-1301 was lower than that of sunitinib (a multi-RTK inhibitor), but the inhibition of downstream signaling pathways (e.g., ROS generation) and subsequent biological changes (e.g., NOX2 induction) by BJ-1301 was superior. Consistently, BJ-1301 inhibited cisplatin-resistant lung cancer cell proliferation more than sunitinib did. In xenograft chick or mouse tumor models, BJ-1301 inhibited lung tumor growth, to an extent greater than that of sunitinib or cisplatin. Treatments with BJ-1301 induced regression of tumor growth, potentially due to downregulation of autocrine-stimulatory ligands for RTKs, such as TGFα and stem cell factor, in tumor tissues. Taken together, the current study demonstrates that BJ-1301 is a promising anticancer drug for the treatment of lung cancer. Mol Cancer Ther; 16(10); 2144–56. ©2017 AACR.

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Exposure-Response Analyses of Ramucirumab from Two Randomized, Phase III Trials of Second-line Treatment for Advanced Gastric or Gastroesophageal Junction Cancer

Ramucirumab is an IgG₁ monoclonal antibody specific for the vascular endothelial growth factor receptor-2. Ramucirumab, 8 mg/kg every 2 weeks, administered as monotherapy (REGARD) or in combination with paclitaxel (RAINBOW), was safe and effective in patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer. We evaluated exposure–efficacy and exposure–safety relationships of ramucirumab from two randomized, placebo-controlled phase III trials. Sparse pharmacokinetic samples were collected, and a population pharmacokinetic analysis was conducted to predict ramucirumab minimum trough concentration at steady state (C_min,ss). Kaplan–Meier methods and Cox proportional hazards models were used to evaluate the ramucirumab exposure (C_min,ss)–efficacy relationship to overall survival (OS) and progression-free survival (PFS). Logistic regression analyses were used to evaluate exposure–safety relationships. Analyses included 321 ramucirumab + paclitaxel and 335 placebo + paclitaxel patients from RAINBOW and 72 ramucirumab and 35 placebo patients from REGARD. Exposure–efficacy analysis showed ramucirumab C_min,ss was a significant predictor of OS and PFS in both trials. Higher ramucirumab exposure was associated with longer OS and PFS. In RAINBOW, grade ≥3 hypertension, leukopenia, and neutropenia, but not febrile neutropenia, significantly correlated with C_min,ss, with increased exposure leading to increased incidence. Exploratory exposure–response analyses suggest a positive relationship between efficacy and ramucirumab exposure with manageable toxicities at exposures generated from a dose of 8 mg/kg ramucirumab given every 2 weeks for patients with advanced gastric/GEJ cancer. These findings suggest an opportunity to further optimize benefit versus risk profiles of ramucirumab treatment in patients with gastric/GEJ cancer. Mol Cancer Ther; 16(10); 2215–22. ©2017 AACR.

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Efficacy of AKT Inhibitor ARQ 092 Compared with Sorafenib in a Cirrhotic Rat Model with Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related mortality worldwide. The AKT pathway has been found activated in 50% of HCC cases, making it a promising target. Therefore, we assess efficacy of the allosteric AKT inhibitor ARQ 092 compared with untreated control and standard treatment, sorafenib, in vitro and in vivo. ARQ 092 blocked phosphorylation of AKT in vitro and strongly inhibited cell growth with significantly higher potency than sorafenib. Similarly, apoptosis and cell migration were strongly reduced by ARQ 092 in vitro. To mimic human advanced HCC, we used a diethylnitrosamine-induced cirrhotic rat model with fully developed HCC. MRI analyses showed that ARQ 092 significantly reduced overall tumor size. Furthermore, number of tumors was decreased by ARQ 092, which was associated with increased apoptosis and decreased proliferation. Tumor contrast enhancement was significantly decreased in the ARQ 092 group. Moreover, on tumor tissue sections, we observed a vascular normalization and a significant decrease in fibrosis in the surrounding liver of animals treated with ARQ 092. Finally, pAKT/AKT levels in ARQ 092–treated tumors were reduced, followed by downregulation of actors of AKT downstream signaling pathway: pmTOR, pPRAS40, pPLC1, and pS6K1. In conclusion, we demonstrated that ARQ 092 blocks AKT phosphorylation in vitro and in vivo. In the HCC-rat model, ARQ 092 was well tolerated, showed antifibrotic effect, and had stronger antitumor effect than sorafenib. Our results confirm the importance of targeting AKT in HCC. Mol Cancer Ther; 16(10); 2157–65. ©2017 AACR.

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JAK1/STAT3 Activation through a Proinflammatory Cytokine Pathway Leads to Resistance to Molecularly Targeted Therapy in Non-Small Cell Lung Cancer

Molecularly targeted drugs have yielded significant therapeutic advances in oncogene-driven non–small cell lung cancer (NSCLC), but a majority of patients eventually develop acquired resistance. Recently, the relation between proinflammatory cytokine IL6 and resistance to targeted drugs has been reported. We investigated the functional contribution of IL6 and the other members of IL6 family proinflammatory cytokine pathway to resistance to targeted drugs in NSCLC cells. In addition, we examined the production of these cytokines by cancer cells and cancer-associated fibroblasts (CAF). We also analyzed the prognostic significance of these molecule expressions in clinical NSCLC samples. In NSCLC cells with acquired resistance to targeted drugs, we observed activation of the IL6–cytokine pathway and STAT3 along with epithelial-to-mesenchymal transition (EMT) features. In particular, IL6 family cytokine oncostatin-M (OSM) induced a switch to the EMT phenotype and protected cells from targeted drug-induced apoptosis in OSM receptors (OSMRs)/JAK1/STAT3–dependent manner. The cross-talk between NSCLC cells and CAFs also preferentially activated the OSM/STAT3 pathway via a paracrine mechanism and decreased sensitivity to targeted drugs. The selective JAK1 inhibitor filgotinib effectively suppressed STAT3 activation and OSMR expression, and cotargeting inhibition of the oncogenic pathway and JAK1 reversed resistance to targeted drugs. In the analysis of clinical samples, OSMR gene expression appeared to be associated with worse prognosis in patients with surgically resected lung adenocarcinoma. Our data suggest that the OSMRs/JAK1/STAT3 axis contributes to resistance to targeted drugs in oncogene-driven NSCLC cells, implying that this pathway could be a therapeutic target. Mol Cancer Ther; 16(10); 2234–45. ©2017 AACR.

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The DNA-Binding Polyamine Moiety in the Vectorized DNA Topoisomerase II Inhibitor F14512 Alters Reparability of the Consequent Enzyme-Linked DNA Double-Strand Breaks

Poisons of topoisomerase II (TOP2) kill cancer cells by preventing religation of intermediate DNA breaks during the enzymatic process and thus by accumulating enzyme–drug–DNA complexes called TOP2 cleavage-complex (TOP2cc). F14512 is a highly cytotoxic polyamine-vectorized TOP2 inhibitor derived from etoposide and currently in clinical trials. It was shown in vitro that F14512 has acquired DNA-binding properties and that the stability of TOP2cc was strongly increased. Paradoxically, at equitoxic concentrations in cells, F14512 induced less DNA breaks than etoposide. Here, we directly compared etoposide and F14512 for their rates of TOP2cc production and resolution in human cells. We report that targeting of TOP2α and not TOP2β impacts cell killing by F14512, contrary to etoposide that kills cells through targeting both isoforms. Then, we show that despite being more cytotoxic, F14512 is less efficient than etoposide at producing TOP2α cleavage-complex (TOP2αcc) in cells. Finally, we report that compared with TOP2αcc mediated by etoposide, those generated by F14512 persist longer in the genome, are not dependent on TDP2 for cleaning break ends from TOP2α, are channeled to a larger extent to resection-based repair processes relying on CtIP and BRCA1 and promote RAD51 recruitment to damaged chromatin. In addition to the addressing of F14512 to the polyamine transport system, the properties uncovered here would be particularly valuable for a therapeutic usage of this new anticancer compound. More generally, the concept of increasing drug cytotoxicity by switching the repair mode of the induced DNA lesions via addition of a DNA-binding moiety deserves further developments. Mol Cancer Ther; 16(10); 2166–77. ©2017 AACR.

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ABCB1 Mediates Cabazitaxel-Docetaxel Cross-Resistance in Advanced Prostate Cancer

Advancements in research have added several new therapies for castration-resistant prostate cancer (CRPC), greatly augmenting our ability to treat patients. However, CRPC remains an incurable disease due to the development of therapeutic resistance and the existence of cross-resistance between available therapies. Understanding the interplay between different treatments will lead to improved sequencing and the creation of combinations that overcome resistance and prolong survival. Whether there exists cross-resistance between docetaxel and the next-generation taxane cabazitaxel is poorly understood. In this study, we use C4-2B and DU145 derived docetaxel-resistant cell lines to test response to cabazitaxel. Our results demonstrate that docetaxel resistance confers cross-resistance to cabazitaxel. We show that increased ABCB1 expression is responsible for cross-resistance to cabazitaxel and that inhibition of ABCB1 function through the small-molecule inhibitor elacridar resensitizes taxane-resistant cells to treatment. In addition, the antiandrogens bicalutamide and enzalutamide, previously demonstrated to be able to resensitize taxane-resistant cells to docetaxel through inhibition of ABCB1 ATPase activity, are also able to resensitize resistant cells to cabazitaxel treatment. Finally, we show that resensitization using an antiandrogen is far more effective in combination with cabazitaxel than docetaxel. Collectively, these results address key concerns in the field, including that of cross-resistance between taxanes and highlighting a mechanism of cabazitaxel resistance involving ABCB1. Furthermore, these preclinical studies suggest the potential in using combinations of antiandrogens with cabazitaxel for increased effect in treating advanced CRPC. Mol Cancer Ther; 16(10); 2257–66. ©2017 AACR.

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New bone formation and trabecular bone microarchitecture of highly porous tantalum compared to titanium implant threads: A pilot canine study

Abstract

Aim

This study evaluated new bone formation activities and trabecular bone microarchitecture within the highly porous region of Trabecular Metal™ Dental Implants (TM) and between the threads of Tapered Screw-Vent® Dental Implants (TSV) in fresh canine extraction sockets.

Materials and methods

Eight partially edentulated dogs received four implants (4.1 mmD × 13 mmL) bilaterally in mandibular fresh extraction sockets (32 TM, 32 TSV implants), and allowed to heal for 2, 4, 8, and 12 weeks. Calcein was administered to label mineralizing bone at 11 and 4 days before euthanasia for dogs undergoing all four healing periods. Biopsies taken at each time interval were examined histologically. Histomorphometric assay was conducted for 64 unstained and 64 stained slides at the region of interest (ROI) (6 mm long × 0.35 mm deep) in the midsections of the implants. Topographical and chemical analyses were also performed.

Results

Histomorphometry revealed significantly more new bone in the TM than in the TSV implants at each healing time (p = .0014, .0084, .0218, and .0251). Calcein-labeled data showed more newly mineralized bone in the TM group than in the TSV group at 2, 8, and 12 weeks (p = .045, .028, .002, respectively) but not at 4 weeks (p = .081). Histologically TM implants exhibited more bone growth and dominant new immature woven bone at an earlier time point than TSV implants. The parameters representing trabecular bone microarchitecture corroborated faster new bone formation in the TM implants when compared to the TSV implants. TM exhibited an irregular faceted topography compared to a relatively uniform microtextured surface for TSV. Chemical analysis showed peaks associated with each implant's composition material, and TSV also showed peaks reflecting the elements of the calcium phosphate blasting media.

Conclusions and clinical implications

Results suggest that the healing pathway associated with the highly porous midsection of TM dental implant could enable faster and stronger secondary implant stability than conventional osseointegration alone; however, prospective clinical studies are needed to confirm these potential benefits in patients with low bone density, compromised healing, or prior implant failure.

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Correction to: Comparison of neuropsychiatric symptoms and diffusion tensor imaging correlates among patients with subcortical ischemic vascular disease and Alzheimer’s disease

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Inhibiting PI3K{beta} with AZD8186 regulates key metabolic pathways in PTEN-null tumours

Purpose: PTEN null tumours become dependent on the PI3Kb isoform and can be targeted by molecules such as the selective PI3Kb inhibitor AZD8186. However beyond the modulation of the canonical PI3K pathway, the consequences of inhibiting PI3Kb are poorly defined. Experimental Design: To determine the broader impact of AZD8186 in PTEN null tumours we performed a genome wide RNAseq analysis of PTEN null triple negative breast tumour xenografts treated with AZD8186. Mechanistic consequences of AZD8186 treatment were examined across a number of PTEN null cell lines and tumour models. Results: AZD8186 treatment resulted in modification of transcript and protein biomarkers associated with cell metabolism. We observed down regulation of cholesterol biosynthesis genes and upregulation of markers associated with metabolic stress. Down regulation of cholesterol biosynthesis proteins such as HMGCS1 occurred in PTEN null cell lines and tumour xenografts sensitive to AZD8186. Therapeutic inhibition of PI3Kb also up-regulated PDHK4 and increased PDH phosphorylation, indicative of reduced carbon flux into the TCA cycle. Consistent with this metabolomic analysis revealed a number of changes in key carbon pathways, nucleotide and amino acid biosynthesis. Conclusions: This study identifies novel mechanistic biomarkers of PI3Kb inhibition in PTEN null tumours supporting the concept that targeting PI3Kb may exploit a metabolic dependency that contributes to therapeutic benefit in inducing cell stress. Considering these additional pathways will guide biomarker and combination strategies for this class of agents.

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A complex network of tumor microenvironment in human high grade serous ovarian cancer

Purpose: Most high grade serous ovarian cancer (HGSOC) patients develop recurrent disease after first line treatment, frequently with fatal outcome. This work aims at studying the molecular biology of both primary and recurrent HGSOC. Experimental design: Gene expression profiles of matched primary and recurrent fresh frozen tumor tissues from 66 HGSOC patients were obtained by RNA sequencing. Clustering analyses and pairwise comparison of the profiles between matched samples and subsequent functional alignment were used for the identification of molecular characteristics of HGSOC. Results: Both primary and recurrent HGSOC samples presented predominant gene expression differences in their microenvironment, determined by a panel of genes covering all major pathways of immune activation together with a number of genes involved in the remodeling of extracellular matrix and adipose tissues. Stratifying tumor tissues into immune active and silent groups, we further discovered that while some recurrent tumors shared the same immune status as their primary counterparts, others switched the immune status, either from silent to active or active to silent. Interestingly, genes belonging to the B7-CD28 immune checkpoint family, known for their major role as negative regulators of the immune response, were overexpressed in the immune active tumors. Searching for potential tumor antigens, CEACAM21, a member of the carcinoembryonic antigen family, was found to be significantly overexpressed in immune active tissues in comparison to the silent ones. Conclusion: The results illustrate the complexity of the tumor microenvironment in HGSOC and reveal the molecular relationship between primary and recurrent tumors, which have multiple therapeutic implications.

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Pharmacogenetic analysis of the UK MRC MAGIC trial: association of polymorphisms with toxicity and survival in patients treated with perioperative ECF chemotherapy

Purpose: Germline polymorphisms may affect chemotherapy efficacy and toxicity. We examined the effect of polymorphisms in drug metabolism and DNA repair genes on pathological response rates, survival, and toxicity for patients randomised to surgery alone or perioperative ECF chemotherapy in the MRC MAGIC trial. Experimental design: DNA was extracted from non-tumor resection FFPE blocks. ERCC1, ERCC2, XRCC1, DYPD, and OPRT SNPs were evaluated using Sequenom, GSTP1, GSTT1 deletion and TYMS (TS) 5' 2R/3R using multiplex PCR. Post PCR amplification TS 2R/3R and GSTT1 samples underwent gel electrophoresis. Results: Polymorphism data was available for 289/456 (63.4%) operated patients. No polymorphism was statistically significantly associated with pathological response to chemotherapy. Median overall survival (OS) for patients treated with surgery alone with any TS genotype was not different (1.76 years 2R/2R, 1.68 years 2R/3R, 2.09 years 3R/3R). Median OS for patients with a TS 2R/2R genotype treated with chemotherapy was not reached, whereas median OS for 2R/3R and 3R/3R patients were 1.44 and 1.60 years respectively (log rank p value 0.0053). The p value for the interaction between treatment arm and genotype (3R/3R and 3R/2R vs 2R/2R) was 0.029. No polymorphism was statistically significantly associated with chemotherapy toxicity. Conclusions: In MAGIC, patients with a TS 2R/2R genotype appeared to derive a larger benefit from perioperative ECF chemotherapy than patients with 3R containing genotypes. Further exploration of this potential predictive biomarker in this patient population is warranted.

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Neuroblastoma Patients' KIR and KIR-ligand Genotypes Influence Clinical Outcome for Dinutuximab-based Immunotherapy: A Report from the Children's Oncology Group

Purpose: In 2010, a Children's Oncology Group (COG) phase III randomized trial for high-risk neuroblastoma patients (ANBL0032) demonstrated improved event-free survival (EFS) and overall survival (OS) following treatment with an immunotherapy regimen of dinutuximab, GM-CSF, IL-2, and isotretinoin compared to treatment with isotretinoin alone. Dinutuximab, a chimeric anti-GD2 monoclonal antibody, acts in part via NK cells. Killer Immunoglobulin-like Receptors (KIRs) on NK cells and their interactions with KIR-ligands can influence NK cell function. We investigated whether KIR/KIR-ligand genotypes were associated with EFS or OS in this trial. Experimental Design: We genotyped patients from COG study, ANBL0032, and evaluated the effect of KIR/KIR-ligand genotypes on clinical outcomes. Cox regression models and log-rank tests were used to evaluate associations of EFS and OS with KIR/KIR-ligand genotypes. Results: In this trial, patients with the "all KIR-ligands present" genotype, as well as patients with inhibitory KIR2DL2 with its ligand (HLA-C1) together with inhibitory KIR3DL1 with its ligand (HLA-Bw4) were associated with improved outcome if they received immunotherapy. In contrast, for patients with the complementary KIR/KIR-ligand genotypes, clinical outcome was not significantly different for patients that received immunotherapy vs. those receiving isotretinoin alone. Conclusions: These data show that administration of immunotherapy is associated with improved outcome for neuroblastoma patients with certain KIR/KIR-ligand genotypes, while this was not seen for patients with other KIR/KIR-ligand genotypes. Further investigation of KIR/KIR-ligand genotypes may clarify their role in cancer-immunotherapy, and may enable KIR/KIR-ligand genotyping to be utilized prospectively for identifying patients likely to benefit from certain cancer immunotherapy regimens.

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The dichotomy between low frequency and delta waves in human sleep: A reappraisal

Publication date: Available online 2 October 2017
Source:Journal of Neuroscience Methods
Author(s): Jean-Pol Lanquart, Pasquale Nardone, Philippe Hubain, Gwénolé Loas, Paul Linkowski
BackgroundWe present the results of an analysis of the low frequency (LF) (0.25–1Hz) and delta (1–4Hz) waves during human sleep. Our objective was to investigate whether LF and delta waves should be considered as separate entities.MethodsThe slow-wave electroencephalogram (EEG) activity of 2 sets of 10 young, healthy volunteers was analysed utilising the rarely-used Lomb-Scargle periodogram. This method has advantages over the more commonly-used Fast Fourier Transform analysis.ResultsDuring the night, the frequencies of the most powerful waves are concentrated in the 0.5–2Hz range and show a continuous tendency to shift towards slower frequencies during sleep.Comparison with existing methodsWhen considering the frequency dynamics of slow-wave activity below 3Hz, the unifying theory of LF and delta waves is more parsimonious than the idea that there is a different origin and regulation for the two sub-bands.ConclusionsThe unifying theory of LF and delta waves is the simplest explanation for the slow-wave activity of the EEG below 3Hz. This finding is important for the clinical use of slow-wave activity.



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Urinary biomarker CXCL10, identifying site specific allograft inflammation in renal transplantation.

No abstract available

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Altered Th17 pathway in tolerant kidney transplant patients: a 'chicken-or-the-egg' dilemma?.

No abstract available

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Long-term effects of pancreas transplantation on diabetic retinopathy and incidence and predictive risk factors for early worsening.

Background: Limited data are available regarding the long-term effects of pancreas transplantation on the progression of diabetic retinopathy (DR) and the incidence of and associated risk factors for early worsening of DR. Methods: Patients who underwent successful pancreas transplantation between January 2007 and October 2015 and were followed for >= 1 year were consecutively enrolled. Variables regarding demographic, systemic, metabolic, and surgical factors were reviewed for each patient. DR progression was defined as i) development or aggravation of macular edema requiring intravitreal injections and/or ii) progression of DR severity requiring panretinal photocoagulation (PRP) and/or pars planar vitrectomy (PPV). Early worsening was defined as progression within 1 year of posttransplant. Results: Three hundred and 3 eyes of 153 patients were included in the analysis. At the pretransplant ocular evaluation, 221 eyes (72.9 %) showed advanced DR with history of PRP and/or PPV. During a mean follow-up period of 4.2 years, 62 eyes (20.5%) experienced DR progression, and early worsening was noted in 57 eyes (18.8%). DR with recent PRP within pretransplant 1 year and pancreas transplant alone were significant risk factors for early worsening. Conclusions: In 4 out 5 patients who received pancreas transplant, the degree of DR remained stable over time after transplantation. Meanwhile, early worsening of DR could occur in patients at risk, particularly within the first posttransplant year. We suggest that physicians should have a high index of suspicion and carefully monitor for early worsening of DR, and timely manage possible ocular deterioration. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Marked decrease in urgent listing for liver transplantation over time: evolution of characteristics and outcomes of Status-1 liver transplantation.

Background: Approximately 5% of liver transplants annually are performed urgently with "status-1" designation. This study aims to determine if the demand, characteristics and outcome for status-1 liver transplantation has changed over time. Methods: We utilized the Scientific Registry of Transplant Patients (2003-2015) to characterize 2352 adult patients who underwent 2408 status-1 liver transplants and compared them between Era1 (2003-6/2009) and Era2 (7/2009 -2015). Results: Overall, there were fewer liver transplants performed with the Status-1 designation in Era2 than Era1 (1099 vs 1309). Although the number of urgent liver transplants was relatively constant with successive years, the proportion transplanted with Status-1 designation decreased markedly over time. Era2 patients were older (43.2 vs 41.7 years, p=0.01) and less likely be ABO-incompatible (1.1% vs 2.4%, p=0.01) or re-transplant (77 vs 124, p=0.03). In terms of disease etiology, the largest group was "ALF, nonspecified" (43.4%). There was no difference in proportion with drug-induced liver injury (DILI), but the subset of herbal/dietary supplements increased in Era2 (1.3% vs 0.46 %, p=0.04). Survival was increased in Era2 in the overall cohort and for patients with autoimmune disease (p

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Role of human CD200 overexpression in pig-to-human xenogeneic immune response compared with human CD47 overexpression.

Background: Macrophages play important roles in xenograft rejection. Here, we investigated whether overexpression of human CD200 or CD47 in porcine endothelial cells (PEC) can suppress macrophages activation in xenogeneic immune responses. Methods: PECs and human macrophages were incubated together, harvested and analyzed for in vitro macrophage phagocytic and cytotoxicity activity, and cytokine release. Next, PEC were injected into renal subcapsular space of humanized mice. On day 10 posttransplantation, we analyzed xenograft survival and perigraft inflammatory cell infiltrations in PEC-to-humanized mouse transplantation. Results: PECs highly expressing human CD200, CD47, or both CD47/CD200 were established by lentiviral vector transduction. Both CD200 and CD47 suppressed in vitro macrophage phagocytic and cytotoxic activity against PECs; decreased TNF-[alpha], IL-1[beta], and IL-6 secretion; and increased IL-10 secretion. However, simultaneous overexpression of CD200 and CD47 did not show additive effects. Next, PECs were transplanted into NSG mice, and human monocytes and lymphocytes were adoptively transferred 1 day after xenotransplantation. PEC xenograft cell death and apoptosis were decreased in the CD200-PEC and CD47/CD200-PEC groups. Perigraft infiltration of human T cells was suppressed by CD47; CD200 suppressed infiltration of human macrophages to a greater extent than CD47; and the CD47/CD200-PEC group exhibited the lowest level of leukocyte infiltration. In summary, overexpression of CD200 in PECs suppressed xenogeneic activation of human macrophages and improved survival of PEC xenografts in humanized mice; however, co-expression of CD200 and CD47 did not show additive effects. Conclusions: Therefore, overexpression of human CD200 in donor pigs could constitute a promising strategy for overcoming xenograft rejection. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Coexistence of Bilirubin >=10 mg/dL and Prothrombin Time-International Normalized Ratio >=1.6 on Day 7: A Strong Predictor of Early Graft Loss after Living Donor Liver Transplantation.

Background: Early allograft dysfunction (EAD) defined by serum total bilirubin (TB) >=10 mg/dL or prothrombin time-international normalized ratio (PT-INR) >=1.6 on postoperative day 7 (POD7) or aminotransferase >2000 IU/L within the first week, is associated with early graft loss after deceased-donor liver transplantation. We aimed to determine the prognostic impact of the EAD definition in living-donor liver transplantation (LDLT). Methods: We analyzed the validity of the EAD definition and its impact on early graft survival in 260 adult recipients who underwent primary LDLT. Results: Eighty-four (32.3%) patients met the EAD criteria; 59 (22.7%) and 46 (17.7%) patients had TB >=10 mg/dL and PT-INR >=1.6 on POD7, respectively, and 22 (8.5%) patients satisfied both criteria. Graft survival differed significantly when stratified according to TB >=10 mg/dL and PT-INR >=1.6 (p=1.6 resulted in higher graft mortality (RR=3.87, p<.0001 at rr="2.97," p as did tb>=10 mg/dL (RR=1.89, p=0.027 at 90-day; RR=1.91, p=0.006 at 180-day). Coexistence of TB >=10 mg/dL and PT-INR >=1.6 was strongly associated with early graft loss (59.1%, RR=6.97 at 90-day; 68.2%, RR=5.75 at 180-day). In Cox regression analysis, PT-INR >=1.6 and TB >=10 mg/dL on POD7 were significant risk factors for early graft loss (hazard ratio =4.10 [95% CI: 2.35-7.18], p=10 mg/dL and/or PT-INR >=1.6 on POD7 predicted early graft loss after LDLT, and their coexistence worsened patient outcomes. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Association between high risk for preterm birth and changes in gingiva parameters during pregnancy—a prospective cohort study

Abstract

Objectives

The objective of this study was to investigate clinical and microbiological gingival changes during pregnancy in women without periodontal disease. Additionally, these parameters were to be compared in women with high risk for preterm birth and women with a normal course of pregnancy.

Method and materials

Group I consisted of 40 subjects at high risk for preterm birth, while group II involved 49 subjects with a normal course of pregnancy. The control group (III) was made up of 50 non-pregnant women. Clinical parameters (plaque index, gingival index, probing pocket depths, gingival swelling, bleeding on probing) and microbiological changes were monitored during pregnancy and 2–4 weeks after parturition.

Results

In the high-risk preterm group (I), 19 women could be included in data analysis. This group was compared to 41 women in the normal pregnancy group (II) and 50 non-pregnant women (III). Gingival inflammation was significantly higher in women with high risk for preterm birth (I) compared to non-risk pregnant women (II, p < 0.05). In addition, in this group (I), the subgingival amounts of Fusobacterium nucleatum (> 10⁵) were found to be significantly higher after childbirth compared to non-pregnant women (p < 0.05).

Conclusions

Even without having periodontal disease, women with high risk for preterm birth showed worse clinical values compared to non-risk pregnant and non-pregnant women and an increased detection of Fusobacterium nucleatum after delivery.

Clinical relevance

High risk for preterm birth might be associated with the occurrence of increased gingival inflammation.

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Monocyte and macrophage immunometabolism in atherosclerosis

Abstract

Atherosclerosis is characterized by chronic low grade inflammation of arteries that results in the development of lipid dense plaques. Chronic inflammation induced by Western-type diet is associated with the risk of developing atherosclerosis, and new insights shed light on the importance of metabolic and functional reprogramming in monocytes and macrophages for progression of atherosclerosis. This review aims to provide an overview of our current understanding into how the metabolic reprogramming of glucose, cholesterol, fatty acid, and amino acid metabolism in macrophages contributes to inflammation during atherosclerosis. Recent insights suggest that transcriptional and epigenetic adaptation within innate immune cells (termed trained immunity) play an important role in the pathogenesis of atherosclerosis. We propose that metabolic changes induced by pro-atherogenic lipoproteins partly mediate these changes in trained macrophages. Finally, we discuss the possibility of manipulating cellular metabolism of immune cells for targeted therapeutic intervention against atherosclerosis.

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Preventing new sensitization and asthma onset by allergen immunotherapy: the current evidence.

Purpose of review: Specific allergen immunotherapy is considered a key candidate for a successful preventive intervention in atopic diseases. The strong association of atopic manifestations such as rhinitis and asthma with atopic sensitizations (specific serum IgE) provide a rationale for early intervention in childhood and adolescence. Recent findings: Currently, the documentation of the disease-modifying intervention effects is limited to the secondary prevention of asthma symptoms in children with allergic rhinoconjunctivitis. These effects appear to be rather allergen specific than nonspecific. Summary: Documentation on disease modification including a reduction of asthma symptoms in children, particularly with grass pollen tablets has become quite robust. It is not clear up to now, if the new onset of allergic sensitizations can be modified. So far data on primary prevention are not conclusive. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Approaches to the removal of T-lymphocytes to minimize graft-versus-host disease in patients with primary immunodeficiencies who do not have a matched sibling donor.

Purpose of review: Since the advent of T-lymphocyte depletion in hematopoietic stem cell transplantation (HSCT) for primary immunodeficiency, survival following this procedure has remained poor compared to results when using matched sibling or matched unrelated donors, over the last 40 years. However, three new techniques are radically altering the approach to HSCT for those with no matched donor, particularly those with primary immunodeficiencies which are not severe combined immunodeficiency. Recent findings: Three main techniques of T-lymphocyte depletion are altering donor choice for patients with primary immunodeficiencies and have improved transplant survival for primary immunodeficiencies to over 90%, equivalent to that for matched sibling and matched unrelated donor transplants. CD3+ T cell receptor (TCR)[alpha][beta]+ CD19+ depletion, CD45RA depletion and use of posttransplant cyclophosphamide give similar overall survival of 90%, although viral reactivation remains a concern. Further modification of CD3+ TCR[alpha][beta]+ CD19+ depletion by adding back inducible caspase-9 suicide gene-modified CD3+ TCR[alpha][beta]+ T-lymphocytes may further improve outcomes for patients with systemic viral infection. Summary: Over the last 5 years, the outcomes of HSCT using new T-lymphocyte depletion methods have improved to the extent that they are equivalent to outcomes of matched sibling donors and may be preferred in the absence of a fully matched sibling donor, over an unrelated donor to reduce the risk of graft versus host disease. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Critical appraisal of the unmet needs in the treatment of chronic spontaneous urticaria with omalizumab: an Italian perspective.

Purpose of review: The humanized anti-IgE antibody omalizumab has been available for patients with chronic spontaneous urticaria (CSU) in Italy since 2015. This review summarizes the unresolved issues and unmet therapeutic needs associated with omalizumab and discusses practical recommendations for its use in the management of CSU. Recent findings: Although modern second-generation H1-antihistamines are the standard of care for patients with CSU, adjunctive treatments (including omalizumab) may be required for effective control of symptoms in many patients. Evidence from clinical trials and experience from daily clinical practice suggest that the use of omalizumab in patients with CSU who have inadequate response to H1-antihistamines remains challenging. Summary: Based on current international guidelines, omalizumab labelling information and our experience in clinical practice, we provide treatment recommendations regarding the use of omalizumab in patients with CSU. These include: optimal treatment duration, the use of concomitant antihistamine therapy, the definition and management of disease relapse after treatment, and the management of patients with late or no response to treatment. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Differential Diagnosis of Intramuscular Schwannoma of the Craniocervical Region

Abstract: Schwannomas in the head and neck are a relatively common condition. However, intramuscular schwannomas in the craniocervical region are extremely rare. The preoperative consideration of schwannomas is very important to preserve adjacent circulation and nerve function during the surgery in this area. Moreover, the treatment and preoperative evaluation of this condition is not firmly established in the past literatures. The authors successfully managed the intramuscular schwannoma in the craniocervical region, and provide the differential diagnoses with appropriate treatments.

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Review of “Alopecia Following Bicoronal Incisions” by Kadakia S, Badhey A, Ashai S, Lee TS, Ducic Y in JAMA Facial Plast Surg 19: 220–224, 2017

No abstract available

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Postoperative Changes After Closed Reduction of Nasal Fracture

Abstract: Nasal bone fracture is the most common facial fracture; however, surgery does not guarantee reduction and complications, such as undercorrection, overcorrection, and deviation, may occur. By analyzing findings of computed tomography (CT) immediately and at 3 months postoperatively, we evaluated the accuracy of reduction and long-term changes to the nasal bone. Patients with pure nasal bone fracture were evaluated from January 1, 2010 to December 31, 2011. First, we categorized fracture types according to the Stranc-Robertson classification system, using preoperative CT findings (ie, F1, F2, L1, and L2). We categorized each result of reduction by immediate postoperative CT scan findings as "Excellent," "Good," "Fair," and "Poor," with "Excellent" and "Good" ratings being considered a "Success." We evaluated changes to the nasal bone at 3 months after reduction, using the same grade. A total of 128 patients were analyzed. The results of patients in the F1 group were better than those of other patients immediately postoperatively, whereas those of the L2 group were worse. The overall success rate was 49.2% (58/118). At 3 months postoperatively, 33 cases exhibited an improvement to a higher grade, whereas 25 cases improved from an unacceptable outcome to a successful outcome, with the overall success rate being 70.3% (83/118). Immediately postoperative CT scans can be helpful for surgeons in determining whether a secondary adjustment is necessary. Incompletely reduced nasal bone showed spontaneous improvement in bony arrangement according to our study, so simple observation could be a choice.

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Evaluation of Protraction Face-Mask Therapy on the Craniofacial and Upper Airway Morphology in Unilateral Cleft Lip and Palate

Introduction: The aim of the authors' study was to evaluate the effects of protraction face-mask therapy on the craniofacial and upper airway morphology in patients with unilateral cleft lip and palate (UCLP). Methods: Twenty-three growing UCLP patients (mean age: 8.3 + 2.4) were enrolled in the study group. Protraction face-mask in combination with Hyrax appliance was applied for the correction of anterior crossbite and maxillary insufficiency. Twenty-six patients with maxillary retrusion (mean age: 8.1 + 2.5) were evaluated as the control group. The pharyngeal airway morphology was assessed via the area measurements of upper airway structures on the lateral cephalometric radiographs. Results: The upper airway morphology was similar compared with the control group subjects at the beginning of the treatment. The pharyngeal airway area was increased significantly following the maxillary expansion and protraction. Nasopharyngeal area increased and the oropharyngeal area decreased significantly. There was an increase in the sagittal and vertical dimensions after the protraction therapy. Conclusion: The pharyngeal morphology in both UCLP patients and control group patients was similarly improved with the protraction face-mask therapy.

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Osseous Flap of Galea and Periosteum Filled With Mesenchymal Stem Cells, Platelet-Rich Plasma, Bone Dust, and Hyaluronic Acid

Abstract: Reconstructive surgery to craniofacial deformities caused by tumor ressections, traumas or congenital malformation are frequent in medicine practice. It aims to provide the patients with better quality of life and functional improvement of speech, breathing, chewing, and swallowing. Many are the techniques described in the literature to recover bone defects. This study evaluated a vascularized galeal and periosteum flap in rabbits, which could possibly substitute the bone graft in reconstructive surgery, especially for facial defects. It involved rabbits, divided into 12 groups, submitted to a surgical procedure to construct the galea and periosteum cranial flap filled with fragments of cranial bone, platelet-rich plasma, mesenchimal stem cells, and hyaluronic acid. The evaluation methods included image examinations and histological analysis. The results demonstrated bone formation with the use of platelet-rich plasma, mesenchimal stem cells, and bone fragments. The use of several enrichment materials of osseous cellular stimulation improved the quality and bone tissue organization. The more enrichment factor used, the better the tissue quality result was. Much research should be done to improve the methods and to analyze if results in human have the same bone formation as it happened in rabbits.

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Formation of the Philtral Column Using a Dermal Graft in Secondary Unilateral Cleft Lip

Introduction: The philtral column has an important aesthetic significance and is especially important in patients with cleft lip. If the integrity of the philtrum cannot be preserved in patients of unilateral clefts, these patients will have profound abnormalities in their facial musculature. The purpose of this study was to analyze the effects of dermal grafting on the philtral column in patients with a unilateral alveolar cleft. Methods: The authors retrospectively studied dermal grafts performed in Konkuk University Medical Center between January 2009 and January 2015. A total of 26 patients with unilateral cleft lip were included in this study; the authors measured philtral symmetry based on differences in convexity and angle using clinical photos. Additionally, panel evaluation was performed. Results: Of 26 patients enrolled, 21 completed follow-up and had adequate photographs. Five patients who were lost to follow-up were excluded. The difference in convexity decreased from 0.25 to 0.15 (P

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Olfactory Dysfunction Associated With Neuro-Behçet Disease

Introduction: Neurologic involvement associated with Behçet disease (BD) is defined as a different entity: Neuro-Behçet disease (NBD). Behçet disease presents with olfactory dysfunction. It is not known whether this is the consequence of mucosal involvement or neurologic involvement. Objective: The aim of this study was to investigate whether olfactory dysfunction was further aggravated as the result of neurologic involvement. Methods: Sixteen patients diagnosed with NBD and 16 healthy control patients with similar demographic characteristics were recruited as the healthy control group. Expanded Disability Status Scale (EDSS) scoring was used for quantification of neurological disability. All diagnoses were confirmed and categorized with magnetic resonance imaging studies in all patients individually: parenchymal or nonparenchymal. A well-established test of orthonasal olfaction developed at the CCCRC was used. Correlation analysis was carried out. Results: The mean CCCRC score of NBD patients was 4.60 out of 7, and this group was diagnosed to be moderately hyposmic, whereas the average score of the control group was 6.5; the difference was significant (P 

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Analysis of Orbital Volume Measurements Following Reduction and Internal Fixation Using Absorbable Mesh Plates and Screws for Patients With Orbital Floor Blowout Fractures

Introduction: Hinge-shaped fractures are common type of orbital floor blowout fractures, for which reduction and internal fixation is ideal. Nonetheless, orbital floor reconstruction using alloplastic materials without reducing the number of bone fragments is the most frequently used procedure. Therefore, this study analyzed and compared the outcomes between open reduction and internal fixation using absorbable mesh plates and screws, and orbital floor reconstruction, by measuring the orbital volume before and after surgery. Method: Among patients with orbital floor blowout fractures, this study was conducted on 28 patients who underwent open reduction and internal fixation, and 27 patients who underwent orbital floor reconstruction from December 2008 to September 2015. The mechanism of injury, ophthalmic symptoms before and after surgery, and the degree of enophthalmos were examined; subsequently, the volumes of the affected and unaffected sides were measured before and after surgery based on computed tomography images. This study compared the degree of recovery in the correction rate of the orbital volume, ophthalmic symptoms, and enophthalmos between the 2 groups. Result: The patients who underwent open reduction and internal fixation, and the patients who underwent orbital floor reconstruction showed average correction rates of 100.36% and 105.24%, respectively. Open reduction and internal fixation showed statistically, significantly superior treatment outcomes compared with orbital floor reconstruction. The ophthalmic symptoms and incidence of enophthalmos completely resolved in both groups. Conclusion: For orbital floor blowout fractures, open reduction and internal fixation using absorbable mesh plates and screws was a feasible alternative to orbital floor reconstruction.

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Reconstruction of Zygomaticomaxillary Buttress With Mandibular Ramus Bone Graft in Atrophic Maxillary Fracture

No abstract available

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Secondary Palatal Elongation: Improvement in Speech Quality

Abstract: Cleft palate is one of the challenging problems in the field of craniofacial surgery. In particular, the conventional methods of bilateral and severe cleft palate repairs have failed to achieve normal speech. In most instances, secondary procedures such as pharyngoplasty and pharyngeal flap surgery are performed to improve speech. This study introduces secondary palatal elongation (SPE) as a new approach to cleft palate repair. The patients included usually had a short palate and unrepaired palatal muscles. The authors' procedure involved dissecting the previously repaired palatal mucosa and pushing back and cutting the nasal mucosa of the palate horizontally and further pushing it back. Then, 1 or 2 buccal mucosal flaps were used to repair the nasal mucosal defect of the palate. In case of unrepaired veloplasty from the primary surgery, the levator muscles were dissected and sutured together to perform veloplasty. The range of palatal elongation was 15 to 25 mm. Secondary palatal elongation has been performed on 17 patients since 2007 with a high rate of speech improvement. Based on this 9-year experience with performing SPE, SPE is a radical anatomic technique of palatal elongation as compared with pharyngoplasty and pharyngeal flap surgery. All 17 patients who underwent SPE showed improvement in speech, from very poor to poor speech and from normal to good speech.

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The Effect of External Approach Septoplasty on Olfactory Function

Objective: Septal deviation-induced nasal obstruction is frequently accompanied by hyposmia. The aim of this study was to evaluate the effect of external approach septoplasty on olfactory function. Methods: Thirty patients (23 males, 7 females) who had external approach septoplasty were included in the study. The age interval was 18 to 60 years (mean 33±12 years). All subjects had olfactory function and acoustic rhinometry tests in both the pre- and postoperative periods (mean interval 6 weeks ± 3 weeks). Olfactory function was determined by the "Sniffin Sticks" test. The minimum cross-sectional area from the nostril to 2.20 cm backward was referred to as MCA1, and the minimum cross-sectional area from 2.20 to 5.40 cm was referred to as MCA2, determined by acoustic rhinometry. Results: Olfactory threshold, discrimination, and identification function improved significantly after external approach septoplasty. A statistically significant difference was also detected between pre- and postoperative left MCA1 and left MCA2 of the nasal cavities. Postoperative hyposmic and anosmic patient improvement was statistically significant. Conclusion: External approach septoplasty has a beneficial effect on olfaction and this effect may be partly due to interactions between the increased perception of nasal air flow, as well as surgery-associated improvement in the internal nasal valve area.

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An Epithelioid Hemangioendothelioma of the Head and Neck

Abstract: An epithelioid hemangioendothelioma (EHE) is a rare vascular tumor of the head and neck region, which carries a risk of recurrence and metastasis. Its etiology is still unclear. It frequently involves the lungs, liver, and bones. Rarely, it may manifest in other parts of the body. Pathologic immunohistochemical investigations are essential to make the definite diagnosis. As it is uncommon, there is no standardized protocol for the treatment of EHE. Herein, the authors report a rare patient with of an EHE localized in the head and neck region.

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Surgical Outcome of Simplified Horse-Shoe Technique With the Traditional Procedure in Children With Trigonocephaly

Abstract: Trigonocephaly is one of the most common types of craniosynostosis leading to triangular-shaped head and neurodevelopmental complications. Several surgical techniques have been suggested for its correction, but the newly suggested technique seems to have optimal outcomes compared with the traditional methods. Thus, the authors retrospectively evaluated the outcomes of the simplified horse-shoe technique with previous procedures performed on 169 children severe trigonocephaly during 1996 to 2015 at Mofid Hospital, Tehran, Iran. Demographic data of the patients and the surgical outcomes and complications and the need for reoperation were recorded and scored using the Whitaker system. The male-to-female ratio was 2.75:1. The mean ±  standard deviation age of all the patients at the time of surgery was 7.09 ± 7.5, 9.95 ± 7.71, 10.53 ± 6.57, and 10.59 ± 7.96 months for the traditional, horse-shoe, and simplified horse-shoe techniques, respectively. The total reoperation rate was 6.5% (4.7% in the traditional technique, 1.2% in the horse-shoe, and 0.6% in the simplified horse-shoe technique) (P 

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Is Horizontal Mattress Suturing More Effective Than Simple Interrupted Suturing on Postoperative Complications and Primary Wound Healing After Impacted Mandibular Third Molar Surgery?

Abstract: The aim of this clinical study was to compare the influence of 2 different suturing techniques on postoperative complications and wound healing after surgical extractions of impacted mandibular third molars. In this randomized split mouth study, 30 patients were examined in whom 60 consecutive surgical extractions of symmetrically positioned impacted mandibular third molars were performed. After the extractions, the surgical flaps were sutured with either the simple interrupted or horizontal mattress suturing technique. Postoperative swelling and trismus were recorded on the 2nd, 7th, and 10th days. Pain was recorded in a 7-day diary and wound dehiscence was recorded on the10th postoperative day. Statistical evaluation of data was made using Mann–Whitney U test and Pearson correlation. There were no statistical differences between the 2 suturing techniques in terms of postoperative pain, trismus, and swelling (P > 0.05). There was significantly less wound dehiscence in the horizontal mattress suturing group than in the simple interrupted suturing group (P: 0017). According to the results of this study, the horizontal mattress suturing technique is more effective than the simple interrupted suturing technique on wound healing after impacted mandibular third molar surgery, although it does not decrease the levels of pain, trismus, and swelling.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2xTNQ48