Radiology

Influence of virtual monochromatic spectral image at different energy levels on motion artifact correction in dual-energy spectral coronary CT angiography Abstract Purpose To investigate the influence of virtual monochromatic spectral (VMS) CT images at different energy levels on the effectiveness of a motion correction technique (SSF) in dual-energy Spectral coronary CT angiography (CCTA). Materials and methods 29 cases suspected of or diagnosed with coronary artery disease underwent Spectral CCTA using a prospective ECG triggering with 250 ms padding time. SSF was applied to the determined least-motion phase to generate 6 additional sets of VMS images with energy levels from 40 to 100 keV. CT value and standard deviation (SD) in the aortic root and epicardial adipose tissue were measured. Image quality of the RCA, LAD and LCX was evaluated on a per-vessel basis in each patient. Two reviewers evaluated the artery using the score of the segment. Results The low energy VMS images increased CT value and image noise compared with higher-energy VMS images, except 90 keV and 100 keV. The CNR of 40–70 keV were higher than those of 80–100 keV (P < 0.05). The image quality scores for images at 50–80 keV were higher than those of 40, 90, and 100 keV (P < 0.05), and the VMS image quality at 50 keV and 60 keV with SSF was the highest. Conclusion SSF can effectively reduce the motion artifacts when coronary vessels have suitable contrast enhancement which can be achieved by adjusting energy levels of VMS images.

Safety margin of radiofrequency ablation for hepatocellular carcinoma: a prospective study using magnetic resonance imaging with superparamagnetic iron oxide Abstract Purpose In radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC), it is difficult to assess the ablative margin (AM) precisely by comparing pre- and post-RFA CT images. We prospectively studied the AMs using magnetic resonance imaging (MRI) with pre-administered superparamagnetic iron oxide (SPIO). SPIO is safe for kidney disease patients. Materials and methods Hepatocellular carcinoma patients were treated with RFA within 8 h of SPIO administration. On T2*-weighted MRI performed 4–7 days later, AM was visualized as a hypointense rim. The ablation status was classified as AM(+) if the rim completely surrounded the tumor, AM(0) if the rim was partly discontinuous without tumor protrusion, and AM(−) if the rim was partly discontinuous with tumor protrusion. The minimal thickness of AM was measured. AM(−) tumors were re-treated consecutively. Results In total, 85 HCCs ablated in 76 patients were evaluated. The local recurrence rate at 3 years was 2% for AM(+) tumors and 34% for AM(0) tumors (p < 0.01). In addition, no local recurrence was seen in the tumors with an AM of ≥ 2 mm. Conclusion MRI with pre-administered SPIO is useful for determining the AM precisely, and an AM of ≥ 2 mm is recommended for curative RFA. Trial registration number This study was registered with UMIN Clinical Trials Registry (UMIN 000025406).

The usefulness of full-iterative reconstruction algorithm for the visualization of cystic artery on CT angiography Abstract Purpose To evaluate the potential of full-iterative reconstruction (IR) for improving image quality of the cystic artery on CT angiography and to assess observer performance. Methods Thirty patients who underwent both liver dynamic CT and conventional angiography were included in this retrospective study. All CT data were reconstructed through filtered back projection (FBP), adaptive iterative dose reduction 3D (AIDR3D), and forward-projected, model-based, iterative reconstruction solution (FIRST), respectively. In objective study, we analyzed mean ΔCT numbers (the difference between the HU peak of the vessel and the background) and full-width at tenth-maximum (FWTM) of three parts of the cystic artery by profile curve method comparing the three reconstructions. Subjectively, visualization was evaluated using a four-point scale performed by two blinded observers. ANOVA was used for statistical analysis. Results In all parts of the cystic artery, the mean ΔCT number of FIRST was shown to be significantly better than that of FBP and AIDR3D (p < 0.05). FWTM in FIRST was the smallest in all of the vessels. The mean visualization score was significantly better with FIRST than with other CT reconstructions (p < 0.05). Conclusions The FIRST algorithm led to improved CTA visualization of the cystic artery.

Postmortem volume change of the spleen and kidney on early postmortem computed tomography: comparison with antemortem computed tomography Abstract Purpose To clarify an early postmortem change, we investigated the volume changes of the spleen and kidney on postmortem CT compared with antemortem CT in the same patients. Materials and methods We retrospectively evaluated the volumes of 56 spleens (56 cases) and 50 kidneys (25 cases) using antemortem and postmortem CT, which were performed within 168 min after death. We divided the cases of spleen analysis into a hemorrhagic group (n = 12) and a non-hemorrhagic group (n = 44). Results The volumes of the organs before and after death were 101.0 ± 70.9 (cm3, mean ± standard deviation) and 81.1 ± 57.8 in spleens, 120.3 ± 49.2 and 109.2 ± 39.2 in kidneys, respectively. Both spleens and kidneys shrank after death (p < 0.05). The volumes of spleens before and after death were 111 ± 66.5 and 67.5 ± 27.7 in the hemorrhagic group, and 98.2 ± 72.5 and 84.9 ± 63.3 in the non-hemorrhagic group, respectively. The median value of the ratio of postmortem splenic volume to antemortem volume in the hemorrhagic group (65.0%) was smaller than the one in the non-hemorrhagic group (90.5%) (p < 0.05). Conclusion We demonstrated that spleens and kidneys significantly reduced in size after death. The rate of shrinkage of spleens in the hemorrhagic group significantly became larger than the one in the non-hemorrhagic group.

CT findings in diagnosis of gastric bare area invasion: potential prognostic factors for proximal gastric carcinoma Abstract Purpose To investigate the correlation between the preoperative CT findings in diagnosis of gastric bare area (GBA) invasion and the 3-year-overall survival (OS) of patients with proximal gastric carcinoma (PGC). Methods 108 consecutive patients with PGC confirmed by biopsy underwent MDCT scan prior to gastrectomy were enrolled retrospectively from Dec 2009 to Dec 2014. GBA invasion in PGC were evaluated by measuring the direct CT signs including transmural involvement and lymph nodes in the GBA. The indirect signs were also evaluated including the infiltration of the diaphragm, gastrophrenic ligament and perigastric fat. Kaplan–Meier estimates with log-rank test and Cox proportional hazard model were used for analysis. Results The two raters achieved excellent agreement. Univariate Kaplan–Meier estimates indicated that postoperative chemotherapy (p = 0.003), transmural involvement (p < 0.001), lymph nodes in the GBA (p = 0.015) and cT staging (p = 0.002) were associated with OS. Cox proportional hazard model indicated that the transmural involvement (HR = 8.194, 95% CI 2.15–31.266), diaphragm involvement (HR = 0.21, 95% CI 0.042–0.986), perigastric fat infiltration (HR = 0.125, 95% CI 0.018–0.885; HR = 0.02, 95% CI 0.001–0.264), and cT staging were independent prognostic factors for OS. Conclusion CT findings of GBA invasion in patients with PGC, not only the transmural involvement but also the indirect signs are independent prognostic factors potentially, which should be given more emphasis in future clinical practice.

Intra-aneurysmal air after flow diversion treatment in intracranial aneurysms: incidence, characteristics and clinical significance Abstract Objective To describe the rate and characteristics of air bubble retention (ABR) within cerebral aneurysms treated by flow diversion. Methods Procedural flat detector CT (FDCT) studies were scrutinized for the presence of air bubbles (density < − 200 HU) in patients treated by flow diversion. Patients with intrasaccular treatment or previous clipping were excluded. Clinical outcomes, procedural angiograms, aneurysm characteristics and imaging features of air within the aneurysm were evaluated. Results Bubbles were noted in 17.1% of 105 aneurysms in 85 FDCTs. Aneurysms with ABR were significantly larger (mean diameter: 18.9 versus 7.5 mm, P < 0.0001). There was a trend for the use of multiple devices during the treatment of these aneurysms (72.2% vs 49.4%, P = 0.071). All of the bubbles were located rostrally in the aneurysm sac and were smaller than 6 mm (mean diameter: 2.1 ± 1.3 mm). None of the patients had post-procedural neurological deterioration. The air had spontaneously disappeared on follow-up CT images (available in 12 patients) obtained at a mean follow-up duration of 48 h. Conclusions ABR is not infrequent in cerebral flow diversion procedures. It is a clinically silent and self-limited technical complication. We propose air entrapment or filtration through the flow diverter as causative factors.

MR enterography: what is next after Crohn's disease? Abstract Within the gastrointestinal system, the small bowel represents the most difficult site to approach with imaging modalities. During the last decades, magnetic resonance enterography has reached an increasing interest, up to be considered an essential part in the diagnostic framework of Crohn's disease patients. Nevertheless, the distention of the intestinal loops provided by the administration of oral contrast medium, the possibility of a dynamic evaluation, and the lack of radiation exposure are huge advantages that can be exploited for the assessment of other clinical conditions affecting the small bowel. Physicians and radiologists should be aware of the possibilities offered by this technique, looking at it as a trustful alternative to the well-worn radiological examinations. In this respect, the purpose of this work is to show some uncommon clinical conditions that can be assessed with magnetic resonance enterography and that fall within the various differential diagnosis of the intestinal disorders.

Risk factors for local recurrence of hepatocellular carcinoma after transcatheter arterial chemoembolization with drug-eluting beads (DEB-TACE) Abstract Purpose To identify the risk factors for local recurrence in hepatocellular carcinoma (HCC) patients treated with transcatheter arterial chemoembolization (TACE) with drug-eluting beads (DEB-TACE). Materials and methods In this retrospective study, 35 patients (27 males, 8 females; median age 73 years) with 116 tumors (median size 14 mm) treated with DEB-TACE from May 2014 to September 2018 were evaluated. Age, sex, etiology, Child–Pugh class, alpha-fetoprotein, des-gamma-carboxyprothrombin, previous conventional TACE, tumor location, tumor size, tumor number, contact with the liver surface, level of embolization, corona enhancement on CT during hepatic arteriography, vascular lakes, additional embolization with gelatin sponge particles, and supplying vessels on digital subtraction angiography (DSA) after embolization were analyzed. Results Univariate analysis showed that advanced age, female, large tumor, contact with the liver surface, and residual supplying vessels were significant risk factors for local recurrence (p = 0.012, 0.0013, 0.0023, 0.025, and < 0.001, respectively). On multivariate logistic analysis, large tumor, contact with the liver surface, and residual supplying vessels on DSA were significant risk factors for local recurrence (p = 0.0026, 0.038, and < 0.001, respectively). Conclusion Large tumor size, contact with the liver surface, and residual supplying vessels on DSA were significant risk factors associated with local recurrence after DEB-TACE for HCC.

Displacement of the transverse colon is a highly specific computed tomography finding for the preoperative diagnosis of a transomental hernia Abstract Purpose A transomental hernia (TOH) is a rare type of internal hernia and is associated with a high strangulation rate and high mortality rate. Displacement of the transverse colon on computed tomography (CT) may be specific to a TOH and may facilitate an early diagnosis. The aim of this study was to verify the effectiveness of a novel approach assessing displacement of the transverse colon for the preoperative diagnosis of a TOH. Materials and methods We retrospectively reviewed the CT and operative data of 113 patients who underwent surgery for small bowel obstruction (SBO) between 2011 and 2018. The proportion of transverse colon loops posterior to dilated intestinal loops (PTPI) was calculated. Results The patients were divided into a TOH group (n = 7) and other SBO group (n = 106). The median PTPI was significantly higher in the TOH group than in the other SBO group (67% [0–97%] vs. 0% [0–100%], Wilcoxon's test, p = 0.03). A receiver operating characteristic curve showed that when the PTPI was ≥ 57%, its sensitivity and specificity for a TOH were 71% and 94%, respectively. Conclusion The PTPI is a reliable quantitative measure to distinguish a TOH from other types of SBOs.

Comparison of magnetization transfer contrast of conventional and simultaneous multislice turbo spin echo acquisitions focusing on excitation time interval Abstract Purpose Image contrast differs between conventional multislice turbo spin echo (conventional TSE) and multiband turbo spin echo (SMS-TSE). Difference in time interval between excitations for adjacent slices (SETI) might cause this difference. This study aimed to evaluate the influence of SETI on MT effect for conventional TSE and compare conventional TSE with SMS-TSE in this respect. Materials and methods Three different agar concentration phantoms were scanned with conventional TSE by adjusting SETI and TR. Signal change for different SETI was evaluated using Pearson's correlation analysis. SMS-TSE was acquired by changing TR similarly. Three human volunteers were scanned with similar settings to evaluate reproducibility of the phantom results in human brain. Results In conventional TSE, shorter SETI induced larger signal reduction. Longer TR and higher agar concentration emphasized this characteristic. Significant linear correlation (P < 0.05) was found in the major cases. The SMS-TSE signal intensity in each TR and phantom was smaller than the assumable levels in conventional TSE when the slices were simultaneously excited. Similar characteristic was observed in human brain. Conclusion Shorter SETI results in larger MT effect in conventional TSE. The contrast change in SMS-TSE was larger than the supposable level from simultaneous excitation, which needs consideration in clinics.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Brain Tumor Pathology

Next-generation whole exome sequencing of glioblastoma with a primitive neuronal component Abstract Glioblastoma with a primitive neuronal component (GBM-PN) was renamed from glioblastoma with primitive neuroectodermal tumor-like component (GBM-PNET) in the new WHO classification of tumors of the central nervous system in 2016. GBM-PN is a rare variant of glioblastoma. There were not so many publications on the investigation of GBM-PN. We did whole exome sequencing for 11 GBM-PN cases and found that the percentage of TP53, PIK3CA, PIK3R1, or PTEN mutation in our GBM-PN cases (72.7%, 27.3%, 27.3%, and 27.3% respectively) was much higher than that in cases in TCGA GBM 2008, TCGA GBM 2013, and TCGA lower-grade glioma databases. The findings indicate that GBM-PN is a distinct variant of glioblastoma. The next-generation sequencing can play a role in the diagnosis of GBM-PN especially for small biopsy cases. Eight out of 11 cases showed mutations in PTEN–PI3K pathway, which indicates that targeted therapeutic agents (PI3K inhibitors, mTORC1 inhibitors or dual PI3K/mTOR inhibitors) may be used for the treatment of GBM-PN in the future.

MN1 rearrangement in astroblastoma: study of eight cases and review of literature Abstract Astroblastomas are unique tumours with unresolved issues in terms of their origin, molecular biology, clinical behaviour, and response to treatment. To decipher the characteristics of this tumour, we reviewed cases histologically diagnosed as astroblastoma in our institute over the past 8 years, with immunohistochemistry, and performed fluorescence in situ hybridisation (FISH), for the newly emerged MN1 rearrangement which was reported in central nervous system high-grade neuroepithelial tumours. The mean age at diagnosis was 18.6 years with all cases seen in females and with supratentorial localisation. The tumours showed typical circumscription and bubbly appearance on imaging. The cohort included eight cases diagnosed as astroblastoma (two low grades; six anaplastic) based on histology and proliferative index. The tumours displayed characteristic astroblastic pseudorosettes with hyalinised vascular core and variable immunopositivity for glial fibrillary acidic protein, pan cytokeratin, and epithelial membrane antigen. MN1 break-apart by FISH was found in 5/8 of our cases (62.5%), which included 2 low-grade and 3 anaplastic tumours. Tumour recurrence was noted in three cases, with MN1 alteration in two. We account for one of the few series to study the MN1rearrangement in astroblastoma and conclude that MN1 alteration is seen in a subset of these tumours.

Clinicopathological characteristics of circumscribed high-grade astrocytomas with an unusual combination of BRAF V600E, ATRX , and CDKN2A/B alternations Abstract We report four cases of high-grade astrocytoma with a BRAF V600E mutation, ATRX inactivation, and CDKN2A/B homozygous deletion. Children to young adults aged 3–46 presented with a well demarcated contrast-enhancing mass in the supratentorial area. Pathological examination revealed packed growth of short spindle to round polygonal cells including some pleomorphic cells. The tumors had less ability to infiltrate into the adjacent brain parenchyma and presented a circumscribed growth pattern. Mitosis was readily found, accompanied by focal necrosis and/or microvascular proliferation. Tumors were histologically similar in part to pleomorphic xanthoastrocytoma (PXA) or anaplastic PXA, but did not fit criteria for either neoplasm. A BRAF V600E mutation and homozygous deletion of CDKN2A/B were observed, which is similar to the genetic features of PXA or epithelioid glioblastoma, but the additional loss of ATRX nuclear immunoreactivity and absence of TERT promoter mutation were unusual findings, indicating a novel genetic profile. Despite their malignant histological features, all patients had a favorable clinical course and remained alive for 6 months to 28 years under standard medical treatment for malignant glioma. In summary, high grade astrocytomas with BRAF V600E, ATRX, and CDKN2A/B alternations had unique clinicopathological features and may be a novel subset of high grade glioma.

High-grade glioneuronal tumor with an ARHGEF2 – NTRK1 fusion gene Abstract Here, we report a highly unusual case of high-grade glioneuronal tumor with a neurotrophic tropomyosin receptor kinase (NTRK) fusion gene. A 13-year-old girl presented with headache and vomiting and MRI detected two cystic lesions bilaterally in the frontal areas with surrounding edema. The left larger tumor was removed by left frontal craniotomy. The tumor was diagnosed as a high-grade glioneuronal tumor, unclassified. Methylation profiling classified it as a diffuse leptomeningeal glioneuronal tumor (DLGNT) with low confidence. This tumor showed genotypes frequently found in DLGNT such as 1p/19q codeletion without IDH mutation and, however, did not have the typical DLGNT clinical and histological features. RNA sequencing identified an ARHGEF2 (encoding Rho/Rac guanine nucleotide exchange factor 2)–NTRK1 fusion gene. The presence of recurrent NTRK fusion in glioneuronal tumors has an important implication in the clinical decision making and opens up a possibility of novel targeted therapy.

A long-term survivor of pediatric midline glioma with H3F3A K27M and BRAF V600E double mutations Abstract We report a case of 2-year-old female with lateral ventricular glioma harboring both H3F3A K27M and BRAF V600E mutations. By the methylation analysis, the tumor was classified as a diffuse midline glioma H3 K27M mutant, WHO grade IV. However, the tumor was pathologically low-grade and likely localized rather than diffusely infiltrating. Further, the patient has survived more than 8 years after gross total resection of the tumor. Whereas both H3F3A K27M and BRAF V600E have been reported as poor prognostic markers in pediatric glioma, our case, along with several other reported cases, suggests that the coexistence of these two mutations might not indicate poor prognosis. The case emphasizes the importance of comprehensive assessment based on pathological, genetic and clinical findings and calls for further investigations of non-diffuse glioma with H3F3A K27M and glioma with H3F3A K27M and BRAF V600E.

Reviewers in 2018

Preface

Pilomyxoid astrocytomas: a short review Abstract Pilomyxoid astrocytoma is a variant of pilocytic astrocytoma and the clinical, histological and molecular data point to a very close relationship as well as a more aggressive biological behavior for the former. WHO 2016 classification does not provide a specific grade for these neoplasms, but there is sufficient evidence in the literature that pilomyxoid astrocytoma has slightly worse prognosis than typical pilocytic astrocytoma. There is increasing evidence that in addition to the MAPK pathway alterations, pilomyxoid astrocytomas harbor genetic alterations that distinguish them from typical pilocytic astrocytoma

Pathologic and molecular aspects of anaplasia in circumscribed gliomas and glioneuronal tumors Abstract Many breakthroughs have been made in the past decade regarding our knowledge of the biological basis of the diffuse gliomas, the most common primary central nervous system (CNS) tumors. These tumors as a group are aggressive, associated with high mortality, and have a predilection for adults. However, a subset of CNS glial and glioneuronal tumors are characterized by a more circumscribed pattern of growth and occur more commonly in children and young adults. They tend to be indolent, but our understanding of anaplastic changes in these tumors continues to improve as diagnostic classifications evolve in the era of molecular pathology and more integrated and easily accessible clinical databases. The presence of anaplasia in pleomorphic xanthoastrocytomas and gangliogliomas is assigned a WHO grade III under the current classification, while the significance of anaplasia in pilocytic astrocytomas remains controversial. Recent data highlight the association of the latter with aggressive clinical behavior, as well as the presence of molecular genetic features of both pilocytic and diffuse gliomas, with the recognition that the precise terminology remains to be defined. We review the current concepts and advances regarding histopathology and molecular understanding of pilocytic astrocytomas, pleomorphic xanthoastrocytomas, and gangliogliomas, with a focus on their anaplastic counterparts.

Overview of DNA methylation in adult diffuse gliomas Abstract Adult diffuse gliomas form a heterogeneous group of tumors of the central nervous system that vary greatly in histology and prognosis. A significant advance during the last decade has been the identification of a set of genetic lesions that correlate well with histology and clinical outcome in diffuse gliomas. Most characteristic driver mutations consist of isocitrate dehydrogenase 1 (IDH1) and IDH2, and H3 histone family member 3A, which are strongly associated with DNA and histone methylation patterns. A well-characterized DNA methylation aberration is on the O6-methylguanine-DNA methyltransferase promoter. This aberration is associated with an improved response to the DNA alkylating agent, temozolomide. Methylation alterations are used for classification or treatment decisions of diffuse gliomas. This supports the importance of considering epigenomic aberrations in the pathogenesis of gliomas. Recent DNA methylation analyses revealed a small group of IDH mutant diffuse gliomas exhibiting decreased DNA hypermethylation resulting in substantial unfavorable prognosis comparable to glioblastoma. Thus, DNA methylation patterns may become a new standard that replaces the conventional grading system based on histological diagnosis. In this review, we summarize recent developments regarding the contributions of methylation patterns to the pathogenesis of adult diffuse glioma, the interactions between methylation patterns and driver mutations, and potential epigenomic targeted therapies.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Advances in Therapy

Current Practices for Outpatient Initiation of Levodopa-Carbidopa Intestinal Gel for Management of Advanced Parkinson's Disease in the United States Abstract In 2015, the US Food and Drug Administration approved levodopa-carbidopa intestinal gel (LCIG; also known as carbidopa-levodopa enteral suspension in the US) for the treatment of motor fluctuations in patients with advanced Parkinson's disease. LCIG provides a continuous infusion of levodopa and carbidopa by means of a portable pump and percutaneous endoscopic gastrojejunostomy tube. The delivery system has a two-fold pharmacokinetic advantage over orally administered carbidopa/levodopa. First, levodopa is delivered in a continuous rather than intermittent, pulsatile fashion. Second, delivery to levodopa's site of absorption in the jejunum bypasses the stomach, thereby avoiding issues with erratic gastric emptying. In blinded prospective clinical trials and observational studies, LCIG has been shown to significantly decrease "off" time, increase "on" time without troublesome dyskinesia, and reduce dyskinesia. Consistent with procedures in previous studies, LCIG initiation and titration in the pivotal US clinical trial were performed in the inpatient setting and followed a standardized protocol. In clinical practice, however, initiation and titration of LCIG have a great degree of flexibility and, in the US, almost always take place in the outpatient setting. Nonetheless, there remains a significant amount of clinician uncertainty regarding titration in outpatient clinical practice. This review aims to shed light on and provide guidance as to the current methods of titration in the outpatient setting, as informed by the medical literature and the authors' experiences. Funding AbbVie, Inc. Plain Language Summary Plain language summary available for this article.

A Randomized, Crossover Study on the Effect of Food on the Pharmacokinetic Characteristics of Morphine ARER (MorphaBond™ ER), an Abuse-Deterrent Formulation of Extended-Release Morphine Abstract Introduction Food can alter the pharmacokinetics of certain abuse-deterrent formulations. Morphine ARER is an oral abuse-deterrent formulation of ER morphine sulfate tablets formulated with physical and chemical properties that contribute to the abuse-deterrent aspects of the drug. This study compared the relative bioavailability of Morphine ARER in the presence and absence of food. Methods This was a randomized, single-dose, two-treatment, crossover study in which healthy adults received Morphine ARER 100 mg under fasting and fed conditions. Subjects were given naltrexone 50 mg to limit opioid effects. Plasma concentrations of morphine and its active metabolite morphine-6-glucuronide (M6G) were obtained up to 48 h post-dose; area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity (AUC0–∞), maximum observed plasma concentration (Cmax) and time to Cmax (Tmax) were calculated. Safety was evaluated by observation or report of adverse events, which were monitored during the treatment periods. Results Of 28 enrolled subjects, 27 completed all treatments; 1 subject in the fasted group withdrew voluntarily. Under fed conditions, the Cmax for morphine was 33% higher (44.78 vs. 33.30 ng/ml for fed and fasted conditions, respectively) and the median Tmax was 30 min longer than under fasted conditions. The overall morphine exposure (AUC0–∞) was similar for fed (440.6 ng · h/ml) vs. fasted conditions (395.1 ng · h/ml). For M6G, the Cmaxand AUC0–∞ were similar under both conditions, and the median Tmax for M6G was 60 min longer under fed conditions. Common adverse events were somnolence and nausea. Conclusion Morphine ARER can be administered without regard to food. Plain Language Summary Plain language summary available for this article. Funding Inspirion Delivery Sciences, LLC.

Clinical Performance Comparison of Two In-Vitro Diagnostic Multivariate Index Assays (IVDMIAs) for Presurgical Assessment for Ovarian Cancer Risk Abstract Introduction Adnexal or pelvic mass is a finding that commonly raises suspicion for malignancy, especially for ovarian cancer. Proper identification prior to surgery would permit appropriate referral to a specialty center in cases likely to be ovarian cancer, as optimal outcomes in such cases are obtained when surgical staging and treatment are provided at the time of initial surgery. Methods We compared the screening capabilities of two in vitro diagnostic multivariate index assays (IVDMIAs), a new IVDMIA (second-generation multivariate index assay: MIA2G) and a currently used triage algorithm (Risk of Ovarian Malignancy Assay: ROMA). Results Among 245 subjects (24.7%) determined to have a malignancy, ROMA misclassified 51 malignancies (including 10 high-grade ovarian malignancies), whereas MIA2G misclassified 22 (including 5 high-grade ovarian malignancies). Early stage cancers were more frequently misclassified by ROMA (20 vs. 8 cases). The rate of "test-negative" malignancies was significantly higher for ROMA, while the rate of "test-positive" benign cases was significantly higher for MIA2G. Conclusion Triage algorithms play an important role in improving clinical outcomes for women presenting with an adnexal mass regardless of the eventual diagnosis. In this study, MIA2G was shown to correctly predict more cases of ovarian cancer than the ROMA algorithm. Funding Aspira Labs/Vermillion Inc.

Population Pharmacokinetic Analysis of Bintrafusp Alfa in Different Cancer Types Abstract Introduction Bintrafusp alfa, an innovative first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking programmed death ligand 1, has shown promising antitumor activity and manageable safety. Methods To support the dosing strategy for bintrafusp alfa, we developed a population pharmacokinetics model using a full covariate modeling approach, based on pharmacokinetic and covariate data from 644 patients with various solid tumors who received bintrafusp alfa intravenously in two clinical studies. Results A two-compartmental linear model best described bintrafusp alfa concentrations, and no time-varying clearance was identified. Using this model, the estimated clearance was 0.0158 l/h (relative standard error, 4.1%), and the central and peripheral volume of distribution were 3.21 l (relative standard error, 3.2%) and 0.483 l (relative standard error, 9.8%), respectively. The estimated mean elimination half-life of bintrafusp alfa was 6.93 days (95% CI 4.69–9.65 days). Several intrinsic factors (bodyweight, albumin, sex, and tumor type) were found to influence bintrafusp alfa pharmacokinetics, but none of these covariate effects was considered clinically meaningful and no dosage adjustments are recommended. Notably, simulations from the model suggested less variability in exposure metrics with flat dosing versus weight-based dosing. Conclusions Pharmacokinetic analysis of bintrafusp alfa supports the use of a flat dose regimen in further clinical trials (recommended phase 2 dose: 1200 mg every 2 weeks). Trial registration ClinicalTrials.gov identifiers: NCT02517398 and NCT02699515. Funding Merck Healthcare KGaA as part of an alliance between Merck Healthcare KGaA and GlaxoSmithKline.

Determining MRI Inflammation Targets When Considering a Rheumatoid Arthritis Treat-to-Target Strategy: Results of a Randomized, Placebo-Controlled Trial Abstract Introduction Magnetic resonance imaging (MRI) is increasingly used in patients with rheumatoid arthritis (RA) to determine residual inflammation after treatment and as a predictor of structural damage progression. Establishing an optimal threshold of inflammatory activity that predicts lower risk of structural damage progression may inform treatment decisions. This post hoc analysis investigated whether patients with RA at low risk of structural damage progression can be identified based on MRI inflammation thresholds. Methods Hand and wrist MRI was performed at baseline, and at months 6 and 12 in a phase 3b, randomized, active-controlled, double-blind trial of abatacept in early RA (AVERT). Pathologies were scored using the OMERACT RA MRI Score. Data were stratified into two risk subgroups (less and more severe inflammation) for structural damage progression (erosion change > 0.5) based on baseline inflammation. In this post hoc analysis, log odds ratios of probability of progression {adjusted for baseline Disease Activity Score in 28 joints [C-reactive protein; DAS28 (CRP)]} were compared between subgroups to test the performance of inflammation thresholds. Results There were 351 randomized and treated patients with baseline MRIs, of whom 276 (78.6%) and 235 (67.0%) had MRIs available at months 6 and 12, respectively. The DAS28 (CRP)-adjusted probabilities of progression from baseline to month 12 based on scores at baseline, and from months 6 to 12 based on month 6 scores, were significantly lower among patients with less inflammation (P < 0.0001–0.0459), independent of clinical disease activity. Predefined thresholds of synovitis ≤ 3 (total score 21), osteitis ≤ 3 (total score 69) and total inflammation score (osteitis double-weighted) ≤ 9 were associated with a lower likelihood of structural damage progression in unadjusted analyses. Conclusion Levels of MRI-determined inflammatory activity below defined thresholds were independently associated with a lower risk of structural damage progression in early RA, providing a potential trial endpoint for levels of inflammation not associated with progression. Trial Registration ClinicalTrials.gov identifier, NCT01142726. Funding Bristol-Myers Squibb.

Pharmacokinetics, Safety and Tolerability of JNJ-56136379, a Novel Hepatitis B Virus Capsid Assembly Modulator, in Healthy Subjects Abstract Introduction Hepatitis B viral capsid assembly is an attractive target for new antiviral treatments. JNJ-56136379 (JNJ-6379) is a potent capsid assembly modulator in vitro with a dual mode of action. In Part 1 of this first-in-human study in healthy adults, the pharmacokinetics (PK), safety and tolerability of JNJ-6379 were evaluated following single ascending and multiple oral doses. Methods This was a double-blind, randomized, placebo-controlled study in 30 healthy adults. Eighteen subjects were randomized to receive single doses of JNJ-6379 (25 to 600 mg) or placebo. Twelve subjects were randomized to receive 150 mg JNJ-6379 or placebo twice daily for 2 days, followed by 100 mg JNJ-6379 or placebo daily for 10 days. Results The maximum observed plasma concentration and the area under the curve increased dose proportionally from 25 to 300 mg JNJ-6379. Following multiple dosing, steady-state conditions were achieved on day 8. Steady-state clearance was similar following single and multiple dosing, suggesting time-linear PK. All adverse events (AEs) reported were mild to moderate in severity. There were no serious AEs or dose-limiting toxicities and no apparent relationship to dose for any AE. Conclusion JNJ-6379 was well tolerated in this study. Based on the safety profile and plasma exposures of JNJ-6379 in healthy subjects, a dosing regimen was selected for Part 2 of this study in patients with chronic hepatitis B. This is anticipated to achieve trough plasma exposures of JNJ-6379 at steady state of more than three times the 90% effective concentration of viral replication determined in vitro. Trial registration Clinicaltrials.gov identifier, NCT02662712. Funding Janssen Pharmaceutica.

A Randomized, Double-Blind, Double-Dummy Study of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Relative to Umeclidinium/Vilanterol Dry Powder Inhaler in COPD Abstract Introduction Glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), formulated using co-suspension delivery technology, is the only approved fixed-dose combination long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) delivered via MDI. Direct comparisons of GFF MDI versus other LAMA/LABAs have not previously been performed. We assessed the efficacy and safety of GFF MDI relative to umeclidinium/vilanterol dry powder inhaler (UV DPI) in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). Methods In this phase IIIb randomized, double-blind, double-dummy, multicenter, 24-week study, patients received GFF MDI 18/9.6 μg (equivalent to glycopyrronium/formoterol fumarate dihydrate 14.4/10 μg; two inhalations per dose, twice-daily; n = 559) or UV DPI 62.5/25 μg (one inhalation, once-daily; n = 560). Primary endpoints were change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) and peak change from baseline in FEV1 within 2 h post-dose, both over 24 weeks. Additional lung function, symptom and safety endpoints were also assessed. Results For the primary endpoints, GFF MDI was non-inferior to UV DPI (using a margin of − 50 mL) for peak FEV1 (least squares mean [LSM] difference − 3.4 mL, 97.5% confidence interval [CI] − 32.8, 25.9) but not for trough FEV1 (LSM difference − 87.2 mL; − 117.0, − 57.4). GFF MDI was nominally superior to UV DPI for onset of action (p < 0.0001) and was nominally non-inferior to UV DPI for all symptom endpoints (Transition Dyspnea Index focal score, Early Morning/Night-Time Symptoms COPD instrument scores, and COPD Assessment Test score). Exacerbation and safety findings were similar between groups. Conclusions Over 24 weeks of treatment, GFF MDI was non-inferior to UV DPI for peak FEV1, but not for morning pre-dose trough FEV1. GFF MDI had a faster onset of action versus UV DPI. There were no clinically meaningful differences between treatments in symptom endpoints. Both treatments were well tolerated with similar safety profiles. Trial registration NCT03162055 (Clinicaltrials.gov) Funding AstraZeneca

Correction to: A Multicenter, Observational, Prospective Study of the Effectiveness of Switching from Budesonide/Formoterol Turbuhaler ® to Budesonide/Formoterol Easyhaler ® Unfortunately, the mean difference in change from baseline ACT was incorrectly reported in the abstract as 19.0 vs. 20.8 instead of 18.9 vs. 20.7

Some Considerations on the WHO Histological Classification of Laryngeal Neoplasms Abstract A new edition of the World Health Organization (WHO) Histological classification of tumours of the hypopharynx, larynx, trachea and parapharyngeal space was published in 2017. We have considered this classification regarding laryngeal neoplasms and discuss the grounds for said revision. Many of the laryngeal neoplasms described in the literature and in the previous WHO edition from 2005 have been omitted from this current revision. Many are described elsewhere in the book but it may give the new generation of pathologists/surgeons/oncologists the false impression that these tumour entities do not exist in the larynx.

Different Solutions for Damaged Nasotracheal Tube during Maxillofacial Surgery: A Case Series Abstract Difficult airway management and intraoperative tube damage are important problems during maxillofacial surgery. Damage occurs frequently during the surgery, and the anesthesiologist must be ready to find a quick and safe solution. Replacing the damaged endotracheal tube involves additional difficulties, and various factors must be evaluated. We present two cases of nasotracheal tube (NTT) damage suffered during maxillofacial surgery. The different intraoperative conditions led us to decide for the replacement of NTT in one case and for conservative action in the other. The purpose of this article is to highlight the difficulties that the anesthesiologist may have in deciding quickly what is the best approach in case the endotracheal tube is damaged during maxillofacial surgery and possibly try to provide a rapid and safe solution for the situation.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Microbiological Research

Transcriptome profiling provides insights into regulatory factors involved in Trichoderma viride-Azotobacter chroococcumbiofilm formation Publication date: October 2019 Source: Microbiological Research, Volume 227 Author(s): Kulandaivelu Velmourougane, Radha Prasanna, Puram Supriya, Balasubramanian Ramakrishnan, Shobit Thapa, Anil Kumar Saxena Abstract Azotobacter chroococcum (Az) and Trichoderma viride (Tv) represent agriculturally important and beneficial plant growth promoting options which contribute towards nutrient management and biocontrol, respectively. When Az and Tv are co-cultured, they form a biofilm, which has proved promising as an inoculant in several crops; however, the basic aspects related to regulation of biofilm formation were not investigated. Therefore, whole transcriptome sequencing (Illumina NextSeq500) and gene expression analyses were undertaken, related to biofilm formation vis a vis Tv and Az growing individually. Significant changes in the transcriptome profiles of biofilm were recorded and validated through qPCR analyses. In-depth evaluation also identified several genes (phoA, phoB, glgP, alg8, sipW, purB, pssA, fadD) specifically involved in biofilm formation in Az, Tv and Tv-Az. Genes coding for RNA-dependent RNA polymerase, ABC transporters, translation elongation factor EF-1, molecular chaperones and double homeobox 4 were either up-regulated or down-regulated during biofilm formation. To our knowledge, this is the first report on the modulation of gene expression in an agriculturally beneficial association, as a biofilm. Our results provide insights into the regulatory factors involved during biofilm formation, which can help to improve the beneficial effects and develop more effective and promising plant- microbe associations.

Comparative analysis of biocontrol agent Trichoderma asperellum ACCC30536 transcriptome during its interaction with Populus davidiana × P. alba var. pyramidalis Publication date: October 2019 Source: Microbiological Research, Volume 227 Author(s): Shida Ji, Zhihua Liu, Bin Liu, Yucheng Wang Abstract After exposure to with Populus davidiana × P. alba var. pyramidalis, the expression of genes in Trichoderma asperellum were compared in four transcriptomes. The top 20 high expression genes included six heat shock proteins and three hydrophobins, indicating that Trichoderma can rapidly adapt to environment stresses and elicit a plant defense response. The genes, involved in the interaction between Trichoderma and plant, showed an increasing expression level, for example sugar transporters, EPL1s, endoxylanases, pectin lyases, and nitrilases. Interestingly, sugar transporters also showed high expression when T. asperellum was cultured on medium lacking a carbon substrate, which would contribute to T. asperellum's survival and domination in ecological niche competition. And the genes related to mycoparasitism were expressed abundantly following T. asperellum's interaction with PdPap, indicating the PdPap induction could enhance the mycoparasitic ability of T. asperellum. Twelve chitinases and five glucanases showed higher expression in transcriptome Cs, indicating that T. asperellum secretes both types of enzyme before interacting with pathogens, allowing T. asperellum to implement mycoparasitism and obtain more energy. Many novel transcripts were obtained in each transcriptome, which may play important roles in the biocontrol process of T. asperellum. Interestingly, T. asperellum undergo constitutive alternative splicing in the biocontrol process: Seven biocontrol genes were alternative spliced via intron retention. qRT-PCR analysis proved that intron retention is negatively associated with the expression of chitinase, oligopeptide transporters, and beta-lactamase. However, the percentage of MAPK intron retention was quite low, suggesting that intron retention has little effect on the function of MAPK.

Toxoplasma gondii secretory proteins and their role in invasion and pathogenesis Publication date: October 2019 Source: Microbiological Research, Volume 227 Author(s): Yang Zhang, Bo Shiun Lai, Mario Juhas, Yun Zhang Abstract T. gondii is a major opportunistic pathogen chronically infecting nearly one third of the world's population. Due to the high infection and mortality rates in immunocompromised patients and newborns, the extent or magnitude of T. gondii pathogenesis is determined mainly by host-pathogen interactions. T. gondii utilizes specialized secretory proteins to modify host cellular factors and facilitate invasion and replication. This review provides update on the recent progress in this field of research with particular emphasis on the T. gondii secretory proteins and their role in invasion and pathogenesis.

Legacy of a Pleistocene bacterial community: Patterns in community dynamics through changing ecosystems Publication date: September 2019 Source: Microbiological Research, Volume 226 Author(s): Shan P. Thomas, Bhavatharini Shanmuganathan, Manoj Kumar Jaiswal, Anbarasu Kumaresan, Senthil Kumar Sadasivam Abstract Bacterial communities are resilient to the environmental changes, yet the effect of long term ecological changes on bacterial communities remain poorly explored. To study the effect of prolonged environmental changes, a 25 m long sediment core was excavated from a paleo beach ridge located on the Cauvery delta, south east coast of India. Geological evidences suggested that the site has experienced multiple marine transgressions and regressions. The three paleosols from Vettaikaraniruppu (VKI) beach ridge, VKI-2 (2.8 m bgl; 3 kybp), VKI-5 (7.2 m bgl; 6 kybp) and VKI-14 (24.5 m bgl; 146 kybp) was chosen for bacterial community analysis based on their formation period. Bacterial community structure of paleosols was reconstructed using V3 hypervariable region of bacterial 16S rDNA targeted Illumina sequencing. The VKI-5 sediment layer which formed under marine environment contained highest bacterial diversity, and the community was a mix up of terrestrial and marine bacterial population. The final community VKI-2 exhibited an approximate structural pattern witnessed in the native bacterial community VKI-14 which formed during marine regression. Furthermore, marine transgression and regression experienced in VKI resulted in the formation of distinct biogeographic patterns.

Agrobacterium-mediated transformation of Ceratocystis albifundus Publication date: September 2019 Source: Microbiological Research, Volume 226 Author(s): M. Sayari, M.A. van der Nest, E.T. Steenkamp, O.O. Adegeye, S. Marincowitz, B.D. Wingfield Abstract Functional association between genomic loci and specific biological traits remains lacking in many fungi, including the African tree pathogen Ceratocystis albifundus. This is mainly because of the absence of suitable transformation systems for allowing genetic manipulation of this and other fungi. Here, we present an optimized protocol for Agrobacterium tumefaciens-mediated transformation of C. albifundus. Strain AGL-1 of A. tumefaciens and four binary T-DNA vectors (conferring hygromycin B or geneticin resistance and/or expressing the green fluorescent protein [GFP]) were used for transforming germinated conidia of three isolates of C. albifundus. Stable expression of these T-DNA-encoded traits was confirmed through sequential sub-culturing of fungal transformants on selective and non-selective media and by using PCR and sequence analysis. Single-copy integration of the respective T-DNAs into the genomes of these fungi was confirmed using Southern hybridization analysis. The range of experimental parameters determined and optimised included: (i) concentrations of hygromycin B and geneticin required for inhibiting growth of the wild type fungus and (ii) the dependence of transformation on acetosyringone for inducing the bacterium's virulence genes, as well as (iii) the duration of fungus-bacterium co-cultivation periods and (iv) the concentrations of fungal conidia and bacterial cells used for the latter. The system developed in this study is stable with a high-efficiency, yielding up to 400 transformants per 106 conidia. This is the first report of a transformation protocol for C. albifundus and its availability will be invaluable for functional studies in this important fungus.

A novel contact-independent T6SS that maintains redox homeostasis via Zn2+ and Mn2+ acquisition is conserved in the Burkholderia pseudomallei complex Publication date: September 2019 Source: Microbiological Research, Volume 226 Author(s): David DeShazer Abstract The Burkholderia pseudomallei complex consists of six phylogenetically related Gram-negative bacterial species that include environmental saprophytes and mammalian pathogens. These microbes possess multiple type VI secretion systems (T6SS) that provide a fitness advantage in diverse niches by translocating effector molecules into prokaryotic and eukaryotic cells in a contact-dependent manner. Several recent studies have elucidated the regulation and function of T6SS-2, a novel contact-independent member of the T6SS family. Expression of the T6SS-2 gene cluster is repressed by OxyR, Zur and TctR and is activated by GvmR and reactive oxygen species (ROS). The last two genes of the T6SS-2 gene cluster encode a zincophore (TseZ) and a manganeseophore (TseM) that are exported into the extracellular milieu in a contact-independent fashion when microbes encounter oxidative stress. TseZ and TseM bind Zn2+ and Mn2+, respectively, and deliver them to bacteria where they provide protection against the lethal effects of ROS. The TonB-dependent transporters that interact with TseZ and TseM, and actively transport Zn2+ and Mn2+ across the outer membrane, have also been identified. Finally, T6SS-2 provides a contact-independent growth advantage in nutrient limited environments and is critical for virulence in Galleria mellonella larvae, but is dispensable for virulence in rodent models of infection. Graphical abstract

Aphicidal activity of Bacillus amyloliquefaciens strains in the peach-potato aphid (Myzus persicae) Publication date: September 2019 Source: Microbiological Research, Volume 226 Author(s): Guadalupe López-Isasmendi, Adriana Elisabet Alvarez, Gabriela Petroselli, Rosa Erra-Balsells, Marcela Carina Audisio Abstract Myzus persicae Sulzer (Hemiptera: Aphididae), is a generalist cosmopolitan insect that infests more than 400 plant species of 40 different families and is one of the major pests infesting potato crops. It causes direct damage and also spread plant viruses. The intensive use of synthetic insecticide to control aphids has led to resistant populations. Therefore, there is a need to develop biopesticides for effective control that minimizes environmental hazards. The bacteria Bacillus amyloliquefaciens is recognized as a producer of a variety of bioactive compounds. The aim here was to evaluate the aphicidal effect of B. amyloliquefaciens strains, CBMDDrag3, PGPBacCA2, and CBMDLO3, and their metabolites on the mortality and fecundity of M. persicae. Cells suspensions, heat-killed cell suspensions, cell-free supernatants, or isolated lipopeptide fractions from B. amyloliquefaciens strains were offered to aphids through artificial diets. The isolated lipopeptide fractions composed mainly of kurstakins, surfactins, iturins, and fengycins, when were administrated through diets, had no aphicidal effect against M. persicae. However, aphids fed on diets with whole cell suspensions and its cell-free supernatant of all three bacteria strains resulted in 100% mortality of adult aphids and nymphs. Specially, B. amyloliquefaciens CBMDLO3, has an effective aphicidal effect on M. persicae, used both bacterial cells and their metabolites. Moreover, heat-killed cells of B. amyloliquefaciens CBMDLO3 also had aphicidal action, although the aphid mortality was lower than on diet with living bacteria. Therefore, these results propose that B. amyloliquefaciens, could function as a novel eco-friendly biopesticide for the control of M. persicae.

Effect of growth temperature on biosynthesis and accumulation of carotenoids in cyanobacterium Anabaena sp. PCC 7120 under diazotrophic conditions Publication date: September 2019 Source: Microbiological Research, Volume 226 Author(s): Kinga Kłodawska, Anna Bujas, Maria Turos-Cabal, Paweł Żbik, Pengcheng Fu, Przemysław Malec Abstract Carotenoid composition has been studied in mesophilic, nitrogen-fixing cyanobacterium Anabaena sp. PCC7120 grown photoautotrophically, under diazotrophic conditions at four different temperatures (15 °C, 23 °C, 30 °C and 37 °C). The relative accumulation of chlorophyll, carotenoids and proteins was the highest at temperature of 23 °C. At a suboptimal temperature (15 °C) β-carotene was the dominant carotenoid compound, whereas the increase in temperature caused ketocarotenoids (echinenone, canthaxanthin, keto-myxoxanthophyll) to accumulate. A significant increase in the accumulation of phytoene synthase (CrtB) transcript was observed at both extreme growth temperatures (15 °C and 37 °C). The relative amount of β-carotene ketolase (CrtW) transcript directly corresponded to the accumulation of its product (keto-myxoxanthophyll) with a maximum at 30 °C and a profound decrease at 37 °C, whereas the transcription level of β-carotene ketolase (CrtO) was significantly decreased only at a suboptimal temperature (15 °C). These results show that temperature affects the functioning of the carotenoid biosynthesis pathway in Anabaena cells under photoautotrophic growth. Specifically, the balance between β-carotene and ketocarotenoids is altered according to temperature conditions. The transcriptional regulation of genes encoding enzymes active both at the early (CrtB) and the final steps (CrtO, CrtW) of the carotenoid biosynthetic pathway may participate in the acclimation mechanism of cyanobacteria to low and high temperatures.

Microscopic analysis of colonization of Colletotrichum abscissum in citrus tissues Publication date: September 2019 Source: Microbiological Research, Volume 226 Author(s): Daiani Cristina Savi, Bruno Janoski Rossi, Gustavo Rodrigues Rossi, Lisandra Santos Ferreira-Maba, Israel Henrique Bini, Edvaldo da Silva Trindade, Eduardo Henrique Goulin, Marcos Antonio Machado, Chirlei Glienke Abstract Postbloom fruit drop (PFD), caused mainly by Colletotrichum abscissum, is one of the most severe citrus diseases and can causes up to 80% fruit loss in favorable climatic conditions. According to the literature, other Colletotrichum species colonize hosts using distinct strategies: intracellular hemibiotrophic or subcuticular intramural necrotrophic colonization. However, so far, for C. abscissum only the necrotrophic stage has been described and some aspects remain unclear in PFD disease cycle. To better understand the disease cycle, microscopy studies could be applied. However, even using eGFP strains (expressing green fluorescent protein), the results are unclear due to the autofluorescence of citrus leaves. To eliminate this problem and to study the interaction between C. abscissum-citrus we used a destaining and staining methodologies, and we observed that in leaves, even applying injury before inoculation, C. abscissum does not colonize adjacent tissues. Apparently, in the leaves the fungus only uses the nutrients exposed in the artificial lesions for growth, and then produces large amount of spores. However, in flowers, C. abscissum penetrated and colonized the tissues of the petals 12 h after inoculation. In the early stages of infection, we observed the development of primary biotrophic hyphae, suggesting this species as a hemibiotrophic fungus, with a short biotrophic phase during flower colonization followed by dominant necrotrophic colonization. In conclusion, the use of an eGFP strain of C. abscissum and a different methodology of destaining and staining allowed a better understanding of the morphology and mechanisms used by this citrus pathogen to colonize the host.

Anti-quorum sensing and anti-biofilm activity of 5-hydroxymethylfurfural against Pseudomonas aeruginosa PAO1: Insights from in vitro, in vivo and in silico studies Publication date: September 2019 Source: Microbiological Research, Volume 226 Author(s): Jobina Rajkumari, Subhomoi Borkotoky, Dhanasekhar Reddy, Saswat Kumar Mohanty, Ranjith Kumavath, Ayaluru Murali, Kitlangki Suchiang, Siddhardha Busi Abstract Pseudomonas aeruginosa is one of the most common pathogens associated with nosocomial infections and a great concern to immunocompromised individuals especially in the cases of cystic fibrosis, AIDS and burn wounds. The pathogenicity of P. aeruginosa is largely directed by the quorum sensing (QS) system. Hence, QS may be considered an important therapeutic target to combat P. aeruginosa infections. The anti-quorum sensing and anti-biofilm efficacy of aromatic aldehyde, 5-hydroxymethylfurfural (5-HMF) against P. aeruginosa PAO1 were assessed. At the sub-inhibitory concentration, 5-HMF suppressed the production of QS-controlled virulence phenotypes and biofilm formation in P. aeruginosa. It was also able to significantly enhance the survival rate of C. elegans infected with P. aeruginosa. The in silico studies revealed that 5-HMF could serve as a competitive inhibitor for the auto-inducer molecules as it exhibited a strong affinity for the regulatory proteins of the QS-circuits i.e. LasR and RhlR. In addition, a significant down-regulation in the expression of QS-related genes was observed suggesting the ability of 5-HMF in mitigating the pathogenicity of P. aeruginosa.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Arteriosclerosis, Thrombosis, and Vascular Biology

Peroxynitrite-Mediated SIRT (Sirtuin)-1 Inactivation Contributes to Nicotine-Induced Arterial Stiffness in Mice Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 39, Issue 7, Page 1419-1431, July 1, 2019.

Disruption of the Extracellular Matrix Progressively Impairs Central Nervous System Vascular Maturation Downstream of β-Catenin Signaling Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 39, Issue 7, Page 1432-1447, July 1, 2019.

Endothelial PAI-1 (Plasminogen Activator Inhibitor-1) Blocks the Intrinsic Pathway of Coagulation, Inducing the Clearance and Degradation of FXIa (Activated Factor XI) Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 39, Issue 7, Page 1390-1401, July 1, 2019.

Albuminuria, the High-Density Lipoprotein Proteome, and Coronary Artery Calcification in Type 1 Diabetes Mellitus Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 39, Issue 7, Page 1483-1491, July 1, 2019.

Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 39, Issue 7, Page 1402-1418, July 1, 2019.

MicroRNA-615-5p Regulates Angiogenesis and Tissue Repair by Targeting AKT/eNOS (Protein Kinase B/Endothelial Nitric Oxide Synthase) Signaling in Endothelial Cells Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 39, Issue 7, Page 1458-1474, July 1, 2019.

Inhibition of MPO (Myeloperoxidase) Attenuates Endothelial Dysfunction in Mouse Models of Vascular Inflammation and Atherosclerosis Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 39, Issue 7, Page 1448-1457, July 1, 2019.

B Cell Fcγ Receptor IIb Modulates Atherosclerosis in Male and Female Mice by Controlling Adaptive Germinal Center and Innate B-1-Cell Responses Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 39, Issue 7, Page 1379-1389, July 1, 2019.

Peripheral Microvascular Function Reflects Coronary Vascular Function Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 39, Issue 7, Page 1492-1500, July 1, 2019.

Metabolomic Pattern Predicts Incident Coronary Heart Disease Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 39, Issue 7, Page 1475-1482, July 1, 2019.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

New for Acta Oncologica and online now on Taylor & Francis Online: Article Radiation doses to brain substructures associated with cognition in radiotherapy of pediatric brain tumors Laura Toussaint, Daniel J. Indelicato, Camilla H. Stokkevåg, Yasmin Lassen-Ramshad, Catia Pedro, Ronni Mikkelsen, Marcos Di Pinto, Zuofeng Li, Stella Flampouri, Anne Vestergaard, Jørgen B. B. Petersen, Henrik Schrøder, Morten Høyer & Ludvig P. Muren Pages: 1-6 | DOI: 10.1080/0284186X.2019.1629014 Letter to the Editor Distinguishing recurrence and new primary tumor as well as the origin of neck metastases in head and neck cancer clinical trials by targeted DNA sequencing Jacob Kinggaard Lilja-Fischer, Mette Saksø, Magnus Stougaard, Torben Steiniche & Jens Overgaard Pages: 1-3 | DOI: 10.1080/0284186X.2019.1629015 Radiation tattoos mimicking melanoma: a clinical observation Roya S. Nazarian, Bijal Amin, Katia Papalezova, Nitin Ohri & Beth N. McLellan Pages: 1-3 | DOI: 10.1080/0284186X.2019.16324

New for Acta Oncologica and online now on Taylor & Francis Online:

Article Radiation doses to brain substructures associated with cognition in radiotherapy of pediatric brain tumors Laura Toussaint, Daniel J. Indelicato, Camilla H. Stokkevåg, Yasmin Lassen-Ramshad, Catia Pedro, Ronni Mikkelsen, Marcos Di Pinto, Zuofeng Li, Stella Flampouri, Anne Vestergaard, Jørgen B. B. Petersen, Henrik Schrøder, Morten Høyer & Ludvig P. Muren Pages: 1-6 | DOI: 10.1080/0284186X.2019.1629014 Letter to the Editor Distinguishing recurrence and new primary tumor as well as the origin of neck metastases in head and neck cancer clinical trials by targeted DNA sequencing Jacob Kinggaard Lilja-Fischer, Mette Saksø, Magnus Stougaard, Torben Steiniche & Jens Overgaard Pages: 1-3 | DOI: 10.1080/0284186X.2019.1629015 Radiation tattoos mimicking melanoma: a clinical observation Roya S. Nazarian, Bijal Amin, Katia Papalezova, Nitin Ohri & Beth N. McLellan Pages: 1-3 | DOI: 10.1080/0284186X.2019.1632478 Original Article Plan-library supported automated replanning for online-adaptive intensity-modulated proton therapy of cervical cancer |  Thyrza Z. Jagt, Sebastiaan Breedveld, Rens van Haveren, Remi A. Nout, Eleftheria Astreinidou, Ben J. M. Heijmen & Mischa S. Hoogeman Pages: 1-6 | DOI: 10.1080/0284186X.2019.1627414 Dual-energy material decomposition for cone-beam computed tomography in image-guided radiotherapy Mikkel Skaarup, Jens M. Edmund, Sabrina Dorn, Marc Kachelriess & Ivan R. Vogelius Pages: 1-6 | DOI: 10.1080/0284186X.2019.1629010 The effect of tumor laterality on survival for non-small cell lung cancer patients treated with radiotherapy Nicolai Jørgensen, Eric Leif Meline, Stefan Starup Jeppesen, Olfred Hansen, Morten Nielsen & Tine Schytte Pages: 1-6 | DOI: 10.1080/0284186X.2019.1629011 Inter-observer variability in target delineation increases during adaptive treatment of head-and-neck and lung cancer Rudi Apolle, Steffen Appold, Henk P. Bijl, Pierre Blanchard, Johan Bussink, Corinne Faivre-Finn, Jonathan Khalifa, Anne Laprie, Yolande Lievens, Indira Madani, Amandine Ruffier, Dirk de Ruysscher, Wouter van Elmpt & Esther G. C. Troost Pages: 1-8 | DOI: 10.1080/0284186X.2019.1629017 Towards a novel small animal proton irradiation platform: the SIRMIO project Katia Parodi, Walter Assmann, Claus Belka, Jonathan Bortfeldt, Dirk-André Clevert, George Dedes, Ronaldo Kalunga, Sonja Kundel, Neeraj Kurichiyanil, Paulina Lämmer, Julie Lascaud, Kirsten Lauber, Giulio Lovatti, Sebastian Meyer, Munetaka Nitta, Marco Pinto, Mohammad J. Safari, Katrin Schnürle, Jörg Schreiber, Peter G. Thirolf, Hans-Peter Wieser & Matthias Würl Pages: 1-6 | DOI: 10.1080/0284186X.2019.1630752 Intensity modulated proton therapy plan generation in under ten seconds |  Michael Matter, Lena Nenoff, Gabriel Meier, Damien C. Weber, Antony J. Lomax & Francesca Albertini Pages: 1-5 | DOI: 10.1080/0284186X.2019.1630753 Evaluation of proton and photon dose distributions recalculated on 2D and 3D Unet-generated pseudoCTs from T1-weighted MR head scans Sebastian Neppl, Guillaume Landry, Christopher Kurz, David C. Hansen, Ben Hoyle, Sophia Stöcklein, Max Seidensticker, Jochen Weller, Claus Belka, Katia Parodi & Florian Kamp Pages: 1-6 | DOI: 10.1080/0284186X.2019.1630754 An investigative expansion of a competing risk model for first failure site in locally advanced non-small cell lung cancer Thomas Lacoppidan, Ivan R. Vogelius, Mette Pøhl, Malene Strange, Gitte F. Persson & Lotte Nygård Pages: 1-7 | DOI: 10.1080/0284186X.2019.1631475 Survival after stereotactic radiotherapy in patients with early-stage non-small cell lung cancer Olfred Hansen, Charlotte Kristiansen, Morten Nielsen, Tine Schytte & Stefan Starup Jeppesen Pages: 1-5 | DOI: 10.1080/0284186X.2019.1631476 Influence of mutagenic versus non-mutagenic pre-operative chemotherapy on the immune infiltration of residual breast cancer Anna-Mária Tőkés, Orsolya Rusz, Gábor Cserni, Erika Tóth, Gábor Rubovszky, Tímea Tőkés, Laura Vízkeleti, Lilla Reiniger, Renáta Kószó, Zsuzsanna Kahán, Janina Kulka, Marco Donia, András Vörös & Zoltan Szallasi Pages: 1-9 | DOI: 10.1080/0284186X.2019.1633015 Review Emerging trends in the treatment of rectal cancer Bruce D. Minsky Pages: 1-9 | DOI: 10.1080/0284186X.2019.1629009