Co-contaminant effects on ofloxacin adsorption onto activated carbon, graphite, and humic acid

Abstract

Given their voluminous application, significant amounts of fluoroquinolones are discharged into the environment through wastewater effluent. Adsorption has been shown to be a critical process controlling the environmental behaviors of fluoroquinolones. Competition between ofloxacin (OFL) and naphthalene (NAP)/bisphenol A (BPA) and their adsorption on activated carbon (AC), graphite (GP), and humic acid (HA) were investigated. The suppressed adsorption of OFL was observed on AC and GP, but not on HA, by NAP or BPA. Moreover, for AC, the competition by NAP was slightly stronger than that by BPA. However, for GP, the competition with BPA was higher than that with NAP. These observations indicate that competitive adsorption of OFL with respect to NAP/BPA depends on the degree of overlap of adsorption sites, as interpreted by the following: (i) AC can provide overlapping adsorption sites for OFL, BPA, and NAP, which include non-specific adsorption sites, such as hydrophobic sites, π-π interactions, and micropore filling; (ii) π-π interactions and hydrogen bonding might be responsible for the strong competitive adsorption between BPA and OFL on GP; and (iii) OFL adsorbs on HA through specific adsorption force—electrostatic attraction, with which NAP and BPA cannot compete.

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Unsaturated nitrogen-rich polymer poly(L-histidine) gated reversibly switchable mesoporous silica nanoparticles using “graft to” strategy for drug controlled release

Publication date: Available online 2 September 2017
Source:Acta Biomaterialia
Author(s): Shengjun Mu, Yongjun Liu, Tianqi Wang, Jing Zhang, Dandan Jiang, Xiaoyue Yu, Na Zhang
A novel and intelligent pH-controlled system having an "on-off" switch based on poly(L-histidine) (PLH) and poly(ethylene glycol) (PEG) coated mesoporous silica nanoparticles (MSNs) (MSNs-PLH-PEG) was designed and evaluated for tumor specific drug release. The unsaturated nitrogen-rich polymer, PLH, which can change its solubility at different pH values, was employed for establishing the reversible "on-off" switch. In vitro drug release results demonstrated that MSNs-PLH-PEG has a pH-controlled "on-off" profile with the change of pH value between pH 7.4 and 5.0. Furthermore, in vitro cellular uptake study results showed that the entrapped drug could be efficiently released from MSNs-PLH-PEG under acidic endosome/lysosome. In vitro cell cytotoxicity and in vivo antitumor studies results indicated that sorafenib loaded MSNs-PLH-PEG exhibited good anti-proliferation and tumor growth inhibition effects. Haemolysis assay and histological analysis of MSNs-PLH-PEG showed negligible haemolysis activity and no visible tissue toxicity at the test dose. This study represents a promising and intelligent pH-controlled intelligent system for drug delivery and controlled release.Statement of SignificanceA novel pH-controlled intelligent and reversible "on-off" switch system based on poly(L-histidine) and poly(ethylene glycol) coated mesoporous silica nanoparticles (MSNs-PLH-PEG) by "graft to" synthesis method was constructed for tumor specific drug release. The unsaturated nitrogen-rich pH-sensitive polymer, PLH, which can change its solubility in different pH values, was employed as the reversible "on-off" switch in MSNs for the first time. The pH-controlled "on-off" switch manner was observed in the drug release results in vitro. In the in vivo antitumor studies, sorafenib loaded MSNs-PLH-PEG could effectively suppressed tumor growth in H22 tumor bearing mice. It is expected that the pH-controlled intelligent "on-off" switch system we designed holds remarkable promise and provides valuable strategy for possible applications in cancer therapy.

Graphical abstract

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Sex effects on spatial learning but not on spatial memory retrieval in healthy young adults

Publication date: 15 January 2018
Source:Behavioural Brain Research, Volume 336
Author(s): Dominique Piber, Jan Nowacki, Sven C. Mueller, Katja Wingenfeld, Christian Otte
ObjectivesSex differences have been found in spatial learning and spatial memory, with several studies indicating that males outperform females. We tested in the virtual Morris Water Maze (vMWM) task, whether sex differences in spatial cognitive processes are attributable to differences in spatial learning or spatial memory retrieval in a large student sample.MethodsWe tested 90 healthy students (45 women and 45 men) with a mean age of 23.5 years (SD=3.5). Spatial learning and spatial memory retrieval were measured by using the vMWM task, during which participants had to search a virtual pool for a hidden platform, facilitated by visual cues surrounding the pool. Several learning trials assessed spatial learning, while a separate probe trial assessed spatial memory retrieval.ResultsWe found a significant sex effect during spatial learning, with males showing shorter latency and shorter path length, as compared to females (all p<0.001). Yet, there was no significant sex effect in spatial memory retrieval (p=0.615). Furthermore, post-hoc analyses revealed significant sex differences in spatial search strategies (p<0.05), but no difference in the number of platform crossings (p=0.375).ConclusionOur results indicate that in healthy young adults, males show faster spatial learning in a virtual environment, as compared to females. Interestingly, we found no significant sex differences during spatial memory retrieval. Our study raises the question, whether men and women use different learning strategies, which nevertheless result in equal performances of spatial memory retrieval.



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Whisker dependent responsiveness of C57BL/6J mice to different behavioral test paradigms

Publication date: 15 January 2018
Source:Behavioural Brain Research, Volume 336
Author(s): Seenu Haridas, Ramya Ganapathi, Mayank Kumar, Kailash Manda
Whisker trimming is very common in C57BL/6J mice. Dewhiskering may lead to an alteration in the thalamocortical connectivity and relevant behavioral functions. Since C57BL/6J is a commonly used strain for neurobehavioral studies, it is important to examine how whisker dependent heterogeneity affects the internal validity of behavioral phenotypes. The present study aimed to investigate the responsiveness of mice to different behavioral test paradigms in the presence or absence of whiskers. We employed two models of whisker deprivation: Acute Whisker Desensitization (AWD) and Chronic Habitual Dewhiskering (CHD). The AWD model blocks whisker sensation by lidocaine application. For CHD model, mice at the age of 12 weeks were carefully scrutinized for presence or absence of whiskers and divided into three groups, the whiskered mice, partially dewhiskered mice and completely dewhiskered mice.The whisker-dependent behavioral functions were assessed using open field test, novel object recognition test, marble burying test and forced swim test. Our results showed that habitual dewhiskering significantly altered the short-term memory and basal anxiety-like functions. Such behavioral alteration due to dewhiskering was significantly different in fully and partially dewhiskered mice, which is indicative of behavioral adaptation to the whisker desensitization. Contrary to CHD, the Acute Whisker Desensitization ameliorated behavioral compulsivity and basal anxiety. Our results suggest that vibrissal desensitization in the mice may lead to changes in their affective and cognitive state. Since, heterogeneity in whisker status may affect behavioral functions, careful inspection of the whisker status of C57BL/6J mice is recommended to increase the reproducibility and reliability of results obtained from behavioral assessments.



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Breast reconstruction surgery: Options and what to expect

In this article, we look at the process of breast reconstruction surgery, the reasons for choosing this surgery, alternative options, and recovery outlook.

http://ift.tt/2wsbWC7

Breast reconstruction surgery: Options and what to expect

In this article, we look at the process of breast reconstruction surgery, the reasons for choosing this surgery, alternative options, and recovery outlook.

http://ift.tt/2wsbWC7

Expanding our research horizons

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RNA sequencing and pathway analysis identify tumor necrosis factor alpha driven small proline-rich protein dysregulation in chronic rhinosinusitis

http://ift.tt/2xGbL4J

Promotion of olfactory receptor neuron differentiation of olfactory neuroepithelial cells by using chitosan solution

http://ift.tt/2x17xaN

Sinus bacteriology in patients with cystic fibrosis or primary ciliary dyskinesia: A systematic review

http://ift.tt/2xGbFKp

An update on the epidemiology of aspirin-exacerbated respiratory disease

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Immunoglobulin G4 sinusitis in association with aspirin-exacerbated respiratory disease

http://ift.tt/2xGbCOJ

Outcomes of sinonasal squamous cell carcinoma with and without association of inverted papilloma: A multi-institutional analysis

http://ift.tt/2x1h95p

Quality-of-life outcomes in patients who underwent subcutaneous immunotherapy and sublingual immunotherapy in a real-world clinical setting

http://ift.tt/2xGcG51

The effect of olfactory training on the odor threshold in patients with traumatic anosmia

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Erratum

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The effect of closed septorhinoplasty on nasal functions and on external and internal nasal valves: A prospective study

http://ift.tt/2x1gVez

Primary endoscopic endonasal dacryocystorhinostomy for pediatric nasolacrimal duct obstruction: A systematic review

http://ift.tt/2vUO0E1

Long-term olfactory outcome after nasoseptal flap reconstructions in midline skull base surgery

http://ift.tt/2wtOXGN

Draf III frontal sinus surgery: “How I do it”

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Utility of intraoperative frozen sections in surgical decision making for acute invasive fungal rhinosinusitis

http://ift.tt/2wuEvPr

Psychiatric Emergencies for Physicians: Clinical Management and Approach to Distinguishing Pheochromocytoma From Psychiatric and Thyrotoxic Diseases in the Emergency Department

Publication date: Available online 2 September 2017
Source:The Journal of Emergency Medicine
Author(s): Albert Leung, Leslie Zun, Kimberly Nordstrom, Michael P. Wilson




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Airway Management in an Infant with a Large Supraglottic Mass after Failed Fiberoptic Intubation

Publication date: Available online 2 September 2017
Source:The Journal of Emergency Medicine
Author(s): Rajeev Sharma, Vidit Kaushal, Mohit Tyagi, Ashish Mittal
BackgroundFiberoptic bronchoscope−guided tracheal intubation is the gold standard for managing patients with supraglottic growths. In infants with a large and overhanging epiglottis, the success of fiberoptic-guided intubation relies heavily on the available space between the inferior surface of the epiglottis and the posterior pharyngeal wall or, more specifically, the superior surface of the supraglottic growth.Case ReportWe describe the inability to negotiate the tip of the fiberscope between the epiglottis and the supraglottic growth and the successful use of direct laryngoscopy to improve the available space along with the usefulness of "bubbling of air" to locate the glottic opening in an infant.Why Should an Emergency Physician Be Aware of This?We emphasize the role of the emergency physician in managing such patients. Most of the time, the setting is not ideal in such emergency situations and the most qualified clinician to treat them is the emergency physician. The knowledge and skills of the emergency physician, along with awareness of the possible techniques for airway management, can be lifesaving.



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How Do We Balance the Long-term Health of a Patient With the Short-term Risk to the Physician?

Publication date: Available online 1 September 2017
Source:The Journal of Emergency Medicine
Author(s): Michael B. Weinstock, Amal Mattu, Erik P. Hess
BackgroundThere is a wide variation in practice patterns among emergency medicine physicians; many factors weigh into the medical decision-making process including the health of the patient as well as short-term risk to the physician.ObjectiveThe objective of our discussion is to illustrate specific scenarios where medical decisions are focused on the physician's short-term risk, then to propose an approach to shifting the balance to the patient's long-term health.MethodsUsing recent data on the evaluation, disposition, and outcomes of patients with low-risk chest pain in the emergency department, we calculate the risk of outpatient evaluation compared to the common practice of admission or observation.ResultsPatients with low-risk chest pain and negative initial evaluation in the emergency department with 2 normal cardiac biomarkers, normal vital signs, and non-ischemic, interpretable ECGs, have an extremely low-risk of a short term clinically relevant adverse cardiac event. There is a suggestion of a higher patient risk from admission, prompting consideration that continued evaluation of the chest pain as an outpatient may be safer than admission or observation.ConclusionA test/intervention should be done if the risk of a missed diagnosis or adverse outcome is greater that the risk of the test/intervention. Involving the patient in the decision-making process may help to shift the management balance from the physician's short-term concern of their own risk, to the patient's long-term health.



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Effect of Cricoid Pressure on the Insertion Efficacy of Six Supraglottic Devices: A Crossover Randomized Simulation Trial

Publication date: Available online 2 September 2017
Source:The Journal of Emergency Medicine
Author(s): Fumihiro Ohchi, Nobuyasu Komasawa, Ryosuke Mihara, Kazuo Hattori, Toshiaki Minami
BackgroundNo study has ever compared the efficacy of various types of supraglottic devices (SGDs) for securing the airway under cricoid pressure.ObjectiveThis study aimed to evaluate the efficacy of six SGDs, LMA-ProSeal (ProSeal), LMA-Classic (Classic), Laryngeal Tube (LT), LMA-Supreme (Supreme), air-Q (air-Q), and i-gel (i-gel), in airway management under cricoid pressure using a manikin.MethodsFifteen novice doctors and 16 experienced doctors used the six SGDs under cricoid or sham pressure on an adult manikin. Insertion time, successful ventilation rate, and subjective insertion difficulty on a visual analogue scale (VAS) were measured.ResultsBoth novice and experienced doctors had a significantly lower ventilation success rate under cricoid pressure than under sham pressure when using the ProSeal, Classic, and LT, but not when using the other three SGDs. Novice doctors required a significantly longer insertion time under cricoid pressure than under sham pressure with all SGDs. Experienced doctors required a significantly longer insertion time under cricoid pressure than with sham pressure when using the ProSeal, Classic, and LT, but not when using the other three SGDs. Subjective insertion difficulty on VAS was significantly higher under cricoid pressure than under sham pressure with all six SGDs.ConclusionVentilation success rate under cricoid pressure was significantly lower than under sham pressure when using the ProSeal, Classic, and LT, but not when using the other three SGDs in both novice and experienced doctors.



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Self Made Xeno-pericardial Aortic Tubes to Treat Native and Aortic Graft Infections

Publication date: Available online 2 September 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Salome Weiss, Eva-Luca Tobler, Hendrik von Tengg-Kobligk, Vladimir Makaloski, Daniel Becker, Thierry P. Carrel, Jürg Schmidli, Thomas R. Wyss
ObjectivesThe most appropriate material for reconstruction of the aorta for native or graft infection remains a matter for debate. This study examines the mid-term outcome of patients and graft durability after in situ aortic reconstruction with self made bovine pericardial tube grafts.MethodsThis was a retrospective analysis of all patients who underwent in situ aortic reconstruction using self made bovine pericardial tube grafts between January 2008 and December 2015 at a tertiary referral centre. Peri-operative and mid-term outcomes including mortality and re-infection were analysed at the end of January 2017. Available follow-up imaging was reviewed to assess graft durability.ResultsBovine pericardial aortic tube grafts were used in 35 patients (86% male) with a median age of 69 years (range 38–84) to reconstruct the ascending aorta or the aortic arch (7), the descending (7), the thoraco-abdominal (7), or the abdominal (14) aorta. Twelve patients (34%) were treated for infection of the native aorta and 23 (66%) for prosthetic graft infection. Twenty-two patients (63%) underwent emergency surgery. Thirty day mortality was 31% (n = 11). Additionally, six patients died during follow-up after a median of 33 months (range 3–70). For the remaining patients, mean follow-up was 48 months (± 26) with a mean Follow-Up Index of 0.98 ± 0.08. There were no readmissions or re-operations for re-infection or graft related complications. Follow-up imaging showed no signs of graft degeneration after a median of 15 months (range 3–68).ConclusionsSurgical treatment of native and aortic graft or endograft infection remains high risk. Self made bovine pericardial tube grafts for in situ reconstruction are a promising option offering many advantages. Despite high early mortality rates, early radiological and mid-term clinical results are good. Definitive eradication of the infection seems feasible after in situ insertion of xeno-pericardial material for aortic repair.



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Outcome after Turndown for Elective Abdominal Aortic Aneurysm Surgery

Publication date: Available online 2 September 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Joshua D. Whittaker, Lewis Meecham, Virginia Summerour, Sheirin Khalil, Georgia Layton, Marianne Yousif, Adrian Jennings, Micheal Wall, Jeremy Newman
ObjectivesThe aim was to assess the survival of patients who had been turned down for repair of an abdominal aortic aneurysm (AAA) and to examine the factors influencing this.MethodsThis was a retrospective observational study of a prospectively maintained database of all patients turned down for AAA intervention by the Black Country Vascular Network multidisciplinary team (MDT) from January 2013 to December 2015. Data on AAA size, cardiopulmonary exercise testing (CPET) and cause of death were recorded.ResultsThere were 112 patients. The median age at turndown was 83.9 years (IQR 10.2 years). The median AAA size at turndown was 63 mm (IQR 16.7 mm). The median follow-up time after turndown was 324 days (IQR 537.5 days). Sixty-four patients (57.1%) were deceased after 2 years, with a median survival time of 462 days (IQR 579 days). Patients who died had a significantly larger AAA dimension (median 65 mm, IQR 18.5 mm) than those surviving to date (median 59 mm, IQR 10 mm, p = .004). Using Cox regression analysis, the probability of 1 year survival in the whole population was 0.614. The probability of 2 year survival was 0.388. When accounting for age, gender, AAA dimension, and British Aneurysm Repair risk score, no factors had significant influence over survival. Of the 64 deceased patients, 30 had an accessible cause of death: 36.7% of these were due to ruptured AAAs. There was no significant difference in AAA size between those dying of ruptures and those dying of other causes (p = .225, mean 74 mm and 67 mm respectively).ConclusionsBeing turned down for AAA repair carries a significant short-term risk of mortality. Those turned down for repair carried significant levels of comorbid disease but no factors considered were found to be independently predictive of the length of survival.



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How to Write a High Quality Multiple Choice Question (MCQ): A Guide for Clinicians

Publication date: Available online 1 September 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): P.A. Coughlin, C.R. Featherstone
Despite the variety of assessment tools available, multiple choice questions (MCQs) still play an integral part in examinations at both a national and speciality board level. MCQs have a number of methodological advantages yet their strength is related to the quality of the question posed. Specifically, there has been a move towards the MCQ testing a taxonomically higher order concept of integration-interpretation and problem solving. This paper focuses on question development and the potential pitfalls to avoid.



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Clinical pharmacology of anti-angiogenic drugs in oncology

Publication date: Available online 1 September 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): P. Gougis, J. Wassermann, J.P. Spano, N. Keynan, C. Funck-Brentano, J.E. Salem
Abnormal vasculature proliferation is one of the so-called hallmarks of cancer. Angiogenesis inhibitor therapies are one of the major breakthroughs in cancer treatment in the last two decades. Two types of anti-angiogenics have been approved: monoclonal antibodies and derivatives, which are injected and target the extracellular part of a receptor, and protein kinase inhibitors, which are orally taken small molecules targeting the intra-cellular Adenosine Triphosphate −pocket of different kinases. They have become an important part of some tumors' treatment, both in monotherapy or in combination. In this review, we discuss the key pharmacological concepts and the major pitfalls of anti-angiogenic prescriptions. We also review the pharmacokinetic and pharmacodynamics profile of all approved anti-angiogenic protein kinase inhibitors and the potential role of surrogate markers and of therapeutic drug monitoring.



http://ift.tt/2xETrZP

The effect of light-emitting diode (590/830 nm)−based low-level laser therapy on posttraumatic edema of facial bone fracture patients

Posttraumatic edema in facial bone fracture patients may interfere with the operation field and delay the schedule. Thus, swiftly reducing the edema alleviates patient discomfort and advances the operation date. Ice packing and compression bandages are often used for such a purpose, but such methods are often inconvenient for the face. In this study, we aim to analyze the effect of light-emitting diode (LED) (590/830 nm)−based low-level laser therapy (LLLT) in posttraumatic edema in facial bone fracture patients.

http://ift.tt/2eyMnZQ

Clinical pharmacology of anti-angiogenic drugs in oncology

Publication date: Available online 1 September 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): P. Gougis, J. Wassermann, J.P. Spano, N. Keynan, C. Funck-Brentano, J.E. Salem
Abnormal vasculature proliferation is one of the so-called hallmarks of cancer. Angiogenesis inhibitor therapies are one of the major breakthroughs in cancer treatment in the last two decades. Two types of anti-angiogenics have been approved: monoclonal antibodies and derivatives, which are injected and target the extracellular part of a receptor, and protein kinase inhibitors, which are orally taken small molecules targeting the intra-cellular Adenosine Triphosphate −pocket of different kinases. They have become an important part of some tumors' treatment, both in monotherapy or in combination. In this review, we discuss the key pharmacological concepts and the major pitfalls of anti-angiogenic prescriptions. We also review the pharmacokinetic and pharmacodynamics profile of all approved anti-angiogenic protein kinase inhibitors and the potential role of surrogate markers and of therapeutic drug monitoring.



http://ift.tt/2xETrZP

Follicular Lymphoma with Hyaline-vascular Castleman-like Features Analysis of 6 Cases and Review of the Literature

Publication date: Available online 2 September 2017
Source:Human Pathology
Author(s): Sergio Pina-Oviedo, Roberto N. Miranda, Pei Lin, John T. Manning, L. Jeffrey Medeiros
Follicular lymphoma (FL) with features reminiscent of hyaline-vascular Castleman disease (CD) is an unusual morphologic variant that may create diagnostic difficulties. To our knowledge, only 5 cases of this variant have been reported. We describe the clinicopathologic features of 6 cases including 2 men and 4 women with a median age of 63years (range, 41–77). Morphologically, all lymph node biopsy specimens showed at least a focal area of conventional FL; 4 cases showed neoplastic follicles with hyalinized blood vessels penetrating into germinal centers (lollipop-like lesions); 4 cases had interfollicular areas with increased vascular stroma, 2 cases showed small neoplastic follicles with prominent, onion skin-like mantle zones, and 1 case showed two or more germinal centers within follicles (twinning). The small neoplastic follicles were more cellular than lymphocyte-deplete follicles of true hyaline-vascular CD and the interface between germinal centers and mantle zones was ill-defined. No cases showed dysplastic follicular dendritic cells. Immunohistochemistry for BCL-2 was positive in all 6 cases. Flow cytometry immunophenotypic analysis showed a monotypic B-cell population in 2 of 3 cases assessed. Conventional cytogenetic or FISH studies performed in 2 cases showed t(14;18)(q32;q21) or IGH-BCL2 supporting the diagnosis of FL. The cases presented here add clinicopathologic data to the few cases of FL with hyaline-vascular CD-like features reported previously in the literature. Distinguishing this variant of FL from hyaline-vascular CD is important given the differences in treatment and prognosis of patients with each disease.



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Frequency and Pathological Characteristics of Drug-Induced Liver Injury in a Tertiary Medical Center

Publication date: Available online 2 September 2017
Source:Human Pathology
Author(s): Mark Ettel, Gabriel Acosta Gonzalez, Shweta Gera, Ogechukwu Eze, Samuel Sigal, James S Park, Ruliang Xu
Drug-induced liver injury (DILI) accounts for approximately 10% of acute hepatitis cases. DILI can arise as idiosyncratic or intrinsic injury from hundreds of drugs, herbals, and nutritional supplements and is essential to recognize as one of the differential diagnoses of hepatitis in a liver biopsy. The purpose of this study is to investigate the frequency and pathological characteristics of DILI related to the variety of hepatotoxic agents. We searched our pathology database for all patients with hepatitis diagnosed on liver biopsy from January 2012 to May 2016, and selected patients with a diagnosis of DILI. Electronic medical records were reviewed for patient medication list, history of herbal medicine or supplement use, and pre-biopsy liver function test (LFT) results. Clinical and pathologic correlation was used to determine the causative or related agents for DILI. We then assessed histopathologic features of liver injury and categorized biopsy findings as primarily bile duct injury, lobular/portal hepatitis, or mixed changes. 604 total liver biopsies for hepatitis or liver injury were identified, of which 70 cases (11.6%) carried the diagnosis of DILI confirmed by clinical correlation. The most common etiologies associated with DILI were supplements and herbal products (31.4%), antimicrobials (14.3%), chemotherapeutics (11.4%), antilipidemics (7.1%) and immunomodulatory agents (7.1%). LFT results positively correlated with histological findings. Nutritional/herbal supplements have emerged as one of the major hepatotoxicity agents. DILI can manifest as predominantly hepatitis, bile duct injury or combination. Histological pattern recognition in the liver biopsy may help identify specific hepatotoxic agents causing DILI.



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Mutation of NRAS is a Rare Genetic Event in Ovarian Low-Grade Serous Carcinoma

Publication date: Available online 2 September 2017
Source:Human Pathology
Author(s): Deyin Xing, Yohan Suryo Rahmanto, Felix Zeppernick, Charlotte G. Hannibal, Susanne K. Kjaer, Russell Vang, Ie-Ming Shih, Tian-Li Wang
Activating mutations involving the members of the RAS signaling pathway, including KRAS, NRAS, and BRAF, have been reported in ovarian low-grade serous carcinoma and its precursor lesion, serous borderline tumor (SBT). Whether additional genetic alterations in the RAS oncogene family accumulate during the progression of serous borderline tumor (SBT) to invasive low grade serous carcinoma (LGSC) remains largely unknown. While mutations of KRAS and BRAF occur at a very early stage of progression, even preceding the development of SBT, additional driving events, such as NRAS mutations, have been postulated to facilitate progression. In this study, we analyzed NRAS exon 3 mutational status in 98 cases that were diagnosed with SBT/atypical proliferative serous tumor (SBT/APST), non-invasive LGSC (niLGSC), or invasive LGSC (iLGSC). Of the latter, NRAS Q61R (CAA to CGA) mutations were detected in only 2 of 56 (3.6%) cases. The same mutation was not detected in any of the SBT/APSTs or niLGSCs. Mutational analysis for hotspots in KRAS and BRAF demonstrated a wildtype pattern of KRAS and BRAF in one of the NRAS-mutated cases. Interestingly, another LGSC case with NRAS mutation harbored a concurrent BRAF V600L mutation. These findings indicate that, although recurrent NRAS mutations are present, their low prevalence indicates that NRAS plays a limited role in the development of LGSC. Further studies to identify other oncogenic drivers of LGSC progression is warranted.



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Pulmonary interstitial glycogenosis associated with a spectrum of neonatal pulmonary disorders

Publication date: Available online 2 September 2017
Source:Human Pathology
Author(s): Ernest Cutz, Rose Chami, Sharon Dell, Jacob Langer, David Manson
Primary or isolated pulmonary interstitial glycogenosis (PIG) is a rare disease presenting as tachypnea and hypoxemia during the perinatal period. A diffuse interstitial infiltrate with focal hyperinflation is visible on chest imaging. The biopsy findings include diffuse expansion of the interstitium by spindle-shaped cells with pale cytoplasm that, on electron microscopy (EM), are poorly differentiated mesenchymal cells containing abundant monoparticulate glycogen. This glycogenosis appears to be a transient abnormality, usually with a favorable prognosis. Recently, cases of PIG, some associated with other pulmonary or systemic abnormalities, have been described. The clinical significance and potential role of PIG changes remain unknown. We report 28 cases of PIG associated with a spectrum of pediatric pulmonary and cardiovascular disorders, including arterial hypertensive changes with and without abnormal alveolar development (n=9), congenital heart disease (CHD; n=4), hyperplasia of pulmonary neuroendocrine cells resembling neuroendocrine hyperplasia of infancy (NEHI, n=5), congenital pulmonary airway malformation (n=5), congenital lobar emphysema (n=4), and Noonan syndrome (n=1). In all cases, PIG was confirmed by positive periodic acid–Schiff (PAS) staining, immunopositivity for vimentin, and EM. Although some patients improved with age, seven died of respiratory failure or complications of CHD, suggesting that PIG may be clinically significant when associated with other severe disorders. The association of PIG with a spectrum of mostly congenital lung disorders supports its origin as a developmental abnormality of interstitial fibroblast differentiation rather than a nonspecific reactive process.



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Immunophenotypic Comparison of Testicular Sclerosing Sertoli Cell Tumors and Sertoli Cell Tumors Not Otherwise Specified

Publication date: Available online 2 September 2017
Source:Human Pathology
Author(s): Hector Mesa, Chen Zhang, Juan C. Manivel, Thomas M. Ulbright
Testicular Sertoli cell tumors (SCT) are rare and most fall into the category of SCT-not otherwise specified (SCT-NOS). Only a few additional types of SCT are recognized. Sclerosing SCT (S-SCT), originally described in 1991, comprises a small fraction of SCTs and was considered a specific entity until the 2016 revision of the World Health Organization classification of non-germ cell tumors, where it was classified as a morphologic variant of SCT-NOS. In a recent study, differences in expression of PAX2/PAX8, inhibin, androgen receptor and S100 protein between SCT-NOS and S-SCT were noted in a small number of cases. In this interinstitutional study, we compared the expression of these markers and β-catenin in 11 cases each of SCT-NOS and S-SCT to determine if differences exist that could justify keeping a separate classification of these neoplasms. PAX2/PAX8 cocktail was the only marker that was significantly overexpressed in S-SCT. Expression of androgen receptors was strong in S-SCT and variable in SCT-NOS, but did not reach statistical significance. Expression of β-catenin was common in both, while inhibin was infrequent. The available material was insufficient for a conclusive evaluation of S100 protein expression. Overall, our results support the inclusion of S-SCT as a morphologic variant of SCT-NOS. Expression of PAX2/PAX8 in S-SCT may reflect an overactive epithelial to mesenchymal transition as has been shown in experimental models of acute and chronic seminiferous tubular injury and might be related to the process generating the stroma in these tumors.



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Histone deacetylases inhibition: a potential diagnostic and therapeutic target for cancers—reply

Publication date: Available online 2 September 2017
Source:Human Pathology
Author(s): Daniel Neureiter, Tobias Kiesslich




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Radiology Research Funding

Publication date: Available online 1 September 2017
Source:Academic Radiology
Author(s): Alison L. Chetlen, Andrew J. Degnan, Mark Guelfguat, Brent Griffith, Jason Itri, Hazem Matta, Angela Tong, Jonathan Flug, Dennis Toy, Nikita Consul, Eric Walker, Lucy Spalluto, Andrew D. Smith, Elizabeth A. Krupinski
Funding for research has become increasingly difficult to obtain in an environment of decreasing clinical revenue, increasing research costs, and growing competition for federal and nonfederal funding sources. This paper identifies critical requirements to build and sustain a successful radiology research program (eg, key personnel and leadership, research training and mentorship, infrastructure, institutional and departmental funding or support), reviews the current state of available funding for radiology (including federal, nonfederal, philanthropy, crowdfunding, and industry), and describes promising opportunities for future funding (eg, health services, comparative effectiveness, and patient-centered outcomes research). The funding climate, especially at the federal level, changes periodically, so it is important to have radiology-specific organizations such as the American College of Radiology and the Academy of Radiology Research serving as our key advocates. Key to obtaining any funding, no matter what the source, is a well-formulated grant proposal, so a review of opportunities specifically available to radiologists to develop and hone their grant-writing skills is provided. Effective and sustained funding for radiology research has the potential to cultivate young researchers, bolster quality research, and enhance health care. Those interested in pursuing research need to be aware of the ever-changing funding landscape, research priority areas, and the resources available to them to succeed. To succeed, radiology researchers need to think about diversification and flexibility in their interests, developing multidisciplinary and multi-institutional projects, and engaging a broader base of stakeholders that includes patients.



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The Economics of Academic Advancement Within Surgery

Publication date: Available online 1 September 2017
Source:Journal of Surgical Education
Author(s): Maria Baimas-George, Brian Fleischer, James R. Korndorffer, Douglas Slakey, Christopher DuCoin
BackgroundThe success of an academic surgeon's career is often viewed as directly related to academic appointment; therefore, the sequence of promotion is a demanding, rigorous process. This paper seeks to define the financial implication of academic advancement across different surgical subspecialties.Study DesignData was collected from the Association of American Medical College's 2015 report of average annual salaries. Assumptions included 30 years of practice, 5 years as assistant professor, and 10 years as associate professor before advancement. The base formula used was: (average annual salary) × (years of practice [30 years − fellowship/research years]) + ($50,000 × years of fellowship/research) = total adjusted lifetime salary income.ResultsThere was a significant increase in lifetime salary income with advancement from assistant to associate professor in all subspecialties when compared to an increase from associate to full professor. The greatest increase in income from assistant to associate professor was seen in transplant and cardiothoracic surgery (35% and 27%, respectively). Trauma surgery and surgical oncology had the smallest increases of 8% and 9%, respectively. With advancement to full professor, the increase in lifetime salary income was significantly less across all subspecialties, ranging from 1% in plastic surgery to 8% in pediatric surgery.ConclusionWhen analyzing the economics of career advancement in academic surgery, there is a substantial financial benefit in lifetime income to becoming an associate professor in all fields; whereas, advancement to full professor is associated with a drastically reduced economic benefit.



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The Role of Simulation in Boosting the Learning Curve in EVAR Procedures

Publication date: Available online 1 September 2017
Source:Journal of Surgical Education
Author(s): Vincenzo Vento, Laura Cercenelli, Chiara Mascoli, Enrico Gallitto, Stefano Ancetti, Gianluca Faggioli, Antonio Freyrie, Emanuela Marcelli, Mauro Gargiulo, Andrea Stella
ObjectiveSimulation may be a useful tool for training in endovascular procedures. The aim of this study was to evaluate the effect of endovascular repair of abdominal aortic aneurysms (EVAR) simulation in boosting trainees' learning curve.DesignTen vascular surgery residents were recruited and divided in 2 groups (Trainee Group and Control group). At a first session (t0), each resident performed 2 simulated EVAR procedures using an endovascular simulator. After 2 weeks, each participant simulated other 2 EVAR procedures in a final session (t1). In the period between t0 and t1, each resident in the Trainee Group performed 6 simulated EVAR procedures, whereas the Control Group did not perform any other simulation. Both quantitative and qualitative performance evaluations were performed at t0 and t1. Quantitative evaluation from simulator metrics included total procedural time (TP), total fluoroscopy time (TF), time for contralateral gate cannulation (TG), and contrast medium volume (CM) injected. Qualitative evaluation was based on a Likert scale used to calculate a total performance score referred to skills involving major EVAR procedural steps.ResultsAll residents in the Trainee Group significantly reduced TP (48 ± 12 vs 32 ± 8 minutes, t0 vs t1, p < 0.05), TF (18 ± 7 vs 11 ± 6 minutes, p < 0.05), and CM used over time (121 ± 37 vs 85 ± 26ml, p < 0.05), but not TG (5 ± 5 vs 3 ± 4 minutes, p = 0.284). In the Control Group metrics did not change significantly in any field (TP = 55 ± 11 vs 46 ± 10 minutes; TF = 25 ± 9 vs 21 ± 4 minutes; CM = 132 ± 51 vs 102 ± 42ml; TG = 6 ± 4 vs 8 ± 5 minutes, all p > 0.05). The average Trainee Group qualitative total performance score improved significantly (p < 0.05) after rehearsal sessions when compared with the Control Group.ConclusionSimulation is an effective method to improve competence of vascular surgery residents with EVAR procedures.



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Communication Skills Training in Ophthalmology: Results of a Needs Assessment and Pilot Training Program

Publication date: Available online 1 September 2017
Source:Journal of Surgical Education
Author(s): Anuradha Mishra, David Browning, Miriam J. Haviland, Mary Lou Jackson, Donna Luff, Elaine C. Meyer, Katherine Talcott, Carolyn E. Kloek
ObjectiveTo conduct a needs assessment to identify gaps in communication skills training in ophthalmology residency programs and to use these results to pilot a communication workshop that prepares residents for difficult conversations.DesignA mixed-methods design was used to perform the needs assessment. A pre-and postsurvey was administered to workshop participants.SettingMass Eye and Ear Infirmary, Harvard Medical School (HMS), Department of Ophthalmology.ParticipantsHMS ophthalmology residents from postgraduate years 2-4 participated in the needs assessment and the workshop. Ophthalmology residency program directors in the United States participated in national needs assessment.MethodsOphthalmology program directors across the United States were queried on their perception of resident communication skills training through an online survey. A targeted needs assessment in the form of a narrative exercise captured resident perspectives on communication in ophthalmology from HMS residents. A group of HMS residents participated in the pilot workshop and a pre- and postsurvey was administered to participants to assess its effectiveness.ResultsThe survey of program directors yielded a response rate of 40%. Ninety percent of respondents agreed that the communication skills training in their programs could be improved. Fifteen of 24 residents (62%) completed the needs assessment. Qualitative analysis of the narrative material revealed four themes; (1) differing expectations, (2) work role and environment, (3) challenges specific to ophthalmology, and (4) successful strategies adopted. Nine residents participated in the workshop. There was a significant improvement post-workshop in resident reported scores on their ability to manage their emotions during difficult conversations (p = 0.03).ConclusionsThere is an opportunity to improve communication skills training in ophthalmology residency through formalized curriculum.



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Epigenetic regulation of epithelial to mesenchymal transition by the Lysine-specific demethylase LSD1/KDM1A

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Susanna Ambrosio, Carmen D. Saccà, Barbara Majello
The Lysine-specific demethylase 1, KDM1A/LSD1, plays a central role in the regulation of Pol II transcription through the removal of the activation mark (mono- and dimethyl lysine 4 of histone H3). LSD1 is often deregulated in human cancers, and it is frequently overexpressed in human solid cancers and leukemia. LSD1 regulates the epithelial mesenchymal transition (EMT) in epithelial cells, i.e., the ability to transition into mesenchymal cells, to lose homotypic adhesion and to acquire migratory capacity. From its initial discovery as a component of the Snail complex, multiple studies highlighted the causative role of LSD1 in cell invasiveness and EMT, describing its direct involvement in different molecular processes through the interaction with specific partners. Here we present an overview of the role of LSD1 in the EMT process, summarizing recent findings on its emerging functions in cell migration and invasion in cancer.



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CELF1 preferentially binds to exon-intron boundary and regulates alternative splicing in HeLa cells

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Heng Xia, Dong Chen, Qijia Wu, Gang Wu, Yanhong Zhou, Yi Zhang, Libin Zhang
The current RIP-seq approach has been developed for the identification of genome-wide interaction between RNA binding protein (RBP) and the bound RNA transcripts, but still rarely for identifying its binding sites. In this study, we performed RIP-seq experiments in HeLa cells using a monoclonal antibody against CELF1. Mapping of the RIP-seq reads showed a biased distribution at the 3′UTR and intronic regions. A total of 15,285 and 1384 CELF1-specific sense and antisense peaks were identified using the ABLIRC software tool. Our bioinformatics analyses revealed that 5′ and 3′ splice site motifs and GU-rich motifs were highly enriched in the CELF1-bound peaks. Furthermore, transcriptome analyses revealed that alternative splicing was globally regulated by CELF1 in HeLa cells. For example, the inclusion of exon 16 of LMO7 gene, a marker gene of breast cancer, is positively regulated by CELF1. Taken together, we have shown that RIP-seq data can be used to decipher RBP binding sites and reveal an unexpected landscape of the genome-wide CELF1-RNA interactions in HeLa cells. In addition, we found that CELF1 globally regulates the alternative splicing by binding the exon-intron boundary in HeLa cells, which will deepen our understanding of the regulatory roles of CELF1 in the pre-mRNA splicing process.



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Integrin linked kinase regulates the transcription of AQP2 by NFATC3

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Marco Hatem-Vaquero, Mercedes Griera, Wieslawa Giermakowska, Alicia Luengo, Laura Calleros, Laura V. Gonzalez Bosc, Diego Rodríguez-Puyol, Manuel Rodríguez-Puyol, Sergio De Frutos
Two processes are associated with progressive loss of renal function: 1) decreased aquaporin-2 (AQP2) expression and urinary concentrating capacity (Nephrogenic Diabetes Insipidus, NDI); and 2) changes in extracellular matrix (ECM) composition, e.g. increased collagen I (Col I) deposition, characteristic of tubule-interstitial fibrosis. AQP2 expression is regulated by both the ECM-to-intracellular scaffold protein integrin-linked kinase (ILK) by NFATc/AP1 and other transcription factors. In the present work, we used in vivo and in vitro approaches to examine ILK participation in NFATc3/AP-1-mediated increases in AQP2 gene expression. Both NFATc3 knock-out mice and ILK conditional-knockdown mice (cKD-ILK) display symptoms of NDI (polyuria and reduced AQP2 expression). NFATc3 is upregulated in the renal medulla tubular cells of cKD-ILK mice but with reduced nuclear localization. Inner medullary collecting duct mIMCD3 cells were subjected to ILK depletion and transfected with reporter plasmids. Pharmacological activators or inhibitors determined the effect of ILK activity on NFATc/AP-1-dependent increases in transcription of AQP2. Finally, mIMCD3 cultured on Col I showed reduced activity of the ILK/GSK3β/NFATc/AQP2 axis, suggesting this pathway is a potential target for therapeutic treatment of NDI.



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BRG1 and SMARCAL1 transcriptionally co-regulate DROSHA, DGCR8 and DICER in response to doxorubicin-induced DNA damage

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Ketki Patne, Radhakrishnan Rakesh, Vijendra Arya, Upasana Bedi Chanana, Ramesh Sethy, Pynskhem Bok Swer, Rohini Muthuswami
Recent investigations have emphasized the role of miRNA biogenesis proteins in the synthesis of non-coding RNA when double-strand DNA breaks are induced by ionizing radiations. However, the role of these non-coding RNA and their regulation in response to doxorubicin-induced DNA damage is not known.In this paper, BRG1 and SMARCAL1, members of the ATP-dependent chromatin remodelling family, are shown to co-regulate the transcription of DROSHA, DGCR8, and DICER in response to double-strand DNA breaks induced by doxorubicin. Both BRG1 and SMARCAL1 are needed for the upregulation of the three miRNA biogenesis genes as absence of BRG1 results in downregulation of DGCR8 and DICER while absence of SMARCAL1 results in downregulation of DROSHA. These two proteins act in coordination to upregulate expression of DROSHA, DGCR8, and DICER when cells are treated with doxorubicin. This transcriptional regulation of the miRNA biogenesis proteins is needed for the formation of 53BP1 foci as downregulation of either BRG1 or SMARCAL1 reduced the number of 53BP1 foci in DNA damaged cells. The foci formation was restored when the downregulated cells were treated with ncRNA purified from doxorubicin treated HeLa cells.From the results obtained, we conclude that the regulation of miRNA biogenesis proteins by SMARCAL1 and BRG1 is needed for the formation of non-coding RNA and thus, 53BP1 foci in response to doxorubicin-induced DNA damage.



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Selective regulation of biological processes by vitamin D based on the spatio-temporal cistrome of its receptor

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Antonio Neme, Sabine Seuter, Carsten Carlberg
The transcription factor vitamin D receptor (VDR) is the exclusive nuclear target of the biologically active form of vitamin D (1,25(OH)2D3). In THP-1 human monocytes we obtained a highly accurate VDR cistrome after 2 and 24h ligand stimulation comprising >11,600 genomic loci, 78% of which were detected exclusively after 24h. In contrast, a group of 510 persistent VDR sites occurred at all conditions and some 2100 VDR loci were only transiently occupied. Machine learning and statistical analysis as well as a comparison with the re-analyzed B cell VDR cistrome indicated a subgroup of 339 highly conserved persistent VDR sites that were suited best for describing vitamin D-triggered gene regulatory scenarios. The 1,25(OH)2D3-dependent transcriptome of THP-1 cells comprised 587 genes, 311 of which were primary targets with main functions in the immune system. More than 97% of the latter genes were located within 1,25(OH)2D3-modulated topologically associated domains (TADs). The number of persistent and transient VDR sites was found to be the main discriminator for sorting these TADs into five classes carrying vitamin D target genes involved in distinct biological processes. In conclusion, specific regulation of biological processes by vitamin D depends on differences in time-dependent VDR binding.



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Title Page/Sections Editors

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9





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ZNF509S1 downregulates PUMA by inhibiting p53K382 acetylation and p53-DNA binding

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Bu-Nam Jeon, Jae-Hyeon Yoon, Dohyun Han, Min-Kyeong Kim, Youngsoo Kim, Seo-Hyun Choi, Jiyang Song, Kyung-Sup Kim, Kunhong Kim, Man-Wook Hur
Expression of the POK family protein ZNF509L, and -its S1 isoform, is induced by p53 upon exposure to genotoxic stress. Due to alternative splicing of the ZNF509 primary transcript, ZNF509S1 lacks the 6 zinc-fingers and C-terminus of ZNF509L, resulting in only one zinc-finger. ZNF509L and -S1 inhibit cell proliferation by activating p21/CDKN1A and RB transcription, respectively. When cells are exposed to severe DNA damage, p53 activates PUMA (p53-upregulated modulator of apoptosis) transcription. Interestingly, apoptosis due to transcriptional activation of PUMA by p53 is attenuated by ZNF509S1. Thus we investigated the molecular mechanism(s) underlying the transcriptional attenuation and anti-apoptotic effects of ZNF509S1. We show that ZNF509S1 modulation of p53 activity is important in PUMA gene transcription by modulating post-translational modification of p53 by p300. ZNF509S1 directly interacts with p53 and inhibits p300-mediated acetylation of p53 lysine K382, with deacetylation of p53 K382 leading to decreased DNA binding at the p53 response element 1 of the PUMA promoter. ZNF509S1 may play a role not only in cell cycle arrest, by activating RB expression, but also in rescuing cells from apoptotic death by repressing PUMA expression in cells exposed to severe DNA damage.



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Identification of new TSGA10 transcript variants in human testis with conserved regulatory RNA elements in 5'untranslated region and distinct expression in breast cancer

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Pouya Salehipour, Mahsa Nematzadeh, Maryam Beigom Mobasheri, Mandana Afsharpad, Kamran Mansouri, Mohammad Hossein Modarressi
Testis specific gene antigen 10 (TSGA10) is a cancer testis antigen involved in the process of spermatogenesis. TSGA10 could also play an important role in the inhibition of angiogenesis by preventing nuclear localization of HIF-1α. Although it has been shown that TSGA10 messenger RNA (mRNA) is mainly expressed in testis and some tumors, the transcription pattern and regulatory mechanisms of this gene remain largely unknown. Here, we report that human TSGA10 comprises at least 22 exons and generates four different transcript variants. It was identified that using two distinct promoters and splicing of exons 4 and 7 produced these transcript variants, which have the same coding sequence, but the sequence of 5'untanslated region (5'UTR) is different between them. This is significant because conserved regulatory RNA elements like upstream open reading frame (uORF) and putative internal ribosome entry site (IRES) were found in this region which have different combinations in each transcript variant and it may influence translational efficiency of them in normal or unusual environmental conditions like hypoxia. To indicate the transcription pattern of TSGA10 in breast cancer, expression of identified transcript variants was analyzed in 62 breast cancer samples. We found that TSGA10 tends to express variants with shorter 5'UTR and fewer uORF elements in breast cancer tissues. Our study demonstrates for the first time the expression of different TSGA10 transcript variants in testis and breast cancer tissues and provides a first clue to a role of TSGA10 5'UTR in regulation of translation in unusual environmental conditions like hypoxia.



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Co-regulation of microRNAs and transcription factors in cardiomyocyte specific differentiation of murine embryonic stem cells: An aspect from transcriptome analysis

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Lin Gan, Bernd Denecke
The differentiation process of embryonic stem cells is a comprehensive process regulated by a variety of factors in response to stimulus. Studies of this process can be focused on cell biology as well as on molecular biology level. In this paper we identified the co-regulation of molecular regulators and their interactions during cardiomyocyte specific differentiation of mouse embryonic stem cells based on parallel genome wide transcriptome analyses of mRNA and microRNA. Differentially expressed mRNAs and microRNAs were identified according to their expression profiles. Subsequently, a primary network was generated by using our genome wide profiling data, predicted sequence target information of transcription factors and microRNAs from various sources, validated microRNA target information, as well as tissue specific transcription factor binding information. Considering only validated microRNA target information and tissue specific transcription factor binding information secondary regulatory networks were extracted from the primary network to identify basic regulatory elements. Eight types of 3-node patterns were identified in this network. Novel regulatory modules, like Meis1 - Gata6 and miR-21/24 - Zic3, were discovered with high plausibility by this procedure without complicated and time-consuming experimental processes.

Graphical abstract

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Histone demethylase PHF8 regulates hypoxia signaling through HIF1α and H3K4me3

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Peterson Kariuki Maina, Peng Shao, Xiongfei Jia, Qi Liu, Shaikamjad Umesalma, Maximo Marin, Donald Long, Samantha Concepción-Román, Hank Heng Qi
Hypoxia through transcription factor HIF1α plays a critical role in cancer development. In prostate cancer, HIF1α interplays with androgen receptor (AR) to contribute to the progression of this disease to its lethal form—castration-resistant prostate cancer (CRPC). Hypoxia upregulates several epigenetic factors including histone demethylase KDM3A which is a critical co-factor of HIF1α. However, how histone demethylases regulate hypoxia signaling is not fully understood. Here, we report that histone demethylase PHF8 plays an essential role in hypoxia signaling. Knockdown or knockout of PHF8 by RNAi or CRISPR-Cas9 system reduced the activation of HIF1α and the induction of HIF1α target genes including KDM3A. Mechanistically, PHF8 regulates hypoxia inducible genes mainly through sustaining the level of trimethylated histone 3 lysine 4 (H3K4me3), an active mark in transcriptional regulation. The positive role of PHF8 in hypoxia signaling extended to hypoxia-induced neuroendocrine differentiation (NED), wherein PHF8 cooperates with KDM3A to regulate the expression of NED genes. Moreover, we discovered that the role of PHF8 in hypoxia signaling is associated with the presence of full-length AR in CRPC cells. Collectively, our study identified PHF8 as a novel epigenetic factor in hypoxia signaling, and the underlying regulatory mechanisms likely apply to general cancer development involving HIF1α. Therefore, targeting PHF8 can potentially be a novel therapeutic strategy in cancer therapy.



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Regulation and evolution of the interaction of the seed B3 transcription factors with NF-Y subunits

Publication date: Available online 1 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): C. Boulard, A. Fatihi, L. Lepiniec, B. Dubreucq
The LAFL genes (LEC2, ABI3, FUS3, LEC1) encode transcription factors that regulate different aspects of seed development, from early to late embryogenesis and accumulation of storage compounds. These transcription factors form a complex network, with members able to interact with various other players to control the switch between embryo development and seed maturation and, at a later stage in the plant life cycle, between the mature seed and germination.In this review, we first summarize our current understanding of the role of each member in the network in the light of recent advances regarding their regulation and structure/function relationships. In a second part, we discuss new insights concerning the evolution of the LAFL genes to address the more specific question of the conservation of LEAFY COTYLEDONS 2 in both dicots and monocots and the putative origin of the network. Last we examine the current major limitations to current knowledge and future prospects to improve our understanding of this regulatory network.



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Transcriptional and epigenetic analyses of the DMD locus reveal novel cis‑acting DNA elements that govern muscle dystrophin expression

Publication date: Available online 1 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Samuele Gherardi, Matteo Bovolenta, Chiara Passarelli, Maria Sofia Falzarano, Paolo Pigini, Chiara Scotton, Marcella Neri, Annarita Armaroli, Hana Osman, Rita Selvatici, Francesca Gualandi, Alessandra Recchia, Marina Mora, Pia Bernasconi, Lorenzo Maggi, Lucia Morandi, Alessandra Ferlini, Giovanni Perini
The dystrophin gene (DMD) is the largest gene in the human genome, mapping on the Xp21 chromosome locus. It spans 2.2Mb and accounts for approximately 0,1% of the entire human genome. Mutations in this gene cause Duchenne and Becker Muscular Dystrophy, X-linked Dilated Cardiomyopathy, and other milder muscle phenotypes. Beside the remarkable number of reports describing dystrophin gene expression and the pathogenic consequences of the gene mutations in dystrophinopathies, the full scenario of the DMD transcription dynamics remains however, poorly understood. Considering that the full transcription of the DMD gene requires about 16h, we have investigated the activity of RNA Polymerase II along the entire DMD locus within the context of specific chromatin modifications using a variety of chromatin-based techniques.Our results unveil a surprisingly powerful processivity of the RNA polymerase II along the entire 2.2Mb of the DMD locus with just one site of pausing around intron 52. We also discovered epigenetic marks highlighting the existence of four novel cis‑DNA elements, two of which, located within intron 34 and exon 45, appear to govern the architecture of the DMD chromatin with implications on the expression levels of the muscle dystrophin mRNA.Overall, our findings provide a global view on how the entire DMD locus is dynamically transcribed by the RNA pol II and shed light on the mechanisms involved in dystrophin gene expression control, which can positively impact on the optimization of the novel ongoing therapeutic strategies for dystrophinopathies.



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DNA methyltransferase homologue TRDMT1 in Plasmodium falciparum specifically methylates endogenous aspartic acid tRNA

Publication date: Available online 26 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Gayathri Govindaraju, C.A. Jabeena, Devadathan Valiyamangalath Sethumadhavan, Nivethika Rajaram, Arumugam Rajavelu
In eukaryotes, cytosine methylation regulates diverse biological processes such as gene expression, development and maintenance of genomic integrity. However, cytosine methylation and its functions in pathogenic apicomplexan protozoans remain enigmatic. To address this, here we investigated the presence of cytosine methylation in the nucleic acids of the protozoan Plasmodium falciparum. Interestingly, P. falciparum has TRDMT1, a conserved homologue of DNA methyltransferase DNMT2. However, we found that TRDMT1 did not methylate DNA, in vitro. We demonstrate that TRDMT1 methylates cytosine in the endogenous aspartic acid tRNA of P. falciparum. Through RNA bisulfite sequencing, we mapped the position of 5-methyl cytosine in aspartic acid tRNA and found methylation only at C38 position. P. falciparum proteome has significantly higher aspartic acid content and a higher proportion of proteins with poly aspartic acid repeats than other apicomplexan pathogenic protozoans. Proteins with such repeats are functionally important, with significant roles in host-pathogen interactions. Therefore, TRDMT1 mediated C38 methylation of aspartic acid tRNA might play a critical role by translational regulation of important proteins and modulate the pathogenicity of the malarial parasite.



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Variable cardiac α-actin (Actc1) expression in early adult skeletal muscle correlates with promoter methylation

Publication date: Available online 26 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Jordan K. Boutilier, Rhonda L. Taylor, Ramesh Ram, Elyshia McNamara, Quang Nguyen, Hayley Goullee, David Chandler, Munish Mehta, Lois Balmer, Nigel G. Laing, Grant Morahan, Kristen J. Nowak
Different genes encode the a-actin isoforms that are predominantly expressed in heart and muscle. Mutations in the skeletal muscle α-actin gene (ACTA1) cause muscle diseases that are mostly lethal in the early postnatal period. We previously demonstrated that the disease phenotype of ACTA1 mouse models could be rescued by transgenic over-expression of cardiac α-actin (ACTC1). ACTC1 is the predominant striated α-actin isoform in the heart but is also expressed in developing skeletal muscle. To develop a translatable therapy, we investigated the genetic regulation of Actc1 expression. Using strains from The Collaborative Cross (CC) genetic resource, we found that Actc1 varies in expression by up to 24-fold in skeletal muscle. We defined significant expression quantitative trait loci (eQTL) associated with early adult Actc1 expression in soleus and heart. eQTL in both heart and soleus mapped to the Actc1 locus and replicate an eQTL mapped for Actc1 in BXD heart and quadriceps. We built on this previous work by analysing genes within the eQTL peak regions to prioritise likely candidates for modifying Actc1 expression. Additionally we interrogated the CC founder haplotype contributions to enable prioritisation of genetic variants for functional analyses. Methylation around the Actc1 transcriptional start site in early adult skeletal muscle negatively correlated with Actc1 expression in a strain-dependent manner, while other marks of regulatory potential (histone modification and chromatin accessibility) were unaltered. This study provides novel insights into the complex genetic regulation of Actc1 expression in early adult skeletal muscles.Author SummaryMutations in the skeletal muscle actin gene (ACTA1) cause a severe muscle disease that is usually fatal within the first year of life. Some patients with mutations in the ACTA1 gene do not have any ACTA1 protein present in their skeletal muscles. We have previously shown that some of these patients retain expression of the foetal isoform of the gene, cardiac actin (ACTC1). Further, patients who have ACTC1 expressed in their skeletal muscles have increased longevity and improved muscle function, suggesting that upregulation of ACTC1 may be a viable therapy for ACTA1 disease patients. Thus, we have investigated the mechanisms regulating expression of Actc1 in a genetically diverse population of different mouse strains with the aim of identifying the regulatory controls that cause the gene to be switched off. We identified a number of sequence variants present in Actc1 regulatory regions and show that increased promoter methylation is inversely correlated with Actc1 expression. We also show that expression of ACTC1 in humans is likely to be influenced by non-coding sequence variation in regulatory regions upstream and downstream of the gene. Our findings build on previous work and identify regulatory regions of the genome that can now be investigated further.



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Radiation induced transcriptional and post-transcriptional regulation of the hsa-miR-23a~27a~24-2 cluster suppresses apoptosis by stabilizing XIAP

Publication date: Available online 26 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Theresa Heider, Lisa Mutschelknaus, Vanja Radulović, Klaudia Winkler, Julia Kimmel, Nataša Anastasov, Michael J. Atkinson, Simone Moertl
The non-coding transcriptome, in particular microRNAs (miRNA), influences cellular survival after irradiation. However, the underlying mechanisms of radiation-induced miRNA expression changes and consequently target expression changes are poorly understood.In this study, we show that ionizing radiation decreases expression of the miR-23a~27a~24-2 cluster through transcriptional regulation by promoter methylation and at the post-transcriptional level by reduced processing through AGO-phosphorylation. Furthermore, we demonstrate that all three mature cluster miRNAs reduce apoptosis by increasing expression of the common target protein XIAP.These findings link a temporal succession of transcriptional and post-transcriptional regulatory mechanisms of the miR~23a~24-2~27a cluster, enabling a dynamic stress response and assuring cellular survival after radiation exposure.

Graphical abstract

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KSRP suppresses cell invasion and metastasis through miR-23a-mediated EGR3 mRNA degradation in non-small cell lung cancer

Publication date: Available online 25 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Ming-Hsien Chien, Wei-Jiunn Lee, Yi-Chieh Yang, Yin-Lin Li, Bo-Rong Chen, Tsu-Yao Cheng, Pei-Wen Yang, Ming-Yang Wang, Yi-Hua Jan, Yen-Kuang Lin, Jang-Ming Lee, Michael Hsiao, Jin-Shing Chen, Kuo-Tai Hua
KH-type splicing regulatory protein (KSRP) is a single-strand RNA binding protein which regulates mRNA stability either by binding to AU-rich elements (AREs) of mRNA 3'UTR or by facilitating miRNA biogenesis to target mRNA. Unlike its well-characterized function at the molecular level in maintaining RNA homeostasis, the role of KSRP in cancer progression remains largely unknown. Here we investigate the role of KSRP in non-small cell lung cancer (NSCLC). We first examined KSRP expression by immunohistochemistry in a cohort containing 196 NSCLC patients and observed a strong positive correlation between KSRP expression and survival of NSCLC patients. Multivariate analysis further identified KSRP as an independent prognostic factor. Manipulating KSRP expression significantly affected in vitro cell mobility and in vivo metastatic ability of NSCLC cells. Microarray analysis identified an ARE-containing gene, EGR3, as a downstream effector of KSRP in NSCLC. Interestingly, we found that KSRP decreased EGR3 mRNA stability in an ARE-independent manner. By screening KSRP-regulated miRNAs in NSCLC cells, we further found that miR-23a directly binds to EGR3 3'UTR, reducing EGR3 expression and thereby inhibiting NSCLC cell mobility. Our findings implicate a targetable KSRP/miR-23a/EGR3 signaling axis in advanced tumor phenotypes.



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HIF-1α coordinates epigenetic activation of SIAH1 in hepatocytes in response to nutritional stress

Publication date: Available online 24 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Zhiwen Fan, Zilong Li, Yuyu Yang, Shuai Liu, Junli Guo, Yong Xu
Hypoxia inducible factor 1 alpha (HIF-1α) regulates a diverse range of pathophysiological processes. It has been demonstrated previously that HIF-1α plays a role in the pathogenesis of steatosis mediating the effects of excessive nutritional insults. In the present study we investigated the role of HIF-1α in trans‑activating the seven in absentia homolog 1 (SIAH1) gene and the underlying mechanism. We report that in response to nutritional stress, SIAH1 expression was up-regulated in the liver in mice and in cultured hepatocytes. In the meantime, HIF-1α started to occupy the SIAH1 promoter. Depletion of HIF-1α with siRNA or inhibition of HIF-1α with chetomin abrogated the induction of SIAH1 expression. HIF-1α knockdown or inhibition paralleled epigenetic alterations surrounding the SIAH1 promoter characterized by the loss of acetylated histone H3 and trimethylated H3K4 as well as the acquisition of dimethylated H3K9. Further analyses revealed that HIF-1α interacted with and recruited the histone demethylase KDM3A to the SIAH1 promoter to activate transcription. HIF-1α also mediated the crosstalk between KDM3A and p300. Depletion of KDM3A coincided with the loss of SIAH1 induction and the accumulation of dimethylated H3K9 surrounding the SIAH1 promoter. Interestingly, KDM3A expression was also up-regulated by nutritional stress in a HIF-1α dependent manner. Together, our data uncover a novel epigenetic pathway that may contribute to the regulation of SIAH1 expression and the pathogenesis of steatosis.



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Correlation between desiccation stress response and epigenetic modifications of genes in Drosophila melanogaster: An example of environment-epigenome interaction

Publication date: Available online 8 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Vineeta Sharma, Surbhi Kohli, Vani Brahmachari
Animals from different phyla including arthropods tolerate water stress to different extent. This tolerance is accompanied by biochemical changes which in turn are due to transcriptional alteration. The changes in transcription can be an indirect effect on some of the genes, ensuing from the effect of stress on the regulators of transcription including epigenetic regulators. Within this paradigm, we investigated the correlation between stress response and epigenetic modification underlying gene expression modulation during desiccation stress in Canton-S. We report altered resistance of flies in desiccation stress for heterozygote mutants of PcG and TrxG members. Pc/+ mutant shows lower survival, while ash1/+ mutants show higher survival under desiccation stress as compared to Canton-S. We detect expression alteration in stress related genes as well the genes of the Polycomb and trithorax complex in Canton-S subjected to desiccation stress. Concomitant with this, there is an altered enrichment of H3K27me3 and H3K4me3 at the upstream regions of the stress responsive genes. The enrichment of activating mark, H3K4me3, is higher in non-stress condition while H3K27me3, the repressive mark, is more pronounced under stress condition, which in turn, can be correlated with the binding of Pc and Ash1. Our results show that desiccation stress induces dynamic switching in expression and enrichment of PcG and TrxG in the upstream region of genes, which correlates with histone modifications. We provide evidence that epigenetic modulation could be one of the mechanisms to adapt to the desiccation stress in Drosophila. Thus, our study proposes the interaction of epigenome and environmental factors.

Graphical abstract

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Title Page/Sections Editors

Publication date: August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 8





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Human OGG1 activity in nucleosomes is facilitated by transient unwrapping of DNA and is influenced by the local histone environment

Publication date: Available online 1 September 2017
Source:DNA Repair
Author(s): Katharina Bilotti, Erin E. Kennedy, Chuxuan Li, Sarah Delaney
If unrepaired, damage to genomic DNA can cause mutations and/or be cytotoxic. Single base lesions are repaired via the base excision repair (BER) pathway. The first step in BER is the recognition and removal of the nucleobase lesion by a glycosylase enzyme. For example, human oxoguanine glycosylase 1 (hOGG1) is responsible for removal of the prototypic oxidatively damaged nucleobase, 8-oxo-7,8-dihydroguanine (8-oxoG). To date, most studies of glycosylases have used free duplex DNA substrates. However, cellular DNA is packaged as repeating nucleosome units, with 145 base pair segments of DNA wrapped around histone protein octamers. Previous studies revealed inhibition of hOGG1 at the nucleosome dyad axis and in the absence of chromatin remodelers. In this study, we reveal that even in the absence of chromatin remodelers or external cofactors, hOGG1 can initiate BER at positions off the dyad axis and that this activity is facilitated by spontaneous and transient unwrapping of DNA from the histones. Additionally, we find that solution accessibility as determined by hydroxyl radical footprinting is not fully predictive of glycosylase activity and that histone tails can suppress hOGG1 activity. We therefore suggest that local nuances in the nucleosome environment and histone-DNA interactions can impact glycosylase activity.



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Construction and comparison of different source neuraminidase candidate vaccine strains for human infection with Eurasian avian-like influenza H1N1 virus

Publication date: Available online 30 August 2017
Source:Microbes and Infection
Author(s): Liqi Liu, Jian Lu, Jianfang Zhou, Zi Li, Heng Zhang, Dayan Wang, Yuelong Shu
Human infections with Eurasian avian-like swine influenza H1N1 viruses have been reported in China in past years. One case resulted in death and others were mild case. In 2016, the World Health Organization recommended the use of A/Hunan/42443/2015(H1N1) virus to construct the first candidate vaccine strain for Eurasian avian-like swine influenza H1N1 viruses. Previous reports showed that the neuraminidase of A/Puerto Rico/8/34(H1N1) might improve the viral yield of reassortant viruses. Therefore, we constructed two reassortant candidate vaccine viruses of A/Hunan/42443/2015(H1N1) by reverse genetic technology, with (6+2) and (7+1) gene constitution, respectively. The (6+2) virus had hemagglutinin and neuraminidase from A/Hunan/42443/2015, and the (7+1) one had hemagglutinin from A/Hunan/42443/2015, while all the other genes were from A/Puerto Rico/8/34. Our data revealed that although the neuraminidase of the (7+1) virus was from high yield A/Puerto Rico/8/34, the hemagglutination titer and the hemagglutinin protein content of the (7+1) virus was not higher than that of the (6+2) virus. Both of the (7+1) and (6+2) viruses reached a similar level to that of A/Puerto Rico/8/34 at the usual harvest time in vitro. Therefore, both reassortant viruses are potential candidate vaccine viruses, which could contribute to pandemic preparedness.



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HIV-1 mutates to adapt in fluxing environments

Publication date: Available online 30 August 2017
Source:Microbes and Infection
Author(s): Masako Nomaguchi, Naoya Doi, Takaaki Koma, Akio Adachi
Human immunodeficiency virus type 1 (HIV-1) is specifically adapted for replication, persistence, transmission, and survival in humans. HIV-1 is highly mutable in nature, and well responds to a variety of environmental pressures by altering its genome sequences. In this review, we have described experimental evidence that demonstrates this phantasmagoric property of HIV-1.



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IL-6-mediated signaling pathways limit Chlamydia muridarum infection and exacerbate its pathogenicity in the mouse genital tract

Publication date: Available online 31 August 2017
Source:Microbes and Infection
Author(s): Xin Sun, Qi Tian, Luying Wang, Min Xue, Guangming Zhong
Chlamydia muridarum induction of mouse hydrosalpinx, depending on both tubal infection and inflammation, has been used for investigating C. trachomatis pathogenesis. We now report that IL-6 both inhibits C. muridarum infection and exacerbates pathogenicity in the mouse genital tract. When intravaginally inoculated with a high dose of C. muridarum, IL-6-deficient mice developed more extensive genital tract infection with severe hydrosalpinx, suggesting that IL-6 is required for controlling the high dose infection but not essential for C. muridarum-induced pathology. However, at a low dose, IL-6-deficient mice still developed more extensive infection in the genital tract but no longer with significant pathology, suggesting that IL-6 is required for both controlling the low dose infection and exacerbating the low dose infection-induced pathology. The lack of hydrosalpinx in IL-6-deficient mice correlated with significantly reduced inflammatory infiltration in the oviduct tissue and decreased spleen CD4+ and CD8+ T cells that produce TNFα. Thus, IL-6-dependent pathways are important for both limiting chlamydial colonization in the genital tract mucosal tissues regardless of the infection doses and exacerbating chlamydial pathogenicity in the upper genital tract when IL-6-independent pathogenic mechanisms are not yet activated with a low infection dose.



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Atopic dermatitis and psoriasis: two different immune diseases or one spectrum?

Publication date: October 2017
Source:Current Opinion in Immunology, Volume 48
Author(s): Emma Guttman-Yassky, James G Krueger
Psoriasis and atopic dermatitis (AD) are common T-cell mediated inflammatory diseases of the skin that can be treated by specific cytokine antagonists or more broad immunosuppressive drugs. The diseases are similar in that epidermal keratinocytes respond to T-cell derived cytokines by altering growth and differentiation responses, accounting for major parts of the overall disease phenotype. When studied across European-American populations, psoriasis and AD display differing T-cell polarity and different arrays of cytokines. Psoriasis is a disease largely driven by Th17 T-cells and associated IL-17 activation, while AD has a strong Th2 component associated with IL-4 and IL-13 over-production, and both diseases have activation of Th22 T-cells and Th1 pathways with increased IL-22 and IFNγ production, respectively. AD is a disease frequently associated with increased IgE production and overt allergies or asthma, most likely due to increased Th2 activation, which is largely lacking in psoriasis. Hence, psoriasis and AD can be viewed as distinct diseases with differing clinical, tissue, and molecular disease phenotypes, but this view does not account for specific subtypes of AD, including Asian-origin, intrinsic, and pediatric AD, that have a prominent IL-17 component and also tissue patterning that overlaps with distinctive psoriasis histopathology. Hence, when considering the range of AD phenotypes, a case can be made that psoriasis and AD exist across a spectrum where polar T-cell axes can be variably present and create some overlapping disease characteristics. Today, ∼90% of psoriasis patients have extremely controlled disease by targeting the IL-23/Th17 T-cell axis with IL-23 or IL-17-targeting antibodies. An outstanding question is whether targeting a single cytokine axis in AD, for example, Th2 axis, will lead to disease suppression in the majority of patients and across all subtypes, including those with higher IL-17 expression, or whether it is necessary to personalize therapies and target multiple T-cell axes to attain similar disease improvement to psoriasis.



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Spatial structure normalises working memory performance in Parkinson’s disease

Publication date: Available online 1 September 2017
Source:Cortex
Author(s): Sean James Fallon, Daniel Bor, Adam Hampshire, Roger A. Barker, Adrian M. Owen
AbstractCognitive deficits are a frequent symptom of Parkinson's disease (PD), particularly in the domain of spatial working memory (WM). Despite numerous demonstrations of aberrant WM in patients, there is a lack of understanding about how, if at all, their WM is fundamentally altered. Most notably, it is unclear whether span – the yardstick upon which most WM models are built – is compromised by the disease. Moreover, it is also unknown whether WM deficits occur in all patients or only exist in a sub-group who are executively impaired. We assessed the factors that influenced spatial span in medicated patients by varying the complexity of to-be-remembered items. Principally, we manipulated the ease with which items could enter - or be blocked from – WM by varying the level of structure in memoranda. Despite having similar levels of executive performance to controls, PD patients were only impaired when remembering information that lacked spatial, easy-to-chunk, structure. Patients' executive function, however, did not influence this effect. The ease with which patients could control WM was further examined by presenting irrelevant information during encoding, varying the level of structure in irrelevant information and manipulating the amount of switching between relevant and irrelevant information. Disease did not significantly alter the effect of these manipulations. Rather, patient's executive performance constrained the detrimental effect of irrelevant information on WM. Thus, PD patients' spatial span is predominantly determined by level of structure in to-be-remembered information, whereas their level of executive function may mitigate against the detrimental effect of irrelevant information.



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Selective attention without a neocortex

Publication date: Available online 1 September 2017
Source:Cortex
Author(s): Richard J. Krauzlis, Amarender R. Bogadhi, James P. Herman, Anil Bollimunta
Selective attention refers to the ability to restrict neural processing and behavioral responses to a relevant subset of available stimuli, while simultaneously excluding other valid stimuli from consideration. In primates and other mammals, descriptions of this ability typically emphasize the neural processing that takes place in the cerebral neocortex. However, non-mammals such as birds, reptiles, amphibians and fish, which completely lack a neocortex, also have the ability to selectively attend. In this article, we survey the behavioral evidence for selective attention in non-mammals, and review the midbrain and forebrain structures that are responsible. The ancestral forms of selective attention are presumably selective orienting behaviors, such as prey-catching and predator avoidance. These behaviors depend critically on a set of subcortical structures, including the optic tectum, thalamus and striatum, that are highly conserved across vertebrate evolution. In contrast, the contributions of different pallial regions in the forebrain to selective attention have been subject to more substantial changes and reorganization. This evolutionary perspective makes plain that selective attention is not a function achieved de novo with the emergence of the neocortex, but instead is implemented by circuits accrued and modified over hundreds of millions of years, beginning well before the forebrain contained a neocortex. Determining how older subcortical circuits interact with the more recently evolved components in the neocortex will likely be crucial for understanding the complex properties of selective attention in primates and other mammals, and for identifying the etiology of attention disorders.



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Spatial distribution of osteopontin, CD44v6 and podoplanin in the lining epithelium of odontogenic keratocyst, and their biological relevance

Publication date: Available online 1 September 2017
Source:Annals of Diagnostic Pathology
Author(s): Khamisah Awang Kechik, Chong Huat Siar
Background and aimsThe odontogenic keratocyst (OKC) remains the most challenging jaw cyst to treat because of its locally-aggressive behaviour and high recurrence potential. Emerging evidence suggests that osteopontin, its receptors CD44v6 and integrin αv, and podoplanin, have a role in the local invasiveness of this cyst. However the spatial distribution characteristics of these pro-invasive markers in the lining epithelium of OKC, and their association with the clinicopathologic parameters of OKC are largely unexplored. This study sought to address these issues in comparison with dentigerous cysts (DCs) and radicular cysts (RCs) and to evaluate their biological relevance.MethodsA sample consisting of 20 OKC cases, 10 DCs and 10 RCs was subjected to immunohistochemical staining for osteopontin, CD44v6 and integrin αv, and podoplanin, and semiquantitative analysis was performed.ResultsAll factors (except integrin αv) were detected heterogeneously in the constitutive layers of the lining epithelium in all three cyst types. Key observations were significant upregulation of CD44v6 and podoplanin in OKC compared to DCs and RCs, suggesting that these protein molecules may play crucial roles in promoting local invasiveness in OKC (P<0.05). Osteopontin underexpression and distribution patterns were indistinctive among all three cysts indicating its limited role as pro-invasive factor. Clinical parameters showed no significant correlations with all protein factors investigated.ConclusionsPresent findings suggest that an osteopontin^low CD44v6^high and podoplanin^high immunoprofile most probably represent epithelial signatures of OKC and are markers of local invasiveness in this cyst.



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Emerging Insights into the Roles of the Paf1 Complex in Gene Regulation

Publication date: Available online 1 September 2017
Source:Trends in Biochemical Sciences
Author(s): S. Branden Van Oss, Christine E. Cucinotta, Karen M. Arndt
The conserved, multifunctional Polymerase-Associated Factor 1 complex (Paf1C) regulates all stages of the RNA polymerase (Pol) II transcription cycle. In this review, we examine a diverse set of recent studies from various organisms that build on foundational studies in budding yeast. These studies identify new roles for Paf1C in the control of gene expression and the regulation of chromatin structure. In exploring these advances, we find that various functions of Paf1C, such as the regulation of promoter-proximal pausing and development in higher eukaryotes, are complex and context dependent. As more becomes known about the role of Paf1C in human disease, interest in the molecular mechanisms underpinning Paf1C function will continue to increase.



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La vision cardiologique de l’exploration fonctionnelle à l’effort

Publication date: Available online 1 September 2017
Source:Revue des Maladies Respiratoires
Author(s): F. Carré




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Identification and phenotyping of circulating autoreactive proteinase 3-specific B cells in patients with PR3-ANCA associated vasculitis and healthy controls

Publication date: Available online 1 September 2017
Source:Journal of Autoimmunity
Author(s): Divi Cornec, Alvise Berti, Amber Hummel, Tobias Peikert, Jacques-Olivier Pers, Ulrich Specks
ObjectivesTo develop a method to detect and phenotype circulating proteinase 3 (PR3)-specific B-cells in patients with PR3-ANCA associated vasculitis (AAV).MethodsRecombinant human PR3 (rPR3) was tagged with FITC or biotin, and its binding characteristics were studied by flow cytometry using three hybridoma cell lines secreting antibodies (Ab) against human PR3, mouse PR3 (no cross-reactivity with human PR3), and human neutrophil elastase. We measured the proportion of PR3-specific B-cells and studied their surface phenotype in patients with PR3-AAV and healthy controls (HC).ResultsLabeled rPR3 efficiently and specifically bound to hybridoma cells producing anti-human-PR3-Ab but not anti-mouse-PR3-Ab or anti-human-elastase-Ab. The proportion of rPR3-stained B cells was higher in patients with PR3-AAV compared to HCs: median (IQR) 1.11% (0.81–2.43) vs 0.45% (0.26–0.62) respectively, p < 0.001. There was a trend towards a higher proportion of PR3-specific B cells among patients with active disease compared to patients in remission: 2.91% (1.18–6.52) vs 0.99% (0.72–1.58), p = 0.09. In HCs, the proportion of PR3-specific B cells was highest among the transitional B-cell subset, and decreased with the maturation of B cells. Conversely, in patients, the proportion of PR3-specific B cells progressively increased with the maturation of B cells (median 1.90% of naïve B cells, 2.30% of unswitched memory B cells, 2.37% of switched memory B cells, and 3.68% of plasmablasts).ConclusionsCirculating PR3-specific B cells can be detected in HC and patients with PR3-AAV. Their progressive enrichment during B-cell maturation suggests that they are actively selected and escape peripheral tolerance checkpoints in patients.



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Epitestosterone- and testosterone-replacement in immature castrated rats changes main testicular developmental characteristics

Publication date: Available online 1 September 2017
Source:Molecular and Cellular Endocrinology
Author(s): Fernanda Carvalho Cavalari, Luciana Abreu da Rosa, Gustavo Monteiro Escott, Tadeu Dourado, Alexandre Luz de Castro, Maria Beatriz da Fonte Kohek, Maria Flávia Marques Ribeiro, Wania Aparecida Partata, Luciano Stürmer de Fraga, Eloísa da Silveira Loss
Epitestosterone is the 17α-epimer of testosterone and has been described as an anti-androgen, since it inhibits the effects produced by testosterone and dihydrotestosterone via the nuclear androgen receptor (nAR). However, epitestosterone also displays an effect which is similar to the non-classical effect of testosterone, depolarizing the membrane potential of Sertoli cells and inducing a rapid Ca²⁺ uptake. This study aimed to investigate the effects of a treatment with epitestosterone on developmental parameters of immature rats. Animals were chemically castrated by using the gonadotropin-releasing hormone (GnRH) antagonist cetrorelix and then received a replacement of 7 days with epitestosterone or testosterone. Replacement with either epitestosterone or testosterone restored the anogenital distance (AGD) and testicular weight which had been reduced by chemical castration. The immunocontent of nAR and the nAR-immunoreactivity were reduced by epitestosterone treatment in the testis of both castrated and non-castrated animals. Furthermore, testosterone was unable of changing the membrane potential of Sertoli cells through its non-classical action in the group of animals castrated and replaced with epitestosterone. In conclusion, in relation to the level of protein expression of nAR epitestosterone acts as an anti-androgen. However, it acts in the same way as testosterone when genital development parameters are evaluated. Moreover, in castrated rats epitestosterone suppressed the non-classical response of testosterone, changing the pattern of testosterone signalling via a membrane mechanism in Sertoli cells.



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Lithium chloride inhibits StAR and progesterone production through GSK-3β and ERK1/2 signaling pathways in human granulosa-lutein cells

Publication date: Available online 1 September 2017
Source:Molecular and Cellular Endocrinology
Author(s): Long Bai, Hsun-Ming Chang, Jung-Chien Cheng, Guiyan Chu, Peter C.K. Leung, Gongshe Yang
Lithium chloride (LiCl) is a widely-used medication to treat neurological disorders that has undesirable side effects on the female reproductive system. It has been show that LiCl can inhibit ovarian folliculogenesis, promote follicle atresia and suppress steroid hormone production in rodents. However, the effects of LiCl on human ovarian steroidogenesis remain completely unknown. In this study, both primary and immortalized human granulosa-lutein (hGL) cells were used to investigate the effects of LiCl on progesterone production and its related enzyme expression as well as the underlying mechanisms. Our results showed that LiCl significantly down-regulated the steroidogenic acute regulatory protein (StAR) expression and subsequent progesterone production in hGL cells. Additionally, LiCl induced the phosphorylation of GSK-3β and ERK1/2 but not AKT or CREB. Knockdown of endogenous GSK-3β or inhibition of ERK1/2 partially reversed LiCl-induced down-regulation of StAR. Furthermore, by using dual inhibition approaches, the results showed that both GSK-3β and ERK1/2 signaling mediated the regulatory effect of LiCl on StAR expression. Our findings deepen our understanding of the pathological effects and the underlying molecular mechanisms of how lithium might affect the female reproductive system.



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PRELIM II(EDI BOARD)

Publication date: September 2017
Source:Neuroscience Research, Volume 122





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Astrocytes in the spinal dorsal horn and chronic itch

Publication date: Available online 1 September 2017
Source:Neuroscience Research
Author(s): Makoto Tsuda
Chronic itch is a hallmark symptom of inflammatory skin conditions, such as atopic dermatitis. Existing treatment for chronic itch is largely ineffective. Despite recent progress in our understanding of the neuronal basis for itch sensation in the peripheral and central nervous systems, the mechanisms underlying how itch turns into a pathological chronic state remain poorly understood. Recent studies have uncovered the causal role of astrocytes in the spinal dorsal horn using mouse models of chronic itch, including atopic dermatitis. Understanding the key roles of astrocytes may provide us with exciting insights into the mechanisms for the chronicity of itch sensation and clues to develop novel therapeutic agents for treating chronic itch.



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The roles of cortical astrocytes in chronic pain and other brain pathologies

Publication date: Available online 1 September 2017
Source:Neuroscience Research
Author(s): Kei Eto, Sun Kwang Kim, Ikuko Takeda, Junichi Nabekura
Astrocytes are the most abundant cell type in the brain. Several decades ago, they were considered to be only support cells in the central nervous system. Recent studies using advanced technologies have clarified that astrocytes play more active roles in regulating neuronal function and remodeling synaptic structures by releasing molecules called gliotransmitters. In addition to various physiological functions, astrocytes are activated under disease conditions, such as chronic pain, releasing molecules that in turn cause reorganization of the central nervous system microstructure and disrupt behavior in pathological conditions. In the present review, we summarize cortical astrocyte function in chronic pain and other neurological disorders and discuss the role of astrocytes in brain pathologies.



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Long-term results of a phase II study of gemcitabine and cisplatin chemotherapy combined with intensity-modulated radiotherapy in locoregionally advanced nasopharyngeal carcinoma

Publication date: October 2017
Source:Oral Oncology, Volume 73
Author(s): Mingyao Wu, Dan Ou, Xiayun He, Chaosu Hu




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Pre-diagnostic dynamic HPV16 IgG seropositivity and risk of oropharyngeal cancer

Publication date: October 2017
Source:Oral Oncology, Volume 73
Author(s): Karen S. Anderson, Garrick Wallstrom, Hilde Langseth, Marshall Posner, Julia N. Cheng, Rizwan Alam, Diego Chowell, Ingegerd E. Furre, Jon Mork
ObjectiveThe aim of this study was to determine the association of HPV16 antibodies (Abs) and oropharyngeal cancer (OPC) risk in sera obtained prior to clinical diagnosis.MethodsWe identified 92 participants with incident OPC and 460 matched controls from the Janus Serum Bank Cohort in Norway. Archived tumor specimens were requested for a subset of the cases. Serum samples were collected from cases, on average, 9.3years before diagnosis (range, 0.1–14.9years). Ten cases had serum samples from multiple time points. IgG seropositivity to 8 HPV16 antigens was determined, and a logistic regression classifier of a panel of all early-antigen (EA) Abs for the predictive diagnosis of OPC was applied.ResultsHPV16 EA seropositivity was present in 25.0% of patients with OPC and 7.6% of controls (odds ratio (OR), 4.1; 95% CI, 2.3–7.2, p<0.0001). Abs to E2 were strongly associated with cases 0–2years pre- diagnosis (OR, 150.1; 95% CI, 27.4–1040.0, p<0.0001), and the probability of seropositivity was inversely associated with time to diagnosis (OR, 0.7 per additional year; 95% CI, 0.6–0.9, p=0.0002). Abs to E2 were also strongly associated with tumor HPV status (OR, 35.6; 95% CI, 8.7–200.0, p<0.0001). A positive score on the binary classifier was associated with an overall OR of 15.8 (95% CI, 5.6–53.4) compared with controls (p<0.05), and was strongly associated with tumor HPV status (OR, 27.4; 95% CI, 8.6–99.6, p<0.001).ConclusionsHPV16 Abs are detectable years prior to diagnosis of OPC, and the probability of seropositivity increases closer to diagnosis.



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A randomized, open-label, Phase III clinical trial of nivolumab vs. therapy of investigator’s choice in recurrent squamous cell carcinoma of the head and neck: A subanalysis of Asian patients versus the global population in checkmate 141

Publication date: October 2017
Source:Oral Oncology, Volume 73
Author(s): Naomi Kiyota, Yasuhisa Hasegawa, Shunji Takahashi, Tomoya Yokota, Chia-Jui Yen, Shigemichi Iwae, Yasushi Shimizu, Ruey-Long Hong, Masahiro Goto, Jin-Hyoung Kang, Wing Sum Kenneth Li, Robert L. Ferris, Maura Gillison, Yoshinobu Namba, Manish Monga, Mark Lynch, Makoto Tahara
ObjectivesTo assess efficacy and safety of nivolumab versus investigator's choice of therapy (IC) in Asian patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).Materials and methodsThirty-four patients from Japan, Taiwan, Hong Kong, and Korea received nivolumab 3mg/kg (n=23) every 2weeks or IC (n=11), as part of a global trial (n=361), until intolerable toxicity or disease progression. The primary endpoint was overall survival (OS).ResultsMedian OS was 9.5months (95% confidence interval [CI] 9.1–NR) with nivolumab and 6.2months (95% CI 2.6–NR) with IC. Seven (30.4%) patients receiving nivolumab and six (54.5%) receiving IC died. The hazard ratio (HR) for risk of death (nivolumab vs. IC) was 0.50 (95% CI 0.17–1.48). Median progression-free survival was 1.9months (95% CI 1.6–7.5) with nivolumab and 1.8months (95% CI 0.4–6.1) with IC (HR 0.57 [95% CI 0.25–1.33]). Objective response rates (complete+partial responses) were 26.1% (6/23 patients; 95% CI 10.2–48.4) for nivolumab and 0% (0/11 patients; 95% CI 0.0–28.5) for IC. Sixteen (69.6%) nivolumab-treated patients and 10 (90.9%) patients receiving IC had a treatment-related adverse event, most commonly decreased appetite (21.7%), pruritus, rash, and fatigue (17.4% each) with nivolumab, and nausea, stomatitis, and decreased appetite (27.3% each) with IC.ConclusionNivolumab demonstrated a survival advantage compared with conventional treatments in Asian patients with platinum-refractory recurrent or metastatic SCCHN, and was well tolerated.Clinical trial registration NCT02105636.



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Oxidative environment causes molecular remodeling in embryonic heart—a metabolomic and lipidomic fingerprinting analysis

Abstract

Environmental factors including pollution affect human health, and the unifying factor in determining toxicity and pathogenesis for a wide array of environmental factors is oxidative stress. Here, we created the oxidative environment with 2,2-azobis (2-amidinopropane) dihydrochloride (AAPH) and consequent cardiac remodeling in chick embryos. The metabolite fingerprint of heart tissue was obtained from Fourier transform infrared (FTIR) spectroscopic analysis. The global lipidomic analysis was done using electrospray ionization coupled with tandem mass spectrometry (ESI-MS/MS) by precursor ion scanning and neutral loss scanning methods. Further, the fatty acid levels were quantified in AAPH-treated H9c2 cardiomyoblasts with gas chromatography-mass spectrometry (GC-MS). Lipidomic fingerprinting study indicated that majority of differentially expressed phospholipids species in heart tissue belonged to ether phosphatidylcholine (ePC) species, and we conclude that excess oxidative environment may alter the phospholipid metabolism at earlier stages of cardiac remodeling.

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