Δευτέρα 9 Απριλίου 2018
IGF-1-based screening reveals a low prevalence of acromegaly in patients with obstructive sleep apnea
Abstract
Purpose
Recent epidemiologic studies suggest a high prevalence of acromegaly. The prevalence of obstructive sleep apnea syndrome (OSAS) in acromegaly patients ranges from 47 to 70%. A recent study identified 2 patients with acromegaly among 567 OSAS patients. However, it remains unclear whether screening for acromegaly among OSAS patients is necessary. The aim was to screen for acromegaly among OSAS patients by measuring IGF-1 levels and performing confirmatory tests if necessary.
Methods
We performed a prospective cross-sectional diagnostic study on the prevalence of acromegaly in patients with OSAS. A total of 507 patients with a confirmed diagnosis of OSAS (357 male, 150 female) were screened.
Results
Seven male and three female patients (1.97% of total) were positively screened for elevated IGF-1 levels. Nine out of ten patients suppressed growth hormone levels during OGTT excluding acromegaly, whereas one individual was identified to have acromegaly according to established criteria (1/507, prevalence 0.2%). Analysis of the data showed no correlation between elevated IGF-1 values and the severity of OSAS or BMI.
Conclusions
Our data demonstrate a low prevalence of acromegaly in patients with OSAS. Until data from population-based studies is available we suggest restricting screening for acromegaly in OSAS to those patients who have additional clinical features of acromegaly.
https://ift.tt/2qlMcmK
The associations of metabolic syndrome with incident hypertension, type 2 diabetes mellitus and chronic kidney disease: a cohort study
Abstract
Purpose
Metabolic syndrome (MetS) has been extensively studied for its long-term health effects, typically through conventional Cox proportional hazards regression modeling of the overall association of MetS with a single outcome. Such an approach neglects the inherent links between MetS-related disease outcomes and fails to provide sufficient insights into the impact of each component of MetS over time.
Methods
We therefore conducted a retrospective cohort study of 63,680 individuals who received health check-ups at the MJ Health Screening Center in Taiwan from 1997–2005 to study the subsequent risks of hypertension, type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) simultaneously for MetS and its components. Multivariate-adjusted hazard ratios (HRs) were calculated using Cox models for multiple failure outcomes.
Results
At baseline, MetS was identified in 7835 participants. Over a median follow-up of 3 years, 8252, 1634, and 6714 participants developed hypertension, T2DM and CKD, respectively. The HR for MetS was 2.41 (95% CI 2.29–2.53) for hypertension, 5.17 (95% CI 4.68–5.71) for T2DM and 1.22 (95% CI 1.15–1.31) for CKD. Three MetS components showed the strongest association with each of the outcomes: elevated blood pressure with hypertension (HR = 3.62, 95% CI 3.46–3.79), raised fasting plasma glucose with T2DM (HR = 8.89, 95% CI 7.86–10.06) and elevated triglycerides with CKD (HR = 1.14, 95% CI 1.08–1.21).
Conclusions
MetS may help identify individuals with metabolic profiles that confer incremental risks for multiple diseases. Additionally, several components of the syndrome should be considered by clinicians, as they show stronger associations with specific diseases than MetS.
https://ift.tt/2GP7jsz
Pancreatic neuroendocrine tumors in MEN1 disease: a mono-centric longitudinal and prognostic study
Abstract
Purpose
Multiple endocrine neoplasia type 1 (MEN1) is an inherited endocrine neoplastic syndrome associated with a greater risk of endocrine tumor development like pancreatic neuroendocrine tumors (p-NET), with different clinical characteristics from sporadic ones. This paper aims to compare clinical, hystological and morphological aspects of p-NET in patients affected from MEN1 (MEN1+) and not-affected ones (MEN1−).
Methods
We performed a retrospective observational study. Data was collected between December 2010 and December 2015, including patients with a histological diagnosis of p-NET and radiological imaging. We compared clinical, histological, radiological, and prognostic aspects of MEN+ p-NET with MEN−1 p-NET.
Results
Of the 45 patients enrolled, 13 MEN1+ and 21 MEN1− cases were analyzed. Frequency of not secreting p-NETs and insulin secreting p-NETs, histopathological grades and Ki67 expression were superimposable between MEN1+ and MEN1− patients. MEN1+ pNETs are more often multicentric compared to MEN1− pNETs. Frequency of liver and nodes metastatic spread was higher in MEN1− p-NET compared to MEN1+ p-NET. Analyzing p-NET according to the disease outcome, we found that recovered and stable p-NETs in MEN1+ patients, compared to MEN1− cases, are diagnosed at lower age (p = 0.04/p = 0.002) and that are more frequently multifocal lesions (p = 0.009/p = 0.002).
Conclusions
In our study pNETs in MEN1+ and pNETs in MEN1− don't significantly differ for prognosis but only for clinical features. p-NET stage disease and prognosis can be positively influenced by early diagnosis and screening in index patients' first-degree relatives
https://ift.tt/2qlMb2a
Complete evaluation of pituitary tumours in a single tertiary care institution
Abstract
Introduction
We retrospectively evaluated all patients with pituitary tumours treated in our department from 1/1/1997 to 01/11/2014.
Patients and methods
Two hundred and fifteen patients (124 females, 91 males, mean age 50.9 years) were treated because of pituitary tumours. All patients underwent basal hormonal analysis and when required dynamic testing in order to check for hormonal activity. Pituitary masses were divided into groups concerning their hormonal status and were further classified according to gender, age at diagnosis, tumour size, and the development of postoperative pituitary insufficiency when neurosurgical intervention was conducted.
Results
One hundred and twenty-one patients had hormonally inactive tumours (non-functional adenomas; 56.3%), 57 prolactinomas (26.5%), 17 growth hormone secreting adenomas (7.9%), 16 Cushing's disease (7.4%), and 4 craniopharyngiomas (1.9%). Tumours with maximum size <1 cm (microadenomas) were detected in 62 patients (28.8%) and ≥1 cm (macroadenomas) in 153 (71.2%) of all cases (rate 1:2.5). Ninty eight patients (45.6%) had surgery (87 transsphenoidal and 11 transcranial), of this group 34 with hormonally active tumours (37.8% of the 90 patients of this subcohort). Indications for surgery were an increased risk or manifestation of chiasma syndrome and clinical symptoms due to hormonal hypersecretion. Complete [32 cases (32.6%)] or partial [33 cases (33.7%)] postoperative insufficiency in minimum one pituitary axis was present in 65/98 (66.3%) of the operated patients.
Conclusions
Pituitary adenoma prevalence is rising due to widely available imaging procedures. The majority of the tumours in our cohort were macroadenomas and hormonally inactive. Tumour extirpation via the transsphenoidal or transcranial route resulted in functional pituitary impairment of variable extent in 2/3 of the patients.
https://ift.tt/2qlMaLE
Low-dose Synachten test with measurement of salivary cortisol in adult patients with β-thalassemia major
Abstract
Purpose
Beta-thalassemia major is a severe, congenital hematological disorder and, if untreated, leads to early mortality. Progress in therapeutical strategies improved clinical outcomes and life expectancy; however, increased survival led to the development of new disorders, including endocrinopathies. Little is known on the possible impairment of adrenocortical function, a potentially life-threatening condition, in long-term thalassaemic survivors. We therefore decided to assess adrenal reserve and the value of salivary cortisol during ACTH stimulation in the diagnosis of adrenocortical insufficiency in adult patients with β-thalassemia major.
Methods
Cross-sectional study including 72 adults with β-thalassemia major. Patients were tested with 1 µg ACTH for serum and salivary cortisol.
Results
Subnormal serum cortisol responses to ACTH stimulation (i.e., <500 nmol/l) were registered in 15 out of 72 patients. Salivary cortisol increased in parallel with serum cortisol and a clear-cut positive correlation was detected at each timepoint. Moreover, peak salivary cortisol values after ACTH stimulation were significantly lower in patients with impaired adrenal reserve (513.6 ± 52.33 vs. 914.1 ± 44.04 nmol/l p < 0.0001).
Conclusions
Our results attest to the need for testing for adrenal insufficiency among adult thalassaemic patients, as up to 20% presented impaired adrenal reserve. Salivary and serum cortisol levels during stimulation with ACTH were closely correlated and the use of salivary cortisol sampling during ACTH testing may represent a surrogate to serum cortisol in these patients.
https://ift.tt/2GMKiGC
Quantitative analysis of surface recession on carbon-based ablators using a high-resolution non-contact profilometer
Publication date: 5 July 2018
Source:Materials & Design, Volume 149
Author(s): Soyoung Lim, Jae Hee Cheon, Myeong Jin Son, Eui Sup Shin
This paper proposes a systematic procedure for the quantitative analysis of the surface changes caused by ablation of carbon-based ablators using a high-resolution non-contact profilometer. The ablation tests were performed under high enthalpy flow conditions using a 0.4MW arc-heated wind tunnel. The high-resolution profilometer was used to measure the surface data of carbon-based ablators. The key parameters for the analysis of the surface changes, such as surface recession and roughness, were calculated by the proposed procedure. In addition, a finite element model of the sample after the ablation test was constructed from the measured surface data. The proposed procedure can be effectively used to perform various analyses of the ablated surface using the measured data and numerical analysis method.
Graphical abstract
https://ift.tt/2HkZNmd
Transurethral vaporesection of prostate: diode laser or thulium laser?
Abstract
This study compared the safety and effectiveness of the diode laser and thulium laser during prostate transurethral vaporesection for treating benign prostate hyperplasia (BPH). We retrospectively analyzed 205 patients with BPH who underwent a diode laser or thulium laser technique for prostate transurethral vaporesection from June 2016 to June 2017 and who were followed up for 3 months. Baseline characteristics of the patients, perioperative data, postoperative outcomes, and complications were compared. We also assessed the International Prostate Symptom Score (IPSS), quality of life (QoL), maximum flow rate (Qmax), average flow rate (AFR), and postvoid residual volume (PVR) at 1 and 3 months postoperatively to evaluate the functional improvement of each group. There were no significant differences between the diode laser and thulium laser groups related to age, prostate volume, operative time, postoperative hospital stays, hospitalization costs, or perioperative data. The catheterization time was 3.5 ± 0.8 days for the diode laser group and 4.7 ± 1.8 days for the thulium laser group (p < 0.05). Each group had dramatic improvements in IPSS, QoL, Qmax, AFR, and PVR compared with the preoperative values (p < 0.05), although there were no significant differences between the two groups. Use of both diode laser and thulium laser contributes to safe, effective transurethral vaporesection in patients with symptomatic BPH. Diode laser, however, is better than thulium laser for prostate transurethral vaporesection because of its shorter catheterization time. The choice of surgical approach is more important than the choice of laser types during clinical decision making for transurethral laser prostatectomy.
https://ift.tt/2GMJ3aG
Obesity as a Disease, Not a Behavior.
Author: Gordon-Larsen, Penny PhD; Heymsfield, Steven B. MD
Page: 1543-1545
https://ift.tt/2HoKjhk
Will His Bundle Pacing Make Cardiac Resynchronization Therapy Obsolete?.
Author: Curtis, Anne B. MD
Page: 1546-1548
https://ift.tt/2uZxjvT
Reversing the Cardiac Effects of Sedentary Aging in Middle Age-A Randomized Controlled Trial: Implications For Heart Failure Prevention.
Author: Howden, Erin J. PhD; Sarma, Satyam MD; Lawley, Justin S. PhD; Opondo, Mildred MD; Cornwell, William MD; Stoller, Douglas MD, PhD; Urey, Marcus A. MD; Adams-Huet, Beverley MS; Levine, Benjamin D. MD
Page: 1549-1560
https://ift.tt/2HnZDe0
Risk Factors of Sudden Cardiac Death in the Young: Multiple-Year Community-Wide Assessment.
Author: Jayaraman, Reshmy MD; Reinier, Kyndaron MPH, PhD; Nair, Sandeep MD; Aro, Aapo L. MD, PhD; Uy-Evanado, Audrey MD; Rusinaru, Carmen MD, PhD; Stecker, Eric C. MD, MPH; Gunson, Karen MD; Jui, Jonathan MD, MPH; Chugh, Sumeet S. MD
Page: 1561-1570
https://ift.tt/2v3vFcG
Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With Versus Without Diabetes Mellitus: Results From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).
Author: Giugliano, Robert P. MD, SM; Cannon, Christopher P. MD; Blazing, Michael A. MD; Nicolau, Jose C. MD; Corbalan, Ramon MD; Spinar, Jindrich MD; Park, Jeong-Gun PhD; White, Jennifer A. MS; Bohula, Erin A. MD, DPhil; Braunwald, Eugene MD; On behalf of the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) Investigators
Page: 1571-1582
https://ift.tt/2HnOcDb
Ezetimibe: Likely to Be Beneficial For All.
Author: Herrington, William G. MRCP, MD; Preiss, David FRCPath, PhD; Armitage, Jane FFPH
Page: 1583-1584
https://ift.tt/2v0rMFt
Surgical Enlargement of the Aortic Root Does Not Increase the Operative Risk of Aortic Valve Replacement.
Author: Rocha, Rodolfo V. MD; Manlhiot, Cedric PhD; Feindel, Christopher M. MD, MSc; Yau, Terrence M. MD, MSc; Mueller, Brigitte PhD; David, Tirone E. MD; Ouzounian, Maral MD, PhD
Page: 1585-1594
https://ift.tt/2Hn0bRn
Novel Desmin Mutation p.Glu401Asp Impairs Filament Formation, Disrupts Cell Membrane Integrity, and Causes Severe Arrhythmogenic Left Ventricular Cardiomyopathy/Dysplasia.
Author: Bermudez-Jimenez, Francisco Jose MD *,,,; Carriel, Victor MSc, MBiol, PhD *,,; Brodehl, Andreas MSc, PhD; Alaminos, Miguel MD, PhD; Campos, Antonio MD, PhD; Schirmer, Ilona MSc; Milting, Hendrik MSc, PhD; Abril, Beatriz Alvarez MD; Alvarez, Miguel MD, PhD; Lopez-Fernandez, Silvia MD; Garcia-Giustiniani, Diego MD; Monserrat, Lorenzo MD, PhD; Tercedor, Luis MD; Jimenez-Jaimez, Juan MD, PhD
Page: 1595-1610
https://ift.tt/2uXzkZG
Arrhythmogenic Cardiomyopathy: Mechanotransduction Going Wrong.
Author: Mestroni, Luisa MD; Sbaizero, Orfeo PhD
Page: 1611-1613
https://ift.tt/2HreS60
Leptin-Aldosterone-Neprilysin Axis: Identification of Its Distinctive Role in the Pathogenesis of the Three Phenotypes of Heart Failure in People With Obesity.
Author: Packer, Milton MD
Page: 1614-1631
https://ift.tt/2v3mr04
Wide QRS Complex After Catheter Ablation.
Author: Jennings, John MD; Jackman, Warren MD; Kay, G. Neal MD
Page: 1634-1637
https://ift.tt/2uZ2BD3
Sudden Cardiovascular Arrest During Sexual Intercourse.
Author: Sharifzadehgan, Ardalan MD, MPH; Marijon, Eloi MD, PhD; Bougouin, Wulfran MD, PhD; Karam, Nicole MD, PhD; Narayanan, Kumar MD, MPH; Waldmann, Victor MD, MPH; Lamhaut, Lionel MD, PhD; Jost, Daniel MD; Dumas, Florence MD, PhD; Cariou, Alain MD, PhD; Jouven, Xavier MD, PhD; On behalf of the Paris-SDEC Investigators
Page: 1638-1640
https://ift.tt/2HoDJqX
Letter by Katritsis Regarding Article, "Preprints and Cardiovascular Science: Prescient or Premature?".
Author: Katritsis, Demosthenes G. MD, PhD
Page: 1641-1642
https://ift.tt/2uZLC3L
Response by Nallamothu and Hill to Letter Regarding Article, "Preprints and Cardiovascular Science: Prescient or Premature?".
Author: Nallamothu, Brahmajee K. MD, MPH; Hill, Joseph A. MD
Page: 1643-1644
https://ift.tt/2HnNV37
Letter by Chertoff et al Regarding Article, "The Effects of Public Access Defibrillation on Survival After Out-of-Hospital Cardiac Arrest: A Systematic Review of Observational Studies".
Author: Chertoff, Jason MD, MPH; Mojadidi, Mohammad Khalid MD; Urbine, Daniel MD
Page: 1645
https://ift.tt/2uZ2qYp
Letter by El-Battrawy et al Regarding Article, "The Effects of Public Access Defibrillation on Survival After Out-of-Hospital Cardiac Arrest: A Systematic Review of Observational Studies".
Author: El-Battrawy, Ibrahim MD; Borggrefe, Martin MD; Akin, Ibrahim MD
Page: 1646-1647
https://ift.tt/2HntanZ
Letter by Karam et al Regarding Article, "The Effects of Public Access Defibrillation on Survival After Out-of-Hospital Cardiac Arrest: A Systematic Review of Observational Studies".
Author: Karam, Nicole MD, PhD; Jouven, Xavier MD, PhD; Marijon, Eloi MD, PhD
Page: 1648-1649
https://ift.tt/2uXgt0J
Response by Baekgaard et al to Letters Regarding Article, "The Effects of Public Access Defibrillation on Survival After Out-of-Hospital Cardiac Arrest: A Systematic Review of Observational Studies".
Author: Baekgaard, Josefine S. MD; Viereck, Soren MD, PhD; Moller, Thea Palsgaard MD, PhD; Ersboll, Annette Kjaer MSc, PhD; Lippert, Freddy MD; Folke, Fredrik MD, PhD
Page: 1650-1651
https://ift.tt/2HmLWfj
Letter by Jin-shan and Xue-bin Regarding Article, "Acute Coronary Syndrome: What Is the Affected Artery? Where Is the Occlusion Located? And How Important Is the Myocardial Mass Involved?".
Author: Jin-shan, He MD; Xue-bin, Li MD
Page: 1652
https://ift.tt/2uWENQe
Effluent concentration and removal efficiency of nine heavy metals in secondary treatment plants in Shanghai, China
Abstract
Wastewater treatment plants (WWTPs) are the most common form of industrial and municipal wastewater control. To evaluate the performance of wastewater treatment and the potential risk of treated wastewater to aquatic life and human health, the influent and effluent concentrations of nine toxic metals were determined in 12 full-scale WWTPs in Shanghai, China. The performance was evaluated based on national standards for reclamation and aquatic criteria published by US EPA, and by comparison with other full-scale WWTPs in different countries. Potential sources of heavy metals were recognized using partial correlation analysis, hierarchical clustering, and principal component analysis (PCA). Results indicated significant treatment effect on As, Cd, Cr, Cu, Hg, Mn, Pb, and Zn. The removal efficiencies ranged from 92% (Cr) to 16.7% (Hg). The results indicated potential acute and/or chronic effect of Cu, Ni, Pb, and Zn on aquatic life and potential harmful effect of As and Mn on human health for the consumption of water and/or organism. The results of partial correlation analysis, hierarchical clustering based on cosine distance, and PCA, which were consistent with each other, suggested common source of Cd, Cr, Cu, and Pb and common source of As, Hg, Mn, Ni, and Zn. Hierarchical clustering based on Jaccard similarity suggested common source of Cd, Hg, and Ni, which was statistically proved by Fisher's exact test.
https://ift.tt/2GRdfgU
A label-free cellulose SERS biosensor chip with improvement of nanoparticle-enhanced LSPR effects for early diagnosis of subarachnoid hemorrhage-induced complications
Publication date: 15 July 2018
Source:Biosensors and Bioelectronics, Volume 111
Author(s): Wansun Kim, Sung Ho Lee, Yong Jin Ahn, Seung Ho Lee, Jiwook Ryu, Seok Keun Choi, Samjin Choi
It is very difficult to predict some complications after subarachnoid hemorrhage (SAH), despite rapid advances in medical science. Herein, we introduce a label-free cellulose surface-enhanced Raman spectroscopy (SERS) biosensor chip with pH-functionalized, gold nanoparticle (AuNP)-enhanced localized surface plasmon resonance (LSPR) effects for identification of SAH-induced cerebral vasospasm and hydrocephalus caused by cerebrospinal fluid (CSF). The SERS biosensor chip was implemented by the synthesis reaction of the AuNPs, which were charged positively through pH level adjustment, onto a negatively-charged cellulose substrate with ξ = –30.7 mV. The zeta potential, nanostructural properties, nanocrystallinity, and computational calculation-based electric field distributions of the cellulose-originated AuNPs were optimized to maximize LSPR phenomena and then characterized. Additionally, the performance of the SERS biosensor was compared under two representative excitation laser sources in the visible region (532 nm) and near-infrared region (785 nm). The Raman activities of our SERS biosensor chip were evaluated by trace small molecules (crystal violet, 2 µL), and the biosensor achieved an enhancement factor of 3.29 × 109 for the analytic concept with an excellent reproducibility of 8.5% relative standard deviation and a detection limit of 0.74 pM. Furthermore, the experimental results revealed that the five proposed SERS-based biomarkers could provide important information for identifying and predicting SAH-induced cerebral vasospasm and hydrocephalus complications (91.1% reliability and 19.3% reproducibility). Therefore, this facile and effective principle of our SERS biosensor chip may inspire the basis and strategies for the development of sensing platforms to predict critical complications in various neurosurgical diagnoses.
Graphical abstract
https://ift.tt/2JACOEG
Polymeric micelles: Theranostic co-delivery system for poorly water-soluble drugs and contrast agents
Source:Biomaterials, Volume 170
Author(s): Jaydev R. Upponi, Kaushal Jerajani, Dattatri K. Nagesha, Praveen Kulkarni, Srinivas Sridhar, Craig Ferris, Vladimir P. Torchilin
Interest in theranostic agents has continued to grow because of their promise for simultaneous cancer detection and therapy. A platform-based nanosized combination agent suitable for the enhanced diagnosis and treatment of cancer was prepared using polymeric polyethylene glycol-phosphatidylethanolamine-based micelles loaded with both, poorly soluble chemotherapeutic agent paclitaxel and hydrophobic superparamagnetic iron oxide nanoparticles (SPION), a Magnetic Resonance Imaging contrast agent. The co-loaded paclitaxel and SPION did not affect each other's functional properties in vitro. In vivo, the resulting paclitaxel-SPION-co-loaded PEG-PE micelles retained their Magnetic Resonance contrast properties and apoptotic activity in breast and melanoma tumor mouse models. Such theranostic systems are likely to play a significant role in the combined diagnosis and therapy that leads to a more personalized and effective form of treatment.
https://ift.tt/2GLABZ1
More Rules, Still Exceptions: Understanding Immunomodulatory Antibody Activity In Vivo
Publication date: 9 April 2018
Source:Cancer Cell, Volume 33, Issue 4
Author(s): Andrea Ipsen-Escobedo, Falk Nimmerjahn
Understanding how agonistic and checkpoint control antibodies mediate their activity in vivo is essential for further development of these promising anti-cancer therapies. In this issue of Cancer Cell, studies by Vargas et al. and Yu et al. provide insights into the mode of action of CTLA-4- and CD40-specific antibodies.
Teaser
Understanding how agonistic and checkpoint control antibodies mediate their activity in vivo is essential for further development of these promising anti-cancer therapies. In this issue of Cancer Cell, studies by Vargas et al. and Yu et al. provide insights into the mode of action of CTLA-4- and CD40-specific antibodies.https://ift.tt/2Hbd96W
T Cell Dysfunction in Cancer
Publication date: 9 April 2018
Source:Cancer Cell, Volume 33, Issue 4
Author(s): Daniela S. Thommen, Ton N. Schumacher
Therapeutic reinvigoration of tumor-specific T cells has greatly improved clinical outcome in cancer. Nevertheless, many patients still do not achieve durable benefit. Recent evidence from studies in murine and human cancer suggest that intratumoral T cells display a broad spectrum of (dys-)functional states, shaped by the multifaceted suppressive signals that occur within the tumor microenvironment. Here we discuss the current understanding of T cell dysfunction in cancer, the value of novel technologies to dissect such dysfunction at the single cell level, and how our emerging understanding of T cell dysfunction may be utilized to develop personalized strategies to restore antitumor immunity.
Teaser
Therapeutic reinvigoration of tumor-specific T cells has greatly improved clinical outcome in cancer. Nevertheless, many patients still do not achieve durable benefit. Recent evidence from studies in murine and human cancer suggest that intratumoral T cells display a broad spectrum of (dys-)functional states, shaped by the multifaceted suppressive signals that occur within the tumor microenvironment. Here we discuss the current understanding of T cell dysfunction in cancer, the value of novel technologies to dissect such dysfunction at the single cell level, and how our emerging understanding of T cell dysfunction may be utilized to develop personalized strategies to restore antitumor immunity.https://ift.tt/2GOaQ6z
The Immune Revolution: A Case for Priming, Not Checkpoint
Publication date: 9 April 2018
Source:Cancer Cell, Volume 33, Issue 4
Author(s): Robert H. Vonderheide
Most tumors are unresponsive to immune checkpoint blockade, especially if deep immunosuppression in the tumor develops prior to and prevents T cell immunosurveillance. Failed or frustrated T cell priming often needs repair before successful sensitization to PD-1/PD-L1 blockade. CD40 activation plays a critical role in generating T cell immunity, by activating dendritic cells, and converting cold tumors to hot. In preclinical studies, agonistic CD40 antibodies demonstrate T cell-dependent anti-tumor activity, especially in combination with chemotherapy, checkpoint inhibitory antibodies, and other immune modulators. With the advent of multiple CD40 agonists with acceptable single-agent toxicity, clinical evaluation of CD40 combinations has accelerated.
Teaser
Most tumors are unresponsive to immune checkpoint blockade, especially if deep immunosuppression in the tumor develops prior to and prevents T cell immunosurveillance. Failed or frustrated T cell priming often needs repair before successful sensitization to PD-1/PD-L1 blockade. CD40 activation plays a critical role in generating T cell immunity, by activating dendritic cells, and converting cold tumors to hot. In preclinical studies, agonistic CD40 antibodies demonstrate T cell-dependent anti-tumor activity, especially in combination with chemotherapy, checkpoint inhibitory antibodies, and other immune modulators. With the advent of multiple CD40 agonists with acceptable single-agent toxicity, clinical evaluation of CD40 combinations has accelerated.https://ift.tt/2HcnlMG
The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy
Publication date: 9 April 2018
Source:Cancer Cell, Volume 33, Issue 4
Author(s): Vancheswaran Gopalakrishnan, Beth A. Helmink, Christine N. Spencer, Alexandre Reuben, Jennifer A. Wargo
The microbiome is receiving significant attention given its influence on a host of human diseases including cancer. Its role in response to cancer treatment is becoming increasingly apparent, with evidence suggesting that modulating the gut microbiome may affect responses to numerous forms of cancer therapy. A working knowledge of the microbiome is vital as we move forward in this age of precision medicine, and an understanding of the microbiome's influence on immune responses and cancer is key. It is also important to understand factors influencing the gut microbiome and strategies to manipulate the microbiome to augment therapeutic responses.
Teaser
The microbiome is receiving significant attention given its influence on a host of human diseases including cancer. Its role in response to cancer treatment is becoming increasingly apparent, with evidence suggesting that modulating the gut microbiome may affect responses to numerous forms of cancer therapy. A working knowledge of the microbiome is vital as we move forward in this age of precision medicine, and an understanding of the microbiome's influence on immune responses and cancer is key. It is also important to understand factors influencing the gut microbiome and strategies to manipulate the microbiome to augment therapeutic responses.https://ift.tt/2GOaL2L
Emerging Concepts for Immune Checkpoint Blockade-Based Combination Therapies
Publication date: 9 April 2018
Source:Cancer Cell, Volume 33, Issue 4
Author(s): Roberta Zappasodi, Taha Merghoub, Jedd D. Wolchok
Checkpoint blockade has formally demonstrated that reactivating anti-tumor immune responses can regress tumors. However, this only occurs in a fraction of patients. Incorporating these therapies in more powerful combinations is thus a logical next step. Here, we review functional roles of immune checkpoints and molecular determinants of checkpoint-blockade clinical activity. Limited-size T cell-infiltrated tumors, differing substantially from "self," generally respond to checkpoint blockade. Therefore, we propose that reducing tumor burden and increasing tumor immunogenicity are key factors to improve immunotherapy. Lastly, we outline criteria to select proper immunotherapy combination partners and highlight the importance of activity biomarkers for timely treatment optimization.
Teaser
Checkpoint blockade has formally demonstrated that reactivating anti-tumor immune responses can regress tumors. However, this only occurs in a fraction of patients. Incorporating these therapies in more powerful combinations is thus a logical next step. Here, we review functional roles of immune checkpoints and molecular determinants of checkpoint-blockade clinical activity. Limited-size T cell-infiltrated tumors, differing substantially from "self," generally respond to checkpoint blockade. Therefore, we propose that reducing tumor burden and increasing tumor immunogenicity are key factors to improve immunotherapy. Lastly, we outline criteria to select proper immunotherapy combination partners and highlight the importance of activity biomarkers for timely treatment optimization.https://ift.tt/2HcngZo
Mechanistic Insights into Transmissible Cancers of Mammals
Publication date: 9 April 2018
Source:Cancer Cell, Volume 33, Issue 4
Author(s): Susan Bullman, Tao Zou, Matthew Meyerson
Transmissible cancers are clonal lineages that spread through populations via contagious cancer cells. In this issue of Cancer Cell, two articles by Stammnitz et al. and Frampton et al. present novel insights into the potential mechanisms underlying the propagation of naturally occurring transmissible cancers in mammals.
Teaser
Transmissible cancers are clonal lineages that spread through populations via contagious cancer cells. In this issue of Cancer Cell, two articles by Stammnitz et al. and Frampton et al. present novel insights into the potential mechanisms underlying the propagation of naturally occurring transmissible cancers in mammals.https://ift.tt/2IGDPK9
Oncolytic Viruses as Antigen-Agnostic Cancer Vaccines
Publication date: 9 April 2018
Source:Cancer Cell, Volume 33, Issue 4
Author(s): Stephen J. Russell, Glen N. Barber
Selective destruction of neoplastic tissues by oncolytic viruses (OVs) leads to antigen-agnostic boosting of neoantigen-specific cytotoxic T lymphocyte (CTL) responses, making OVs ideal companions for checkpoint blockade therapy. Here we discuss the mechanisms whereby OVs modulate both adjuvanticity and antigenicity of tumor cells. Suppression of antitumor immunity after OV therapy has not been observed, possibly because viral antigen expression diminishes as the antiviral response matures, thereby progressively honing the CTL response to tumor neoantigens. By combining direct in situ tumor destruction with the ability to boost antitumor immunity, OVs also have the potential to be powerful standalone cancer therapies.
https://ift.tt/2HcncJ8
The Origins and Vulnerabilities of Two Transmissible Cancers in Tasmanian Devils
Publication date: 9 April 2018
Source:Cancer Cell, Volume 33, Issue 4
Author(s): Maximilian R. Stammnitz, Tim H.H. Coorens, Kevin C. Gori, Dane Hayes, Beiyuan Fu, Jinhong Wang, Daniel E. Martin-Herranz, Ludmil B. Alexandrov, Adrian Baez-Ortega, Syd Barthorpe, Alexandra Beck, Francesca Giordano, Graeme W. Knowles, Young Mi Kwon, George Hall, Stacey Price, Ruth J. Pye, Jose M.C. Tubio, Hannah V.T. Siddle, Sukhwinder Singh Sohal, Gregory M. Woods, Ultan McDermott, Fengtang Yang, Mathew J. Garnett, Zemin Ning, Elizabeth P. Murchison
Transmissible cancers are clonal lineages that spread through populations via contagious cancer cells. Although rare in nature, two facial tumor clones affect Tasmanian devils. Here we perform comparative genetic and functional characterization of these lineages. The two cancers have similar patterns of mutation and show no evidence of exposure to exogenous mutagens or viruses. Genes encoding PDGF receptors have copy number gains and are present on extrachromosomal double minutes. Drug screening indicates causative roles for receptor tyrosine kinases and sensitivity to inhibitors of DNA repair. Y chromosome loss from a male clone infecting a female host suggests immunoediting. These results imply that Tasmanian devils may have inherent susceptibility to transmissible cancers and present a suite of therapeutic compounds for use in conservation.
Graphical abstract
Teaser
Stammnitz et al. show that the two transmissible cancer clones that affect Tasmanian devils are very similar in their tissues-of-origin, mutational patterns and driver gene candidates. Importantly, these cancers are both highly sensitive to inhibitors of some receptor tyrosine kinases as well as to inhibitors of DNA repair.https://ift.tt/2GLicaJ
Molecular Signatures of Regression of the Canine Transmissible Venereal Tumor
Publication date: 9 April 2018
Source:Cancer Cell, Volume 33, Issue 4
Author(s): Dan Frampton, Hagen Schwenzer, Gabriele Marino, Lee M. Butcher, Gabriele Pollara, Janos Kriston-Vizi, Cristina Venturini, Rachel Austin, Karina Ferreira de Castro, Robin Ketteler, Benjamin Chain, Richard A. Goldstein, Robin A. Weiss, Stephan Beck, Ariberto Fassati
The canine transmissible venereal tumor (CTVT) is a clonally transmissible cancer that regresses spontaneously or after treatment with vincristine, but we know little about the regression mechanisms. We performed global transcriptional, methylation, and functional pathway analyses on serial biopsies of vincristine-treated CTVTs and found that regression occurs in sequential steps; activation of the innate immune system and host epithelial tissue remodeling followed by immune infiltration of the tumor, arrest in the cell cycle, and repair of tissue damage. We identified CCL5 as a possible driver of CTVT regression. Changes in gene expression are associated with methylation changes at specific intragenic sites. Our results underscore the critical role of host innate immunity in triggering cancer regression.
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Teaser
By analyzing serial biopsies of vincristine-treated canine transmissible venereal tumors, Frampton et al. show that tumor regression occurs in sequential steps involving the activation of the innate immune system and immune infiltration of the tumor, and they identify CCL5 as a possible driver of regression.https://ift.tt/2Hcn64e
Dysregulated IL-18 Is a Key Driver of Immunosuppression and a Possible Therapeutic Target in the Multiple Myeloma Microenvironment
Publication date: 9 April 2018
Source:Cancer Cell, Volume 33, Issue 4
Author(s): Kyohei Nakamura, Sahar Kassem, Alice Cleynen, Marie-Lorraine Chrétien, Camille Guillerey, Eva Maria Putz, Tobias Bald, Irmgard Förster, Slavica Vuckovic, Geoffrey R. Hill, Seth L. Masters, Marta Chesi, P. Leif Bergsagel, Hervé Avet-Loiseau, Ludovic Martinet, Mark J. Smyth
Tumor-promoting inflammation and avoiding immune destruction are hallmarks of cancer. Here, we demonstrate that the pro-inflammatory cytokine interleukin (IL)-18 is critically involved in these hallmarks in multiple myeloma (MM). Mice deficient for IL-18 were remarkably protected from Vk∗MYC MM progression in a CD8+ T cell-dependent manner. The MM-niche-derived IL-18 drove generation of myeloid-derived suppressor cells (MDSCs), leading to accelerated disease progression. A global transcriptome analysis of the immune microenvironment in 73 MM patients strongly supported the negative impact of IL-18-driven MDSCs on T cell responses. Strikingly, high levels of bone marrow plasma IL-18 were associated with poor overall survival in MM patients. Furthermore, our preclinical studies suggested that IL-18 could be a potential therapeutic target in MM.
Graphical abstract
Teaser
Nakamura et al. show that IL-18 produced by the multiple myeloma (MM) niche promotes MM progression in a CD8+ T cell-dependent manner in a mouse model and that IL-18 could be a potential therapeutic target in MM. High levels of bone marrow plasma IL-18 are associated with poor overall survival in MM patients.https://ift.tt/2IGDFT3
Adipocyte p62/SQSTM1 Suppresses Tumorigenesis through Opposite Regulations of Metabolism in Adipose Tissue and Tumor
Publication date: 9 April 2018
Source:Cancer Cell, Volume 33, Issue 4
Author(s): Jianfeng Huang, Angeles Duran, Miguel Reina-Campos, Tania Valencia, Elias A. Castilla, Timo D. Müller, Matthias H. Tschöp, Jorge Moscat, Maria T. Diaz-Meco
Obesity is a leading risk factor for cancer. However, understanding the crosstalk between adipocytes and tumor cells in vivo, independently of dietary contributions, is a major gap in the field. Here we used a prostate cancer (PCa) mouse model in which the signaling adaptor p62/Sqstm1 is selectively inactivated in adipocytes. p62 loss in adipocytes results in increased osteopontin secretion, which mediates tumor fatty acid oxidation and invasion, leading to aggressive metastatic PCa in vivo. Furthermore, p62 deficiency triggers in adipocytes a general shutdown of energy-utilizing pathways through mTORC1 inhibition, which supports nutrient availability for cancer cells. This reveals a central role of adipocyte's p62 in the symbiotic adipose tissue-tumor collaboration that enables cancer metabolic fitness.
Graphical abstract
Teaser
Huang et al. show in a prostate cancer mouse model that p62 loss in adipocytes leads to aggressive disease by increasing osteopontin secretion, which mediates tumor fatty acid oxidation and invasion. P62 deficiency also represses energy-consuming pathways in adipocytes, increasing nutrient availability for tumors.https://ift.tt/2Hcn0JU
Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma
Publication date: 9 April 2018
Source:Cancer Cell, Volume 33, Issue 4
Author(s): Yong Yu, Kolja Schleich, Bin Yue, Sujuan Ji, Philipp Lohneis, Kristel Kemper, Mark R. Silvis, Nouar Qutob, Ellen van Rooijen, Melanie Werner-Klein, Lianjie Li, Dhriti Dhawan, Svenja Meierjohann, Maurice Reimann, Abdel Elkahloun, Steffi Treitschke, Bernd Dörken, Christian Speck, Frédérick A. Mallette, Leonard I. Zon, Sheri L. Holmen, Daniel S. Peeper, Yardena Samuels, Clemens A. Schmitt, Soyoung Lee
https://ift.tt/2IHQZGJ
Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms
Publication date: 9 April 2018
Source:Cancer Cell, Volume 33, Issue 4
Author(s): Maria Kleppe, Richard Koche, Lihua Zou, Peter van Galen, Corinne E. Hill, Lauren Dong, Sofie De Groote, Efthymia Papalexi, Amritha V. Hanasoge Somasundara, Keith Cordner, Matthew Keller, Noushin Farnoud, Juan Medina, Erin McGovern, Jaime Reyes, Justin Roberts, Matthew Witkin, Franck Rapaport, Julie Teruya-Feldstein, Jun Qi, Raajit Rampal, Bradley E. Bernstein, James E. Bradner, Ross L. Levine
https://ift.tt/2HcmX0G
Modelling Motor Neuron Disease in Fruit Flies: Lessons from Spinal Muscular Atrophy
Source:Journal of Neuroscience Methods
Author(s): Beppe Aquilina, Ruben J. Cauchi
Motor neuron disease (MND) is characterised by muscle weakness and paralysis downstream of motor neuron degeneration. Genetic factors play a major role in disease pathogenesis and progression. This is best underscored by spinal muscular atrophy (SMA), the most common MND affecting children. Although SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene, partial compensation by the paralogous SMN2 gene and/or genetic modifiers influence age of onset and disease severity. SMA is also the first MND that is treatable thanks to the recent development of a molecular-based therapy. This key milestone was possible following an intense research campaign in which animal models had a starring role. In this review, we specifically focus on the fruit fly Drosophila melanogaster and highlight its sterling contributions aimed at furthering our understanding of SMA pathogenesis. Methods of gene disruption utilised to generate SMA fly models are discussed and ways through which neuromuscular defects have been characterised are elaborated on. A phenotypic overlap with patients and mammalian models, allowed the use of SMA fly models to identify genetic modifiers, hence spurring investigators to discover pathways that are perturbed in disease. Targeting these can potentially lead to complimentary therapies for SMA. The same output is expected from the use of SMA fly models to identify therapeutic compounds that have an ameliorative effect. We believe that lessons gained from SMA will allow researchers to eagerly exploit Drosophila to confirm novel genes linked to MND, reveal disease mechanisms and ultimately identify therapeutics.
https://ift.tt/2EBoLuU
Metastasis of Circulating Tumor Cells: Speed Matters
Publication date: 9 April 2018
Source:Developmental Cell, Volume 45, Issue 1
Author(s): Vanessa Morais Freitas, Georg Hilfenhaus, M. Luisa Iruela-Arispe
The mechanisms involved in tumor cell extravasation during metastasis remain incompletely understood. In this issue of Developmental Cell, Follain and colleagues (2018) demonstrate that blood flow velocity is an important regulator of circulating tumor cell exit from the bloodstream.
Teaser
The mechanisms involved in tumor cell extravasation during metastasis remain incompletely understood. In this issue of Developmental Cell, Follain and colleagues (2018) demonstrate that blood flow velocity is an important regulator of circulating tumor cell exit from the bloodstream.https://ift.tt/2GJPMCd
Mitosis-Resistant Adhesions Provide Molecular Memory to Dividing Cells
Publication date: 9 April 2018
Source:Developmental Cell, Volume 45, Issue 1
Author(s): Guillaume Jacquemet, Johanna Ivaska
During mitosis, animal cells disassemble focal adhesions and round up while remaining attached to the substrata via actin cables and unknown adhesive structures. In this issue of Developmental Cell, Dix et al. (2018) describe integrin-positive adhesions, devoid of classical focal adhesion components, that persist throughout mitosis to contribute to re-spreading.
Teaser
During mitosis, animal cells disassemble focal adhesions and round up while remaining attached to the substrata via actin cables and unknown adhesive structures. In this issue of Developmental Cell, Dix et al. (2018) describe integrin-positive adhesions, devoid of classical focal adhesion components, that persist throughout mitosis to contribute to re-spreading.https://ift.tt/2qkNQVt
A Tale of Two Cycles
Publication date: 9 April 2018
Source:Developmental Cell, Volume 45, Issue 1
Author(s): Kai Wang, John C. Larkin
Two of the fundamental rhythms of eukaryotic life are the circadian clock and the cell division cycle. In this issue of Developmental Cell, Fung-Uceda and colleagues (2018) have elucidated a molecular mechanism linking the circadian clock to the cell cycle in the plant Arabidopsis thaliana.
Teaser
Two of the fundamental rhythms of eukaryotic life are the circadian clock and the cell division cycle. In this issue of Developmental Cell, Fung-Uceda and colleagues (2018) have elucidated a molecular mechanism linking the circadian clock to the cell cycle in the plant Arabidopsis thaliana.https://ift.tt/2GNraZm
Neurovascular Communication during CNS Development
Publication date: 9 April 2018
Source:Developmental Cell, Volume 45, Issue 1
Author(s): Isidora Paredes, Patricia Himmels, Carmen Ruiz de Almodóvar
A precise communication between the nervous and the vascular systems is crucial for proper formation and function of the central nervous system (CNS). Interestingly, this communication does not only occur by neural cells regulating the growth and properties of the vasculature, but new studies show that blood vessels actively control different neurodevelopmental processes. Here, we review the current knowledge on how neurons in particular influence growing blood vessels during CNS development and on how vessels participate in shaping the neural compartment. We also review the identified molecular mechanisms of this bidirectional communication.
Teaser
Paredes et al. review the bidirectional communication mechanisms between blood vessels and neurons. The authors focus particularly on the developmental aspect of this crosstalk in several areas of the brain and spinal cord.https://ift.tt/2qkNKx5
Hemodynamic Forces Tune the Arrest, Adhesion, and Extravasation of Circulating Tumor Cells
Publication date: 9 April 2018
Source:Developmental Cell, Volume 45, Issue 1
Author(s): Gautier Follain, Naël Osmani, Ana Sofia Azevedo, Guillaume Allio, Luc Mercier, Matthia A. Karreman, Gergely Solecki, Marìa Jesùs Garcia Leòn, Olivier Lefebvre, Nina Fekonja, Claudia Hille, Vincent Chabannes, Guillaume Dollé, Thibaut Metivet, François Der Hovsepian, Christophe Prudhomme, Angélique Pichot, Nicodème Paul, Raphaël Carapito, Siamak Bahram, Bernhard Ruthensteiner, André Kemmling, Susanne Siemonsen, Tanja Schneider, Jens Fiehler, Markus Glatzel, Frank Winkler, Yannick Schwab, Klaus Pantel, Sébastien Harlepp, Jacky G. Goetz
Metastatic seeding is driven by cell-intrinsic and environmental cues, yet the contribution of biomechanics is poorly known. We aim to elucidate the impact of blood flow on the arrest and the extravasation of circulating tumor cells (CTCs) in vivo. Using the zebrafish embryo, we show that arrest of CTCs occurs in vessels with favorable flow profiles where flow forces control the adhesion efficacy of CTCs to the endothelium. We biophysically identified the threshold values of flow and adhesion forces allowing successful arrest of CTCs. In addition, flow forces fine-tune tumor cell extravasation by impairing the remodeling properties of the endothelium. Importantly, we also observe endothelial remodeling at arrest sites of CTCs in mouse brain capillaries. Finally, we observed that human supratentorial brain metastases preferably develop in areas with low perfusion. These results demonstrate that hemodynamic profiles at metastatic sites regulate key steps of extravasation preceding metastatic outgrowth.
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Follain et al. demonstrate that blood flow forces tune both the arrest and extravasation of circulating tumor cells in vivo. Permissive flow forces allow stable intravascular arrest of circulating tumor cells. Flow forces drive endothelial remodeling around arrested tumor cells, favoring extravasation preceding metastatic outgrowth.https://ift.tt/2GMA0GL
HCMV Assembly Is Totally Tubular
Publication date: 9 April 2018
Source:Developmental Cell, Volume 45, Issue 1
Author(s): Shelby M. Lyon, Robert F. Kalejta
Microtubules are normally organized at centrosomes, but other sites can also serve as microtubule organizing centers (MTOCs). In this issue of Developmental Cell, Procter et al. (2018) show that the human cytomegalovirus virion assembly compartment acts as a dynamic Golgi-derived MTOC where EB3 nucleates microtubules and regulates infectious virion production.
Teaser
Microtubules are normally organized at centrosomes, but other sites can also serve as microtubule organizing centers (MTOCs). In this issue of Developmental Cell, Procter et al. (2018) show that the human cytomegalovirus virion assembly compartment acts as a dynamic Golgi-derived MTOC where EB3 nucleates microtubules and regulates infectious virion production.https://ift.tt/2qlCb99
Coordination of Receptor Tyrosine Kinase Signaling and Interfacial Tension Dynamics Drives Radial Intercalation and Tube Elongation
Publication date: 9 April 2018
Source:Developmental Cell, Volume 45, Issue 1
Author(s): Neil M. Neumann, Matthew C. Perrone, Jim H. Veldhuis, Robert J. Huebner, Huiwang Zhan, Peter N. Devreotes, G. Wayne Brodland, Andrew J. Ewald
We sought to understand how cells collectively elongate epithelial tubes. We first used 3D culture and biosensor imaging to demonstrate that epithelial cells enrich Ras activity, phosphatidylinositol (3,4,5)-trisphosphate (PIP3), and F-actin to their leading edges during migration within tissues. PIP3 enrichment coincided with, and could enrich despite inhibition of, F-actin dynamics, revealing a conserved migratory logic compared with single cells. We discovered that migratory cells can intercalate into the basal tissue surface and contribute to tube elongation. We then connected molecular activities to subcellular mechanics using force inference analysis. Migration and transient intercalation required specific and similar anterior-posterior ratios of interfacial tension. Permanent intercalations were distinguished by their capture at the boundary through time-varying tension dynamics. Finally, we integrated our experimental and computational data to generate a finite element model of tube elongation. Our model revealed that intercalation, interfacial tension dynamics, and high basal stress are together sufficient for mammary morphogenesis.
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Neumann et al. demonstrate that the spatial asymmetries and molecular logic of migration are conserved between epithelial cells within mammalian tissues and single cells on flat substrates. Force inference techniques and finite element modeling further define a set of mechanical properties and cell behaviors, including radial intercalation, that elongate tubes.https://ift.tt/2GOGAN2
The HCMV Assembly Compartment Is a Dynamic Golgi-Derived MTOC that Controls Nuclear Rotation and Virus Spread
Publication date: 9 April 2018
Source:Developmental Cell, Volume 45, Issue 1
Author(s): Dean J. Procter, Avik Banerjee, Masatoshi Nukui, Kevin Kruse, Vadim Gaponenko, Eain A. Murphy, Yulia Komarova, Derek Walsh
Human cytomegalovirus (HCMV), a leading cause of congenital birth defects, forms an unusual cytoplasmic virion maturation site termed the "assembly compartment" (AC). Here, we show that the AC also acts as a microtubule-organizing center (MTOC) wherein centrosome activity is suppressed and Golgi-based microtubule (MT) nucleation is enhanced. This involved viral manipulation of discrete functions of MT plus-end-binding (EB) proteins. In particular, EB3, but not EB1 or EB2, was recruited to the AC and was required to nucleate MTs that were rapidly acetylated. EB3-regulated acetylated MTs were necessary for nuclear rotation prior to cell migration, maintenance of AC structure, and optimal virus replication. Independently, a myristoylated peptide that blocked EB3-mediated enrichment of MT regulatory proteins at Golgi regions of the AC also suppressed acetylated MT formation, nuclear rotation, and infection. Thus, HCMV offers new insights into the regulation and functions of Golgi-derived MTs and the therapeutic potential of targeting EB3.
Teaser
Live-cell imaging reveals the dynamic nature of the human cytomegalovirus (HCMV) assembly compartment (AC), which acts as a Golgi-derived microtubule-organizing center. Specific recruitment of microtubule plus-end binding EB3 facilitates acetylated MT formation at the AC and nuclear rotation prior to cell migration. EB3 targeting with myristoylated peptides suppresses infection.https://ift.tt/2qjUQCk
The RAB11A-Positive Compartment Is a Primary Platform for Autophagosome Assembly Mediated by WIPI2 Recognition of PI3P-RAB11A
Publication date: 9 April 2018
Source:Developmental Cell, Volume 45, Issue 1
Author(s): Claudia Puri, Mariella Vicinanza, Avraham Ashkenazi, Matthew J. Gratian, Qifeng Zhang, Carla F. Bento, Maurizio Renna, Fiona M. Menzies, David C. Rubinsztein
Autophagy is a critical pathway that degrades intracytoplasmic contents by engulfing them in double-membraned autophagosomes that are conjugated with LC3 family members. These membranes are specified by phosphatidylinositol 3-phosphate (PI3P), which recruits WIPI2, which, in turn, recruits ATG16L1 to specify the sites of LC3-conjugation. Conventionally, phosphatidylinositides act in concert with other proteins in targeting effectors to specific membranes. Here we describe that WIPI2 localizes to autophagic precursor membranes by binding RAB11A, a protein that specifies recycling endosomes, and that PI3P is formed on RAB11A-positive membranes upon starvation. Loss of RAB11A impairs the recruitment and assembly of the autophagic machinery. RAB11A-positive membranes are a primary direct platform for canonical autophagosome formation that enables autophagy of the transferrin receptor and damaged mitochondria. While this compartment may receive membrane inputs from other sources to enable autophagosome biogenesis, RAB11A-positive membranes appear to be a compartment from which autophagosomes evolve.
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Teaser
Puri et al. report that key events preceding completion of autophagosome formation occur on a RAB11A- and transferrin receptor-positive membrane compartment, likely the recycling endosome. RAB11A recruits WIPI2 for ATG16L-mediated LC3 conjugation, suggesting that this RAB11A compartment, beyond contributing membrane to autophagosomes, is a primary platform on which autophagosomes form.https://ift.tt/2GMp1gu
The Role of Mitotic Cell-Substrate Adhesion Re-modeling in Animal Cell Division
Publication date: 9 April 2018
Source:Developmental Cell, Volume 45, Issue 1
Author(s): Christina L. Dix, Helen K. Matthews, Marina Uroz, Susannah McLaren, Lucie Wolf, Nicholas Heatley, Zaw Win, Pedro Almada, Ricardo Henriques, Michael Boutros, Xavier Trepat, Buzz Baum
Animal cells undergo a dramatic series of shape changes as they divide, which depend on re-modeling of cell-substrate adhesions. Here, we show that while focal adhesion complexes are disassembled during mitotic rounding, integrins remain in place. These integrin-rich contacts connect mitotic cells to the underlying substrate throughout mitosis, guide polarized cell migration following mitotic exit, and are functionally important, since adherent cells undergo division failure when removed from the substrate. Further, the ability of cells to re-spread along pre-existing adhesive contacts is essential for division in cells compromised in their ability to construct a RhoGEF-dependent (Ect2) actomyosin ring. As a result, following Ect2 depletion, cells fail to divide on small adhesive islands but successfully divide on larger patterns, as the connection between daughter cells narrows and severs as they migrate away from one another. In this way, regulated re-modeling of cell-substrate adhesions during mitotic rounding aids division in animal cells.
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Dix et al. show that the integrin-positive adhesive contacts that remain following mitotic rounding are essential for division in non-transformed adherent cells in culture. Further, these adhesion sites guide polarized daughter cell migration—a process that is sufficient to drive abscission in the absence of a visible contractile actomyosin ring.https://ift.tt/2qlBQDp
Bayesian convolutional neural network based MRI brain extraction on nonhuman primates
Source:NeuroImage, Volume 175
Author(s): Gengyan Zhao, Fang Liu, Jonathan A. Oler, Mary E. Meyerand, Ned H. Kalin, Rasmus M. Birn
Brain extraction or skull stripping of magnetic resonance images (MRI) is an essential step in neuroimaging studies, the accuracy of which can severely affect subsequent image processing procedures. Current automatic brain extraction methods demonstrate good results on human brains, but are often far from satisfactory on nonhuman primates, which are a necessary part of neuroscience research. To overcome the challenges of brain extraction in nonhuman primates, we propose a fully-automated brain extraction pipeline combining deep Bayesian convolutional neural network (CNN) and fully connected three-dimensional (3D) conditional random field (CRF). The deep Bayesian CNN, Bayesian SegNet, is used as the core segmentation engine. As a probabilistic network, it is not only able to perform accurate high-resolution pixel-wise brain segmentation, but also capable of measuring the model uncertainty by Monte Carlo sampling with dropout in the testing stage. Then, fully connected 3D CRF is used to refine the probability result from Bayesian SegNet in the whole 3D context of the brain volume. The proposed method was evaluated with a manually brain-extracted dataset comprising T1w images of 100 nonhuman primates. Our method outperforms six popular publicly available brain extraction packages and three well-established deep learning based methods with a mean Dice coefficient of 0.985 and a mean average symmetric surface distance of 0.220 mm. A better performance against all the compared methods was verified by statistical tests (all p-values < 10−4, two-sided, Bonferroni corrected). The maximum uncertainty of the model on nonhuman primate brain extraction has a mean value of 0.116 across all the 100 subjects. The behavior of the uncertainty was also studied, which shows the uncertainty increases as the training set size decreases, the number of inconsistent labels in the training set increases, or the inconsistency between the training set and the testing set increases.
https://ift.tt/2uYFRmO
Conflict monitoring mechanism at the single-neuron level in the human ventral anterior cingulate cortex
Source:NeuroImage, Volume 175
Author(s): Irit Shapira-Lichter, Ido Strauss, Noga Oren, Tomer Gazit, Francesco Sammartino, Peter Giacobbe, Sidney Kennedy, William D. Hutchison, Itzhak Fried, Talma Hendler, Andres M. Lozano
Life requires monitoring and adjusting behavior in the face of conflicts. The conflict monitoring theory implicates the anterior cingulate cortex (ACC) in these processes; its ventral aspect (vACC) specializes in emotional conflict. To elucidate the underpinning neural mechanism, we recorded vACC extracellular activity from 12 patients with mood disorders or epilepsy who performed the face-emotional Stroop task. Behaviorally, both conflict detection and adaptation to conflict were evident. The firing rate of neurons in the vACC represented current conflict, i.e., current-congruency. The late onset of the effect is compatible with a role in monitoring. Additionally, early responses of some neurons represented the immediate history of conflicts, i.e., previous-trial-congruency. Finally, in some neurons the response to the current-trial was modulated by previous-trial-congruency, laying the ground for adjusting-to-conflicts. Our results uncover a single neuron level mechanism in the vACC that encodes and integrates past and present emotional conflicts, allowing humans to accommodate their responses accordingly.
https://ift.tt/2HmPeyZ
Intra-hemispheric integration underlies perception of tilt illusion
Source:NeuroImage, Volume 175
Author(s): Chen Song, Geraint Rees
The integration of inputs across the entire visual field into a single conscious experience is fundamental to human visual perception. This integrated nature of visual experience is illustrated by contextual illusions such as the tilt illusion, in which the perceived orientation of a central grating appears tilted away from its physical orientation, due to the modulation by a surrounding grating with a different orientation. Here we investigated the relative contribution of local, intra-hemispheric and global, inter-hemispheric integration mechanisms to perception of the tilt illusion. We used Dynamic Causal Modelling of fMRI signals to estimate effective connectivity in human early visual cortices (V1, V2, V3) during bilateral presentation of a tilt illusion stimulus. Our analysis revealed that neural responses associated with the tilt illusion were modulated by intra- rather than inter-hemispheric connectivity. Crucially, across participants, intra-hemispheric connectivity in V1 correlated with the magnitude of the tilt illusion, while no such correlation was observed for V1 inter-hemispheric connectivity, or V2, V3 connectivity. Moreover, when the illusion stimulus was presented unilaterally rather than bilaterally, the illusion magnitude did not change. Together our findings suggest that perception of the tilt illusion reflects an intra-hemispheric integration mechanism. This is in contrast to the existing literature, which suggests inter-hemispheric modulation of neural activity as early as V1. This discrepancy with our findings may reflect the diversity and complexity of integration mechanisms involved in visual processing and visual perception.
https://ift.tt/2uWHrWh
Lateral prefrontal cortex lesion impairs regulation of internally and externally directed attention
Source:NeuroImage, Volume 175
Author(s): Julia W.Y. Kam, Anne-Kristin Solbakk, Tor Endestad, Torstein R. Meling, Robert T. Knight
Our capacity to flexibly shift between internally and externally directed attention is crucial for successful performance of activities in our daily lives. Neuroimaging studies have implicated the lateral prefrontal cortex (LPFC) in both internally directed processes, including autobiographical memory retrieval and future planning, and externally directed processes, including cognitive control and selective attention. However, the causal involvement of the LPFC in regulating internally directed attention states is unknown. The current study recorded scalp EEG from patients with LPFC lesions and healthy controls as they performed an attention task that instructed them to direct their attention either to the external environment or their internal milieu. We compared frontocentral midline theta and posterior alpha between externally and internally directed attention states. While healthy controls showed increased theta power during externally directed attention and increased alpha power during internally directed attention, LPFC patients revealed no differences between the two attention states in either electrophysiological measure in the analyzed time windows. These findings provide evidence that damage to the LPFC leads to dysregulation of both types of attention, establishing the important role of LPFC in supporting sustained periods of internally and externally directed attention.
https://ift.tt/2Hmzqwi
Statistical power comparisons at 3T and 7T with a GO / NOGO task
Source:NeuroImage, Volume 175
Author(s): Salvatore Torrisi, Gang Chen, Daniel Glen, Peter A. Bandettini, Chris I. Baker, Richard Reynolds, Jeffrey Yen-Ting Liu, Joseph Leshin, Nicholas Balderston, Christian Grillon, Monique Ernst
The field of cognitive neuroscience is weighing evidence about whether to move from standard field strength to ultra-high field (UHF). The present study contributes to the evidence by comparing a cognitive neuroscience paradigm at 3 Tesla (3T) and 7 Tesla (7T). The goal was to test and demonstrate the practical effects of field strength on a standard GO/NOGO task using accessible preprocessing and analysis tools. Two independent matched healthy samples (N = 31 each) were analyzed at 3T and 7T. Results show gains at 7T in statistical strength, the detection of smaller effects and group-level power. With an increased availability of UHF scanners, these gains may be exploited by cognitive neuroscientists and other neuroimaging researchers to develop more efficient or comprehensive experimental designs and, given the same sample size, achieve greater statistical power at 7T.
https://ift.tt/2uYxM1j
Distinct phase-amplitude couplings distinguish cognitive processes in human attention
Source:NeuroImage, Volume 175
Author(s): Ravi V. Chacko, Byungchan Kim, Suh Woo Jung, Amy L. Daitch, Jarod L. Roland, Nicholas V. Metcalf, Maurizio Corbetta, Gordon L. Shulman, Eric C. Leuthardt
Spatial attention is the cognitive function that coordinates the selection of visual stimuli with appropriate behavioral responses. Recent studies have reported that phase-amplitude coupling (PAC) of low and high frequencies covaries with spatial attention, but differ on the direction of covariation and the frequency ranges involved. We hypothesized that distinct phase-amplitude frequency pairs have differentiable contributions during tasks that manipulate spatial attention. We investigated this hypothesis with electrocorticography (ECoG) recordings from participants who engaged in a cued spatial attention task. To understand the contribution of PAC to spatial attention we classified cortical sites by their relationship to spatial variables or behavioral performance. Local neural activity in spatial sites was sensitive to spatial variables in the task, while local neural activity in behavioral sites correlated with reaction time. We found two PAC frequency clusters that covaried with different aspects of the task. During a period of cued attention, delta-phase/high-gamma (DH) PAC was sensitive to cue direction in spatial sites. In contrast, theta-alpha-phase/beta-low-gamma-amplitude (TABL) PAC robustly correlated with future reaction times in behavioral sites. Finally, we investigated the origins of TABL PAC and found it corresponded to behaviorally relevant, sharp waveforms, which were also coupled to a low frequency rhythm. We conclude that TABL and DH PAC correspond to distinct mechanisms during spatial attention tasks and that sharp waveforms are elements of a coupled dynamical process.
https://ift.tt/2Hnu3wY
Can anomalous diffusion models in magnetic resonance imaging be used to characterise white matter tissue microstructure?
Source:NeuroImage, Volume 175
Author(s): Qiang Yu, David Reutens, Viktor Vegh
PurposeDuring the time window of diffusion weighted magnetic resonance imaging experiments (DW-MRI), water diffusion in tissue appears to be anomalous as a transient effect, with a mean squared displacement that is not a linear function of time. A number of statistical models have been proposed to describe water diffusion in tissue, and parameters describing anomalous as well as Gaussian diffusion have previously been related to measures of tissue microstructure such as mean axon radius. We analysed the relationship between white matter tissue characteristics and parameters of existing statistical diffusion models.MethodsA white matter tissue model (ActiveAx) was used to generate multiple b-value diffusion-weighted magnetic resonance imaging signals. The following models were evaluated to fit the diffusion signal: 1) Gaussian models - 1a) mono-exponential decay and 1b) bi-exponential decay; 2) Anomalous diffusion models - 2a) stretched exponential, 2b) continuous time random walk and 2c) space fractional Bloch-Torrey equation. We identified the best candidate model based on the relationship between the diffusion-derived parameters and mean axon radius and axial diffusivity, and applied it to the in vivo DW-MRI data acquired at 7.0 T from five healthy participants to estimate the same selected tissue characteristics. Differences between simulation parameters and fitted parameters were used to assess accuracy and in vivo findings were compared to previously reported observations.ResultsThe space fractional Bloch-Torrey model was found to be the best candidate in characterising white matter on the base of the ActiveAx simulated DW-MRI data. Moreover, parameters of the space fractional Bloch-Torrey model were sensitive to mean axon radius and axial diffusivity and exhibited low noise sensitivity based on simulations. We also found spatial variations in the model parameter β to reflect changes in mean axon radius across the mid-sagittal plane of the corpus callosum.ConclusionSimulations have been used to define how the parameters of the most common statistical magnetic resonance imaging diffusion models relate to axon radius and diffusivity. The space fractional Bloch-Torrey equation was identified as the best model for the characterisation of axon radius and diffusivity. This model allows changes in mean axon radius and diffusivity to be inferred from spatially resolved maps of model parameters.
https://ift.tt/2uYFPLI
Distinctive heritability patterns of subcortical-prefrontal cortex resting state connectivity in childhood: A twin study
Publication date: 15 July 2018
Source:NeuroImage, Volume 175
Author(s): Michelle Achterberg, Marian J. Bakermans-Kranenburg, Marinus H. van Ijzendoorn, Mara van der Meulen, Nim Tottenham, Eveline A. Crone
Connectivity between limbic/subcortical and prefrontal-cortical brain regions develops considerably across childhood, but less is known about the heritability of these networks at this age. We tested the heritability of limbic/subcortical-cortical and limbic/subcortical-subcortical functional brain connectivity in 7- to 9-year-old twins (N = 220), focusing on two key limbic/subcortical structures: the ventral striatum and the amygdala, given their combined influence on changing incentivised behavior during childhood and adolescence. Whole brain analyses with ventral striatum (VS) and amygdala as seeds in genetically independent groups showed replicable functional connectivity patterns. The behavioral genetic analyses revealed that in general VS and amygdala connectivity showed distinct influences of genetics and environment. VS-prefrontal cortex connections were best described by genetic and unique environmental factors (the latter including measurement error), whereas amygdala-prefrontal cortex connectivity was mainly explained by environmental influences. Similarities were also found: connectivity between both the VS and amygdala and ventral anterior cingulate cortex (vACC) showed influences of shared environment, while connectivity with the orbitofrontal cortex (OFC) showed heritability. These findings may inform future interventions that target behavioral control and emotion regulation, by taking into account genetic dispositions as well as shared and unique environmental factors such as child rearing.
https://ift.tt/2Hok6iO
Statistical learning of multisensory regularities is enhanced in musicians: An MEG study
Source:NeuroImage, Volume 175
Author(s): Evangelos Paraskevopoulos, Nikolas Chalas, Panagiotis Kartsidis, Andreas Wollbrink, Panagiotis Bamidis
The present study used magnetoencephalography (MEG) to identify the neural correlates of audiovisual statistical learning, while disentangling the differential contributions of uni- and multi-modal statistical mismatch responses in humans. The applied paradigm was based on a combination of a statistical learning paradigm and a multisensory oddball one, combining an audiovisual, an auditory and a visual stimulation stream, along with the corresponding deviances. Plasticity effects due to musical expertise were investigated by comparing the behavioral and MEG responses of musicians to non-musicians. The behavioral results indicated that the learning was successful for both musicians and non-musicians. The unimodal MEG responses are consistent with previous studies, revealing the contribution of Heschl's gyrus for the identification of auditory statistical mismatches and the contribution of medial temporal and visual association areas for the visual modality. The cortical network underlying audiovisual statistical learning was found to be partly common and partly distinct from the corresponding unimodal networks, comprising right temporal and left inferior frontal sources. Musicians showed enhanced activation in superior temporal and superior frontal gyrus. Connectivity and information processing flow amongst the sources comprising the cortical network of audiovisual statistical learning, as estimated by transfer entropy, was reorganized in musicians, indicating enhanced top-down processing. This neuroplastic effect showed a cross-modal stability between the auditory and audiovisual modalities.
https://ift.tt/2v4JLL4
Nrf2 signaling and autophagy are complementary in protecting breast cancer cells during glucose deprivation
Publication date: Available online 9 April 2018
Source:Free Radical Biology and Medicine
Author(s): Alyssa Walker, Anju Singh, Ellen Tully, Juhyung Woo, Anne Le, Tu Nguyen, Shyam Biswal, Dipali Sharma, Edward Gabrielson
Autophagy can serve as a mechanism for survival of cells during nutrient deprivation by recycling cellular macromolecules and organelles transiently to provide essential metabolic substrates. However, autophagy itself causes metabolic stress to cells, and other cellular protective mechanisms likely cooperate with autophagy to promote cell survival during nutrient deprivation. In this study, we explored protective mechanisms in breast cancer cells in the setting of glucose deprivation. While breast cancer cells (MCF7 and T47D) survive in glucose-free medium for three days or more, autophagy is induced in this setting. Blocking autophagy pharmacologically with chloroquine or by knock-out of an essential autophagy gene, such as Beclin 1 or ATG7, markedly reduces the ability of cells to survive during glucose deprivation. Autophagy previously was shown to degrade p62, a protein that sequesters KEAP1, and KEAP1 in turn sequesters Nrf2, a master regulator of the antioxidant response. Hence, we investigated how the Nrf2 signaling pathway might be affected by glucose deprivation and autophagy. We found that while glucose deprivation does cause decreased cellular levels of p62, Nrf2 protein levels and activity unexpectedly increase in this setting. Moreover, this increase in Nrf2 activity provides important protection to breast cancer cells during glucose deprivation, since siRNA knockdown of Nrf2 markedly impairs survival during glucose deprivation. Antioxidants, N-acetyl cysteine and glutathione also protect these cells during glucose deprivation, leading us to conclude that Nrf2 signaling via its antioxidant activity has a critical and previously undescribed role of protecting cells during glucose deprivation-induced autophagy.
Graphical abstract
https://ift.tt/2qhTzfF
Honokiol alleviates the degeneration of intervertebral disc via suppressing the activation of TXNIP-NLRP3 inflammasome signal pathway
Publication date: Available online 9 April 2018
Source:Free Radical Biology and Medicine
Author(s): Pan Tang, Jia-Ming Gu, Zi-Ang Xie, Yu Gu, Zhi-Wei Jie, Kang-Mao Huang, Ji-Ying Wang, Shun-Wu Fan, Xue-Sheng Jiang, Zhi-Jun Hu
Intervertebral disc degeneration (IVDD) is a multifactorial disease and responsible for many spine related disorders, causes disability in the workforce and heavy social costs all over the world. Honokiol, a low molecular weight natural product, could penetrate into and distribute in IVDs to achieve therapeutic effect in a rat tail model. Therefore, the present study was undertaken to examine the antiinflammatory, antioxidation and chondroprotective effect of honokiol using nucleus pulposus cells and investigate its mechanisms to provide a new basis for future clinical treatment of IVDD. In the current study, we demonstrated that honokiol inhibits the H2O2-induced apoptosis (caspase-9, caspase-3, and bax), levels of oxidative stress mediators (ROS, MDA), expression of inflammatory mediators (Interleukin-6, COX-2, and iNOS), major matrix degrading proteases (MMP-3, MMP-13, ADAMTS5, and ADAMTS4) associated with nucleus pulposus degradation. Furthermore, we found nucleus pulposus protective ability of honokiol by up-regulating extra cellular matrix anabolic factors like type II collagen (Col II) and SOX9 in nucleus pulposus. We also found that honokiol suppressed the phosphorylation of NF-kB and JNK, and activation of TXNIP-NLRP3 inflammasome in H2O2-stimulated nucleus pulposus cells, thereby inhibiting the activation of downstream inflammatory mediators such as Interleukin-1β. Furthermore, honokiol showed a cartilage protective effect in the progression of IVDD in a rat model induced by puncture. Thus, our results demonstrate that honokiol inhibited the H2O2 induced apoptosis, oxidative stress, and inflammatory responses through the depression of TXNIP/NLRP3/caspase-1/ Interleukin −1β signaling axis and the activation of NF-kB and JNK. Honokiol possess nucleus pulposus protective properties and may be of value in suppressing the pathogenesis of IVDD.
Graphical abstract
https://ift.tt/2GNWa7p
Spatio-temporal monitoring of lipid peroxyl radicals in live cell studies combining fluorogenic antioxidants and fluorescence microscopy methods
Publication date: Available online 9 April 2018
Source:Free Radical Biology and Medicine
Author(s): Lana E. Greene, Richard Lincoln, Gonzalo Cosa
Lipid peroxidation of polyunsaturated fatty acids in cells may occur via their catalytic autoxidation through peroxyl radicals under oxidative stress conditions. Lipid peroxidation is related to a number of pathologies, and may be invoked in new forms of regulated cell death, yet it may also have beneficial roles in cell signaling cascades. Antioxidants are a natural line of defense against lipid peroxidation, and may accordingly impact the biological outcome associated with the redox chemistry of lipid peroxidation. Critical to unraveling the physiological and pathological role of lipid peroxidation is the development of novel probes with the partition, chemical sensitivity and more importantly, molecular specificity, enabling the spatial and temporal imaging of peroxyl radicals in the lipid membranes of live cells, reporting on the redox status of the cell membrane. This review describes our recent progress to visualize lipid peroxidation in model membrane systems and in live cell studies. Our work portrays the mechanistic insight leading to the development of a highly sensitive probe to monitor lipid peroxyl radicals (LOO•). It also describes technical aspects including reagents and fluorescence microscopy methodologies to consider in order to achieve the much sought after monitoring of rates of lipid peroxyl radical production in live cell studies, be it under oxidative stress but also under cell homeostasis. This review seeks to bring attention to the study of lipid redox reactions and to lay the groundwork for the adoption of fluorogenic antioxidant probes and related fluorescence microscopy methods toward gaining rich spatiotemporal information on lipid peroxidation in live cells.
Graphical abstract
https://ift.tt/2qiegYR
High-speed 3D imaging of cellular activity in the brain using axially-extended beams and light sheets
Publication date: June 2018
Source:Current Opinion in Neurobiology, Volume 50
Author(s): Elizabeth MC Hillman, Venkatakaushik Voleti, Kripa Patel, Wenze Li, Hang Yu, Citlali Perez-Campos, Sam E Benezra, Randy M Bruno, Pubudu T Galwaduge
As optical reporters and modulators of cellular activity have become increasingly sophisticated, the amount that can be learned about the brain via high-speed cellular imaging has increased dramatically. However, despite fervent innovation, point-scanning microscopy is facing a fundamental limit in achievable 3D imaging speeds and fields of view. A range of alternative approaches are emerging, some of which are moving away from point-scanning to use axially-extended beams or sheets of light, for example swept confocally aligned planar excitation (SCAPE) microscopy. These methods are proving effective for high-speed volumetric imaging of the nervous system of small organisms such as Drosophila (fruit fly) and D. Rerio (Zebrafish), and are showing promise for imaging activity in the living mammalian brain using both single and two-photon excitation. This article describes these approaches and presents a simple model that demonstrates key advantages of axially-extended illumination over point-scanning strategies for high-speed volumetric imaging, including longer integration times per voxel, improved photon efficiency and reduced photodamage.
Graphical abstract
https://ift.tt/2Jyz1aS
Wound outcomes in negative pressure dressings (wound) study – a randomised trial in lower limb skin cancer
The incidence of skin cancer in New Zealand is one of the highest in the world.1 Surgical excision is the mainstay of treatment for these lesions. While excision and primary closure is desirable, wounds in the lower limb are often too large or complex to obtain direct apposition and split thickness skin grafting is used to achieve wound closure without tissue tension.2,3 Grafting in the lower limb carries a high risk of failure. Over the years, various methods have been employed to reduce the risk of graft failure.
https://ift.tt/2GOKTUe
Activation of Hepatic Stellate Cells During Liver Carcinogenesis Requires Fibrinogen/Integrin αvβ5 in Zebrafish
Publication date: May 2018
Source:Neoplasia, Volume 20, Issue 5
Author(s): Chuan Yan, Qiqi Yang, Zhiyuan Gong
Hepatocellular carcinoma (HCC) is one of the most common cancers and it usually develops from a background of liver fibrosis or inflammation. The crosstalk between tumor cells and stromal cells plays an important and stimulating role during tumor progression. Previously we found in a krasV12–induced zebrafish HCC model that oncogenic hepatocytes activate hepatic stellate cells (HSCs) by up-regulation of serotonin and activate neutrophils and macrophages by up-regulation of cortisol. In the present study, we found a novel signaling transduction mechanism between oncogenic hepatocytes and HSCs. After krasV12 induction, fibrinogen was up-regulated in oncogenic hepatocytes. We reasoned that fibrinogen may bind to integrin αvβ5 on HSCs to activate HSCs. Consistent with this notion, pharmaceutical treatment using an antagonist of integrin αvβ5, cilengitide, significantly blocked HSC activation and function, accompanied by attenuated proliferation of oncogenic hepatocytes and progression of liver fibrosis. On the contrary, adenosine 5'-diphosphate, an agonist of αvβ5, activated HSCs significantly that further stimulated the tumor progression and liver fibrosis. Interestingly, in human liver disease samples, we detected an increased level of fibrinogen during tumor progression which indicated the potential role of fibrinogen signaling in HCC progression. Thus, we concluded a novel interaction between oncogenic hepatocytes and HSCs through the fibrinogen related pathway in both the zebrafish HCC model and human liver disease samples.
https://ift.tt/2GKkh6V
Exposure to 2,4-dichlorophenoxyacetic acid induced PPARβ-dependent disruption of glucose metabolism in HepG2 cells
Abstract
2,4-Dichlorophenoxyacetic acid is one of the most widely used herbicides. Its impact on health is increasingly attracting great attentions. This study aimed to investigate the effect of 2,4-dichlorophenoxyacetic acid on glucose metabolism in HepG2 cells and the underlying mechanism. After 24 h exposure to 2,4-dichlorophenoxyacetic acid, glycogen was measured by PAS staining and glucose by ELISA in HepG2 cells. The expression of genes involved in glucose metabolism was measured by real-time PCR, Western blotting, and immunofluorescence. HepG2 cells presented more extracellular glucose consumption and glycogen content after exposed to 2,4-dichlorophenoxyacetic acid. Expression of gluconeogenesis-related genes, FoxO1, and CREB is significantly elevated. Moreover, PPARβ was up-regulated dose-dependently. SiRNA knockdown of PPARβ completely rescued the increase of glycogen accumulation and glucose uptake, and the up-regulation of FOXO1 and CREB expression. Our findings propose novel mechanisms that 2,4-dichlorophenoxyacetic acid causes glucose metabolism dysfunction through PPARβ in HepG2 cells.
https://ift.tt/2v5jyMk
Interplay Between Genetic Substrate, QTc Duration, and Arrhythmia Risk in Patients With Long QT Syndrome
AbstractBackground
Long QT syndrome (LQTS) is a common inheritable arrhythmogenic disorder, often secondary to mutations in the KCNQ1, KCNH2, and SCN5A genes. The disease is characterized by a prolonged ventricular repolarization (QTc interval) that confers susceptibility to life-threatening arrhythmic events (LAEs).
ObjectivesThis study sought to create an evidence-based risk stratification scheme to personalize the quantification of the arrhythmic risk in patients with LQTS.
MethodsData from 1,710 patients with LQTS followed up for a median of 7.1 years (interquartile range [IQR]: 2.7 to 13.4 years) were analyzed to estimate the 5-year risk of LAEs based on QTc duration and genotype and to assess the antiarrhythmic efficacy of beta-blockers.
ResultsThe relationship between QTc duration and risk of events was investigated by comparison of linear and cubic spline models, and the linear model provided the best fit. The 5-year risk of LAEs while patients were off therapy was then calculated in a multivariable Cox model with QTc and genotype considered as independent factors. The estimated risk of LAEs increased by 15% for every 10-ms increment of QTc duration for all genotypes. Intergenotype comparison showed that the risk for patients with LQT2 and LQT3 increased by 130% and 157% at any QTc duration versus patients with LQT1. Analysis of response to beta-blockers showed that only nadolol reduced the arrhythmic risk in all genotypes significantly compared with no therapy (hazard ratio: 0.38; 95% confidence interval: 0.15 to 0.93; p = 0.03).
ConclusionsThe study provides an estimator of risk of LAEs in LQTS that allows a granular estimate of 5-year arrhythmic risk and demonstrate the superiority of nadolol in reducing the risk of LAEs in LQTS.
https://ift.tt/2GOlQVy
Prediction of Abnormal Myocardial Relaxation From Signal Processed Surface ECG
AbstractBackground
Myocardial relaxation is impaired in almost all cases with left ventricular diastolic dysfunction (LVDD) and is a strong predictor of cardiovascular and all-cause mortality.
ObjectivesThis study investigated the feasibility of signal-processed surface electrocardiography (spECG) as a diagnostic tool for predicting the presence of abnormal cardiac muscle relaxation.
MethodsA total of 188 outpatients referred for coronary computed tomography (CT) angiography underwent an echocardiogram for assessment of LVDD. The use of 12-lead spECG for predicting myocardial relaxation abnormalities as identified using tissue Doppler echocardiography was validated with machine-learning approaches.
ResultsA total of 188 subjects underwent diagnostic testing, with 133 (70%) showing abnormal myocardial relaxation on tissue Doppler imaging. A 12-lead spECG showed an area under the curve of 91% (95% confidence interval: 86% to 95%) for prediction of abnormal myocardial mechanical relaxation with a sensitivity and specificity of 80% and 84%, respectively. The spECG demonstrated more accurate diagnostic performance in individuals age ≥60 years as well as those with obesity or hypertension, compared with their respective counterparts. Prediction of low early diastolic relaxation velocity (e') also correctly identified concomitant significant underlying coronary artery disease in 23 of 28 cases (82%). Furthermore, a superior integrated discrimination and net reclassification improvement was observed for spECG over clinical features and traditional ECG.
ConclusionsThe spECG provides a robust prediction of abnormal myocardial relaxation. These data suggest a potential role for spECG as a novel screening strategy for identifying patients at risk for LVDD who would benefit undergoing echocardiographic evaluations.
https://ift.tt/2GKmQtH
Restenosis, Stent Thrombosis, and Bleeding Complications: Navigating Between Scylla and Charybdis
Abstract
The field of interventional cardiology has significantly evolved over 40 years by overcoming several challenges. The introduction of first-generation drug-eluting stents significantly reduced the rates of restenosis, but at the expense of an increase of late stent thrombosis. Prolonged antithrombotic therapy reduced rates of stent thrombosis, but at the cost of increased bleeding. Although the advent of second-generation drug-eluting stents subsequently reduced the incidence of late stent thrombosis, its permanent nature prevents full recovery of vascular structure and function with accordant risk of very late stent failure. In the present era of interventional cardiology, the tradeoff between stent thrombosis, restenosis, and bleeding presents as a particularly complex challenge. In this review, the authors highlight major contributors of late/very late stent thrombosis while targeting stent restenosis, and they discuss evolutionary advances in stent technology and antiplatelet therapy, to further improve upon the care of patients with coronary artery disease.
https://ift.tt/2GKL1IH
Myocardial Interstitial Fibrosis in Heart Failure: Biological and Translational Perspectives
Abstract
Myocardial interstitial fibrosis contributes to left ventricular dysfunction leading to the development of heart failure. Basic research has provided abundant evidence for the cellular and molecular mechanisms behind this lesion and the pathways by which it imparts a detrimental impact on cardiac function. Translation of this knowledge, however, to improved diagnostics and therapeutics for patients with heart failure has not been as robust. This is partly related to the paucity of biomarkers to accurately identify myocardial interstitial fibrosis and to the lack of personalized antifibrotic strategies to treat it in an effective manner. This paper summarizes current knowledge of the mechanisms and detrimental consequences of myocardial interstitial fibrosis, discusses the potential of circulating and imaging biomarkers available to recognize different phenotypes of this lesion and track their clinical evolution, and reviews the currently available and potential future therapies that allow its individualized management in heart failure patients.
https://ift.tt/2qjVOOF
Assessing the Malignant Ventricular Arrhythmic Substrate in Patients With Brugada Syndrome
AbstractBackground
Guidelines recommend the use of implanted cardioverter-defibrillators in patients with Brugada syndrome and induced ventricular tachyarrhythmias, but there is no evidence supporting it.
ObjectivesThis prospective registry study was designed to explore clinical and electrophysiological predictors of malignant ventricular tachyarrhythmia inducibility in Brugada syndrome.
MethodsA total of 191 consecutive selected patients with (group 1; n = 88) and without (group 2; n = 103) Brugada syndrome–related symptoms were prospectively enrolled in the registry. Patients underwent electrophysiological study and substrate mapping or ablation before and after ajmaline testing (1 mg/kg/5 min).
ResultsOverall, before ajmaline testing, 53.4% of patients had ventricular tachyarrhythmia inducibility, which was more frequent in group 1 (65.9%) than in group 2 (42.7%; p < 0.001). Regardless of clinical presentation, larger substrates with more fragmented long-duration ventricular potentials were found in patients with inducible arrhythmias than in patients without inducible arrhythmias (p < 0.001). One extrastimulus was used in more extensive substrates (median 13 cm2; p < 0.001), and ventricular fibrillation was the more frequently induced rhythm (p < 0.001). After ajmaline, patients without arrhythmia inducibility had arrhythmia inducibility without a difference in substrate characteristics between the 2 groups. The substrate size was the only independent predictor of inducibility (odds ratio: 4.51; 95% confidence interval: 2.51 to 8.09; p < 0.001). A substrate size of 4 cm2 best identified patients with inducible arrhythmias (area under the curve: 0.98; p < 0.001). Substrate ablation prevented ventricular tachyarrhythmia reinducibility.
ConclusionsIn Brugada syndrome dynamic substrate variability represents the pathophysiological basis of lethal ventricular tachyarrhythmias. Substrate size is independently associated with arrhythmia inducibility, and its determination after ajmaline identifies high-risk patients missed by clinical criteria. Substrate ablation is associated with electrocardiogram normalization and not arrhythmia reinducibility. (Epicardial Ablation in Brugada Syndrome [BRUGADA_I]; NCT02641431; Epicardial Ablation in Brugada Syndrome: An Extension Study of 200 BrS Patients; NCT03106701)
https://ift.tt/2GK4DMN
Impact of Cardiovascular Risk on the Relative Benefit and Harm of Intensive Treatment of Hypertension
AbstractBackground
The lower rate of primary outcome events in the intensive treatment group in SPRINT (Systolic Pressure Intervention Trial) was associated with increased clinically significant serious adverse events (SAEs). In 2017, the American College of Cardiology/American Heart Association issued risk-based blood pressure treatment guidelines. The authors hypothesized that stratification of the SPRINT population by degree of future cardiovascular disease (CVD) risk might identify a group which could benefit the most from intensive treatment.
ObjectivesThis study investigated the effect of baseline 10-year CVD risk on primary outcome events and all-cause SAEs in SPRINT.
MethodsStratifying by quartiles of baseline 10-year CVD risk, Cox proportional hazards models were used to examine the associations of treatment group with the primary outcome events and SAEs. Using multiplicative Poisson regression, a predictive model was developed to determine the benefit-to-harm ratio as a function of CVD risk.
ResultsWithin each quartile, there was a lower rate of primary outcome events in the intensive treatment group, with no differences in all-cause SAEs. From the first to fourth quartiles, the number needed to treat to prevent primary outcomes decreased from 91 to 38. The number needed to harm for all-cause SAEs increased from 62 to 250. The predictive model demonstrated significantly increasing benefit-to-harm ratios (± SE) of 0.50 ± 0.15, 0.78 ± 0.26, 2.13 ± 0.73, and 4.80 ± 1.86, for the first, second, third, and fourth quartile, respectively (p for trend <0.001). All possible pairwise comparisons of between-quartile mean values of benefit-to-harm ratios were significantly different (p < 0.001).
ConclusionsIn SPRINT, those with lower baseline CVD risk had more harm than benefit from intensive treatment, whereas those with higher risk had more benefit. With the 2017 American College of Cardiology/American Heart Association blood pressure treatment guidelines, this analysis may help providers and patients make decisions regarding the intensity of blood pressure treatment.
https://ift.tt/2IDXl9R
Implementation of Transcatheter Aortic Valve Replacement in France
AbstractBackground
Transcatheter aortic valve replacement (TAVR) has emerged as an alternative to surgical aortic valve replacement (SAVR), but unbiased data regarding evolution of the treatment of patients with aortic stenosis at the nationwide level are scarce.
ObjectivesThis study sought to evaluate the number of aortic valve replacements (AVRs) performed in France, changes over time, and the effect of the adoption of TAVR.
MethodsBased on a French administrative hospital-discharge database, the study collected all consecutive AVRs performed in France between 2007 and 2015.
ResultsA total of 131,251 interventions were performed: 109,317 (83%) SAVR and 21,934 (17%) TAVR. AVR linearly increased (from 10,892 to 18,704; p for trend <0.0001) mainly due to a marked increase in TAVR (from 244 to 6,722; p for trend = 0.0004), whereas SAVR remained stable (from 10,892 to 11,982; p for trend = 0.18). Parallel to a decrease in the Charlson index (p for trend <0.05), SAVR and TAVR in-hospital mortality rates significantly declined (both p for trend <0.01). The number of TAVRs significantly increased in all age categories (<75, 75 to 79, 80 to 84, and ≥85 years of age; all p for trend = 0.003), but reached or even exceeded SAVR in the 2 oldest categories. Although mortality rates declined for both isolated SAVR and TAVR, it became similar or slightly lower for TAVR than for isolated SAVR in 2015 in the 3 oldest age categories even if it did not reach statistical significance (p = 0.66, p = 0.47, and p = 0.06, respectively).
ConclusionsThe number of AVRs markedly increased in France between 2007 and 2015 due to the wide adoption of TAVR, which represented one-third of all AVRs in 2015. Patients' profile improved, suggesting that patients are referred earlier, and in-hospital mortality declined in all AVR subsets. Despite a worse clinical profile, the immediate outcome of TAVR compared favorably to isolated SAVR in patients >75 years of age. The results may have major implications for clinical practice and policymakers.
https://ift.tt/2IDXhXF
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