Disseminated CD8-positive, CD30-positive cutaneous lymphoproliferative eruption with overlapping features of mycosis fungoides and primary cutaneous anaplastic large cell lymphoma following remote solitary lesional presentation

Abstract

CD8-positive, CD30-positive cutaneous lymphoproliferative disorders comprise a rare subset of T-cell lymphoproliferative conditions, including variants of primary cutaneous anaplastic large cell lymphoma, mycosis fungoides, lymphomatoid papulosis type D, cutaneous gamma-delta T-cell lymphoma, and cutaneous peripheral T-cell lymphoma. These entities share overlapping clinical, histopathologic, and immunophenotypic features, presenting both a clinical and pathological diagnostic challenge. Presented here is a 73-year-old man with a disseminated, indolent CD30+, CD8+ cutaneous lymphoproliferative disorder with overlapping clinical and histopathological features of both mycosis fungoides and primary cutaneous anaplastic large cell lymphoma, as well as features of lymphomatoid papulosis. To our knowledge, this is the first case of a generalized CD8+, CD30+ eruption with features of both mycosis fungoides and primary cutaneous anaplastic large cell lymphoma arising following an episode of solitary primary cutaneous CD8-positive anaplastic large cell lymphoma.

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Enhanced plasticity and corrosion resistance of high strength Al-Zn-Mg-Cu alloy processed by an improved thermomechanical processing

Publication date: 5 September 2017
Source:Journal of Alloys and Compounds, Volume 716
Author(s): Jinrong Zuo, Longgang Hou, Jintao Shi, Hua Cui, Linzhong Zhuang, Jishan Zhang
An improved thermomechanical processing double step hot rolling (DHR) was proposed to manufacture fine-grained Al-Zn-Mg-Cu alloys based on pre-deformation, short time intermediate annealing and final hot rolling. The corresponding microstructure evolution, mechanical properties and corrosion resistance were investigated. The DHR processing can produce high-quality sheets with finer grains than the conventional hot rolling (CHR). The grain refinement is mainly proceeded via dislocation rearrangement and low angle grain boundary transition. The grain boundary area (with coarse grains) is small in the CHR alloy and enormous solute atoms could move from intra-granular area to grain boundaries. Therefore, coarse particles precipitated continuously along grain boundaries. However, larger grain boundary area is obtained in DHR alloy by finer grain structures leading to the formation of discontinuous grain boundary precipitates. The results reveal that the present DHR treated alloy possesses improved tensile plasticity and corrosion resistance than the CHR alloy because of refined grains and discontinuous grain boundary precipitates. Thus, the present DHR processing is a promising manufacturing process for obtaining fine grained heat-treatable Al alloy sheets.



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Comparison between dispersive solid-phase and dispersive liquid–liquid microextraction combined with spectrophotometric determination of malachite green in water samples based on ultrasound-assisted and preconcentration under multi-variable experimental design optimization

Publication date: November 2017
Source:Ultrasonics Sonochemistry, Volume 39
Author(s): Ebrahim Alipanahpour Dil, Mehrorang Ghaedi, Arash Asfaram, Fahimeh Zare, Fatemeh Mehrabi, Fardin Sadeghfar
The ultrasound-assisted dispersive solid-phase microextraction (USA-DSPME) and the ultrasound-assisted dispersive liquid–liquid microextraction (USA-DLLME) developed for as an ultra preconcentration and/or technique for the determination of malachite green (MG) in water samples. Central composite design based on analysis of variance and desirability function guide finding best operational conditions and represent dependency of response to variables viz. volume of extraction, eluent and disperser solvent, pH, adsorbent mass and ultrasonication time has significant influence on methods efficiency. Optimum conditions was set for USA-DSPME as: 1mg CNTs/Zn:ZnO@Ni2P-NCs; 4min sonication time and 130μL eluent at pH 6.0. Meanwhile optimum point for USA-DLLME conditions were fixed at pH 6.0; 4min sonication time and 130, 650μL and 10mL of extraction solvent (CHCl3), disperser solvent (ethanol) and sample volume, respectively. Under the above specified best operational conditions, the enrichment factors for the USA-DSPME and USA-DLLME were 88.89 and 147.30, respectively. The methods has linear response in the range of 20.0 to 4000.0ngmL⁻¹ with the correlation coefficients (r) between 0.9980 to 0.9995, while its reasonable detection limits viz. 1.386 to 2.348ngmL⁻¹ and good relative standard deviations varied from 1.1% to 2.8% (n=10) candidate this method for successful monitoring of analyte from various media. The relative recoveries of the MG dye from water samples at spiking level of 500ngmL⁻¹ were in the range between 94.50% and 98.86%. The proposed methods has been successfully applied to the analysis of the MG dye in water samples, and a satisfactory result was obtained.

Graphical abstract

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Enhanced visible-light photocatalytic activity of ZnS/g-C3N4 type-II heterojunction nanocomposites synthesized with atomic layer deposition

Publication date: 15 October 2017
Source:Applied Surface Science, Volume 419
Author(s): Won Jun Kim, Eunyong Jang, Tae Joo Park
Atomic layer deposition (ALD) is proposed to synthesize ZnS-coated g-C3N4 photocatalysts which form an effective heterojunction for charge separation by reducing carrier recombination. It also, enables decrease in processing time from few days to several hours and circumvents collection process of synthesized powder which leads improvement in the productivity. In ZnS/g-C3N4 heterojunction composite, ZnS quantum-dots are uniformly distributed on g-C3N4 rather than conformal ZnS film due to hydrophobic nature of g-C3N4 surface. Photocatalytic activity of the ZnS/g-C3N4 heterojunction composites is enhanced up to 2.6 times compared to pristine g-C3N4 by tailoring ZnS ALD cycles. A range of ALD cycles from 2 to 50 have applied, out of which 5 cycles are found optimum for best efficiency, above and below 5 cycles it becomes either saturated or less potent, respectively.

Graphical abstract

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Electrochemical behavior of Zn-xSn high-temperature solder alloys in 0.5 M NaCl solution

Publication date: 5 September 2017
Source:Journal of Alloys and Compounds, Volume 716
Author(s): Zhenghong Wang, Chuantong Chen, Jinting Jiu, Shijo Nagao, Masaya Nogi, Hirotaka Koga, Hao Zhang, Gong Zhang, Katsuaki Suganuma
Electrochemical behavior of Zn-xSn (x = 40 wt%,30 wt%,20 wt%) high-temperature lead-free alloys was investigated in aerated 0.5 M NaCl solution by open circuit potential (OCP), electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization techniques. OCP results show that the corrosion state of the alloys working surface reached a relatively dynamic equilibrium after the alloys were immersed in 0.5 M NaCl solution for 100 h. EIS analysis reveals that the total corrosion resistance Rt of alloys depended on the amount of Sn, and Zn-40Sn possessed the highest value 2228.2 Ω cm². No passivation behavior was observed during corrosion process by potentiodynamic polarization measurement. The dominant corrosion products were confirmed as Zn5(OH)8Cl2·H2O, ZnO and Zn(OH)2. Moreover, the surface and cross-section morphology of corrosion product suggested that the corrosion layer was more homogeneous and denser for higher Sn-content, Zn-40Sn obtained the best protective layer from corrosion product. The results recommend that Zn-xSn high-temperature solder alloy with higher Sn content appears to be more attractive in terms of superior corrosion properties. The exact corrosion process was also discussed in detail.



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25 Stereotactic Radiosurgery

Publication date: 2018
Source:Neurocritical Care Management of the Neurosurgical Patient
Author(s): Navjot Chaudhary, Anna K. Finley Caulfield, Steven D. Chang




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Chapter 3 Kinase Inhibitors

Publication date: 2017
Source:Adverse Events and Oncotargeted Kinase Inhibitors
Author(s): Giuseppe Tridente
The fundamental characteristics of cancer are self-sufficiency of proliferative signals, insensitivity to antigrowth signals, resistance to cell death induction (including apoptosis), limitless replicative potential, sustained angiogenesis, and capacity of tissue invasion/metastasis. All these functional aspects are largely under the control of kinases and their typical phosphorylation mechanism. The overall tumor capability is sustained by a network of pathways, intracellular cross talk subcircuits, and a series of extracellular stimuli derived not only from the transformed cell population, but also from normal tissue components that contribute to modulate tumor progression. An additional and unique condition that also characterizes malignant cells is the addiction to a single signal pathway, which turns into an advantage for targeted inhibition. On this basis, a number of kinase inhibitors have been developed with the aim of interfering with vital signs that preferably lead to neoplastic growth, as well as signaling pathways that support tumor survival and adaptation to host environment. After fundamental preliminary investigation, the discovery of imatinib, directed against the BCR-ABL oncogenic kinase protein, opened an enthusiastic search for a number of kinase inhibitors directed to various kinase members, which rapidly and successfully reached the clinical level. The chapter deals with general characteristics and classification criteria of these powerful drugs and in particular with mechanistic aspects related to their pharmacologic activity and potential capacity of induction of adverse events.



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18 Nonviral Infections of the Liver

Publication date: 2018
Source:Practical Hepatic Pathology: a Diagnostic Approach
Author(s): Venancio Avancini Ferreira Alves, Edson Abdalla




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41 Recurrent Fever, Infections, Immune Disorders, and Autoinflammatory Diseases

Publication date: 2018
Source:Nelson Pediatric Symptom-Based Diagnosis
Author(s): James W. Verbsky, John R. Routes




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43 Combined and Specialty Surgery

Publication date: 2018
Source:Neurocritical Care Management of the Neurosurgical Patient
Author(s): Lori A. Shutter, Carl H. Snyderman, Paul A. Gardner




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37 Clinical Aspects of Liver Transplantation

Publication date: 2018
Source:Practical Hepatic Pathology: a Diagnostic Approach
Author(s): Richard S. Mangus, A. Joseph Tector




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27 Unusual Behaviors

Publication date: 2018
Source:Nelson Pediatric Symptom-Based Diagnosis
Author(s): Ryan Byrne, Kirstin Kirschner




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17 Human Immunodeficiency Virus Infection of the Liver

Publication date: 2018
Source:Practical Hepatic Pathology: a Diagnostic Approach
Author(s): Maria Irma Seixas Duarte, Amaro Nunes Duarte Neto




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31 Premalignant and Early Malignant Hepatocellular Lesions in Chronic Hepatitis/Cirrhosis

Publication date: 2018
Source:Practical Hepatic Pathology: a Diagnostic Approach
Author(s): Massimo Roncalli, Young Nyun Park, Mauro Borzio, Angelo Sangiovanni, Amedeo Sciarra, Luca Di Tommaso




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38 Pathology of Liver Transplantation

Publication date: 2018
Source:Practical Hepatic Pathology: a Diagnostic Approach
Author(s): Romil Saxena, M. Isabel Fiel




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Chapter 2 Pathobiology of Novel Approaches to Treatment

Publication date: 2018
Source:Interstitial Lung Disease
Author(s): Silvia Puglisi, Carlo Vancheri
Comprehension of the pathobiology of any disease is crucial to identifying the cellular and molecular mechanisms through which that disease arises and evolves. This may lead to the discovery of new drugs that, acting on specific targets, may be effective in slowing or stopping the disease. Idiopathic pulmonary fibrosis (IPF) is a complex disease involving exogenous risk factors, genetic predisposition, and aging. Nevertheless, substantial information about the cellular and molecular pathways involved in IPF is, at least in part, clear. By virtue of this, two different drugs—pirfenidone and nintedanib—have been developed and approved for the treatment of IPF, and a number of preclinical and clinical studies are currently under way exploring new potential drugs.



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Chapter 5 Nonpharmacologic Therapy for Idiopathic Pulmonary Fibrosis

Publication date: 2018
Source:Interstitial Lung Disease
Author(s): Leann L. Silhan, Sonye K. Danoff
The care of patients with idiopathic pulmonary fibrosis requires multidisciplinary management integrating disease-specific therapy with treatment of comorbidities as well as symptom palliation. This review focuses on the role of nonpharmacologic therapy in the care of patients with idiopathic pulmonary fibrosis and describes the integration of this aspect of care in the overall patient-centered model. Nonpharmacologic care in idiopathic pulmonary fibrosis (IPF) is focused primarily on symptom management and falls in the realm of palliative care. This includes interventions to abate disease-specific symptoms such as cough and dyspnea, as well as more general comorbidities such as gastroesophageal reflux disease, fatigue, depression, and anxiety. Another aspect of nonpharmacologic therapy for IPF is lung transplantation for carefully selected individuals. Patient-centered care for IPF requires thoughtful consideration of disease-specific management, symptom management, and management of comorbidities. Central to this process are communication between the patient and provider and engagement of the patient to determine individualized goals of treatment. This approach should include nonpharmacologic therapies, as well as consideration of lung transplantation in a small group of patients.



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Chapter 7 Approach to the Diagnosis of Interstitial Lung Disease

Publication date: 2018
Source:Interstitial Lung Disease
Author(s): Jürgen Behr
Interstitial lung diseases (ILDs) encompass a wide range of diffuse pulmonary disorders, characterized by a variable degree of inflammatory and fibrotic changes of the alveolar wall and eventually the distal bronchiolar airspaces. ILDs may occur in isolation or in association with systemic diseases. The clinical evaluation of a patient with ILD includes a thorough medical history and detailed physical examination; obligatory diagnostic testing includes laboratory testing, chest radiography, and high-resolution computed tomography and comprehensive pulmonary function testing and blood gas analysis. To optimize the diagnostic yield, a dynamic interaction between the pulmonologist, radiologist, and pathologist is mandatory.



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Chapter 10 Idiopathic Pulmonary Fibrosis

Publication date: 2018
Source:Interstitial Lung Disease
Author(s): Aditi Shah, Charlene D. Fell
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and ultimately fatal disease of the lung with an unknown etiology and few treatment options. Recognition of patients who fall into phenotypic subsets may provide earlier opportunities for initiation of therapy or referral to transplant. In addition, identification and management of comorbidities may improve quality of life, and this may be more important to some patients than extending survival. This chapter updates prior summaries of proposed phenotypes and comorbidities in IPF (Fell, 2012).



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Chapter 11 Acute Exacerbations in Patients With Idiopathic Pulmonary Fibrosis

Publication date: 2018
Source:Interstitial Lung Disease
Author(s): Dong Soon Kim
In spite of many studies, the real nature, etiology, pathobiology, and therapy of acute exacerbation (AEx) of idiopathic pulmonary fibrosis (IPF) are not clear. It seemed that AEx-IPF may be an acute acceleration of the underlying fibroproliferative process triggered by various extrinsic or unknown insults in the patients with IPF, who have a predisposition to abnormal wound healing and exaggerated fibrosis. This chapter summarizes the previous studies on etiology/triggering factors, risk factors, prognosis, and therapeutic trials with the introduction of the new consensus definition and diagnostic criteria, which remove "idiopathic" from the 2007 consensus definition, to improve the feasibility of future researches.



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Chapter 13 Interstitial Lung Disease in the Connective Tissue Diseases

Publication date: 2018
Source:Interstitial Lung Disease
Author(s): Danielle Antin-Ozerkis, Ami Rubinowitz, Janine Evans, Robert J. Homer, Richard A. Matthay
The connective tissue diseases (CTDs) are inflammatory, immune-mediated disorders in which interstitial lung disease (ILD) is common and clinically important. ILD may be the first manifestation of a CTD in a previously healthy patient. CTD-associated ILD frequently presents with the gradual onset of cough and dyspnea, although rarely may present with fulminant respiratory failure. Infection and drug reaction should always be ruled out. A diagnosis of idiopathic ILD should never be made without a careful search for subtle evidence of underlying CTD. Treatment of CTD-ILD typically includes corticosteroids and immunosuppressive agents. The authors discuss the diagnostic approach to CTD-ILD and provide a focused discussion of treatment for several common forms of CTD-ILD.



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13 Gastrointestinal Bleeding

Publication date: 2018
Source:Nelson Pediatric Symptom-Based Diagnosis
Author(s): Julia Fritz, Bernadette Vitola




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14 Hepatomegaly

Publication date: 2018
Source:Nelson Pediatric Symptom-Based Diagnosis
Author(s): Grzegorz W. Telega




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Title Page/Sections Editors

Publication date: June 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 6





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CRNDE Expression Positively Correlates with EGFR Activation and Modulates Glioma Cell Growth

Abstract

Background

The long non-coding RNA CRNDE has emerged as an important regulator in carcinogenesis and cancer progression. While CRNDE has previously been found to be the most highly upregulated lncRNA in glioma, detailed information on its roles in regulating cancer cell growth remains limited.

Objective

In the present study, we aimed at exploring the functional roles and underlying mechanisms of CRNDE in glioma.

Methods

We applied microarray data analysis to determine the prognostic significance of CRNDE in glioma patients and its correlation with epidermal growth factor receptor (EGFR) activation. EGFR inhibition was used to confirm the role of EGFR in regulating CRNDE expression. Functional studies were performed upon CRNDE silencing to explore its role in gliomagenesis.

Results

We confirm that CRNDE acts as an oncogene that is highly up-regulated in glioma, and high CRNDE expression correlates with poor prognosis in glioma patients. We further demonstrate that the expression of CRNDE correlates with EGFR activation. EGF and EGFR tyrosine kinase inhibitor (TKI) enhance and block the up-regulation of CRNDE expression, respectively, suggesting that EGFR signaling may positively regulate CRNDE expression. Functional assays show that CRNDE depletion inhibits glioma cell growth both in vitro and in vivo, and is associated with induced cellular apoptosis with decreased Bcl2/Bax ratio.

Conclusions

Our findings suggest that the aberrant expression of CRNDE may be mediated by activated EGFR signaling and play significant roles in gliomagenesis.

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Current FDA-approved injection pattern versus targeted peripheral nerve–directed injection pattern. The current FDA-approved injection pattern includes chemodenervation of 7 head and neck muscle groups (A–C). The total units of BOTOX injected for each site bilaterally include: corrugators 10U, procerus 5U, frontalis 20U (A), temporalis 40U (B), occipitalis 30U, cervical paraspinal 20U, and trapezius 30U (C). By comparison, peripheral nerve–directed BOTOX injection targets fewer sites with a smaller total quantity of BOTOX (D–F). The total units of BOTOX injected for each site bilaterally include: supraorbital nerve/supratrochlear nerve 25U (D), zygomaticotemporal nerve 37.5U (E), and greater occipital nerve 50U (F). Source Targeted Peripheral Nerve-directed Onabotulinumtoxin A Injection for Effective Long-term Therapy for Migraine Headache

http://otorhinolaryngology-crete.blogspot.com/2017/05/current-fda-approved-injection-pattern.html

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

6948891480

alsfakia@gmail.com

Autologous Platelet-rich Plasma Glue : Seroma and hematoma formations are the most common complications after plastic surgery. The aim of this study was to assess the efficacy of autologous platelet-rich plasma (A-PRP) glue to reduce postoperative wound complications and improve surgical outcomes.

http://otorhinolaryngology-crete.blogspot.com/2017/05/autologous-platelet-rich-plasma-glue.html

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

6948891480

alsfakia@gmail.com

Mapping the pharmacological modulation of brain oxygen metabolism: The effects of caffeine on absolute CMRO2 measured using dual calibrated fMRI

Publication date: 15 July 2017
Source:NeuroImage, Volume 155
Author(s): Alberto Merola, Michael A. Germuska, Esther AH Warnert, Lewys Richmond, Daniel Helme, Sharmila Khot, Kevin Murphy, Peter J. Rogers, Judith E. Hall, Richard G. Wise
This study aims to map the acute effects of caffeine ingestion on grey matter oxygen metabolism and haemodynamics with a novel MRI method. Sixteen healthy caffeine consumers (8 males, age=24.7±5.1) were recruited to this randomised, double-blind, placebo-controlled study. Each participant was scanned on two days before and after the delivery of an oral caffeine (250mg) or placebo capsule.Our measurements were obtained with a newly proposed estimation approach applied to data from a dual calibration fMRI experiment that uses hypercapnia and hyperoxia to modulate brain blood flow and oxygenation. Estimates were based on a forward model that describes analytically the contributions of cerebral blood flow (CBF) and of the measured end-tidal partial pressures of CO2 and O2 to the acquired dual-echo GRE signal. The method allows the estimation of grey matter maps of: oxygen extraction fraction (OEF), CBF, CBF-related cerebrovascular reactivity (CVR) and cerebral metabolic rate of oxygen consumption (CMRO2). Other estimates from a multi inversion time ASL acquisition (mTI-ASL), salivary samples of the caffeine concentration and behavioural measurements are also reported.We observed significant differences between caffeine and placebo on average across grey matter, with OEF showing an increase of 15.6% (SEM±4.9%, p<0.05) with caffeine, while CBF and CMRO2 showed differences of −30.4% (SEM±1.6%, p<0.01) and −18.6% (SEM±2.9%, p<0.01) respectively with caffeine administration. The reduction in oxygen metabolism found is somehow unexpected, but consistent with a hypothesis of decreased energetic demand, supported by previous electrophysiological studies reporting reductions in spectral power with EEG.Moreover the maps of the physiological parameters estimated illustrate the spatial distribution of changes across grey matter enabling us to localise the effects of caffeine with voxel-wise resolution. CBF changes were widespread as reported by previous findings, while changes in OEF were found to be more restricted, leading to unprecedented mapping of significant CMRO2 reductions mainly in frontal gyrus, parietal and occipital lobes.In conclusion, we propose the estimation framework based on our novel forward model with a dual calibrated fMRI experiment as a viable MRI method to map the effects of drugs on brain oxygen metabolism and haemodynamics with voxel-wise resolution.



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Large-scale sparse functional networks from resting state fMRI

Publication date: 1 August 2017
Source:NeuroImage, Volume 156
Author(s): Hongming Li, Theodore D. Satterthwaite, Yong Fan
Delineation of large-scale functional networks (FNs) from resting state functional MRI data has become a standard tool to explore the functional brain organization in neuroscience. However, existing methods sacrifice subject specific variation in order to maintain the across-subject correspondence necessary for group-level analyses. In order to obtain subject specific FNs that are comparable across subjects, existing brain decomposition techniques typically adopt heuristic strategies or assume a specific statistical distribution for the FNs across subjects, and therefore might yield biased results. Here we present a novel data-driven method for detecting subject specific FNs while establishing group level correspondence. Our method simultaneously computes subject specific FNs for a group of subjects regularized by group sparsity, to generate subject specific FNs that are spatially sparse and share common spatial patterns across subjects. Our method is built upon non-negative matrix decomposition techniques, enhanced by a data locality regularization term that makes the decomposition robust to imaging noise and improves spatial smoothness and functional coherences of the subject specific FNs. Our method also adopts automatic relevance determination techniques to eliminate redundant FNs in order to generate a compact set of informative sparse FNs. We have validated our method based on simulated, task fMRI, and resting state fMRI datasets. The experimental results have demonstrated our method could obtain subject specific, sparse, non-negative FNs with improved functional coherence, providing enhanced ability for characterizing the functional brain of individual subjects.



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The impact of individuation on the bases of human empathic responding

Publication date: 15 July 2017
Source:NeuroImage, Volume 155
Author(s): John E. Kiat, Jacob E. Cheadle
While there is substantial overlap in the neural systems underlying empathy for people we know as opposed to strangers, social distance has been shown to significantly moderate empathic neural responses towards the negative experiences of others. Intriguingly however, variance in empathic neural responses towards known and unknown targets has not been reflected by behavioral differences as indexed by self-reported empathic ratings. One explanation for this disconnect is that empathic evaluations of known and unknown individuals draw on different bases (e.g. target identity/reactions) within the empathic process. To test this hypothesis, we utilized high density EEG to assess how individuating targets with personal names moderated the link between behavioral pain ratings and attentional processing oriented towards (a) initial target processing and (b) subsequent expressions target discomfort. Consistent with prior findings, no differences in pain ratings between individuated and unindividuated targets was observed. However, individual mean pain rating differences for individuated targets was strongly positively related to attentional processing levels, indexed by the P300, during the initial presentation of those targets, a relationship absent for unindividuated targets. In contrast, pain ratings for unindividuated targets was positively related to levels of attentional processing, indexed by the Late Positive Potential (LPP), during the subsequent discomfort expression stage. Furthermore, the LPP response to individuated target discomfort was positively linked to behavioral measures of emotional expressivity whereas the LPP response to unindividuated target discomfort was positively associated with cognitive appraisal. These findings suggest that individuation can significantly shift the bases of empathic responding.



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Attentional processes, not implicit mentalizing, mediate performance in a perspective-taking task: Evidence from stimulation of the temporoparietal junction

Publication date: 15 July 2017
Source:NeuroImage, Volume 155
Author(s): Idalmis Santiesteban, Simran Kaur, Geoffrey Bird, Caroline Catmur
Mentalizing is a fundamental process underpinning human social interaction. Claims of the existence of 'implicit mentalizing' represent a fundamental shift in our understanding of this important skill, suggesting that preverbal infants and even animals may be capable of mentalizing. One of the most influential tasks supporting such claims in adults is the dot perspective-taking task, but demonstrations of similar performance on this task for mentalistic and non-mentalistic stimuli have led to the suggestion that this task in fact measures domain-general processes, rather than implicit mentalizing. A mentalizing explanation was supported by fMRI data claiming to show greater activation of brain areas involved in mentalizing, including right temporoparietal junction (rTPJ), when participants made self-perspective judgements in a mentalistic, but not in a non-mentalistic condition, an interpretation subsequently challenged. Here we provide the first causal test of the mentalizing claim using disruptive transcranial magnetic stimulation of rTPJ during self-perspective judgements. We found no evidence for a distinction between mentalistic and non-mentalistic stimuli: stimulation of rTPJ impaired performance on all self-perspective trials, regardless of the mentalistic/non-mentalistic nature of the stimulus. Our data support a domain-general attentional interpretation of performance on the dot perspective-taking task, a role which is subserved by the rTPJ.



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A novel GLM-based method for the Automatic IDentification of functional Events (AIDE) in fNIRS data recorded in naturalistic environments

Publication date: 15 July 2017
Source:NeuroImage, Volume 155
Author(s): Paola Pinti, Arcangelo Merla, Clarisse Aichelburg, Frida Lind, Sarah Power, Elizabeth Swingler, Antonia Hamilton, Sam Gilbert, Paul W. Burgess, Ilias Tachtsidis
Recent technological advances have allowed the development of portable functional Near-Infrared Spectroscopy (fNIRS) devices that can be used to perform neuroimaging in the real-world. However, as real-world experiments are designed to mimic everyday life situations, the identification of event onsets can be extremely challenging and time-consuming. Here, we present a novel analysis method based on the general linear model (GLM) least square fit analysis for the Automatic IDentification of functional Events (or AIDE) directly from real-world fNIRS neuroimaging data. In order to investigate the accuracy and feasibility of this method, as a proof-of-principle we applied the algorithm to (i) synthetic fNIRS data simulating both block-, event-related and mixed-design experiments and (ii) experimental fNIRS data recorded during a conventional lab-based task (involving maths). AIDE was able to recover functional events from simulated fNIRS data with an accuracy of 89%, 97% and 91% for the simulated block-, event-related and mixed-design experiments respectively. For the lab-based experiment, AIDE recovered more than the 66.7% of the functional events from the fNIRS experimental measured data. To illustrate the strength of this method, we then applied AIDE to fNIRS data recorded by a wearable system on one participant during a complex real-world prospective memory experiment conducted outside the lab. As part of the experiment, there were four and six events (actions where participants had to interact with a target) for the two different conditions respectively (condition 1: social-interact with a person; condition 2: non-social-interact with an object). AIDE managed to recover 3/4 events and 3/6 events for conditions 1 and 2 respectively. The identified functional events were then corresponded to behavioural data from the video recordings of the movements and actions of the participant. Our results suggest that "brain-first" rather than "behaviour-first" analysis is possible and that the present method can provide a novel solution to analyse real-world fNIRS data, filling the gap between real-life testing and functional neuroimaging.



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Fatal haemorrhagic duodenal Mucormycosis in a Non-Immunocompromised Host: A case report

Publication date: Available online 11 May 2017
Source:Medical Mycology Case Reports
Author(s): Simbarashe G. Mungazi, Blessing Zambuko, David Muchuweti, Edwin G. Muguti, Sizolwenkosi Mlotshwa
Mucormycosis is an opportunistic infection caused by the fungi of the Mucorales order of the class Zygomycetes. Gastrointestinal mucormycosis is an uncommon, fatal condition accounting for only 7% of the cases. We present the case of a gastroduodenal mucormycosis presenting as recurrent massive hematemesis. We report this case to alert clinicians of this rare but fatal condition and to encourage further research into its pathogenesis and management.



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Analysis of copy number variations in Holstein-Friesian cow genomes based on whole-genome sequence data

Publication date: Available online 10 May 2017
Source:Journal of Dairy Science
Author(s): M. Mielczarek, M. Frąszczak, R. Giannico, G. Minozzi, John L. Williams, K. Wojdak-Maksymiec, J. Szyda
Thirty-two whole genome DNA sequences of cows were analyzed to evaluate inter-individual variability in the distribution and length of copy number variations (CNV) and to functionally annotate CNV breakpoints. The total number of deletions per individual varied between 9,731 and 15,051, whereas the number of duplications was between 1,694 and 5,187. Most of the deletions (81%) and duplications (86%) were unique to a single cow. No relation between the pattern of variant sharing and a family relationship or disease status was found. The animal-averaged length of deletions was from 5,234 to 9,145 bp and the average length of duplications was between 7,254 and 8,843 bp. Highly significant inter-individual variation in length and number of CNV was detected for both deletions and duplications. The majority of deletion and duplication breakpoints were located in intergenic regions and introns, whereas fewer were identified in noncoding transcripts and splice regions. Only 1.35 and 0.79% of the deletion and duplication breakpoints were observed within coding regions. A gene with the highest number of deletion breakpoints codes for protein kinase cGMP-dependent type I, whereas the T-cell receptor α constant gene had the most duplication breakpoints. The functional annotation of genes with the largest incidence of deletion/duplication breakpoints identified 87/112 Kyoto Encyclopedia of Genes and Genomes pathways, but none of the pathways were significantly enriched or depleted with breakpoints. The analysis of Gene Ontology (GO) terms revealed that a cluster with the highest enrichment score among genes with many deletion breakpoints was represented by GO terms related to ion transport, whereas the GO term cluster mostly enriched among the genes with many duplication breakpoints was related to binding of macromolecules. Furthermore, when considering the number of deletion breakpoints per gene functional category, no significant differences were observed between the "housekeeping" and "strong selection" categories, but genes representing the "low selection pressure" group showed a significantly higher number of breakpoints.



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Short communication: Nutrient consumption patterns of Lactobacillus acidophilus KLDS 1.0738 in controlled pH batch fermentations

Publication date: Available online 10 May 2017
Source:Journal of Dairy Science
Author(s): Xuepeng Lv, Gefei Liu, Xiaomei Sun, Hongyu Chen, Jiahui Sun, Zhen Feng
This work focused on elucidating the nutrient consumption patterns of Lactobacillus acidophilus to guide the design of media for high-cell-density culture. We investigated the nutrient consumption patterns of L. acidophilus KLDS 1.0738 in chemically defined media in controlled pH batch fermentations. The most abundantly consumed amino acids, vitamins, ions, and purines and pyrimidines were Glu and Gly, pyridoxine and nicotinamide, K⁺ and PO4³⁻, and guanine and uracil, respectively. The highest consumption rates for amino acids, vitamins, ions, and purines and pyrimidines were Asp and Arg, folic acid and pyridoxine, Fe²⁺ and Mn²⁺, and uracil and thymine, respectively. Furthermore, most of the amino acids, as well as guanine, thymine, pyridoxine, folic acid, nicotinamide, Mg²⁺, PO4³⁻, and K⁺ had the highest bioavailability from the end of the lag growth phase to the mid-exponential growth phase. The overall consumption of glucose, adenine nucleotides, 2'-deoxyguanosine monohydrate, calcium pantothenate, Fe²⁺ and Mn²⁺ decreased with increasing average growth rate, indicating more effective use of these nutritional components at a higher average growth rate, as biomass yield based on nutritional component consumption increased. Our findings help to formulate complex media for high-cell-density cultivation and provide a theoretical basis for L. acidophilus feeding strategies.



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Understanding the gut microbiome of dairy calves: Opportunities to improve early-life gut health

Publication date: Available online 10 May 2017
Source:Journal of Dairy Science
Author(s): Nilusha Malmuthuge, Le Luo Guan
Early gut microbiota plays a vital role in the long-term health of the host. However, understanding of these microbiota is very limited in livestock species, especially in dairy calves. Neonatal calves are highly susceptible to enteric infections, one of the major causes of calf death, so approaches to improving gut health and overall calf health are needed. An increasing number of studies are exploring the microbial composition of the gut, the mucosal immune system, and early dietary interventions to improve the health of dairy calves, revealing possibilities for effectively reducing the susceptibility of calves to enteric infections while promoting growth. Still, comprehensive understanding of the effect of dietary interventions on gut microbiota—one of the key aspects of gut health—is lacking. Such knowledge may provide in-depth understanding of the mechanisms behind functional changes in response to dietary interventions. Understanding of host–microbial interactions with dietary interventions and the role of the gut microbiota during pathogenesis at the site of infection in early life is vital for designing effective tools and techniques to improve calf gut health.



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Short communication: Associations between blood glucose concentration, onset of hyperketonemia, and milk production in early lactation dairy cows

Publication date: Available online 10 May 2017
Source:Journal of Dairy Science
Author(s): J. Ruoff, S. Borchardt, W. Heuwieser
The objectives of this study were to describe the associations between hypoglycemia and the onset of hyperketonemia (HYK) within the first 6 wk of lactation, to evaluate the effects of body condition score at calving on glucose concentration, and to study the effects of hypoglycemia on milk production. A total of 621 dairy cows from 6 commercial dairy farms in Germany were enrolled between 1 and 4 d in milk (DIM). Cows were tested twice weekly using an electronic handheld meter for glucose and β-hydroxybutyrate (BHB), respectively, for a period of 42 d. Hypoglycemia was defined as glucose concentration ≤2.2 mmol/L. Hyperketonemia was defined as a BHB concentration ≥1.2 mmol/L. The onset of HYK was described as early onset (first HYK event within the first 2 wk postpartum) and late onset (first HYK event in wk 3 to 6 postpartum). The effect of ketosis status on blood glucose within 42 DIM was evaluated using a generalized linear mixed model. No effect was observed of HYK on glucose concentration in primiparous cows. Multiparous cows with early-onset HYK had a lower glucose concentration (−0.21 mmol/L) compared with nonketotic cows. Overall, primiparous cows had a lower prevalence and incidence of hypoglycemia than multiparous cows. Hypoglycemia in multiparous cows was associated with higher first test-day milk production and 100 DIM milk production. In conclusion, hypoglycemia mainly occurred in multiparous cows with early-onset HYK, whereas primiparous cows were at a lower risk for hypoglycemia.



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The genetics of antibody response to paratuberculosis in dairy cattle

Publication date: Available online 10 May 2017
Source:Journal of Dairy Science
Author(s): T. Pritchard, R. Mrode, M. Coffey, K. Bond, E. Wall
Genetic parameters were estimated for antibody response to paratuberculosis (Mycobacterium avium ssp. paratuberculosis) using milk ELISA test results, collected and analyzed by National Milk Records, from Holstein Friesian cows on UK dairy farms in their first 3 lactations. Milk ELISA test results were obtained from 2007 to 2012 and combined with milk recording data and pedigree information. The reduced data set edited for the purposes of genetic parameter estimation consisted of 148,054 milk ELISA records from 64,645 lactations in 40,142 cows of 908 sires, recorded in 641 herds. Milk ELISA test results were loge-transformed and univariate analysis of 3 alternative animal models and equivalent sire models were considered. The most appropriate model included additive genetic and permanent environmental random effects, whereas maternal effects were significant according to likelihood ratio test and Akaike's information criterion but not for Bayesian information criterion. Heritability and repeatability estimates were 0.06 and 0.37, respectively, for the chosen animal model and its equivalent sire model. A subset of the data including herds with greater than 10% positive tests gave a slightly higher heritability of 0.08. Favorable but generally low significant genetic correlations were obtained between antibody response with 305-d milk yield (−0.16), 305-d protein yield (−0.16), loge-transformed lactation-average somatic cell count (0.15), and the number of mastitis episodes (0.22). Thus, selection on the antibody response to paratuberculosis, should not be detrimental to production or udder health traits. Testing cattle for paratuberculosis is important for its use in control programs and although the heritability of antibody response was low, breeding against the disease might be a good prospect as a preventative measure to assist together with other approaches in an overall control strategy.



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Machine-learning-based calving prediction from activity, lying, and ruminating behaviors in dairy cattle

Publication date: Available online 10 May 2017
Source:Journal of Dairy Science
Author(s): M.R. Borchers, Y.M. Chang, K.L. Proudfoot, B.A. Wadsworth, A.E. Stone, J.M. Bewley
The objective of this study was to use automated activity, lying, and rumination monitors to characterize prepartum behavior and predict calving in dairy cattle. Data were collected from 20 primiparous and 33 multiparous Holstein dairy cattle from September 2011 to May 2013 at the University of Kentucky Coldstream Dairy. The HR Tag (SCR Engineers Ltd., Netanya, Israel) automatically collected neck activity and rumination data in 2-h increments. The IceQube (IceRobotics Ltd., South Queensferry, United Kingdom) automatically collected number of steps, lying time, standing time, number of transitions from standing to lying (lying bouts), and total motion, summed in 15-min increments. IceQube data were summed in 2-h increments to match HR Tag data. All behavioral data were collected for 14 d before the predicted calving date. Retrospective data analysis was performed using mixed linear models to examine behavioral changes by day in the 14 d before calving. Bihourly behavioral differences from baseline values over the 14 d before calving were also evaluated using mixed linear models. Changes in daily rumination time, total motion, lying time, and lying bouts occurred in the 14 d before calving. In the bihourly analysis, extreme values for all behaviors occurred in the final 24 h, indicating that the monitored behaviors may be useful in calving prediction. To determine whether technologies were useful at predicting calving, random forest, linear discriminant analysis, and neural network machine-learning techniques were constructed and implemented using R version 3.1.0 (R Foundation for Statistical Computing, Vienna, Austria). These methods were used on variables from each technology and all combined variables from both technologies. A neural network analysis that combined variables from both technologies at the daily level yielded 100.0% sensitivity and 86.8% specificity. A neural network analysis that combined variables from both technologies in bihourly increments was used to identify 2-h periods in the 8 h before calving with 82.8% sensitivity and 80.4% specificity. Changes in behavior and machine-learning alerts indicate that commercially marketed behavioral monitors may have calving prediction potential.



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Effect of conjugated linoleic acid and acetate on milk fat synthesis and adipose lipogenesis in lactating dairy cows

Publication date: Available online 10 May 2017
Source:Journal of Dairy Science
Author(s): N. Urrutia, K.J. Harvatine
During biohydrogenation-induced milk fat depression (MFD), nutrients are spared from milk fat synthesis and are available for other metabolic uses. Acetate is the major carbon source spared and it may increase lipid synthesis in adipose tissue during MFD. The objective of this study was to compare the effect of trans-10, cis-12 conjugated linoleic acid (CLA) and the amount of acetate spared during CLA-induced MFD on adipose tissue lipogenesis. Nine multiparous, lactating, ruminally cannulated Holstein cows (244 ± 107 d in milk; 25 ± 8.4 kg of milk/d; mean ± standard deviation) were randomly assigned to treatments in a 3 × 3 Latin square design. Experimental periods were 4 d followed by a 10-d washout. Treatments were control (CON), ruminal infusion of acetate (AC; continuous infusion of 7 mol/d adjusted to pH 6.1 with sodium hydroxide), or abomasal infusion of CLA (10 g/d of both trans-10, cis-12 CLA and cis-9, trans-11 CLA). Dry matter intake, milk yield, and milk protein yield and percentage were not affected by treatments. Compared with CON, milk fat yield decreased 23% and fat percent decreased 28% in CLA, and milk fat yield increased 20% in AC. Concentration and yield of milk de novo synthesized fatty acids (<C16) were reduced and concentration of preformed fatty acids (>C16) was increased by CLA, compared with CON. Yield of de novo synthesized fatty acids and palmitic acid was increased by AC, compared with CON. Lipogenesis capacity of adipose tissue explants was decreased 72% by CLA, but was not affected by AC. Acetate oxidation by adipose explants was not affected by treatments. Treatments had no effect on expression of key lipogenic factors, lipogenic enzymes, and leptin; however, expression of fatty acid binding protein 4 was reduced in CLA compared with CON. Additionally, hormone-sensitive lipase and perilipin 1 were decreased by CLA and acetate. Plasma glucose and glucagon concentrations were not affected by treatments; however, CLA increased nonesterified fatty acids 17.7%, β-hydroxybutyrate 16.1%, and insulin 27.8% compared with CON, and AC increased plasma β-hydroxybutyrate 18%. In conclusion, during CLA-induced MFD in low-producing cow adipose tissue was sensitive to the anti-lipogenic effects of CLA, while spared acetate did not stimulate adipose lipogenesis. However, acetate may play an important role in stimulating lipogenesis and improving energy status in the mammary gland under normal conditions.



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Effect of different fat supplements on performance of dairy calves during cold season

Publication date: Available online 10 May 2017
Source:Journal of Dairy Science
Author(s): E. Ghasemi, M. Azad-Shahraki, M. Khorvash
The objective of this experiment was to evaluate the effects of starter supplementation with fat sources differing in their fatty acid (FA) profile on performance of dairy calves during cold season. Sixty Holstein calves (3 d of age; 39.7 ± 3.8 kg of body weight) were randomly assigned to 1 of 5 starter diets supplemented with (1) no fat or oil source (control), (2) 3% palm fat (PLF), (3) 3% soybean oil (SBO), (4) 3% tallow (TAL), and (5) a 3.2% mixture (MIX) of PLF, SBO, and fish oil. The fat supplements were substituted for corn in the basal starter diet. Both the control and fat-supplemented diets contained similar amounts of dietary crude protein (19.4%), but the latter had a slightly higher quantity of calculated metabolizable energy (3.17 vs. 3.07 Mcal/kg) than did the former. Calves were reared outdoor in individual pens during the cold of winter with a mean ambient temperature of 5.0°C during the study period. Whole milk was offered twice daily from d 3 to 45 and once from d 46 to 49. The animals were weaned on d 50 and monitored in their individual pens until d 70. Supplementation with SBO and MIX increased both the dietary concentration and ratio of essential FA (n-6 and n-3), whereas supplementation with TAL and PLF made no change in the essential FA profile. Starter intake and average daily gain were not affected by PLF and TAL supplements, but were reduced as a result of feeding MIX. Feeding supplemental SBO did not affect starter intake, but tended to improve average daily gain and final body weight. Fat sources had no effects on body skeletal measurements, fecal score, digestibility, ruminal pH, ammonia, and total volatile FA concentrations; however, feeding MIX increased rumen molar proportion of propionate. No differences were observed in blood metabolites across the treatments during the preweaning period. Plasma concentrations of triacylglycerol and cholesterol increased when fat sources were supplemented and glucose concentration increased when SBO was supplemented during the postweaning period. Overall, addition of 3% PLF or TAL to the diet of young calves failed to improve growth performance. Although addition of SBO and MIX increased the dietary essential FA concentration, calf performance was only improved when SBO was supplemented.



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Effects of dietary crude protein concentration on late-lactation dairy cow performance and indicators of nitrogen utilization

Publication date: Available online 10 May 2017
Source:Journal of Dairy Science
Author(s): T. Barros, M.A. Quaassdorff, M.A. Aguerre, J. J. Olmos Colmenero, S.J. Bertics, P.M. Crump, M.A. Wattiaux
The objectives of this study were to measure performance responses and to evaluate indictors of N utilization in late-lactation cows fed diets with incremental reductions in crude protein (CP) concentration. Holstein cows (n = 128; 224 ± 54 d in milk) were stratified by parity and days pregnant (86 ± 25 d) and randomly assigned to 1 of 16 pens in a randomized complete block design. For 3 wk, all cows received a covariate diet containing 16.9% CP [dry matter (DM) basis]. For the subsequent 12 wk, pens were randomly assigned to 1 of 4 treatments that contained 16.2, 14.4, 13.1, or 11.8% CP (DM basis). Diets were offered once daily and contained 32.5% corn silage, 32.5% alfalfa silage, 13.5% high-moisture corn, and 21.5% concentrate mix. A reduction in dietary CP was achieved by replacing soybean meal with soy hulls in the concentrate mix (DM basis). Dry matter intake, milk urea N (MUN; mg/dL), and the yield of milk urea N (g/d) decreased linearly with dietary CP. Compared with a 16.2% CP diet, a 14.4% CP diet did not alter milk yield throughout the study, but the 13.1 and 11.8% CP diets reduced milk yield after 4 and 1 wk, respectively. Furthermore, milk protein percentage was reduced for all dietary CP less than 16.2%, but this negative effect was temporary and disappeared after 7 wk for the 14.4% CP diet. In contrast, MUN adjusted to a new steady state within 1 wk for all dietary treatments. Modeling quadratic responses with a plateau led to predictions of no reduction in fat- and protein-corrected milk (32.6 kg/d) and yields of fat (1.31 kg/d), lactose (1.49 kg/d), and true protein (1.12 kg/d) until dietary CP decreased below 15.5, 15.3, 15.9, and 16.2%, respectively. In this study, MUN and the yield of MUN were highly correlated with N intake, milk protein yield, and fat- and protein-corrected milk. Surprisingly, N use efficiency (milk protein N/intake N) was not correlated with any variables related to N utilization and reached an apparent upper limit of approximately 30%. Although this observation may be associated with feeding diets deficient in metabolizable protein, late-lactation cows in this study adjusted to low dietary CP concentration better than anticipated as milk production was 2.6, 3.6, 6.4, and 8.0 kg/d higher than National Research Council (2001)-predicted metabolizable protein-allowable milk for dietary CP of 16.2, 14.4, 13.1, and 11.8%, respectively.



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Effects of dietary energy allowance and decline in dry matter intake during the dry period on responses to glucose and insulin in transition dairy cows

Publication date: Available online 10 May 2017
Source:Journal of Dairy Science
Author(s): S. Salin, A. Vanhatalo, K. Elo, J. Taponen, R.C. Boston, T. Kokkonen
We assessed whether high energy intake during the early dry period [144% of metabolizable energy (ME) requirements/d] followed by a gradual restriction of energy intake in the close-up dry period (119% of ME/d; HEI) impaired whole-body insulin sensitivity compared with a controlled energy intake (100% of ME/d; CEI) throughout the 6-wk dry period. Multiparous Ayrshire dairy cows (n = 16) were blocked by body weight, body condition score, and expected date of parturition and were used in a randomized complete block design until 10 d after parturition. Cows were fed either HEI or CEI diets based on grass silage during the first 3 wk of the dry period and grass silage supplemented with a commercial concentrate (30% of ME intake) during the final 3 wk of gestation. After calving, all cows were fed grass silage ad libitum and an increasing amount of commercial concentrate (maximum 9 kg at d 10 postpartum). Intravenous glucose tolerance tests (IVGTT) and intravenous insulin challenges were performed −10 ± 5 d (n = 15) and +10 ± 1 d (n = 14) relative to parturition. Following glucose injection, we did not find any treatment effects on glucose and insulin responses. The prepartal nonesterified fatty acid (NEFA) response of the HEI group was blunted, basal NEFA and the decrement of NEFA were smaller, and the area under the response curve (AUC) of NEFA was less negative in HEI cows than in CEI cows. The NEFA response reversed after parturition; the NEFA AUC of the HEI group was more negative than that of the CEI group. We did not find similar responses after insulin injection. Across the treatments, NEFA AUC correlated strongly with the basal NEFA concentration during the IVGTT pre- and postpartum. Calculated and model-based indices characterizing the overall glucose tolerance and β-cell function and the insulin sensitivity were higher after parturition than during the dry period. Consistent with the lower basal insulin, the acute insulin release after the glucose infusion was smaller in postpartal IVGTT than in prepartal IVGTT. The results suggest that whole-body insulin sensitivity of the cows increased after parturition. However, the role of peripheral insulin sensitivity in the regulation of glucose partitioning seems to be minor relative to the major change in insulin secretion and clearance during the periparturient period.



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Effect of inhibiting the lactogenic signal at calving on milk production and metabolic and immune perturbations in dairy cows

Publication date: Available online 10 May 2017
Source:Journal of Dairy Science
Author(s): N. Vanacker, S. Ollier, F. Beaudoin, R. Blouin, P. Lacasse
During the periparturient period, the abrupt increase in energy demand for milk production often induces metabolic and immunological disturbances in dairy cows. Our previous work has shown that reducing milk output by milking once a day or incompletely in the first few days of lactation reduces these disturbances. The aim of this study was to reduce metabolic and immunological disturbances by limiting milk production during the first week of lactation by inhibiting the lactogenic signal driven by prolactin. Twenty-two fresh cows received 8 i.m. injections of the prolactin-release inhibitor quinagolide (QUIN; 2 mg) or water as a control (CTL). The first injection was given just after calving, and the subsequent 7 injections were given every 12 h. Milk production was measured until d 28 after calving. Blood samples were taken from d 1 (calving) to d 5 and then on d 7, 10, 14, 21, and 28 to measure concentrations of urea, phosphorus, calcium, glucose, nonesterified fatty acids (NEFA), β-hydroxybutyrate, and prolactin. Other blood samples were taken on d 2, 5, 10, and 28 to analyze oxidative burst, phagocytosis, and the effect of the serum on the lymphoproliferation of peripheral blood mononuclear cells from donor cows. Blood prolactin concentration was lower from d 2 to 5 but higher from d 10 to 28 in the QUIN cows than in the CTL cows. Milk production was lower from d 2 to 6 in the QUIN cows than in the CTL cows (24.3 ± 6.4 and 34.8 ± 4.1 kg/d on average, respectively). We observed no residual effect of quinagolide on milk production after d 6. During the first week of lactation, blood glucose and calcium concentrations were higher and β-hydroxybutyrate concentration was lower in the QUIN cows than in the CTL cows. Blood NEFA, urea, and phosphorus concentrations were not affected by the treatment. At d 2 and 5, the phagocytosis ability of polymorphonuclear leukocytes was not affected by treatment; however, quinagolide injection enhanced the proportion of cells that entered oxidative burst, The mitogen-induced proliferation of peripheral blood mononuclear cells was greater when they were incubated with serum harvested from the CTL cows and was negatively correlated with the NEFA concentration in the serum. Reducing the prolactin peak at calving was effective in reducing milk production during the first week of lactation without compromising the dairy cow's overall productivity. Slowing the increase in milk production allowed a more gradual transition from pregnancy to lactation and led to a reduction in metabolic stress and an improvement in some immune system aspects during this period.



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Amino acid composition of rumen bacteria and protozoa in cattle

Publication date: Available online 10 May 2017
Source:Journal of Dairy Science
Author(s): M. Sok, D.R. Ouellet, J.L. Firkins, D. Pellerin, H. Lapierre
Because microbial crude protein (MCP) constitutes more than 50% of the protein digested in cattle, its AA composition is needed to adequately estimate AA supply. Our objective was to update the AA contributions of the rumen microbial AA flowing to the duodenum using only studies from cattle, differentiating between fluid-associated bacteria (FAB), particle-associated bacteria (PAB), and protozoa, based on published literature (53, 16, and 18 treatment means were used for each type of microorganism, respectively). In addition, Cys and Met reported concentrations were retained only when an adequate protection of the sulfur groups was performed before the acid hydrolysis. The total AA (or true protein) fraction represented 82.4% of CP in bacteria. For 10 AA, including 4 essential AA, the AA composition differed between protozoa and bacteria. The most noticeable differences were a 45% lower Lys concentration and 40% higher Ala concentration in bacteria than in protozoa. Differences between FAB and PAB were less pronounced than differences between bacteria and protozoa. Assuming 33% FAB, 50% PAB, and 17% of protozoa in MCP duodenal flow, the updated concentrations of AA would decrease supply estimates of Met, Thr, and Val originating from MCP and increase those of Lys and Phe by 5 to 10% compared with those calculated using the FAB composition reported previously. Therefore, inclusion of the contribution of PAB and protozoa to the duodenal MCP flow is needed to adequately estimate AA supply from microbial origin when a factorial method is used to estimate duodenal AA flow. Furthermore, acknowledging the fact that hydrolysis of 1 kg of true microbial protein yields 1.16 kg of free AA substantially increases the estimates of AA supply from MCP.



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Milk production and composition, nitrogen utilization, and grazing behavior of late-lactation dairy cows as affected by time of allocation of a fresh strip of pasture

Publication date: Available online 10 May 2017
Source:Journal of Dairy Science
Author(s): R.E. Vibart, M. Tavendale, D. Otter, B.H. Schwendel, K. Lowe, P. Gregorini, D. Pacheco
Eighty late-lactation dairy cows were used to examine the effects of allocating a new pasture strip of a sward based on ryegrass (Lolium perenne L.) in the morning (a.m.; ∼0730 h) or in the afternoon (p.m.; ∼1530 h) on milk production and composition, nitrogen (N) utilization, and grazing behavior. Cows grazed the same pasture strips for 24 h and were offered the same daily herbage allowance. Herbage composition differed among treatments; p.m. herbage had greater dry matter (DM; 22.7 vs. 19.9%), organic matter (OM; 89.5 vs. 88.9%), and water-soluble carbohydrate (10.9 vs. 7.6%) concentrations and lesser crude protein (20.5 vs. 22.2%) and neutral detergent fiber (48.8 vs. 50.4%) concentrations compared with a.m. herbage. Total fatty acids (FA), α-linolenic acid, and polyunsaturated FA (PUFA) were greater in a.m. herbage, whereas monounsaturated FA were greater in p.m. herbage. Estimates of herbage DM intake did not differ among treatments. Daily milk yields and milk fat and milk protein concentrations were similar among treatments, whereas milk fat (684 vs. 627 g/cow), milk protein (545 vs. 505 g/cow), and milk solids (milk fat + milk protein) yields (1,228 vs. 1,132 g/cow) tended to be greater for cows on p.m. herbage. Rumenic acid and total PUFA in milk were greater for cows on a.m. herbage, whereas oleic acid was greater for cows on p.m. herbage. Estimates of urinary N excretion (g/d) did not differ among treatments, but urinary N concentrations were greater for cows on a.m. herbage (5.85 vs. 5.36 g/L). Initial herbage mass (HM) available (kg of DM/ha) and instantaneous HM disappearance rates (kg of DM/ha and kg of DM/h) did not differ, but fractional disappearance rates (0.56 vs. 0.74 per hour for a.m. vs. p.m., respectively) differed. Under the current conditions, timing of pasture strip allocation altered the herbage nutrient supply to cows; allocating a fresh strip of pasture later in the day resulted in moderate increases in milk and milk solids yields in late-lactation dairy cows. Conversely, a greater concentration of precursor FA in a.m. herbage resulted in a greater concentration of beneficial FA in milk, compared with cows on p.m. herbage.



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Use of calcitriol to maintain postpartum blood calcium and improve immune function in dairy cows

Publication date: Available online 10 May 2017
Source:Journal of Dairy Science
Author(s): A. Vieira-Neto, I.R.P. Lima, F. Lopes, C. Lopera, R. Zimpel, L.D.P. Sinedino, K.C. Jeong, K. Galvão, W.W. Thatcher, C.D. Nelson, J.E.P. Santos
Our objectives were to determine the effects of an injectable formulation of calcitriol on mineral metabolism and immune function in postpartum Holstein cows that received an acidogenic diet prepartum to minimize hypocalcemia. In experiment 1, cows within 6 h of calving received calcitriol (0, 200, or 300 μg) to determine the dose needed to increase plasma concentrations of Ca; 300 μg was sufficient to sustain Ca for at least 3 d. In experiment 2, multiparous cows were assigned randomly to receive only vehicle (control, n = 25) or 300 μg of calcitriol (n = 25) subcutaneously within the first 6 h after calving. Blood was sampled before treatment and 12 h later, then daily until 15 d in milk (DIM), and analyzed for concentrations of ionized Ca (iCa), total Ca (tCa), total Mg (tMg), and total P (tP), metabolites, and hormones. Urine was sampled in the first 7 DIM and analyzed for concentrations of tCa, tMg, and creatinine. Neutrophil function was evaluated in the first week postpartum. Dry matter intake and production performance were evaluated for the first 36 DIM. Calcitriol administration increased concentrations of calcitriol in plasma within 12 h of application from 51 to 427 pg/mL, which returned to baseline within 5 d. Concentrations of iCa and tCa increased 24 h after treatment with calcitriol. Concentrations of iCa (control = 1.08 vs. calcitriol = 1.20 mM), tCa (control = 2.23 vs. calcitriol = 2.33 mM), and tP (control = 1.47 vs. calcitriol = 1.81 mM) remained elevated in cows treated with calcitriol until 3, 5, and 7 DIM, respectively, whereas concentration of tMg (control = 0.76 vs. calcitriol = 0.67 mM) was less in calcitriol cows than control cows until 3 DIM. Concentrations of parathyroid hormone decreased in calcitriol cows compared with control cows (control = 441 vs. calcitriol = 336 pg/mL). Calcitriol tended to increase plasma concentrations of β-hydroxybutyrate and serotonin, but concentrations of glucose, nonesterified fatty acids, and C-telopeptide of type I collagen in plasma did not differ between treatments. Cows treated with calcitriol excreted more urinary tCa (control = 0.5 vs. calcitriol = 2.1 g/d) and tMg (control = 4.5 vs. calcitriol = 5.0 g/d) in the first 7 and 2 DIM, respectively, than control cows. Compared with control, calcitriol improved the proportion of neutrophils with oxidative burst (control = 31.9 vs. calcitriol = 40.6%), mean fluorescence intensity for oxidative burst (control = 90,900 vs. calcitriol = 99,746), and mean fluorescence intensity for phagocytosis (control = 23,887 vs. calcitriol = 28,080). Dry matter intake, yields of milk, and milk components did not differ between treatments. Administration of 300 μg of calcitriol at calving was safe and effective in increasing blood concentration of iCa and plasma concentrations of calcitriol, tCa, and tP for the first 6 d after treatment, and improved measures of innate immune function in early-lactation Holstein cows.



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Thiamine supplementation facilitates thiamine transporter expression in the rumen epithelium and attenuates high-grain-induced inflammation in low-yielding dairy cows

Publication date: Available online 10 May 2017
Source:Journal of Dairy Science
Author(s): X.H. Pan, L. Yang, Y. Beckers, F.G. Xue, Z.W. Tang, L.S. Jiang, B.H. Xiong
An experiment was conducted to uncover the effects of increasing dietary grain levels on expression of thiamine transporters in ruminal epithelium, and to assess the protective effects of thiamine against high-grain-induced inflammation in dairy cows. Six rumen-fistulated, lactating Holstein dairy cows (627 ± 16.9 kg of body weight, 180 ± 6 d in milk; mean ± standard deviation) were randomly assigned to a replicated 3 × 3 Latin square design trial. Three treatments were control (20% dietary starch, dry matter basis), high-grain diet (HG, 33.2% dietary starch, DM basis), and HG diet supplemented with 180 mg of thiamine/kg of dry matter intake. On d 19 and 20 of each period, milk performance was measured. On d 21, ruminal pH, endotoxic lipopolysaccharide (LPS), and thiamine contents in rumen and blood, and plasma inflammatory cytokines were detected; a rumen papillae biopsy was taken on d 21 to determine the gene and protein expression of toll-like receptor 4 (TLR4) signaling pathways. The HG diet decreased ruminal pH (5.93 vs. 6.49), increased milk yield from 17.9 to 20.2 kg/d, and lowered milk fat and protein from 4.28 to 3.83%, and from 3.38 to 3.11%, respectively. The HG feeding reduced thiamine content in rumen (2.89 vs. 8.97 μg/L) and blood (11.66 vs. 17.63 μg/L), and the relative expression value of thiamine transporter-2 (0.37-fold) and mitochondrial thiamine pyrophosphate transporter (0.33-fold) was downregulated by HG feeding. The HG-fed cows exhibited higher endotoxin LPS in rumen fluid (134,380 vs. 11,815 endotoxin units/mL), and higher plasma concentrations of lipopolysaccharide binding protein and pro-inflammatory cytokines when compared with the control group. The gene and protein expression of tumor necrosis factor α (TNFα), IL1B, and IL6 in rumen epithelium increased when cows were fed the HG diet, indicating that local inflammation occurred. The depressions in ruminal pH, milk fat, and protein of HG-fed cows were reversed by thiamine supplementation. Thiamine supplementation increased thiamine contents in rumen and blood, and also upregulated the relative expression of thiamine transporters compared with the HG group. Thiamine supplementation decreased ruminal LPS (49,361 vs. 134,380 endotoxin units/mL) and attenuated the HG-induced inflammation response as indicated by a reduction in plasma IL6, and decreasing gene and protein expression of pro-inflammatory cytokines in rumen epithelium. Western bottling analysis showed that thiamine suppressed the protein expression of TLR4 and the phosphorylation of nuclear factor kappa B (NFκB) unit p65. In conclusion, HG feeding inhibits thiamine transporter expression in ruminal epithelium. Thiamine could attenuate the epithelial inflammation during high-grain feeding, and the protective effects may be due to its ability to suppress TLR4-mediated NFκB signaling pathways.



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Effect of feeding strategies and cropping systems on greenhouse gas emission from Wisconsin certified organic dairy farms

Publication date: Available online 10 May 2017
Source:Journal of Dairy Science
Author(s): D. Liang, F. Sun, M.A. Wattiaux, V.E. Cabrera, J.L. Hedtcke, E.M. Silva
Organic agriculture continues to expand in the United States, both in total hectares and market share. However, management practices used by dairy organic producers, and their resulting environmental impacts, vary across farms. This study used a partial life cycle assessment approach to estimate the effect of different feeding strategies and associated crop production on greenhouse gas emissions (GHG) from Wisconsin certified organic dairy farms. Field and livestock-driven emissions were calculated using 2 data sets. One was a 20-yr data set from the Wisconsin Integrated Cropping System Trial documenting management inputs, crop and pasture yields, and soil characteristics, used to estimate field-level emissions from land associated with feed production (row crop and pasture), including N2O and soil carbon sequestration. The other was a data set summarizing organic farm management in Wisconsin, which was used to estimate replacement heifer emission (CO2 equivalents), enteric methane (CH4), and manure management (N2O and CH4). Three combinations of corn grain (CG) and soybean (SB) as concentrate (all corn = 100% CG; baseline = 75% CG + 25% SB; half corn = 50% CG + 50% SB) were assigned to each of 4 representative management strategies as determined by survey data. Overall, GHG emissions associated with crop production was 1,297 ± 136 kg of CO2 equivalents/t of ECM without accounting for soil carbon changes (ΔSC), and GHG emission with ΔSC was 1,457 ± 111 kg of CO2 equivalents/t of ECM, with greater reliance on pasture resulting in less ΔSC. Higher levels of milk production were a major driver associated with reduction in GHG emission per metric tonne of ECM. Emissions per metric tonne of ECM increased with increasing proportion of SB in the ration; however, including SB in the crop rotation decreased N2O emission per metric tonne of ECM from cropland due to lower applications of organically approved N fertility inputs. More SB at the expense of CG in the ration reduced enteric CH4 emission per metric tonne of ECM (because of greater dietary fat content) but increased N2O emission per metric tonne of ECM from manure (because of greater N content). An increased reliance on pasture for feed at the expense of grain resulted in decreased in milk production, subsequently leading to substantially higher emissions per metric tonne of ECM.



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A shortened tamoxifen induction scheme to induce CreER recombinase without side effects on the male mouse skeleton

Publication date: Available online 11 May 2017
Source:Molecular and Cellular Endocrinology
Author(s): Ferran Jardí, Michaël R. Laurent, Vanessa Dubois, Rougin Khalil, Ludo Deboel, Dieter Schollaert, Ludo Van Den Bosch, Brigitte Decallonne, Geert Carmeliet, Frank Claessens, Dirk Vanderschueren
The selective estrogen receptor modulator tamoxifen exerts estrogen agonistic or antagonistic actions on several tissues, including bone. The off-target effects of tamoxifen are one of the most widely recognized pitfalls of tamoxifen-inducible Cre recombinases (CreERs), potentially confounding the phenotypic findings. Still, the validation of tamoxifen induction schemes that minimize the side effects of the drug has not been addressed. Here, we compared the side effects on the skeleton and other androgen-responsive targets of a shortened tamoxifen regimen (2 doses of 190 mg/kg body weight by oral gavage) to a standard protocol (4 doses) and determined their efficiency in inducing CreER-mediated gene deletion. In addition, both a vehicle- and a 10-dose group, which served as a positive control for tamoxifen side effects, were also included. For this purpose, we generated male mice with a floxed androgen receptor (AR) and a neuron-specifically expressed CreER. Treatment with two doses of tamoxifen was the only regimen that did not diminish androgenic bioactivity, as assessed by both seminal vesicles and levator ani/bulbocavernosus muscle weights and serum testosterone concentrations. Similarly, trabecular and cortical femoral bone structure were dramatically altered by both the standard and high-dose protocols but not by the shortened version. Serum osteocalcin and bone-gene expression analyses confirmed the absence of effects on bone by 2 doses of tamoxifen. This protocol decreased AR mRNA levels efficiently and specifically in the nervous system. Thus, we optimized a protocol for tamoxifen-induced CreER gene deletion in mice without off-target effects on bone and male reproductive organs.



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Comprehensive Genomic Profiling of Esthesioneuroblastoma Reveals Additional Treatment Options

Background.

Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant neoplasm of the olfactory mucosa. Despite surgical resection combined with radiotherapy and adjuvant chemotherapy, ENB often relapses with rapid progression. Current multimodality, nontargeted therapy for relapsed ENB is of limited clinical benefit.

Materials and Methods.

We queried whether comprehensive genomic profiling (CGP) of relapsed or refractory ENB can uncover genomic alterations (GA) that could identify potential targeted therapies for these patients. CGP was performed on formalin-fixed, paraffin-embedded sections from 41 consecutive clinical cases of ENBs using a hybrid-capture, adaptor ligation based next-generation sequencing assay to a mean coverage depth of 593X. The results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes (amplifications and homozygous deletions).

Results.

Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in clinical trials. A total of 28 ENBs harbored GA, with a mean of 1.5 GA per sample. Approximately half of the ENBs (21, 51%) featured at least one CRGA, with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), with GA in PIK3CA, NF1, CDKN2A, and CDKN2C occurring in 7% of samples.

Conclusion.

We report comprehensive genomic profiles for 41 ENB tumors. CGP revealed potential new therapeutic targets, including targetable GA in the mTOR, CDK and growth factor signaling pathways, highlighting the clinical value of genomic profiling in ENB. The Oncologist 2017;22:1–9

Implications for Practice.

Comprehensive genomic profiling of 41 relapsed or refractory ENBs reveals recurrent alterations or classes of mutation, including amplification of tyrosine kinases encoded on chromosome 5q and mutations affecting genes in the mTOR/PI3K pathway. Approximately half of the ENBs (21, 51%) featured at least one clinically relevant genomic alteration (CRGA), with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), and alterations in PIK3CA, NF1, CDKN2A, or CDKN2C were identified in 7% of samples. Responses to treatment with the kinase inhibitors sunitinib, everolimus, and pazopanib are presented in conjunction with tumor genomics.

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Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis

Background.

Despite unprecedented efficacy across multiple tumor types, immune checkpoint inhibitor therapy is associated with a unique and wide spectrum of immune-related adverse events (irAEs), including neurologic events ranging from mild headache to potentially life-threatening encephalitis. Here, we summarize neurologic irAEs associated with nivolumab and ipilimumab melanoma treatment, present cases of treatment-related encephalitis, and provide practical guidance on diagnosis and management.

Methods.

We searched a Global Pharmacovigilance and Epidemiology database for neurologic irAEs reported over an 8-year period in patients with advanced melanoma receiving nivolumab with or without ipilimumab from 12 studies sponsored by Bristol-Myers Squibb. Serious neurologic irAEs were reviewed, and relationship to nivolumab or ipilimumab was assigned.

Results.

In our search of 3,763 patients, 35 patients (0.93%) presented with 43 serious neurologic irAEs, including neuropathy (n = 22), noninfective meningitis (n = 5), encephalitis (n = 6), neuromuscular disorders (n = 3), and nonspecific adverse events (n = 7). Study drug was discontinued (n = 20), interrupted (n = 8), or unchanged (n = 7). Most neurologic irAEs resolved (26/35 patients; 75%). Overall, median time to onset was 45 days (range 1–170) and to resolution was 32 days (2–809+). Median time to onset of encephalitis was 55.5 days (range 18–297); four cases resolved and one was fatal.

Conclusion.

Both oncologists and neurologists need to be aware of signs and symptoms of serious but uncommon neurologic irAEs associated with checkpoint inhibitors. Prompt diagnosis and management using an established algorithm are critical to minimize serious complications from these neurologic irAEs. The Oncologist 2017;22:1–10

Implications for Practice: With increasing use of checkpoint inhibitors in cancer, practicing oncologists need to be aware of the potential risk of neurologic immune-related adverse events and be able to provide prompt treatment of this uncommon, but potentially serious, class of adverse events. We summarize neurologic adverse events related to nivolumab alone or in combination with ipilimumab in patients with advanced melanoma from 12 studies and examine in depth 6 cases of encephalitis. We also provide input and guidance on the existing neurologic adverse events management algorithm for nivolumab and ipilimumab.

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Targeting BRAF-Mutant Non-Small Cell Lung Cancer: From Molecular Profiling to Rationally Designed Therapy

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths globally. However, the identification of oncogenic driver alterations involved in the initiation and maintenance of NSCLC, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase translocation, has led to the development of novel therapies that directly target mutant proteins and associated signaling pathways, resulting in improved clinical outcomes. As sequencing techniques have improved, the molecular heterogeneity of NSCLC has become apparent, leading to the identification of a number of potentially actionable oncogenic driver mutations. Of these, one of the most promising therapeutic targets is B-Raf proto-oncogene, serine/threonine kinase (BRAF). Mutations in BRAF, observed in 2%–4% of NSCLCs, typically lead to constitutive activation of the protein and, as a consequence, lead to activation of the mitogen-activated protein kinase signaling pathway. Direct inhibition of mutant BRAF and/or the downstream mitogen-activated protein kinase kinase (MEK) has led to prolonged survival in patients with BRAF-mutant metastatic melanoma. This comprehensive review will discuss the clinical characteristics and prognostic implications of BRAF-mutant NSCLC, the clinical development of BRAF and MEK inhibitors from melanoma to NSCLC, and practical considerations for clinicians involving BRAF mutation screening and the choice of targeted therapy. The Oncologist 2017;22:1–11

Implications for Practice.

Personalized medicine has begun to provide substantial benefit to patients with oncogene-driven non-small cell lung cancer (NSCLC). However, treatment options for patients with oncogenic driver mutations lacking targeted treatment strategies remain limited. Direct inhibition of mutant B-Raf proto-oncogene, serine/threonine kinase (BRAF) and/or downstream mitogen-activated protein kinase kinase has the potential to change the course of the disease for patients with BRAF-mutant NSCLC, as it has in BRAF-mutant melanoma. Optimization of screening strategies for rare mutations and the choice of appropriate agents on an individual basis will be key to providing timely and successful intervention.

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Overall Survival and Clinical Characteristics of BRCA-Associated Cholangiocarcinoma: A Multicenter Retrospective Study

Background.

Biliary tract malignancies, in particular cholangiocarcinomas (CCA), are rare tumors that carry a poor prognosis. BRCA2 mutation carriers have an increased risk of developing CCA with a reported relative risk of ~5 according to the Breast Cancer Linkage Consortium. In addition to this risk, there are potential therapeutic implications in those harboring somatic and/or germline (GL) BRCA mutations. Therefore, it is important to define the clinical characteristics of GL/somatic BRCA1/2 variants in CCA patients.

Materials and Methods.

We performed a multicenter retrospective analysis of CCA patients diagnosed between January 2000 and December 2013 with GL or somatic variants in BRCA1/2 genes detected by GL mutations testing and/or by tumor next generation sequencing. Cases were identified from clinical databases at participating institutions. Data including demographics, clinical history, surgical procedures, and systemic chemotherapy or radiation were extracted from patients' records.

Results.

Overall, 18 cases were identified: 5 carriers of GL BRCA1/2 mutations (4 BRCA2; 1 BRCA1) and 13 harboring somatic variations (7 BRCA1; 6 BRCA2). Mean age at diagnosis was 60, SD ± 10 years (range 36–75 years), with male and female prevalence rates of 61.2% and 38.8%, respectively. Stage at diagnosis was I (n = 4), II (n = 3), III (n = 3), and IV (n = 8). Six patients had extrahepatic CCA and the rest intrahepatic CCA. Thirteen patients received platinum-based therapy and four were treated with poly ADP ribose polymerase inhibitors, of whom one experienced sustained disease response with a progression-free survival of 42.6 months. Median overall survival from diagnosis for patients with stage I/II in this study was 40.3 months (95% confidence interval [CI], 6.73–108.15) and with stages III/IV was 25 months (95% CI, 15.23–40.57).

Conclusion.

BRCA-associated CCA is uncommon. This multicenter retrospective study provides a thorough clinical analysis of a BRCA-associated CCA cohort, which can serve as a benchmark for future development and design of expanded analyses and clinical trials. The Oncologist 2017;22:1–7

Implications for Practice.

BRCA-associated CCA is uncommon but a very important subtype of hepatic malignancies, due to its rising prevalence. Better clinical characterization of this subtype might allow application of targeted therapy for CCA patients with germline or somatic mutations in BRCA1/2 genes, especially due to previously reported success of such therapies in other BRCA-associated malignancies. Thus this study, first of its kind, provides a basis for future multi-centered analyses in larger cohorts, as well as clinical trials. Additionally, this study emphasizes the importance of both germline and somatic genotyping for all CCA patients.

http://ift.tt/2q7tfFF

Geriatric Assessment Predicts Survival and Competing Mortality in Elderly Patients with Early Colorectal Cancer: Can It Help in Adjuvant Therapy Decision-Making?

Background.

The challenge when selecting elderly patients with colorectal cancer (CRC) for adjuvant therapy is to estimate the likelihood that death from other causes will preclude cancer events from occurring. The aim of this paper is to evaluate whether comprehensive geriatric assessment (CGA) can predict survival and cancer-specific mortality in elderly CRC patients candidates for adjuvant therapy.

Material and Methods.

One hundred ninety-five consecutive patients aged ≥75 with high-risk stage II and stage III CRC were prospectively included from May 2008 to May 2015. All patients underwent CGA, which evaluated comorbidity, polypharmacy, functional status, geriatric syndromes, mood, cognition, and social support. According to CGA results, patients were classified into three groups—fit, medium-fit, and unfit—to receive standard therapy, adjusted treatment, and best supportive care, respectively. We recorded survival and cause of death and used the Fine-Gray regression model to analyze competing causes of death.

Results.

Following CGA, 85 (43%) participants were classified as fit, 57 (29%) as medium-fit, and 53 (28%) as unfit. The univariate 5-year survival rates were 74%, 52%, and 27%. Sixty-one (31%) patients died due to cancer progression (53%), non-cancer-related cause (46%), and unknown reasons (1%); there were no toxicity-related deaths. Fit and medium-fit participants were more likely to die due to cancer progression, whereas patients classified as unfit were at significantly greater risk of non-cancer-related death.

Conclusion.

CGA showed efficacy in predicting survival and discriminating between causes of death in elderly patients with high-risk stage II and stage III resected CRC, with potential implications for shaping the decision-making process for adjuvant therapies. The Oncologist 2017;22:1–10

Implications for Practice.

Adjuvant therapy in elderly patients with colorectal cancer is controversial due to the high risk for competing events among these patients. In order to effectively select older patients for adjuvant therapy, we have to weigh the risk of cancer-related mortality and the potential survival benefits with treatment against the patient's life expectancy, irrespective of cancer. This prospective study focused on the prognostic value of geriatric assessment for survival using a competing-risk analysis approach, providing an important contribution on the treatment decision-making process and helping clinicians to identify elderly patients who might benefit from adjuvant chemotherapy among those who will not.

http://ift.tt/2r676ou

The National Cancer Institute Community Cancer Centers Program (NCCCP): Sustaining Quality and Reducing Disparities in Guideline-Concordant Breast and Colon Cancer Care

Background.

The National Cancer Institute Community Cancer Centers Program (NCCCP) pilot was designed to improve quality of cancer care and reduce disparities at community hospitals. The NCCCP's primary intervention was the implementation of the Commission on Cancer Rapid Quality Reporting System (RQRS). The RQRS is a hospital-based data collection and evaluation system allowing near real-time assessment of selected breast and colon cancer quality of care measures. Building on previous NCCCP analyses, this study examined whether improvements in quality cancer care within NCCCP hospitals early in the program were sustained and whether improvements were notable for minority or underserved populations.

Methods.

We compared changes in concordance with three breast and two colon cancer quality measures approved by the National Quality Forum for patients diagnosed at NCCCP hospitals from 2006 to 2007 (pre-RQRS), 2008 to 2010 (early-RQRS), and 2011 to 2013 (later-RQRS). Data were obtained from NCCCP sites participating in the Commission on Cancer Rapid Quality Reporting System. Logistic regression analyses were performed to identify predictors of concordance with breast and colon cancer quality measures.

Results.

The sample included 13,893 breast and 5,546 colon cancer patients. After RQRS initiation, all five quality measures improved significantly and improvements were sustained through 2013. Quality of care measures showed sustained improvements for both breast and colon cancer patients and for vulnerable patient subgroups including black, uninsured, and Medicaid-covered patients.

Conclusions.

Quality improvements in NCCCP hospitals were sustained throughout the duration of the program, both overall and among minority and underserved patients. Because many individuals receive cancer treatment at community hospitals, facilitating high-quality care in these environments must be a priority. The Oncologist 2017;22:1–8

Implications for Practice.

Quality improvement programs often improve practice, but the methods are not maintained over time. The implementation of a real-time quality reporting system and a network focused on improving quality of care sustained quality improvement at select community cancer centers. The NCCCP pilot increased numbers of patients receiving guideline-concordant care for breast and colon cancer in community settings, and initial improvements noted in earlier years of RQRS were sustained into later years, both overall and among minority and underserved patients. National initiatives that improve care for diverse patient groups are important for reducing and eliminating barriers to care.

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Male Breast Cancer as a Second Primary Cancer: Increased Risk Following Lymphoma

Background.

Male breast cancer (MBC) as a second primary cancer (SPC) has a known association with prior MBC. However, its association with non-breast index malignancies, relative to population risk, has not been previously reported.

Materials and Methods.

Using Surveillance, Epidemiology, and End Results program (9 catchment area) data, we identified MBCs diagnosed from 1973–2012 as their SPC. Information regarding the index malignancy was also obtained. Standardized incidence ratios (SIR) of MBC as SPC were estimated, along with incidence rates and trends. Kaplan-Meier curves were used to estimate survival.

Results.

Over a 38-year period, 464 MBCs were identified as SPC. The most common index malignancies were breast (SIR 30.86, 95% confidence interval [CI] 21.50–42.92, p < .001), lymphoma (SIR 1.58, 95% CI 1.08–2.22, p = .014), melanoma (SIR 1.26, 95% CI 0.80–1.89), urinary (SIR 1.05, 95% CI 0.74–1.43), colorectal (SIR 0.94, 95% CI 0.69–1.24), and prostate (SIR 0.93 95% CI 0.81–1.07). Apart from the known association with prior breast cancer, the only significant association was with lymphoma as an index cancer, although not significant with a Bonferroni correction. From 1975–2012, incidence of breast cancer as a first cancer increased at an annual percentage change of 1.3% while breast cancer as a SPC increased at 4.7% (both p values < .001).

Conclusion.

Male breast cancer as a SPC has increased markedly over 4 decades. Men with a history of lymphoma may experience higher-than-expected rates of breast SPC. These observations warrant further research, and suggest possible etiologic connections with disease biology, prior therapy, or genetics. The Oncologist 2017;22:1–6

Implications for Practice.

This study reports that men are presenting more frequently to the clinic with breast cancer, both as an initial cancer and as a second cancer following an earlier malignancy. We also report the novel observation that men who survive lymphoma are at increased risk of developing a subsequent breast cancer. Further work is needed to better understand possible treatment or biologic causes of this association. More immediately, these findings suggest the need for heightened vigilance for male breast cancer overall and, in particular, for male lymphoma survivors.

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Role of micro RNAs in stem cells, cardiac differentiation and cardiovascular diseases

Publication date: September 2017
Source:Gene Reports, Volume 8
Author(s): Mohammad Reza Hashemzadeh
MicroRNAs (miRNAs or miRs) are non-coding small RNAs which act as a mediator in gene expression by annealing to messenger RNA (mRNA) and degradation of it or translational repression. These regulating RNAs guide processes of cellular functions such as stem cell state and self-renewal as well as their differentiation not only for a single gene, but also controlling the levels of a large cohort of gene products and also involved in some diseases. Cardiovascular diseases are a worldwide disorder and a major cause of human morbidity and mortality. Moreover, surgery and intervention, cell therapy via stem cells transplantation and miRNAs are new therapeutic methods hold great promise for regenerative medicine and the treatment of cardiovascular diseases. Regarding to most of cardiovascular diseases has a genetic-impaired base, miRNA therapeutics via the use of antisense oligonucleotide-mediated knockdown or miRNA-mimic-based overexpression techniques could be used. Also, we could be able to change the functional potency of stem cells through miRNA regulating methods before cell transplantation for cardiovascular diseases.



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Behavioural characterization of AnkyrinG deficient mice, a model for ANK3 related disorders

Publication date: 15 June 2017
Source:Behavioural Brain Research, Volume 328
Author(s): I.M. van der Werf, D. Van Dam, S. Missault, B. Yalcin, P.P. De Deyn, G. Vandeweyer, R.F. Kooy
ANK3 encodes AnkyrinG (AnkG), a member of the Ankyrin family that is expressed in several different isoforms in many tissues. A unique serine-rich domain and tail domain in the two largest isoforms of AnkG (270 and 480kDa), restrict AnkG to the axon initial segment and nodes of Ranvier of myelinated neurons. At these sites, AnkG is a master regulator, coordinating the strict clustering of components necessary for proper action potential initiation and propagation along the axon. These components include voltage-gated sodium channels, potassium channels and members of the L1 cell adhesion molecule family. Genetic variation in the ANK3 gene has been linked to a range of neuropsychiatric and neurodevelopmental disorders in human, including schizophrenia, bipolar disorder, intellectual disability and autism spectrum disorders. Here, we study the effect of reduced expression of the large isoforms of Ank3 on cognition and behaviour using a heterozygous knockout mouse model. In three independent behavioural tests, being the open field test, elevated plus maze and social interaction test, we found evidence for increased anxiety in our Ank3 mouse model. Besides, we observed specific neuroanatomical defects in heterozygous knockout mice, including a smaller cingulate cortex, granular retrosplenial cortex, primary motor cortex and fimbria of the hippocampus.



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Targeting synovial neoangiogenesis in rheumatoid arthritis

Publication date: June 2017
Source:Autoimmunity Reviews, Volume 16, Issue 6
Author(s): Agathe Leblond, Yannick Allanore, Jérôme Avouac
In Rheumatoid arthritis (RA), neoangiogenesis is an early and crucial event to promote the development of the hyperplasic proliferative pathologic synovium. Endothelial cells are critical for the formation of new blood vessels since they highly contribute to angiogenesis and vasculogenesis. Current therapies in RA target the inflammatory consequences of autoimmune activation and despite major improvements these last years still refractory patients or incomplete responders may be seen raising the point of the need to identify complementary additive and innovative therapies. This review resumes the mechanisms of synovial neoangiogenesis in RA, including recent insights on the implication of vasculogenesis, and the regulation of synovial neoangiogenesis by angiogenic and inflammatory mediators. In line with the recent development of vascular-targeted therapies used in cancer and beyond, we also discuss possible therapeutic implications in RA, in particular the combination of targeted immunotherapies with anti-angiogenic molecules.



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Emerging Novel Therapeutic Agents in the Treatment of Patients with Gastroesophageal and Gastric Adenocarcinoma

Publication date: June 2017
Source:Hematology/Oncology Clinics of North America, Volume 31, Issue 3
Author(s): Gayathri Anandappa, Ian Chau

Teaser

With further understanding of the biology of gastric and gastroesophageal adenocarcinomas, strides are being made to find effective treatments through novel trial designs. This article focuses on the ongoing trials of drugs targeting specific hallmarks of gastric and gastroesophageal cancers, including oncogene addiction proliferative pathways (fibroblast growth factor receptor 2 amplified tumors), stem cell inhibition, apoptotic induction through claudin inhibitors, and matrix metalloproteinase inhibition. In developing novel therapeutics in treatment of patients with gastroesophageal adenocarcinomas, parallel research efforts to refine target population and biomarkers are crucial, and targeting the tumor genomics and microenvironment may be key in improving overall survival.


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Redox regulation of ischemic limb neovascularization – What we have learned from animal studies

Publication date: August 2017
Source:Redox Biology, Volume 12
Author(s): Reiko Matsui, Yosuke Watanabe, Colin E. Murdoch
Mouse hindlimb ischemia has been widely used as a model to study peripheral artery disease. Genetic modulation of the enzymatic source of oxidants or components of the antioxidant system reveal that physiological levels of oxidants are essential to promote the process of arteriogenesis and angiogenesis after femoral artery occlusion, although mice with diabetes or atherosclerosis may have higher deleterious levels of oxidants. Therefore, fine control of oxidants is required to stimulate vascularization in the limb muscle. Oxidants transduce cellular signaling through oxidative modifications of redox sensitive cysteine thiols. Of particular importance, the reversible modification with abundant glutathione, called S-glutathionylation (or GSH adducts), is relatively stable and alters protein function including signaling, transcription, and cytoskeletal arrangement. Glutaredoxin-1 (Glrx) is an enzyme which catalyzes reversal of GSH adducts, and does not scavenge oxidants itself. Glrx may control redox signaling under fluctuation of oxidants levels. In ischemic muscle increased GSH adducts through Glrx deletion improves in vivo limb revascularization, indicating endogenous Glrx has anti-angiogenic roles. In accordance, Glrx overexpression attenuates VEGF signaling in vitro and ischemic vascularization in vivo. There are several Glrx targets including HIF-1α which may contribute to inhibition of vascularization by reducing GSH adducts. These animal studies provide a caution that excess antioxidants may be counter-productive for treatment of ischemic limbs, and highlights Glrx as a potential therapeutic target to improve ischemic limb vascularization.



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Antiangiogenic Therapy in Gastroesophageal Cancer

Publication date: June 2017
Source:Hematology/Oncology Clinics of North America, Volume 31, Issue 3
Author(s): Zhaohui Jin, Harry H. Yoon

Teaser

Antiangiogenesis therapy is one of only 2 biologically targeted approaches shown to improve overall survival over standard of care in advanced adenocarcinoma of the stomach or gastroesophageal junction (GEJ). Therapeutic targeting of vascular endothelial growth factor receptor 2 improves overall survival in patients with previously treated advanced gastric/GEJ adenocarcinoma. No antiangiogenesis therapy has demonstrated an overall survival benefit in patients with chemo-naïve or resectable esophagogastric cancer or in patients whose tumors arise from the esophagus. Promising ongoing clinical investigations include the combination of antiangiogenesis therapy with immune checkpoint inhibition and anti–human epidermal growth factor receptor 2 therapy.


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