Respiratory sinus arrhythmia: Modeling longitudinal change from 6 weeks to 2 years of age among low-income Mexican Americans

Abstract

Parasympathetically-mediated heart rate variability (HRV), commonly indexed via respiratory sinus arrhythmia (RSA), is theorized to support the physiological regulation of emotion; however, little is known about the trajectory of change in resting RSA across early development among high-risk populations for whom emotion regulation is crucial. This study characterized resting RSA change from 6 weeks to 2 years of age among 312 low-income Mexican American infants. RSA was assessed longitudinally at 6, 12, 18, 24, 52, 78, and 104 weeks of age. On average, resting RSA increased as infants aged, and this change accelerated over time. There was significant variance between infants in resting RSA at 6 weeks of age, and in the slope, and acceleration of resting RSA change. Intraclass correlation among infants' resting RSA measures was minimal, indicating that resting RSA may not be "trait-like" during infancy. Results characterize early RSA development among a high-risk sample, which can inform theoretical understanding of the development of emotional, and behavioral self-regulation in a high-risk population, as well as efforts to promote wellbeing across early childhood.

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Effect of carpal tunnel release on median nerve epineurial flux

Publication date: Available online 29 November 2017
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Zofia Bochen, Magdalena Murawska, Bartlomiej H. Noszczyk




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Medikamentöse Therapie neuroendokriner Neoplasien des Gastrointestinaltrakts

Zusammenfassung

Hintergrund

Neuroendokrine Neoplasien (NEN) des Verdauungstrakts stellen eine seltene und heterogene Gruppe von Tumorerkrankungen dar. Dies erschwert die Vorgabe einheitlicher Therapieschemata.

Ziel

Die aktuelle Datenlage zur medikamentösen Therapie gastrointestinaler NEN soll dargestellt werden.

Methoden

Diskussion publizierter Studien und Expertenempfehlungen zur medikamentösen Therapie von gastroenteropankreatischen neuroendokrinen Neoplasien (GEP-NEN)

Ergebnisse

Wichtigstes therapeutisches Prinzip ist die komplette chirurgische Tumorentfernung. Ist diese nicht möglich, erfolgt die Therapie in der Regel multimodal und multidisziplinär und orientiert sich an der Tumorentität, dem individuellen Spontanverlauf sowie der Beschwerdesymptomatik. Bei Vorliegen eines spezifischen klinischen Hormonsyndroms sind langwirksame Somatostatinanaloga (SSA) die Therapie der Wahl. Sie stellen auch die Grundlage der antiproliferativen Therapie gut differenzierter gastroenteropankreatischer neuroendokriner Tumoren (GEP-NET) dar. Bei ausreichender Somatostatinrezeptor-Expression des Tumors steht als systemische Therapieoption die Peptidradiorezeptortherapie (PRRT) zur Verfügung. Bei gering differenzierten neuroendokrinen Karzinomen und NET des Pankreas stellen Platin- bzw. Streptozotocin-basierte Chemotherapien eine wichtige Therapieoption dar. Der Multityrosinkinaseinhibitor Sunitinib und der mTOR-Inhibitor Everolimus sind für die Behandlung pankreatischer NET zugelassen, Everolimus zudem auch für gastrointestinale NEN.

Schlussfolgerungen

Zur Behandlung von GEP-NEN stehen eine Reihe effektiver therapeutischer Optionen zur Verfügung. Die Entscheidung für ein Therapiekonzept sollte individuell im Rahmen eines in der Behandlung dieser Tumoren erfahrenen interdisziplinären Tumorboards festgelegt werden.

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Medikamentöse Therapie neuroendokriner Neoplasien des Gastrointestinaltrakts

Zusammenfassung

Hintergrund

Neuroendokrine Neoplasien (NEN) des Verdauungstrakts stellen eine seltene und heterogene Gruppe von Tumorerkrankungen dar. Dies erschwert die Vorgabe einheitlicher Therapieschemata.

Ziel

Die aktuelle Datenlage zur medikamentösen Therapie gastrointestinaler NEN soll dargestellt werden.

Methoden

Diskussion publizierter Studien und Expertenempfehlungen zur medikamentösen Therapie von gastroenteropankreatischen neuroendokrinen Neoplasien (GEP-NEN)

Ergebnisse

Wichtigstes therapeutisches Prinzip ist die komplette chirurgische Tumorentfernung. Ist diese nicht möglich, erfolgt die Therapie in der Regel multimodal und multidisziplinär und orientiert sich an der Tumorentität, dem individuellen Spontanverlauf sowie der Beschwerdesymptomatik. Bei Vorliegen eines spezifischen klinischen Hormonsyndroms sind langwirksame Somatostatinanaloga (SSA) die Therapie der Wahl. Sie stellen auch die Grundlage der antiproliferativen Therapie gut differenzierter gastroenteropankreatischer neuroendokriner Tumoren (GEP-NET) dar. Bei ausreichender Somatostatinrezeptor-Expression des Tumors steht als systemische Therapieoption die Peptidradiorezeptortherapie (PRRT) zur Verfügung. Bei gering differenzierten neuroendokrinen Karzinomen und NET des Pankreas stellen Platin- bzw. Streptozotocin-basierte Chemotherapien eine wichtige Therapieoption dar. Der Multityrosinkinaseinhibitor Sunitinib und der mTOR-Inhibitor Everolimus sind für die Behandlung pankreatischer NET zugelassen, Everolimus zudem auch für gastrointestinale NEN.

Schlussfolgerungen

Zur Behandlung von GEP-NEN stehen eine Reihe effektiver therapeutischer Optionen zur Verfügung. Die Entscheidung für ein Therapiekonzept sollte individuell im Rahmen eines in der Behandlung dieser Tumoren erfahrenen interdisziplinären Tumorboards festgelegt werden.

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BranchAnalysis2D/3D automates morphometry analyses of branching structures

Publication date: 15 January 2018
Source:Journal of Neuroscience Methods, Volume 294
Author(s): Aditya Srinivasan, Jesús Muñoz-Estrada, Justin R. Bourgeois, Julia W. Nalwalk, Kevin M. Pumiglia, Volney L. Sheen, Russell J. Ferland
BackgroundMorphometric analyses of biological features have become increasingly common in recent years with such analyses being subject to a large degree of observer bias, variability, and time consumption. While commercial software packages exist to perform these analyses, they are expensive, require extensive user training, and are usually dependent on the observer tracing the morphology.New methodTo address these issues, we have developed a broadly applicable, no-cost ImageJ plugin we call 'BranchAnalysis2D/3D', to perform morphometric analyses of structures with branching morphologies, such as neuronal dendritic spines, vascular morphology, and primary cilia.ResultsOur BranchAnalysis2D/3D algorithm allows for rapid quantification of the length and thickness of branching morphologies, independent of user tracing, in both 2D and 3D data sets.Comparison with existing methodsWe validated the performance of BranchAnalysis2D/3D against pre-existing software packages using trained human observers and images from brain and retina. We found that the BranchAnalysis2D/3D algorithm outputs results similar to available software (i.e., Metamorph, AngioTool, Neurolucida), while allowing faster analysis times and unbiased quantification.ConclusionsBranchAnalysis2D/3D allows inexperienced observers to output results like a trained observer but more efficiently, thereby increasing the consistency, speed, and reliability of morphometric analyses.



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Sequence-Specific DNA Recognition with Designed Peptides

Inspired by natural transcription factors (TFs), researchers have explored the potential of artificial peptides for the recognition of specific DNA sequences, developing increasingly sophisticated systems that not only display excellent DNA binding properties, but also are endowed with new properties not found in their natural counterparts. Here we review some of the developments in the field of artificial peptide-based DNA binders, focusing on the supramolecular and molecular design aspects of such systems.

Researchers have for many years tried to develop sequence-specific DNA-binding peptides that can reproduce the recognition properties of natural transcription factors. We present a historical perspective of those efforts from a supramolecular perspective.

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Hexafluoroisopropanol and Acetyl Chloride Promoted Catalytic Hydroarylation with Phenols

We report a catalytic hydroarylation method to convert phenols to dihydrocoumarins in hexafluoroisopropanol (HFIP) using acid generated from sub-stoichiometric amounts of acetyl chloride as catalyst. Attractive elements include easy set-up and isolation, and applicability to a range of phenols including natural product substrates.

HFIP facilitates the mild catalytic hydroarylation of phenols to provide dihydrocoumarins using sub-stoichiometric amounts of acetyl chloride as catalyst.

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Implementing noninvasive follicular thyroid neoplasm with papillary-like nuclear features may potentially impact the risk of malignancy for thyroid nodules categorized as AUS/FLUS and FN/SFN

Background

Noninvasive encapsulated follicular variant of papillary thyroid carcinoma (PTC) has recently been reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Implementation of the new terminology may alter the implied risk of malignancy (ROM) across the six categories of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC).

Methods

The study cohort consisted of thyroid fine needle aspiration (FNA) cases which were assessed between January 2011 and June 2016 and led to surgical resections. For each case, patient demographics as well as cytologic and corresponding histologic diagnoses were recorded. The surgical specimens diagnosed as follicular variant of PTC (FVPTC) were re-reviewed to identify cases that met the diagnostic criteria for NIFTP. The ROM with and without exclusion of NIFTP from malignant categorization, as well as the relative change in ROM were calculated for individual categories of TBSRTC.

Results

A total of 908 FNA cases with surgical follow-up were retrieved and PTC was identified in 252 (27.8%) surgical specimens. Twenty-nine of 252 (11.5%) were initially classified as FVPTC, of which 17 (6.7%) were reclassified as NIFTP. The cytologic interpretations for the majority of NIFTP cases were atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS, n = 8) or follicular neoplasm/suspicious for neoplasm/(FN/SFN, n = 4). Excluding NIFTP from malignant categorization resulted in a relative decrease in ROM in AUS/FLUS (25.8%) and FN/SFN (22.3%) categories.

Conclusion

Our institutional data demonstrates that eliminating NIFTP from malignant categorization may result in a reduction of the implied ROM for AUS/FLUS and FN/SFN categories.

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Primary cutaneous mucoepidermal carcinoma

Mucoepidermal carcinoma (MEC) is a tumour having mixed components of mucus secreting and epidermoid cells. Salivary glands are the the most common site of origin. Primary cutaneous MEC is a rare presentation. We report a primary cutaneous MEC in a 98-year-old woman presenting a noduloulcerative lesion over the dorsum of the nose. Histopathology of the tumour showed nests of epidermoid cells with glandular differentiation and mucin production. The diagnosis was confirmed by immunohistochemistry.

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Systemic thrombolysis in a patient with massive pulmonary embolism and recent glioblastoma multiforme resection

While trials of systemic thrombolysis for submassive and massive pulmonary embolism (PE) report intracranial haemorrhage (ICH) rates of 2%–3%, the risk of ICH in patients with recent brain surgery or intracranial neoplasm is unknown since these patients were excluded from these trials. We report a case of massive PE treated with systemic thrombolysis in a patient with recent neurosurgery for an intracranial neoplasm. We discuss the risks and benefits of systemic thrombolysis for massive PE in the context of previous case reports, prior cohort studies and trials, and current guidelines. There may be times when the immediate risk of death from massive PE outweighs the risk of ICH from systemic thrombolysis, even when guideline-listed major contraindications exist. This case provides an example of how the haemodynamic benefit of systemic thrombolysis outweighed the impact of ICH in a patient who had undergone recent neurosurgical resection of a glioblastoma multiforme tumour.

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Lyric hearing aid: a rare cause of benign necrotising otitis externa/external ear canal cholesteatoma

An 80-year-old Caucasian man presented with an incidental and asymptomatic lesion in his right ear thought to be secondary to his use of hearing aids for presbycusis. He used Lyric hearing aids, designed for 24 hours-a-day use for 4 months at a time and had no other previous otological problems. He underwent a bony meatoplasty and vascular flap reconstruction via a retroauricular approach to remove the lesion for histological analysis and regrafting of the area. The lesion was confirmed on histopathology as an ear canal cholesteatoma.

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Primary cutaneous mucoepidermal carcinoma

Mucoepidermal carcinoma (MEC) is a tumour having mixed components of mucus secreting and epidermoid cells. Salivary glands are the the most common site of origin. Primary cutaneous MEC is a rare presentation. We report a primary cutaneous MEC in a 98-year-old woman presenting a noduloulcerative lesion over the dorsum of the nose. Histopathology of the tumour showed nests of epidermoid cells with glandular differentiation and mucin production. The diagnosis was confirmed by immunohistochemistry.

http://ift.tt/2By0S71

Lyric hearing aid: a rare cause of benign necrotising otitis externa/external ear canal cholesteatoma

An 80-year-old Caucasian man presented with an incidental and asymptomatic lesion in his right ear thought to be secondary to his use of hearing aids for presbycusis. He used Lyric hearing aids, designed for 24 hours-a-day use for 4 months at a time and had no other previous otological problems. He underwent a bony meatoplasty and vascular flap reconstruction via a retroauricular approach to remove the lesion for histological analysis and regrafting of the area. The lesion was confirmed on histopathology as an ear canal cholesteatoma.

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Follicular bronchiolitis in an HIV-infected individual on combination antiretroviral therapy with low CD4+ cell count but sustained viral suppression

A 36-year-old Danish man, living in Asia, was diagnosed with Pneumocystis pneumonia (PCP) and HIV in 2013 (CD4+ count: 6 cells/µL; viral load: 518 000 copies/mL). He initiated combination antiretroviral therapy. Later that year, he was also diagnosed with granulomatosis with polyangiitis and was treated with prednisolone. Despite complete viral suppression and increasing CD4+ count (162 cells/µL), he was readmitted with PCP in April 2015. Subsequently, he returned to Denmark (CD4+ count: 80 cells/µL, viral suppression). Over the following months, he developed progressive dyspnoea. Lung function tests demonstrated severely reduced lung capacity with an obstructive pattern and a moderately reduced diffusion capacity. High resolution computer tomography revealed minor areas with tree-in-bud pattern and no signs of air trapping on expiratory views. Lung biopsy showed lymphocytic infiltration surrounding the bronchioles with sparing of the alveolar septa. He was diagnosed with follicular bronchiolitis. The patient spontaneously recovered along with an improvement of the immune system.

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Cu6S6 clusters as a building block for the stabilization of coordination polymers with NiAs, NaCl and related structures: synthesis, structure and catalytic studies

New three-dimensional heterometallic coordination polymers (CPs), [{Zn3(Hen)(OH)}{Cu6(6-mna)6}.(H2O)6], (I), [{Zn2(OH)(en)}{Cu6(6-mna)6}0.5.(H2O)2.EtOH], (II), [{Zn3(dap)3(H2O)} {Cu6(6-mna)6}.(H2O)4], (III) and [{Zn2(4,4'-bpy)0.5(OH)(H2O)}{Cu6(6-mna)6}0.5.(H2O)], (IV), (en = ethylenediamine, 6-H2mna = 6-mercaptonicotinic acid, dap = 1,2-diamino propane, 4,4'-bpy = 4,4'- bipyridine), were synthesized and their structures determined by single crystal X-ray crystallography. The structures of the compounds have Cu6S6 octahedral clusters linked through the carboxylates with different zinc-oxo clusters. The compounds have CuI based clusters and ZnII based clusters, which are not observed commonly in coordination polymer structures. Compound I stabilizes in NiAs-related structure, compound II and IV in a NaCl related structure and compound III forms a new type of network structure. All the compounds were active for the heterogeneous nitroaldol reaction.

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Relevance of genetic relationship in GWAS and genomic prediction

Abstract

The objective of this study was to analyze the relevance of relationship information on the identification of low heritability quantitative trait loci (QTLs) from a genome-wide association study (GWAS) and on the genomic prediction of complex traits in human, animal and cross-pollinating populations. The simulation-based data sets included 50 samples of 1000 individuals of seven populations derived from a common population with linkage disequilibrium. The populations had non-inbred and inbred progeny structure (50 to 200) with varying number of members (5 to 20). The individuals were genotyped for 10,000 single nucleotide polymorphisms (SNPs) and phenotyped for a quantitative trait controlled by 10 QTLs and 90 minor genes showing dominance. The SNP density was 0.1 cM and the narrow sense heritability was 25%. The QTL heritabilities ranged from 1.1 to 2.9%. We applied mixed model approaches for both GWAS and genomic prediction using pedigree-based and genomic relationship matrices. For GWAS, the observed false discovery rate was kept below the significance level of 5%, the power of detection for the low heritability QTLs ranged from 14 to 50%, and the average bias between significant SNPs and a QTL ranged from less than 0.01 to 0.23 cM. The QTL detection power was consistently higher using genomic relationship matrix. Regardless of population and training set size, genomic prediction provided higher prediction accuracy of complex trait when compared to pedigree-based prediction. The accuracy of genomic prediction when there is relatedness between individuals in the training set and the reference population is much higher than the value for unrelated individuals.

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Randomized Split-face, Controlled Comparison of Treatment with 1565 nm Non-ablative Fractional Laser for Enlarged Facial Pores

Abstract

Enlarged pores are common cosmetic concerns¹. Though non-ablative fractional lasers (NAFLs) have been used reducing enlarged facial pores, a prospective, split-face, controlled study with objective assessment is still in blank. 1,565 nm NAFL (M22 ^™ ResurFX^™, Lumenis^® Ltd, Yokneam, Israel), proved effective on skin elasticity and stretch marks², was further aimed to assess for its safety and efficacy on enlarged facial pores.

This article is protected by copyright. All rights reserved.

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Implementing near real-time vaccine safety surveillance using the Clinical Practice Research Datalink (CPRD)

Publication date: 14 December 2017
Source:Vaccine, Volume 35, Issue 49, Part B
Author(s): Andreia Leite, Sara L. Thomas, Nick J. Andrews
IntroductionNear real-time vaccine safety surveillance (NRTVSS) using electronic health records is increasingly used to rapidly detect vaccine safety signals. NRTVSS has not been fully implemented in the UK. We assessed the feasibility of implementing this surveillance using the UK Clinical Practice Research Datalink (CPRD).MethodsWe selected seasonal influenza vaccine/Guillain-Barré Syndrome (GBS) as an example of a rare outcome and measles-mumps-rubella (MMR) vaccine/febrile seizures as a positive control. For influenza/GBS we implemented a system for the 2013/2014 and 2014/2015 influenza seasons; for MMR/seizures the surveillance period was July 2014–June 2015. We used the continuous Poisson-based maximized sequential probability ratio test (PMaxSPRT), comparing observed-to-expected events, for both pairs. We calculated an age-sex-adjusted rate using 5years of historic data and used this rate to calculate the expected number of events in pre-specified post-vaccination risk-window (GBS: 0–42days, seizures: 6–21days). For MMR/seizures we also implemented the system using the Binominal-based maximized sequential probability ratio test (BMaxSPRT). For this, we compared seizures in the risk-window (6–21days) to a control window (0–5 and 22–32days). Delays in recording outcomes influence the data available, so we adjusted the expected number of events using a historical distribution of delays in recording GBS/febrile seizures. Analyses were run using data up to each CPRD monthly release. We also performed power calculations for detecting increases in relative risk (RR) from 1.5 to 10.ResultsFor influenza/GBS we implemented a system in both seasons with no signal. Power to detect a signal was >80% for RR≥4. For MMR/seizures we were able to identify a signal with PMaxSPRT but not with BMaxSPRT. Power≥80% for RR≥2.5 for both tests.ConclusionCPRD is a potential data source to implement NRTVSS to exclude large increases in the risk of rare outcomes after seasonal influenza and lower increases in risk for more frequent outcomes.



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Editorial Board/Aims and Scope

Publication date: 14 December 2017
Source:Vaccine, Volume 35, Issue 49, Part B





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Attitudes about vaccines to prevent Ebola virus disease in Guinea at the end of a large Ebola epidemic: Results of a national household survey

Publication date: 14 December 2017
Source:Vaccine, Volume 35, Issue 49, Part B
Author(s): Kathleen L. Irwin, Mohamed F. Jalloh, Jamaica Corker, Barry Alpha Mahmoud, Susan J. Robinson, Wenshu Li, Nyuma E. James, Musa Sellu, Mohammad B. Jalloh, Alpha Ahmadou Diallo, LaRee Tracy, Rana Hajjeh, Amanda VanSteelandt, Rebecca Bunnell, Lise Martel, Pratima L. Raghunathan, Barbara Marston
IntroductionIn 2014–2016, an Ebola epidemic devastated Guinea; more than 3800 cases and 2500 deaths were reported to the World Health Organization. In August 2015, as the epidemic waned and clinical trials of an experimental, Ebola vaccine continued in Guinea and neighboring Sierra Leone, we conducted a national household survey about Ebola-related knowledge, attitudes, and practices (KAP) and opinions about "hypothetical" Ebola vaccines.MethodsUsing cluster-randomized sampling, we selected participants aged 15+ years old in Guinea's 8 administrative regions, which had varied cumulative case counts. The questionnaire assessed socio-demographic characteristics, experiences during the epidemic, Ebola-related KAP, and Ebola vaccine attitudes. To assess the potential for Ebola vaccine introduction in Guinea, we examined the association between vaccine attitudes and participants' characteristics using categorical and multivariable analyses.ResultsOf 6699 persons invited to participate, 94% responded to at least 1 Ebola vaccine question. Most agreed that vaccines were needed to fight the epidemic (85.8%) and that their family would accept safe, effective Ebola vaccines if they became available in Guinea (84.2%). These measures of interest and acceptability were significantly more common among participants who were male, wealthier, more educated, and lived with young children who had received routine vaccines. Interest and acceptability were also significantly higher among participants who understood Ebola transmission modes, had witnessed Ebola response teams, knew Ebola-affected persons, believed Ebola was not always fatal, and would access Ebola treatment centers. In multivariable analyses of the majority of participants living with young children, interest and acceptability were significantly higher among those living with vaccinated children than among those living with unvaccinated children.DiscussionThe high acceptability of hypothetical vaccines indicates strong potential for introducing Ebola vaccines across Guinea. Strategies to build public confidence in use of Ebola vaccines should highlight any similarities with safe, effective vaccines routinely used in Guinea.



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Ethics, pregnancy, and ZIKV vaccine research & development

Publication date: 14 December 2017
Source:Vaccine, Volume 35, Issue 49, Part B
Author(s): The Ethics Working Group on ZIKV Research and PregnancyRuth R.FadenCarleigh B.KrubinerAnne D.LyerlyMargaret O.LittleAllisonAugustRichard H.BeigiAnna P.DurbinRuth A.KarronNancy E.KassFlorenciaLunaRicardoPalaciosAlexander RobertoPreciosoCarlaSaenzJeanne S.SheffieldBeatrizThoméCorresponding author.




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Randomized Split-face, Controlled Comparison of Treatment with 1565 nm Non-ablative Fractional Laser for Enlarged Facial Pores

Abstract

Enlarged pores are common cosmetic concerns¹. Though non-ablative fractional lasers (NAFLs) have been used reducing enlarged facial pores, a prospective, split-face, controlled study with objective assessment is still in blank. 1,565 nm NAFL (M22 ^™ ResurFX^™, Lumenis^® Ltd, Yokneam, Israel), proved effective on skin elasticity and stretch marks², was further aimed to assess for its safety and efficacy on enlarged facial pores.

This article is protected by copyright. All rights reserved.

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Identification of a novel compound targeting the nuclear export of influenza A virus nucleoprotein

Abstract

Although antiviral drugs are available for the treatment of influenza infection, it is an urgent requirement to develop new antiviral drugs regarding the emergence of drug-resistant viruses. The nucleoprotein (NP) is conserved among all influenza A viruses (IAVs) and has no cellular equivalent. Therefore, NP is an ideal target for the development of new IAV inhibitors. In this study, we identified a novel anti-influenza compound, ZBMD-1, from a library of 20,000 compounds using cell-based influenza A infection assays. We found that ZBMD-1 inhibited the replication of H1N1 and H3N2 influenza A virus strains in vitro, with an IC₅₀ ranging from 0.41–1.14 μM. Furthermore, ZBMD-1 inhibited the polymerase activity and specifically impaired the nuclear export of NP. Further investigation indicated that ZBMD-1 binds to the nuclear export signal 3 (NES3) domain and the dimer interface of the NP pocket. ZBMD-1 also protected mice that were challenged with lethal doses of A/PR/8/1934 (H1N1) virus, effectively relieving lung histopathology changes, as well as strongly inhibiting the expression of pro-inflammatory cytokines/chemokines, without inducing toxicity effects in mice. These results suggest that ZBMD-1 is a promising anti-influenza compound which can be further investigated as a useful strategy against IAVs in the future.

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Exercise Alters Gut Microbiota Composition and Function in Lean and Obese Humans

PURPOSE Exercise is associated with altered gut microbial composition, but studies have not investigated whether the gut microbiota and associated metabolites are modulated by exercise training in humans. We explored the impact of six weeks of endurance exercise on the composition, functional capacity, and metabolic output of the gut microbiota in lean and obese adults with multiple-day dietary controls prior to outcome variable collection. METHODS Thirty-two lean (n=18 [9 female]) and obese (n=14 [11 female]), previously sedentary subjects participated in six weeks of supervised, endurance-based exercise training (3 days/wk) that progressed from 30 to 60 minutes/day and from moderate (60% of heart rate reserve [HRR]) to vigorous intensity (75% HRR). Subsequently, participants subsequently returned to a sedentary lifestyle activity for a six week washout period. Fecal samples were collected before and after six weeks of exercise, as well as after the sedentary washout period, with 3-day dietary controls in place prior to each collection. RESULTS β-diversity analysis revealed that exercise-induced alterations of the gut microbiota were dependent on obesity status. Exercise increased fecal concentrations of short chain fatty acids (SCFAs) in lean, but not obese, participants. Exercise-induced shifts in metabolic output of the microbiota paralleled changes in bacterial genes and taxa capable of SCFA production. Lastly, exercise-induced changes in the microbiota were largely reversed once exercise training ceased. CONCLUSION These findings suggest that exercise training induces compositional and functional changes in the human gut microbiota that are dependent on obesity status, independent of diet and contingent on the sustainment of exercise. Corresponding Author: Jeffrey A. Woods, PhD, 906 S. Goodwin Ave., 348 Louise Freer Hall, University of Illinois at Urbana-Champaign, Urbana IL 61801, Woods1@illinois.edu, 217-244-8815 This work was partially funded by a doctoral student research grant from the American College of Sports Medicine (ACSM). Authors have no professional relationships with companies or manufacturers who will benefit from the results of the present study. Results of the present study do not constitute endorsement by ACSM. Results of the study are presented clearly, honestly and without fabrication, falsification, or inappropriate data manipulation. Accepted for Publication: 6 November 2017 © 2017 American College of Sports Medicine

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Adipose Lipolysis Unchanged by Preexercise Carbohydrate regardless of Glycemic Index

ABSTRACT PURPOSE To determine the impact of pre-exercise carbohydrate of different glycemic indices on subcutaneous abdominal adipose tissue (SCAAT) metabolism and running performance. METHODS Ten trained male runners completed three experimental trials consisting of 30 min at 60% VO2max, 30 min at 75% VO2max, and a 5-km time trial (TT). Thirty min prior to exercise, participants consumed one of three beverages: 1) 75 g low glycemic index modified starch supplement (UCAN), 2) 75 g high glycemic index glucose-based supplement (G), or 3) a flavor-matched non-caloric placebo (PL). SCAAT lipolysis was assessed via microdialysis. RESULTS Prior to exercise, blood glucose and insulin were elevated with G vs. PL (+53.0 ± 21.3 mg[BULLET OPERATOR]dL-1 [SD]; p

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Biological/Genetic Regulation of Physical Activity Level: Consensus from GenBioPAC

ABSTRACT PURPOSE Physical activity unquestionably maintains and improves health; however, physical activity levels globally are low and not rising despite all the resources devoted to this goal. Attention in both the research literature and the public policy domain has focused on social-behavioral factors; however, a growing body of literature suggests that biological determinants play a significant role in regulating physical activity levels. For instance, physical activity level, measured in various manners, has a genetic component in both humans and non-human animal models. This consensus paper, developed as a result of an ACSM-sponsored round table, provides a brief review of the theoretical concepts and existing literature that supports a significant role of genetic and other biological factors in the regulation of physical activity. CONCLUSION Future research on physical activity regulation should incorporate genetics and other biological determinants of physical activity instead of a sole reliance on social and other environmental determinants. Corresponding Author: J. Timothy Lightfoot, Department of Health and Kinesiology, Texas A&M University, College Station, TX, TLightfoot@tamu.edu The results of the present study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Funding: The authors would like to thank the organizations that provided supporting funds for this Roundtable: The American College of Sports Medicine, The Texas A&M Vice-President of Research office, the Texas A&M Institute for Genome Sciences and Society, The Sydney and JL Huffines Institute of Sports Medicine and Human Performance, and the Omar Smith Endowment. T.G. is supported by NIH/NICHD R21HD084856 and NSF DEB-1655362. M.dH. is supported by project grants from the Swedish Research Council (2015-03657), the Swedish Heart-Lung Foundation (20140543), and NIH (R01DK106236). J.K. is an Academy of Finland funded Research Professor (grants #265240, 263278). Conflict of Interest: The authors report no conflict of interest. The results of the present study do not constitute endorsement by the American College of Sports Medicine. Accepted for Publication: 14 November 2017 © 2017 American College of Sports Medicine

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Strength, Affect Regulation, and Subcortical Morphology in Military Pilots

Introduction Previous studies have shown links of body composition and fitness measures with brain structure, as well as with different aspects of emotional adjustment and well-being. However, the possible role of trait emotion-regulation success in the relationship between fitness/body composition and emotion-related subcortical structures have never been directly addressed Methods 23 elite helicopter pilots were assessed in fat mass percentage, an endurance test to volitional exhaustion, bench-press power output, and negative urgency (trait affect regulation failure). Their brains were scanned using magnetic resonance imaging (MRI) to estimate the size of the accumbens/amygdala complex and the thalamus. Resulting correlations were used to test the relationship between body composition/fitness measures and brain structures' size, and the role of negative urgency therein, using structural equation modelling. Results Fat mass percentage was associated with the size of the thalamus and the amygdala/accumbens complex. In the latter case, negative urgency and bench-press power output predicted structure size (and explained the effect of fat mass percentage away). In other words, bench-press power output and emotion regulation success (but not endurance performance) were associated with a larger amygdala-accumbens size. Conclusion Bench-press power output and emotion regulation success are independently associated with a larger amygdala-accumbens size, although present evidence does not allow determination of causal directionality. Corresponding author: David Cárdenas, Department of Physical Education and Sport, Faculty of Sport Sciences, University of Granada, Carretera de Alfacar s/n, 18011 Granada, Spain. Tel: +34 958244375. Fax: +34 958244369. E-mail: dcardena@ugr.es Research by the first author is funded by a Spanish Ministry of Economy and Competitiveness grant (State Secretariat for Research, Development and Innovation Secretary DEP2013-48211-R), and grant PIN 11 from CEMIX (Centro Mixto UGR-MADOC, Spain). Research by the fourth author is supported by the Spanish Government (Ministerio de Economía y Competitividad, Secretaría de Estado de Invetigación, Desarrollo e Innovación; Convocatoria 2013 de Proyectos I+D de Excelencia), under grant with reference number PSI2013-45055-P (G-Brain). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. No conflicting financial, consultant, institutional, or other interests exist. Results of the present study do not constitute endorsement by the American College of Sports Medicine. Accepted for Publication: 12 November 2017 © 2017 American College of Sports Medicine

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Cardiometabolic Impact of Changing Sitting, Standing, and Stepping in the Workplace

ABSTRACT Background According to cross-sectional and acute experimental evidence, reducing sitting time should improve cardio-metabolic health risk biomarkers. Furthermore, the improvements obtained may depend on whether sitting is replaced with standing or ambulatory activities. Based on data from the Stand Up Victoria multi-component workplace intervention, we examined this issue using compositional data analysis — a method that can examine and compare all activity changes simultaneously. Methods Participants receiving the intervention (n=136 ≥0.6 full-time equivalent desk-based workers, 65% women, mean±SD age=44.6 ±9.1 years from seven worksites) were asked to improve whole-of-day activity by standing up, sitting less and moving more. Their changes in the composition of daily waking hours (activPAL-assessed sitting, standing, stepping) were quantified, then tested for associations with concurrent changes in cardio-metabolic risk (CMR) scores and 14 biomarkers concerning body composition, glucose, insulin and lipid metabolism. Analyses were by mixed models, accounting for clustering (3 months, n=105–120; 12 months, n=80–97). Results Sitting reduction was significantly (p

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Using voltage-sensor toxins and their molecular targets to investigate NaV1.8 gating

Abstract

Voltage-gated sodium (Na_V) channel gating is a complex phenomenon which involves a distinct contribution of four integral voltage-sensing domains (VSDI, VSDII, VSDIII, and VSDIV). Utilizing accrued pharmacological and structural insights, we build on an established chimera approach to introduce animal toxin sensitivity in each VSD of an acceptor channel by transferring in portable S3b-S4 motifs from the four VSDs of a toxin-susceptible donor channel (Na_V1.2). By doing so, we observe that in Na_V1.8, a relatively unexplored channel subtype with distinctly slow gating kinetics, VSDI-III participate in channel opening whereas VSDIV can regulate opening as well as fast inactivation. These results illustrate the effectiveness of a pharmacological approach to investigate the mechanism underlying gating of a mammalian Na_V channel complex.

This article is protected by copyright. All rights reserved

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SoftHand at the CYBATHLON: a user’s experience

Roughly one-quarter of upper limb prosthesis users reject their prosthesis. Reasons for rejection range from comfort, to cost, aesthetics, function, and more. This paper follows a single user from training wit...

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Anti-tumour necrosis factor-α antibodies and B cell homeostasis in human inflammatory bowel diseases

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): Caterina Defendenti, Fabiola Atzeni, Sergio Malandrin, Sandro Ardizzone, Piero Luigi Almasio, Simone Saibeni, Cristina Bezzio, Simona Bollani, Raffaele Salerno, Paolo Declich, Zoe Sarno, Savino Bruno, Rossella Talotta, Piercarlo Sarzi-Puttini
BackgroundThe expression of CD70 on T cells is greatly enhanced by antigen-presenting cell (APC)-associated signals, such as tumour necrosis factor(TNF)-α, which is constitutionally high in patients with inflammatory bowel disease (IBD). Experimentally, the chronic activation of CD27 as a result of the constitutive expression of CD70 leads to the demise of B cells in bone marrow (BM) and the secondary lymphoid organs. The aim of this study was to assess the number and phenotype of circulating B cell in untreated IBD patients and their counterparts treated with biological anti-TNF drugs.MethodsThe study involved 13 untreated IBD patients, 36 IBD patients treated with biological drugs, and 10 healthy controls. The B cell phenotypes were assessed by means of flow cytometry using monoclonal antibodies specific for CD20, CD19, CD3, CD27 and CD43. In order to evaluate B cell development in bone marrow and peripheral B cell activation, we identified four B cell subsets: hematogones (HBs: CD20⁺19⁺3⁻27⁻43⁺), memory B cells (MBs: CD20⁺19⁺3⁻27⁺43⁻), pre-plasmablasts (PPBs: CD20⁺19⁺3⁻27⁺43⁺), and plasmablasts (PBs: CD20⁻19⁺3⁻27⁺43⁺).ResultsThe total number of B cells in the untreated patients was three times lower than that in the patients treated with biological drug (p<0.001), and half that in the healthy controls (p=0.03). The between-group differences (including the healthy donors) were statistically significant in the case of HBs and MBs, but not in the case of PPBs and PBs. Only one treated patient showed a transiently large increase in PPBs. There were statistically significant differences in all of the parameters between the untreated patients and those receiving biological therapy, and in some cases between the untreated patients and healthy controls, but never between the controls and the treated patients. Four non-responders to anti-TNF therapy had a smaller number of total circulating B cells than the untreated patients.ConclusionsAnti-TNF drugs disinhibit B cell production in IBD patients, but maintain the constant homeostasis of circulating B cells. The presence of individual variations may allow the activity of anti-TNF drugs to be monitored by studying B cell subgroups.



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Chemical characterization of PM 2.5 collected from a rural coastal island of the Bay of Bengal (Bhola, Bangladesh)

Abstract

This work focuses on the chemical characterization of fine aerosol particles (PM_2.5) collected from a rural remote island of the Bay of Bengal (Bhola, Bangladesh) from April to August, 2013. PM_2.5 particle-loaded filters were analyzed for organic carbon (OC), elemental carbon (EC), water-soluble ions, and selected saccharides (levoglucosan, mannosan, galactosan, arabitol, and mannitol). The average PM_2.5 mass was 15.0 ± 6.9 μg m⁻³. Organic carbon and elemental carbon comprised roughly half of the analyzed components. Organic carbon was the predominant contributor to total carbon (TC) and accounting for about 28% of PM_2.5 mass. Secondary organic carbon (SOC) was inferred to be ~ 26% of OC. The sum of ions comprised ~ 27% of PM_2.5 mass. The contribution of sea salt aerosol was smaller than expected for a sea-near site (17%), and very high chloride depletion was observed (78%). NssSO₄²⁻ was a dominant ionic component with an average concentration of 2.0 μg m⁻³ followed by Na⁺, NH₄⁺, and nssCa²⁺. The average concentration of arabitol and mannitol was 0.11 and 0.14 μg m⁻³, respectively, while levoglucosan and its stereoisomers (mannosan and galactosan) were bellow detection limit. NH₄⁺/SO₄²⁻ equivalent ratio was 0.30 ± 0.13 indicating that secondary inorganic aerosol is not the main source of SO₄²⁻. Enrichment factor (EF) analysis showed that SO₄²⁻ and NO₃⁻ were enriched in atmospheric particles compared to sea aerosol and soil indicating their anthropogenic origin. Higher OC/EC ratio (3.70 ± 0.88) was a good indicator of the secondary organic compounds formation. Other ratios (OC/EC, K⁺/EC, nssSO₄²⁻/EC) and correlation analysis suggested mixed sources for carbonaceous components. Arabitol and mannitol both showed strong correlation with EC having R ² value 0.89 and 0.95, respectively. Air mass trajectories analysis showed that concentrations of soil and anthropogenic species were lower for air masses originating from the sea (May–August) and were higher when air came from land (April).

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Urine cell-free microRNA as biomarkers for transitional cell carcinoma

MicroRNA (miRNA) are short nucleotide strands with a regulatory function in the cell. Several miRNAs have been shown to be useful as biomarkers for different neoplasms. The aim of this project was to assess wh...

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Social media usage among health care providers

The objective of this study was to evaluate the use of social media among healthcare workers in an attempt to identify how it affects the quality of patient care.

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Experiencing physical warmth affects implicit attitudes and altruistic behavior toward outgroup in females

Experiencing physical warmth has been demonstrated to influence interpersonal warmth. However, the effects of this metaphorical link in an intergroup context is not clear. The current study aimed to investigat...

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Operational research within the national tuberculosis control programme in Benin

To document whether the placement of operational research (OR) fellows within disease control programmes in low and middle income countries leads to the implementation of operational research and improvements ...

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Polymorphism rs13334190 in zinc finger protein 469 (ZNF469) is not a risk factor for keratoconus in a Saudi cohort

Polymorphism rs13334190 in the zinc finger protein 469 gene has been suggested to predispose toward a "thin" cornea, which then becomes keratoconic or is directly pathogenic. Thus, we genotyped polymorphism rs...

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Acute Chest Syndrome: An Ongoing Challenge for Physicians Caring for Children with Sickle Cell Disease

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


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Diet, Lung Function, and Asthma Exacerbations in Puerto Rican Children

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


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Neutrophil–Lymphocyte Ratio in Children with Recurrent Wheezing

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


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Developing a Mobile Health Intervention for Low-Income, Urban Caregivers of Children with Asthma: A Pilot Study

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


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Acute Chest Syndrome: An Ongoing Challenge for Physicians Caring for Children with Sickle Cell Disease

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


http://ift.tt/2zBqZZj

Diet, Lung Function, and Asthma Exacerbations in Puerto Rican Children

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


http://ift.tt/2neFT63

Neutrophil–Lymphocyte Ratio in Children with Recurrent Wheezing

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


http://ift.tt/2zCVQF7

Developing a Mobile Health Intervention for Low-Income, Urban Caregivers of Children with Asthma: A Pilot Study

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


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Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC

Abstract

Merkel cell carcinoma (MCC) is a highly aggressive, often lethal neuroendocrine cancer. Its carcinogenesis may be either caused by the clonal integration of the Merkel cell polyomavirus into the host genome or by UV-induced mutations. Notably, virally-encoded oncoproteins and UV-induced mutations affect comparable signaling pathways such as RB restriction of cell cycle progression or p53 inactivation. Despite its low incidence, MCC recently received much attention based on its exquisite immunogenicity and the resulting major success of immune modulating therapies. Here, we summarize current knowledge on epidemiology, biology and therapy of MCC as conclusion of the project 'Immune Modulating strategies for treatment of Merkel Cell Carcinoma', which was funded over a 5-year period by the European Commission to investigate innovative immunotherapies for MCC.

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Chasing Seasonal Influenza — The Need for a Universal Influenza Vaccine

As clinicians in the United States prepare for the start of another influenza season, experts have been watching the Southern Hemisphere winter for hints of what might be in store for us in the North. Reports from Australia have caused mounting concern, with record-high numbers of…

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Chasing Seasonal Influenza — The Need for a Universal Influenza Vaccine

As clinicians in the United States prepare for the start of another influenza season, experts have been watching the Southern Hemisphere winter for hints of what might be in store for us in the North. Reports from Australia have caused mounting concern, with record-high numbers of…

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Ih Interacts with Somato-Dendritic Structure to Determine Frequency Response to Weak Alternating Electric Field Stimulation

Transcranial current stimulation (tCS) modulates brain dynamics using weak electric fields. Given the pathological changes in brain network oscillations in neurological and psychiatric illnesses, using alternating electric field waveforms that engage rhythmic activity has been proposed as a targeted, network-level treatment approach. Previous studies have investigated the effects of electric fields at the neuronal level. However, the biophysical basis of the cellular response to electric fields has remained limited. Here, we characterized the frequency-dependent response of different compartments in a layer V pyramidal neuron to exogenous electric fields to dissect the relative contributions of voltage-gated ion channels and neuronal morphology. Hyperpolarization-activated cation current (I_h) in the distal dendrites was the primary ionic mechanism shaping the model response to electric field stimulation and caused subthreshold resonance in the tuft at 20 ± 4 Hz. In contrast, subthreshold I_h-mediated resonance in response to local sinusoidal current injection was present in all model compartments at 11 ± 2 Hz. The frequencies of both resonance responses were modulated by I_h conductance density. We found that the difference in resonance frequency between the two stimulation types can be explained by the fact that exogenous electric fields simultaneously polarize the membrane potentials at the distal ends of the neuron (relative to field direction) in opposite directions. Our results highlight the role of I_h in shaping the cellular response to electric field stimulation and suggest that the common model of tCS as a weak somatic current injection fails to capture the cellular effects of electric field stimulation.

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Time course of functional recovery during first three months after surgical transection and repair of nerves to feline soleus and lateral gastrocnemius muscles

Locomotion outcomes after peripheral nerve injury and repair in cats have been described in the literature for the period immediately following the injury (muscle denervation period) and then again for an ensuing period of long-term recovery (at three months and longer) resulting in muscle self-reinnervation. Little is known about the changes in muscle activity and walking mechanics during mid-recovery, i.e. the early reinnervation period that takes place between 5 and 10 weeks of recovery. Here, we investigated hindlimb mechanics and EMG activity of ankle extensors in six cats during level and slope walking before and every two weeks thereafter in a 14-week period of recovery after the soleus (SO) and lateral gastrocnemius (LG) muscle nerves in one hindlimb were surgically transected and repaired. We found that the continued increase in SO and LG EMG magnitudes and corresponding changes in hindlimb mechanics coincided with the formation of neuromuscular synapses revealed in muscle biopsies. Throughout the recovery period, EMG magnitude of SO and LG during the stance phase and the duration of the stance-related activity were load-dependent, similar to those in the intact synergistic medial gastrocnemius and plantaris. These results and the fact that EMG activity of ankle extensors and locomotor mechanics during level and upslope walking recovered 14 weeks after nerve transection and repair suggest that loss of the stretch reflex in self-reinnervated muscles may be compensated by the recovered force-dependent feedback in self-reinnervated muscles, by increased central drive and increased gain in intermuscular motion-dependent pathways from intact ankle extensors.

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Clustering of Heading Selectivity and Perception-Related Activity in the Ventral Intraparietal Area

The ventral intraparietal area (VIP) of the macaque brain is a multimodal cortical region, with many cells tuned to both optic flow and vestibular stimuli. Responses of many VIP neurons also show robust correlations with perceptual judgments during a fine heading discrimination task. Previous studies have shown that heading tuning based on optic flow is represented in a clustered fashion in VIP. However, it is unknown whether vestibular self-motion selectivity is clustered in VIP. Moreover, it is not known whether stimulus- and choice-related signals in VIP show clustering in the context of a heading discrimination task. To address these issues, we compared the response characteristics of isolated single units (SUs) with those of the undifferentiated multiunit (MU) activity corresponding to several neighboring neurons recorded from the same microelectrode. We find that MU activity typically shows selectivity similar to that of simultaneously recorded SUs, for both the vestibular and visual stimulus conditions. In addition, the choice-related activity of MU signals, as quantified using choice-probabilities (CPs), is correlated with the choice-related activity of SUs. Overall, these findings suggest that both sensory and choice-related signals regarding self-motion are clustered in VIP.

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Complementary metrics of human auditory nerve function derived from compound action potentials

Declines in auditory nerve (AN) function contribute to suprathreshold auditory processing and communication deficits in individuals with normal hearing, hearing loss, hyperacusis, and tinnitus. Procedures to characterize AN loss or dysfunction in humans are limited. We report several novel complementary metrics using the compound action potential (CAP), a direct measure of summated AN activity. Together, these metrics may be used to characterize AN function noninvasively in humans. We examined how these metrics change with stimulus intensity, and interpreted these changes within a framework of known physiological properties of the basilar membrane and AN. Our results reveal how neural synchrony and the recruitment of AN fibers with longer first-spike latencies likely contribute to the CAP, affect auditory processing, and differ with noise exposure history in younger adults with normal pure-tone thresholds. Moving forward, this new battery of metrics provides a crucial step towards new diagnostics of AN function in humans.

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Implantable computer-controlled adaptive multi-electrode positioning system (AMEP)

Acute neuronal recordings performed with metal microelectrodes in non-human primates allow investigating the neural substrate of complex cognitive behaviors. Yet, the daily re-insertion and positioning of the electrodes prevents recording from many neurons simultaneously, limiting the suitability of these types of recordings for brain-computer-interface applications or for large-scale population statistical methods on a trial-by-trial basis. In contrast, chronically implanted multi-electrode arrays offer the opportunity to record from many neurons simultaneously, but immovable electrodes prevent optimization of the signal during and after implantation and cause the tissue response to progressively impair the transduced signal quality, thereby limiting the number of different neurons that can be recorded over the lifetime of the implant. Semi-chronically implanted matrices of electrodes, instead, allow individually movable electrodes in depth and achieve higher channel count compared to acute methods, hence partially overcome these limitations. Existing semi-chronic systems with higher channel count lack computerized control of electrode movements, leading to limited user-friendliness and uncertainty in depth-positioning. Here we demonstrate a chronically-implantable Adaptive Multi-Electrode Positioning (AMEP) system with detachable drive for computerized depth-adjustment of individual electrodes over several millimeters. This semi-chronic 16-channel system is designed to optimize the simultaneous yield of units in an extended period following implantation since the electrodes can be independently depth-adjusted with minimal effort and their signal quality continuously assessed. Importantly, the electrode array is designed to remain within a chronic recording chamber for a prolonged time, or can be used for acute recordings with high signal-to-noise ratio in the cerebral cortex of non-human primates.

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Quantitative relations between BOLD responses, cortical energetics and impulse firing

The blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal arises as a consequence of changes in blood flow (CBF) and oxygen usage (CMR$_{O_2}$) that in turn are modulated by changes in neural activity. Much attention has been given to both theoretical and experimental aspects of the energetics but not to the neural activity. Here we identify the best energetic theory for the steady-state BOLD signal on the basis of correct predictions of experimental observations. This theory is then used, together with the recently determined relationship between energetics and neural activity, to predict how the BOLD signal changes with activity. Unlike existing treatments, this new theory incorporates a non-zero baseline activity in a completely consistent way, and is thus able to account for both positive and negative BOLD signals. We also show that the increase in BOLD signal for a given increase in activity is significantly smaller the larger the baseline activity, as is experimentally observed. Furthermore, the decline of the BOLD signal arising from deeper cortical lamina in response to an increase in neural firing is shown to arise as a consequence of the larger baseline activity in deeper lamina. Finally, we provide quantitative relations integrating BOLD responses, energetics and impulse firing, which amongst other predictions, provides the same results as existing theories when the baseline activity is zero.

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Estimating properties of the fast and slow adaptive processes during sensorimotor adaptation

Experience of a prediction error recruits multiple motor learning processes: some that learn strongly from error but have weak retention, some that learn weakly from error but exhibit strong retention. These processes are not generally observable, but are inferred from their collective influence on behavior. Is there a robust way to uncover the hidden processes? A standard approach is to consider a state-space model where the hidden states change following experience of error, and then fit the model to the measured data by minimizing the squared error between measurement and model prediction. We found that this least-squares algorithm (LMSE) often yielded unrealistic predictions about the hidden states, possibly due to its neglect of the stochastic nature of error-based learning. We found that behavioral data during adaptation was better explained by a system in which both error-based learning and movement production were stochastic processes. To uncover the hidden states of learning, we developed a generalized Expectation Maximization (EM) algorithm. In simulation, we found that while LMSE tracked the measured data marginally better than EM, EM was far more accurate in unmasking the timecourses and properties of the hidden states of learning. In a power analysis designed to measure the effect of an intervention on sensorimotor learning, EM significantly reduced the number of subjects that were required for effective hypothesis testing. In summary, we developed a new approach for analysis of data in sensorimotor experiments. The new algorithm improved the ability to uncover the multiple processes that contribute to learning from error.

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Quantitative input: output relationships between human soleus muscle spindle afferents and motoneurons

A method is described which, for the first time, allows instantaneous estimation of the Ia fiber input to human soleus motoneurons following electrical stimulation of the tibial nerve. The basis of the method is to determine the thresholds of the most and least excitable 1a fibers to electrical stimulation, and to treat the intervening thresholds as having a normal distribution about the mean; the validity of this approach is discussed. It was found that, for the same Ia fibre input, the percentage of soleus motoneurons contributing to the H (Hoffmann)-reflex differed considerably among subjects; when the results were pooled, however, there was an approximately linear relationship between Ia input and motoneuron output. Weak extension of the great toe diminished the soleus motoneuron reflex discharge in all but 2 of 16 subjects; the results for weak ankle plantarflexion were less consistent but overall there was a reduction in soleus motoneuron output also. The methodology should provide new insights into disorders of movement and tone, especially as it permits estimates of motoneuron depolarization to be made.

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Effect of Sensory Attenuation on Cortical Movement-Related Oscillations

This study examined the impact of induced sensory deficits on cortical, movement-related oscillations measured using electroencephalography (EEG). We hypothesized that EEG patterns in healthy subjects with induced sensory reduction would be comparable to EEG found after chronic loss of sensory feedback. EEG signals from 64 scalp locations were measured from 10 healthy subjects. Participants dorsiflexed their ankle after prolonged vibration of the tibialis anterior (TA). Beta band time frequency decompositions were calculated using wavelets and compared across conditions. Changes in patterns of movement-related brain activity were observed following attenuation of sensory feedback. A significant decrease in beta power of event related resynchronization was associated with simple ankle dorsiflexion after prolonged vibration of the TA. Attenuation of sensory feedback in young, healthy subjects leads to a corresponding decrease in beta band synchronization. This temporary change in beta oscillations suggests that these modulations are a mechanism for sensorimotor integration. The loss of sensory feedback found in SCI patients contributes to changes in EEG signals underlying motor commands. Similar alterations in cortical signals in healthy subjects with reduced sensory feedback implies these changes reflect normal sensorimotor integration after reduced sensory input rather than brain plasticity.

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Modeling spatial navigation in the presence of dynamic obstacles: a differential games approach

Obstacle circumvention strategies can be shaped by the dynamic interaction of an individual (evader) and an obstacle (pursuer). We have developed a mathematical model with predictive and emergent components, using experimental data from seven healthy young adults walking towards a target while avoiding collision with a stationary or moving obstacle (approaching head-on, or diagonally 30° left or right) in a virtual environment. Two linear properties from the predictive component enable the evader to predict the minimum distance between itself and the obstacle at all times, including the future intersection of trajectories. The emergent component uses the classical differential games model to solve for an optimal circumvention while reaching the target, wherein the locomotor strategy is influenced by the obstacle, target, and the evader velocity. Both model components were fitted to a different set of experimental data obtained from five post-stroke and healthy participants to derive the minimum predicted distance (predictive component) and obstacle influence dimensions (emergent component) during circumvention. Minimum predicted distance between evader and pursuer was kept constant when the evader was closest to the obstacle in all participants. Obstacle influence dimensions varied depending on obstacle approach condition and preferred side of circumvention, reflecting differences in locomotor strategies between post-stroke and healthy individuals. Additionally, important associations between model outputs and observed experimental outcomes were found. The model, supported by experimental data, suggests that both predictive and emergent processes can shape obstacle circumvention strategies in healthy and post-stroke individuals.

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Bayesian Diallel Analysis Reveals Mx1-Dependent and Mx1-Independent Effects on Response to Influenza A Virus in Mice

Influenza A virus (IAV) is a respiratory pathogen that causes substantial morbidity and mortality during both seasonal and pandemic outbreaks. Infection outcomes in unexposed populations are affected by host genetics, but this host genetic architecture is not well understood. Here we obtain a broad view of how heritable factors affect a mouse model of response to IAV infection using an 8x8 diallel of the eight inbred founder strains of the Collaborative Cross (CC). Expanding on a prior statistical framework for modeling treatment response in diallels, we explore how a range of heritable effects modify acute host response to IAV through 4 days post-infection. Heritable effects in aggregate explained about 57% of the variance in IAV-induced weight loss. Much of this was attributable to a pattern of additive effects that became more prominent through day 4 post-infection and was consistent with previous reports of anti-influenza myxovirus resistance 1 (Mx1) polymorphisms segregating between these strains; the additive effects largely recapitulated haplotype effects observed at the Mx1 locus in a previous study of the incipient CC (pre-CC), and are also replicated here in a CC recombinant intercross (CC-RIX) population. Genetic dominance of protective Mx1 haplotypes was observed to differ by subspecies origin: relative to the domesticus null Mx1 allele, musculus acts dominantly whereas castaneus acts additively. After controlling for Mx1, heritable effects, though less distinct, accounted for about 34% of the phenotypic variance. Implications for future mapping studies are discussed.

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Dissecting the Genetic Architecture of Shoot Growth in Carrot (Daucus carota L.) Using a Diallel Mating Design

Carrot production suffers yield losses under weed pressure, and thus improved competitive ability is a breeding priority. However, continued improvement and in-depth genetic studies for these traits relies on knowledge of the underlying genetic architecture. This study estimated heritable and non-heritable components of carrot shoot growth from a diallel mating design using a Bayesian mixed model. Results directly contribute to improvement efforts by ranking hybrids, identifying useful tester lines, and estimating the genetic and non-genetic influences on traits for improved competitive ability in carrot.

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Dependency of Heterochromatin Domains on Replication Factors

Chromatin structure regulates both genome expression and dynamics in eukaryotes where large heterochromatic regions are epigenetically silenced through the methylation of histone H3K9, histone deacetylation, and assembly of repressive complexes. Previous genetic screens with the fission yeast Schizosaccharomyces pombe have led to the identification of key enzymatic activities and structural constituents of heterochromatin. We report here on additional factors discovered by screening a library of deletion mutants for silencing defects at the edge of a heterochromatic domain bound by its natural boundary - the IR-R⁺ element - or by ectopic boundaries. We found that several components of the DNA replication progression complex (RPC) including Mrc1/Claspin, Mcl1/Ctf4, Swi1/Timeless, Swi3/Tipin and the FACT subunit Pob3 are essential to robust heterochromatic silencing, as are the ubiquitin ligase components Pof3 and Def1 that have been implicated in the removal of stalled DNA and RNA polymerases from chromatin. Moreover, the search identified the cohesin release factor Wpl1 and the forkhead protein Fkh2, both likely to function through genome organization, as well as the Ssz1 chaperone, the Fkbp39 proline cis-trans isomerase, that acts on histone H3P30 and P38 in S. cerevisiae, and the chromatin remodeler Fft3. In addition to their effects in the mating-type region, these factors take part in heterochromatic silencing in pericentromeric regions and telomeres, to various extent, revealing for many a general effect in heterochromatin. This list of factors provides precious new clues with which to study the spatio-temporal organization and dynamics of heterochromatic regions in connection with DNA replication.

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Identifying Genetic Differences Between Dongxiang Blue-Shelled and White Leghorn Chickens Using Sequencing Data

The Dongxiang Blue-shelled chicken is one of the most valuable Chinese indigenous poultry breeds. However, compared to the Italian native White Leghorn, although this Chinese breed possesses numerous favorable characteristics, it also exhibits lower growth performance and fertility. We utilize genotyping sequencing data in this paper obtained via genome reduction on a sequencing platform to detect 100,114 single nucleotide polymorphisms (SNPs) and perform further biological analysis and functional annotation. We employed cross-population extended haplotype homozygosity (XP-EHH), EigenGWAS, and efficient mixed-model association eXpedited (EMMAX) methods to detect areas of the genome which are potential selected regions (PSR) in both chicken breeds, and performed gene ontology (GO) enrichment and quantitative trait loci (QTL) analyses annotating using the Kyoto Encyclopedia of Genes and Genomes (KEGG).The results of this study reveal a total of 2,424 outlier loci (p-value<0.01) of which 2,144 occur in the White Leghorn breed and 280 occur in the Dongxiang Blue-shelled chicken. These correspond to 327 and 94 potentially selected regions containing 297 and 54 genes, respectively. The most significantly selected genes in Blue-shelled chicken are TMEM141 and CLIC3, while the SLCO1B3 gene, related to eggshell color, was identified via EigenGWAS. We show that the White Leghorn genes JARID2, RBMS3, GPC3, TRIB2，ROBO1, SAMSN1, OSBP2 and IGFALS are involved in immunity, reproduction, and growth, and thus might represent footprints of the selection process. In contrast, we identified six significantly enriched pathways in the Dongxiang Blue-shelled chicken that are related to amino acid and lipid metabolism as well as signal transduction. Our results also reveal the presence of a GO term associated with cell metabolism that mainly occurs in the White Leghorn breed, while the most significant QTL regions mapped to the Chicken QTL Database (GG_4.0) for the Dongxiang Blue-shelled breed are predominantly related to lesions, bone mineral content and other related traits compared to tibia length and body weight (i.e. at 14 days, 28 days, 42 days, 70 days) in the White Leghorn. The results of this study highlight differences in growth, immunity and egg quality traits between the two breeds and provide a foundation for the exploration of their genetic mechanisms.

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Enhanced Mechanical and Helical Properties with Achiral Calix[4]arene in Co-Assembled Hydrogel which Exhibited the Helical Structure

A mixture of the building blocks 1A and 2G having D-alanine moieties and glycine-functionalized calix[4]arene moieties, respectively, formed co-assembled hydrogel. In particular, the remarkable enhancement of helical intensity of co-assembled gel was controlled by achiral calix[4]arene 2G, which was attributed the bridge effect helically between 1A and 2G like helical structure. Furthermore, the improvements of mechanical strength (G´ and G" values) of co-assembled hydrogel prepared with 1.0 equiv. of 2G were ca. 7000% and ca. 4400% as compared to the gel prepared from the 0.25 equiv. of 2G, respectively. The improved mechanical strength was attributed to the formation of network structure with the H-bonding interaction between 1A and 2G. The results indicate that the helical and mechanical strength enhanced of co-assembled gel could be controlled by achiral component 2G.

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MicroRNA dynamics at the onset of primordial germ and somatic cells sex differentiation during mouse embryonic gonad development [Bioinformatics]

IIn mammals, commitment and specification of germ cell lines implies involves complex programs that include sex differentiation, control of proliferation and meiotic initiation. Regulation of these processes is genetically controlled by fine-tuned mechanisms of gene regulation in which microRNAs (miRNAs) are involved. We have characterized, by small-RNAseq and bioinformatics analyses, the miRNA expression patterns of male and female mouse Primordial Germ Cells (PGCs) and gonadal somatic cells at embryonic stages: E11.5, E12.5 and E13.5. Differential expression analyses revealed differences in the regulation of key miRNA clusters such as miR-199-214, miR-182-183-96 and miR-34c-5p whose targets have defined roles during gonadal sexual determination in both germ and somatic cells. Extensive analyses of miRNA sequences revealed an increase in non-canonical isoforms on PGCs at E12.5 and dramatic changes of 3' isomiR expres-sion and 3' non-template nucleotide additions in female PGCs at E13.5. Additionally, RT-qPCR analyses of genes encoding proteins involved in miRNA biogenesis and 3' nucleotide addition uncovered sexually and developmentally specific expression, char-acterized by the decay of Drosha, Dgcr8 and Xpo5 expression along gonadal develop-ment. These results demonstrate that miRNAs, their isomiRs and miRNA machinery are differentially regulated and participate actively in gonadal sexual differentiation in both PGCs and gonadal somatic cells.

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Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib

Purpose: Vandetanib is well-tolerated in patients with advanced medullary thyroid carcinoma (MTC). Long-term outcomes and mechanisms of MTC progression have not been reported previously.  Experimental Design:We monitored toxicities and disease status in patients taking vandetanib for hereditary, advanced MTC. Tumor samples were analyzed for molecular mechanisms of disease progression. Results: Seventeen patients (8 male, age 13 (9-17)* years) enrolled; 16 had a RET p.Met918Thr germline mutation. The duration of vandetanib therapy was 6.1 (0.1-9.7+)* years with treatment ongoing in nine patients. Best response was partial response (PR) in ten, stable disease (SD) in six, and progressive disease (PD) in one patient. Duration of response was 7.4 (0.6-8.7+)* and 4.9 (0.6-7.8+)* years in patients with PR and SD, respectively. Six patients died 2.0 (0.4-5.7)* years after progression. Median progression free survival (PFS) was 6.7 years (95% CI: 2.3 years-undefined) and 5-year overall survival (OS) was 88.2% (95% CI 60.6-96.9%). Of 16 patients with a RET p.Met918Thr mutation, progression free survival was 6.7 years (95% CI 3.1-undefined) and 5-year overall survival was 93.8% (95% CI 63.2-99.1%). No patients terminated treatment because of toxicity. DNA sequencing of tissue samples (n=11) identified an increase in copy number alterations across the genome as a potential mechanism of drug resistance. Conclusions:This study demonstrates that vandetanib is safe and results in sustained responses in children and adolescents with hereditary MTC. Our preliminary molecular data suggest that an increase in copy number abnormalities may be associated with tumor progression in hereditary MTC patients treated with vandetanib.

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Premature birth affects the degree of airway dysanapsis and mechanical ventilatory constraints

Abstract

Adult survivors of very preterm birth (≤32 weeks gestational age) without (PRE) and with bronchopulmonary dysplasia (BPD) have obstructive lung disease as evidenced by reduced expiratory airflow at rest and have significant mechanical ventilatory constraints during exercise. Airflow obstruction, under any condition, could be due to several factors including small airways. PRE and/or BPD could have smaller airways than their counterparts born at full-term (CON) due to a greater degree of dysanaptic airway development during the pre- and/or post-natal period. Thus, the purpose of the present study was to compare the dysanapsis ratio (DR), as an index of airway size, between PRE, BPD, and CON. To do so, we calculated DR in PRE (n = 21), BPD (n = 14) and CON (n = 34) individuals, as well as examined flow-volume loops at rest and during sub-maximal exercise. DR, using multiple estimates of static recoil pressure, was significantly smaller in PRE and BPD (0.16 ± 0.05 and 0.10 ± 0.03 AU) compared to CON (0.22 ± 0.04 AU; both P < 0.001) and smallest in BPD (P < 0.001). DR was significantly correlated to peak expiratory airflow at rest (r = 0.42; P < 0.001) and the extent of expiratory flow limitation during exercise (r = 0.60; P < 0.001). Our findings suggest that PRE/BPD may have anatomically smaller airways than CON, which may help explain their lower expiratory airflow rate at rest and during exercise and further our understanding of the consequences of preterm birth and neonatal O₂ therapy.

This article is protected by copyright. All rights reserved

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Genotypic characterization of gentamicin and cephalosporin resistant Escherichia coli isolates from blood cultures in a Norwegian university hospital 2011–2015

Cephalosporin resistance in clinical E. coli isolates is increasing internationally. The increase has been caused by virulent and often multidrug-resistant clones, especially the extended spectrum β-lactamase (ES...

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Prognostic Factors for Survival After Transarterial Chemoembolization Combined with Sorafenib in the Treatment of BCLC Stage B and C Hepatocellular Carcinomas

Publication date: Available online 29 November 2017
Source:Academic Radiology
Author(s): Jia-yan Ni, Jian Kong, Hong-liang Sun, Yao-ting Chen, Jiang-hong Luo, Wei-dong Wang, Dong Chen, Xiong-ying Jiang, Lin-feng Xu
Rationale and ObjectiveThe objective of this study was to analyze prognostic factors for survival after transarterial chemoembolization (TACE) combined with sorafenib for hepatocellular carcinoma (HCC) of Barcelona Clinic Liver Cancer (BCLC) stages B and C.Materials and MethodsClinical data of 198 patients with BCLC stage B and C HCCs who underwent TACE combined with sorafenib between June 2012 and January 2017 were retrospectively collected and analyzed. Survival curves were detected using log-rank test. Univariate analysis was performed using log-rank test with respect to 11 prognostic factors potentially affecting survival. All statistically significant prognostic factors identified by univariate analysis were entered into a Cox proportion hazards regression model to identify independent predictors of survival. P values were two-sided and P < 0.05 was considered statistically significant.ResultsBy the end of this study, the median follow-up duration was 43.6 months. The median overall survival (OS) of the patients was 21.0 months (95% confidence interval [CI]: 16.94–25.05), and the 1-, 2-, 3- and 5-year OS rates were 72%, 43%, 28%, and 4%, respectively. Tumor size (χ² = 33.607, P < 0.0001), tumor number (χ² = 4.084, P = 0.043), Child-Pugh class (χ² = 33.187, P < 0.0001), BCLC stage (χ² = 50.224, P < 0.0001), portal vein tumor thrombus (χ² = 88.905, P < 0.0001), Eastern Cooperative Oncology Group (ECOG) performance status (χ² = 98.007, P < 0.0001), extrahepatic spread (χ² = 34.980, P < 0.0001), TACE times (χ² = 8.350, P = 0.015), and sorafenib treatment strategy (χ² = 81.593, P < 0.0001) were found to be significantly associated with OS by univariate analysis. Multivariate analysis showed that BCLC stage (95% CI: 1.133–3.982, P = 0.019), extrahepatic spread (95% CI: 1.136–2.774, P = 0.012), and sorafenib treatment duration (95% CI: 0.352–0.574, P = 0.000) were independent prognostic factors associated with OS. There were no serious treatment-related adverse events.ConclusionsThis study showed that extrahepatic spread was a risk factor, and sorafenib treatment and superior BCLC stage were protective factors. Therefore, the study indicated that TACE combined with sorafenib was an effective and safe treatment for patients with BCLC stage B HCC without extrahepatic spread.



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The Study of Clear Cell Renal Cell Carcinoma with MR Diffusion Kurtosis Tensor Imaging and Its Histopathologic Correlation

Publication date: Available online 29 November 2017
Source:Academic Radiology
Author(s): Guangyu Wu, Zizhou Zhao, Qiuying Yao, Wen Kong, Jianrong Xu, Jin Zhang, Guiqin Liu, Yongming Dai
Rationale and ObjectivesThe objective of this study was to compare the performance of diffusion kurtosis tensor imaging and diffusion-weighted imaging in the characterization of clear cell renal cell carcinoma (ccRCC) and their correlations with tumor histopathology.Materials and MethodsNinety-one patients diagnosed with ccRCC who underwent diffusion kurtosis tensor imaging were included in this study. Fractional anisotropy, mean diffusivity, radial diffusivity, axial diffusivity, mean kurtosis (MK), radial kurtosis (Krad), and axial kurtosis (Kax) data were produced. A nuclear grade of 1–4 (G1–4) was assigned for each case based on the Fuhrman grading system, whereas tumor histopathology was characterized by the nuclear-to-cytoplasm ratio, the cell nuclei count, and the cell volume fraction.ResultsAll of the metric values except for Kax and fractional anisotropy could be used to discriminate G1 vs G3, G1 vs G4, G2 vs G3, and G2 vs G4, whereas MK and Kax could be used to discriminate G3 vs G4 (P < 0.05). Moreover, the MK and Krad values exhibited better performance in differentiating G2 from G3 (P < 0.04 compared to the other metrics). The nuclear-to-cytoplasm ratio was positively correlated with the MK, Krad, and Kax values (P < 0.001) and negatively correlated with the mean diffusivity, radial diffusivity, and axial diffusivity values (P < 0.001), whereas the cell volume fraction and the cell nuclei count did not correlate with any metric examined.ConclusionThe kurtosis metrics were superior to the diffusion metrics in grading ccRCC.



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High-risk Plaque and Calcification Detected by Coronary CT Angiography to Predict Future Cardiovascular Events After Percutaneous Coronary Intervention

Publication date: Available online 29 November 2017
Source:Academic Radiology
Author(s): Nobuo Tomizawa, Kodai Yamamoto, Shinichi Inoh, Takeshi Nojo, Sunao Nakamura
Rationale and ObjectivesThe purpose of this study was to investigate whether high-risk plaque (HRP) and calcium assessed by coronary computed tomography (CT) could predict future cardiovascular events after second-generation drug-eluting stent (DES) placement.Materials and MethodsWe analyzed 317 patients from December 2012 to April 2015 who underwent coronary CT followed by DES placement. HRP was defined as a plaque with positive remodeling and low attenuation or a plaque with a napkin-ring sign. Coronary calcium was assessed by Agatston score (AS). Patients were divided into three groups: low risk, HRP negative and AS <400; intermediate risk, HRP positive and AS ≥400; high risk, HRP positive and AS ≥400. The primary end point was a composite of all-cause mortality, myocardial infarction, fatal arrhythmia, or repeated revascularization. Kaplan-Meier analysis was used to estimate the distribution of time to events.ResultsA total of 74 events (23%) occurred during a median follow-up of 25.8 months. Patients with primary end points had HRP more frequently (70% vs 51%, P = 0.003) and were more calcified (AS, 471 [interquartile range, 143–1614] vs 289 [interquartile range, 63–787]; P = 0.01) than patients without primary end points. The frequency of primary end point increased significantly in the intermediate- and high-risk patients (P = 0.0011). Multivariate analysis showed that the hazard ratio of the intermediate- and high-risk groups was 1.91 (95% confidence interval, 1.04–3.77; P = 0.037) and 2.66 (95% confidence interval, 1.27–5.73; P = 0.009), respectively.ConclusionPlaque and calcification analysis by coronary CT could predict future cardiovascular events after second-generation DES placement.



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Anti-inflammatory evaluation of the methanolic extract of Taraxacum officinale in LPS-stimulated human umbilical vein endothelial cells

Atherosclerosis is a chronic vascular inflammatory disease. Since even low-level endotoxemia constitutes a powerful and independent risk factor for the development of atherosclerosis, it is important to find t...

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Jia-Wei-Jiao-Tai-Wan ameliorates type 2 diabetes by improving β cell function and reducing insulin resistance in diabetic rats

Jia-Wei-Jiao-Tai-Wan (JWJTW), composed of Jiao-Tai-Wan (Cinnamomum cassia and Rhizoma coptidis) and other antidiabetic herbs, including Astragalus membranaceus, Herba Gynostemmatis, Radix Puerariae Lobatae, Foliu...

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PTBP3-mediated regulation of ZEB1 mRNA stability promotes epithelial-mesenchymal transition in breast cancer

The RNA polypyrimidine tract binding protein PTBP3 is a little studied paralog of PTBP1 which has oncogenic properties. In this study, we demonstrate that PTBP3 induces epithelial-mesenchymal transition (EMT) in breast tumor cells and promotes their invasive growth and metastasis. Elevated expression of PTBP3 associated significantly with lymph node metastasis, advanced histology grade, TNM stage, and poor 5-year overall survival of patients. In human mammary epithelial cells, PTBP3 overexpression was sufficient to induce EMT and enhance cell migration, invasion, and cancer stem-like cell properties. PTBP3 regulated expression of the EMT regulatory transcription factor ZEB1 by binding the 3'UTR of its mRNA, thereby preventing its degradation. Conversely, ZEB1 ablation blocked the ability of PTBP3 to induce EMT. Overall, our findings define PTBP3 as a regulator of EMT that acts by governing expression of ZEB1, and they establish an oncogenic function of PTBP3 suggesting its candidacy as a theranostic target.

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Modeling the subclonal evolution of cancer cell populations

Increasing evidence shows that tumor clonal architectures are often the consequence of a complex branching process, yet little is known about the expected dynamics and extent to which these divergent subclonal expansions occur. Here we develop and implement more than 88,000 instances of a stochastic evolutionary model simulating genetic drift and neoplastic progression. Under different combinations of population genetic parameter values, including those estimated for colorectal cancer and glioblastoma multiforme, the distribution of sizes of subclones carrying driver mutations had a heavy right tail at the time of tumor detection, with only 1-4 dominant clones present at ≥10% frequency. In contrast, the vast majority of subclones were present at <10% frequency, many of which had higher fitness than currently dominant clones. The number of dominant clones (≥10% frequency) in a tumor correlated strongly with the number of subclones (<10% of the tumor). Overall, these subclones were frequently below current standard detection thresholds, frequently harbored treatment-resistant mutations and were more common in slow-growing tumors.

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HER2-driven Breast Tumorigenesis Relies upon Interactions of the Estrogen Receptor with Coactivator MED1

Studies of the estrogen receptor (ER) coactivator protein MED1 have revealed its specific roles in pubertal mammary gland development and potential contributions to breast tumorigenesis, based on co-amplification of MED1 and HER2 in certain breast cancers. In this study, we generated a mouse model of mammary tumorigenesis harboring the MMTV-HER2 oncogene and mutation of MED1 to evaluate its role in HER2-driven tumorigenesis. MED1 mutation in its ER-interacting LxxLL motifs was sufficient to delay tumor onset and impair tumor growth, metastasis and cancer stem-like cell formation in this model. Mechanistic investigations revealed that MED1 acted directly to regulate ER signaling through the downstream IGF-1 pathway but not the AREG pathway. Our findings show that MED1 is critical for HER2-driven breast tumorigenesis, suggesting its candidacy as a disease-selective therapeutic target.

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LSR antibody therapy inhibits ovarian epithelial tumor growth by inhibiting lipid uptake

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy but it still lacks effective treatment options. In this study, we utilized proteomic technology to identify lipolysis-stimulated lipoprotein receptor (LSR) as a new tumor antigen of EOC. Immunohistochemical analysis of EOC tissues in conjunction with survival analysis of EOC patients showed that high expression of LSR is associated with poor prognosis. High LSR expression also occurred in tumor metastases including to the lymph node and omentum. To evaluate the possible benefits of blocking this antigen in EOC, we raised a new monoclonal antibody (mAb) to human LSR (hLSR). In mouse xenograft models of hLSR-positive EOC (cell lines or patient-derived tumors), we found that administration of anti-hLSR mAb inhibited tumor growth in a manner independent of both antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity. Mechanistic investigations showed that hLSR expression increased incorporation of very low-density lipoprotein (VLDL) into EOC cells and that anti-hLSR mAb inhibited lipid uptake in vitro and in vivo. Moreover, VLDL promoted cell proliferation in hLSR-positive EOC cells in vitro and this effect was inhibited by anti-hLSR mAb. While the anti-hLSR mAb studied cross-reacted with the mouse antigen, we observed no adverse effects on normal organs and lipid metabolism in murine hosts. Our findings suggest that hLSR plays a key functional role in EOC development and that this antigen can be therapeutically targeted by specific mAb to improve EOC treatment.

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Photodynamic priming mitigates chemotherapeutic selection pressures and improves drug delivery

Physiological barriers to drug delivery and selection for drug resistance limit survival outcomes in cancer patients. In this study, we present preclinical evidence that a subtumoricidal photodynamic priming (PDP) strategy can relieve drug delivery barriers in the tumor microenvironment to safely widen the therapeutic window of a nanoformulated cytotoxic drug. In orthotopic xenograft models of pancreatic cancer, combining PDP with nanoliposomal irinotecan (nal-IRI) prevented tumor relapse, reduce metastasis and increase both progression-free survival and 1-year disease-free survival. PDP enabled these durable improvements by targeting multiple tumor compartments to (1) increase intratumoral drug accumulation by >10-fold, (2) increase the duration of drug exposure above a critical therapeutic threshold, and (3) attenuate surges in CD44 and CXCR4 expression which mediate chemoresistance often observed after multi-cycle chemotherapy. Overall, our results offer preclinical proof of concept for the effectiveness of PDP to minimize risks of tumor relapse, progression and drug resistance and to extend patient survival.

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The E3 ligase RING1 targets p53 for degradation and promotes cancer cell proliferation and survival

As a component of the transcriptional repression complex 1 (PRC1), the ring finger protein RING1 participates in the epigenetic regulation in cancer. However, the contributions of RING1 to cancer etiology or development are unknown. In this study, we report that RING1 is a critical negative regulator of p53 homeostasis in human hepatocellular and colorectal carcinomas. RING1 acts as an E3 ubiquitin (Ub) ligase to directly interact with and ubiquitinate p53, resulting in its proteasome-dependent degradation. The RING domain of RING1 was required for its E3 Ub ligase activity. RING1 depletion inhibited the proliferation and survival of the p53 wild-type cancer cells by inducing cell cycle arrest, apoptosis and senescence, with only modest effects on p53-deficient cells. Its growth inhibitory effect was partially rescued by p53 silencing, suggesting an important role for the RING1-p53 complex in human cancer. In clinical specimens of hepatocellular carcinoma, RING1 upregulation was evident in association with poor clinical outcomes. Collectively, our results elucidate a novel PRC1-independent function of RING1 and provide a mechanistic rationale for its candidacy as a new prognostic marker and/or therapeutic target in human cancer.

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PPAR{delta} elicits ligand-independent repression of Trefoil Factor Family to limit prostate cancer growth

The nuclear receptor PPAR-β/δ (PPARD) has essential roles in fatty acid catabolism and energy homeostasis as well as cell differentiation, inflammation and metabolism. However, its contributions to tumorigenesis are uncertain and have been disputed. Here we provide evidence of tumor suppressive activity of PPARD in prostate cancer through a non-canonical and ligand-independent pathway. PPARD was downregulated in prostate cancer specimens. In murine prostate epithelium, PPARD gene deletion resulted in increased cellularity. Genetic modulation of PPARD in human prostate cancer cell lines validated the tumor suppressive activity of this gene in vitro and in vivo. Mechanistically, PPARD exerted its activity in a DNA binding-dependent and ligand-independent manner. We identified a novel set of genes repressed by PPARD that failed to respond to ligand-mediated activation. Among these genes, we observed robust regulation of the secretory trefoil factor family (TFF) members, including a causal and correlative association of TFF1 to prostate cancer biology in vitro and in patient specimens. Overall, our results illuminate the oncosuppressive function of PPARD and understanding of the pathogenic molecular pathways elicited by this nuclear receptor.

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Delivering type I interferon to dendritic cells empowers tumor eradication and immune combination treatments

An ideal generic cancer immunotherapy should mobilize the immune system to destroy tumor cells without harming healthy cells and remain active in case of recurrence. Furthermore, it should preferably not rely on tumor-specific surface markers, as these are only available in a limited set of malignancies. Despite approval for treatment of various cancers, clinical application of cytokines is still impeded by their multiple toxic side effects. Type I interferon (IFN) has a long history in the treatment of cancer, but its multifaceted activity pattern and complex side effects prevent its clinical use. Here we develop AcTakines (Activity-on-Target cytokines), optimized (mutated) immunocytokines that are up to 1000-fold more potent on target cells, allowing specific signaling in selected cell types only. Type I IFN-derived AcTaferon-targeting Clec9A+ dendritic cells (DC) displayed strong antitumor activity in murine melanoma, breast carcinoma, and lymphoma models and against human lymphoma in humanized mice without any detectable toxic side effects. Combined with immune checkpoint blockade, chemotherapy, or low-dose TNF, complete tumor regression and long-lasting tumor immunity were observed, still without adverse effects. Our findings indicate that DC-targeted AcTaferons provide a novel class of highly efficient, safe, and broad-spectrum off-the-shelf cancer immunotherapeutics with no need for a tumor marker.

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