Hematopoietic Stem Cell Gene Therapy: Progress and Lessons Learned

Publication date: 2 November 2017
Source:Cell Stem Cell, Volume 21, Issue 5
Author(s): Richard A. Morgan, David Gray, Anastasia Lomova, Donald B. Kohn
The use of allogeneic hematopoietic stem cells (HSCs) to treat genetic blood cell diseases has become a clinical standard but is limited by the availability of suitable matched donors and potential immunologic complications. Gene therapy using autologous HSCs should avoid these limitations and thus may be safer. Progressive improvements in techniques for genetic correction of HSCs, by either vector gene addition or gene editing, are facilitating successful treatments for an increasing number of diseases. We highlight the progress, successes, and remaining challenges toward the development of HSC gene therapies and discuss lessons they provide for the development of future clinical stem cell therapies.

Teaser

Morgan et al. discuss the progress, successes, and remaining challenges toward the development of hematopoietic stem cell gene therapies and highlight lessons learned and how they can inform the development of future clinical stem cell therapies.


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Targeting Glioma Stem Cell-Derived Pericytes Disrupts the Blood-Tumor Barrier and Improves Chemotherapeutic Efficacy

Publication date: 2 November 2017
Source:Cell Stem Cell, Volume 21, Issue 5
Author(s): Wenchao Zhou, Cong Chen, Yu Shi, Qiulian Wu, Ryan C. Gimple, Xiaoguang Fang, Zhi Huang, Kui Zhai, Susan Q. Ke, Yi-Fang Ping, Hua Feng, Jeremy N. Rich, Jennifer S. Yu, Shideng Bao, Xiu-Wu Bian
The blood-tumor barrier (BTB) is a major obstacle for drug delivery to malignant brain tumors such as glioblastoma (GBM). Disrupting the BTB is therefore highly desirable but complicated by the need to maintain the normal blood-brain barrier (BBB). Here we show that targeting glioma stem cell (GSC)-derived pericytes specifically disrupts the BTB and enhances drug effusion into brain tumors. We found that pericyte coverage of tumor vasculature is inversely correlated with GBM patient survival after chemotherapy. Eliminating GSC-derived pericytes in xenograft models disrupted BTB tight junctions and increased vascular permeability. We identified BMX as an essential factor for maintaining GSC-derived pericytes. Inhibiting BMX with ibrutinib selectively targeted neoplastic pericytes and disrupted the BTB, but not the BBB, thereby increasing drug effusion into established tumors and enhancing the chemotherapeutic efficacy of drugs with poor BTB penetration. These findings highlight the clinical potential of targeting neoplastic pericytes to significantly improve treatment of brain tumors.

Graphical abstract

Teaser

The blood-brain barrier (BBB) blocks entry of harmful materials into normal brains, but the blood-tumor barrier (BTB) prevents anti-cancer drugs from penetrating GBM tumors. Targeting GSC-derived neoplastic pericytes selectively disrupted the BTB, but not BBB, and potently enhanced drug delivery to effectively improve GBM treatment.


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Long-Range GABAergic Inputs Regulate Neural Stem Cell Quiescence and Control Adult Hippocampal Neurogenesis

Publication date: 2 November 2017
Source:Cell Stem Cell, Volume 21, Issue 5
Author(s): Hechen Bao, Brent Asrican, Weidong Li, Bin Gu, Zhexing Wen, Szu-Aun Lim, Issac Haniff, Charu Ramakrishnan, Karl Deisseroth, Benjamin Philpot, Juan Song
The quiescence of adult neural stem cells (NSCs) is regulated by local parvalbumin (PV) interneurons within the dentate gyrus (DG). Little is known about how local PV interneurons communicate with distal brain regions to regulate NSCs and hippocampal neurogenesis. Here, we identify GABAergic projection neurons from the medial septum (MS) as the major afferents to dentate PV interneurons. Surprisingly, dentate PV interneurons are depolarized by GABA signaling, which is in sharp contrast to most mature neurons hyperpolarized by GABA. Functionally, these long-range GABAergic inputs are necessary and sufficient to maintain adult NSC quiescence and ablating them leads to NSC activation and subsequent depletion of the NSC pool. Taken together, these findings delineate a GABAergic network involving long-range GABAergic projection neurons and local PV interneurons that couples dynamic brain activity to the neurogenic niche in controlling NSC quiescence and hippocampal neurogenesis.

Graphical abstract

Teaser

Bao et al. demonstrate that long-range GABAergic projections from the medial septum control adult hippocampal neurogenesis through depolarizing GABA signaling onto local PV interneurons. Functionally, these long-range inputs are required for maintaining NSC quiescence and ablating them depletes the NSC pool and impairs neurogenesis.


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TGF-β-Induced Quiescence Mediates Chemoresistance of Tumor-Propagating Cells in Squamous Cell Carcinoma

Publication date: 2 November 2017
Source:Cell Stem Cell, Volume 21, Issue 5
Author(s): Jessie A. Brown, Yoshiya Yonekubo, Nicole Hanson, Ana Sastre-Perona, Alice Basin, Julie A. Rytlewski, Igor Dolgalev, Shane Meehan, Aristotelis Tsirigos, Slobodan Beronja, Markus Schober
Squamous cell carcinomas (SCCs) are heterogeneous tumors sustained by tumor-propagating cancer cells (TPCs). SCCs frequently resist chemotherapy through still unknown mechanisms. Here, we combine H2B-GFP-based pulse-chasing with cell-surface markers to distinguish quiescent from proliferative TPCs within SCCs. We find that quiescent TPCs resist DNA damage and exhibit increased tumorigenic potential in response to chemotherapy, whereas proliferative TPCs undergo apoptosis. Quiescence is regulated by TGF-β/SMAD signaling, which directly regulates cell-cycle gene transcription to control a reversible G1 cell-cycle arrest, independent of p21^CIP function. Indeed, genetic or pharmacological TGF-β inhibition increases the susceptibility of TPCs to chemotherapy because it prevents entry into a quiescent state. These findings provide direct evidence that TPCs can reversibly enter a quiescent, chemoresistant state and thereby underscore the need for combinatorial approaches to improve treatment of chemotherapy-resistant SCCs.

Graphical abstract

Teaser

Heterogeneous tumors, such as squamous cell carcinomas, are often chemoresistant and comprise subpopulations of poorly characterized tumor-propagating cancer cells (TPCs). Brown et al. demonstrate that TPCs reversibly enter a quiescent, chemoresistant state and inhibiting TGF-β signaling can increase their susceptibility to chemotherapy by preventing cell-cycle withdrawal in tumors.


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An endosiRNA-Based Repression Mechanism Counteracts Transposon Activation during Global DNA Demethylation in Embryonic Stem Cells

Publication date: 2 November 2017
Source:Cell Stem Cell, Volume 21, Issue 5
Author(s): Rebecca V. Berrens, Simon Andrews, Dominik Spensberger, Fátima Santos, Wendy Dean, Poppy Gould, Jafar Sharif, Nelly Olova, Tamir Chandra, Haruhiko Koseki, Ferdinand von Meyenn, Wolf Reik
Erasure of DNA methylation and repressive chromatin marks in the mammalian germline leads to risk of transcriptional activation of transposable elements (TEs). Here, we used mouse embryonic stem cells (ESCs) to identify an endosiRNA-based mechanism involved in suppression of TE transcription. In ESCs with DNA demethylation induced by acute deletion of Dnmt1, we saw an increase in sense transcription at TEs, resulting in an abundance of sense/antisense transcripts leading to high levels of ARGONAUTE2 (AGO2)-bound small RNAs. Inhibition of Dicer or Ago2 expression revealed that small RNAs are involved in an immediate response to demethylation-induced transposon activation, while the deposition of repressive histone marks follows as a chronic response. In vivo, we also found TE-specific endosiRNAs present during primordial germ cell development. Our results suggest that antisense TE transcription is a "trap" that elicits an endosiRNA response to restrain acute transposon activity during epigenetic reprogramming in the mammalian germline.

Graphical abstract

Teaser

In this issue of Cell Stem Cell, Berrens et al. report the control of transposable elements by endosiRNAs during global DNA demethylation induced in mouse embryonic stem cells. The study uncovered an "immediate" repression of transposons accomplished by endosiRNAs followed by their "chronic/long-term" silencing by repressive histone modifications.


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A Morbidly Obese Man With an Enlarging Right Thigh Mass.

No abstract available

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Melanocytic Matricoma With Consumption of the Epidermis: An Atypical Histologic Attribute or a Malignant Variant?.

Melanocytic matricoma is a recently described cutaneous adnexal tumor composed of matrical and supramatrical cells admixed with pigmented dendritic melanocytes, thought to recapitulate the anagen bulb of the hair follicle. We report a case of a 75-year-old white man, which demonstrates consumption of the epidermis that is defined as thinning of the epidermis with attenuation of the basal and suprabasal layers and loss of the normal rete architecture in areas of direct contact with neoplastic cells. It has been associated with aggressive histologic features in melanoma and likely represents an early phase of ulceration due to attenuation. Epidermal consumption has not been previously reported in nonmelanocytic tumors and it is uncertain whether this atypical histologic feature represents a sign of malignant behavior in this rare tumor. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Eccrine-Centric Melanocytic Nevus.

Benign melanocytic neoplasms present with a diverse array of well-known histopathologic patterns. It is imperative to recognize the benign patterns to render accurate diagnoses. We describe here an interesting and hitherto not described low-power architectural pattern of a benign melanocytic lesion: eccrine-centric melanocytic nevus. The patient was a 50-year-old African American woman who noticed a new mole on her foot that began as a dark speck but quickly grew larger. The lesion was excised to exclude the possibility of melanoma. Upon review of the specimen, the lesion was noted to demonstrate a distinctive pattern consistent with a melanocytic nevus of possible congenital onset. Remarkably, the ducts of eccrine glands were increased in density and the nests of melanocytes were found solely in a peri-eccrine distribution without melanocytes in any other locations (ie, interstitial, perifollicular). Additionally, all melanocytes in the nevus were rather heavily pigmented. Although this pattern demonstrated no atypical features that would cause one to consider it malignant to the trained eye, this presentation could implicate a metastatic disease (well-delineated nests in the dermis without concomitant interstitial component) and it is important to recognize. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Holocrine Poroma: A Distinctive Adnexal Tumor.

There are 36 cases of complex poroid tumors with folliculosebaceous and apocrine differentiation reported in the literature. The authors evaluated 111 poroid tumors including 63 typical eccrine poromas and 48 poroid tumors with folliculosebaceous elements. Folliculosebaceous poroid tumors (FSPT) had basaloid and squamous cells (100%), ducts with steatocystoma-like cuticles and holocrine secretions (89.6%), infundibular follicular structures (66.7%), and entrapped sebocytes (56.3%). No definite apocrine decapitation secretions in FSPT were found. Immunohistochemistry was strongly positive for CK903 and focally positive for CAM5.2, epithelial membrane antigen, and carcinoembryonic antigen. No loss of MLH-1, MSH-2, or MSH-6 mismatch repair proteins was found. FSPT had distinctive features that differentiate them from eccrine poromas including the frequent head and neck locations (62.5% vs. 20.6%, P

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Cytotoxic CD8+ Granulomatous Cutaneous T-Cell Lymphoma Associated With Human Immunodeficiency Virus Infection: A Diagnostic Challenge.

No abstract available

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Comparison of MRI sequences in ideal fiducial maker-based radiotherapy for prostate cancer

Publication date: November–December 2017
Source:Reports of Practical Oncology & Radiotherapy, Volume 22, Issue 6
Author(s): Osamu Tanaka, Hisao Komeda, Mitsuyoshi Hattori, Shigeki Hirose, Eiichi Yama, Masayuki Matsuo
AimProstate contouring using CT alone is difficult. To overcome the uncertainty, CT/MRI registration using a fiducial marker is generally performed. However, visualization of the marker itself can be difficult with MRI. This study aimed to determine the optimal MRI pulse sequence for defining the marker as well as the prostate outline among five sequences.Materials and methodsA total of 21 consecutive patients with prostate cancer were enrolled. Two gold fiducial markers were placed before CT/MRI examination. We used the following five sequences: T1-weighted spin-echo (T1WI; TR/TE, 400–650/8ms); T2-weighted fast spin-echo (T2WI; 4000/80); T2*-2D-weighted gradient echo (T2*2D; 700/18); T2*-3D-weighted gradient echo (T2*3D; TR/TE1/deltaTE, 37/14/7.3); and contrast-enhanced T1-weighted spin-echo (CE-T1WI; 400–650/8). Qualitative image analysis of the sequences was performed by three observers. These observers subjectively scored all images on a scale of 1–3 (1=unclear, 2=moderate, 3=well visualized). A higher score indicated better visualization.ResultsT2WI was significantly superior to the other sequences in terms of prostate definition. T2*2D and T2*3D were strongly superior to the other sequences and were significantly superior in terms of fiducial marker definition.ConclusionsT2*2D and T2*3D are superior to the other sequences for prostate contouring and marker identification. Therefore, we recommend initial T2*3D and T2*2D examinations.



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Clinical outcomes with MRI-guided image-based brachytherapy in cervical cancer: An institutional experience

Publication date: Available online 1 November 2017
Source:Brachytherapy
Author(s): Vijai Simha, Bhavana Rai, Firuza D. Patel, Rakesh Kapoor, Suresh C. Sharma, Oinam A. Singh, Veenu Singla, Bhaswanth Dhanireddy, Sushmita Ghoshal
PurposeTo evaluate the long-term disease control and toxicity to the organs at risk after dose-escalated image-based adaptive brachytherapy (BT) in cervical cancer.Methods and MaterialsSixty patients of cervical cancer were treated with external radiotherapy 46 Gy in 23 fractions with weekly cisplatin and MRI-guided BT 7 Gy × 4 fractions with a minimum dose of 85.7 Gy (EQD2) to the high-risk clinical target volume (HRCTV). The BT dose was initially prescribed to point A and plans were optimized to ensure coverage of both point A and HRCTV while maintaining doses to the organs at risk within the recommended constraints. Patients were followed up clinically every three months for the first two years and six months thereafter. Toxicity scoring for urinary and bowel symptoms was done using CTCAE version 3.0.ResultsThe mean doses to the point A and D90 HRCTV were 85.5 (±2.75) Gy and 98.4 (±9.6) Gy EQD2 respectively. The mean 2 cc EQD2, the bladder, rectum, and sigmoid were 90.6 Gy, 70.2 Gy, and 74.2 Gy respectively. The overall survival at a median followup of 49.8 months was 91.66%. Six (10%) patients developed grade 3 gastrointestinal toxicity. One patient developed grade 3 bladder toxicity. The incidence of bladder, rectal, and sigmoid toxicity increased significantly with doses >85 Gy, 66 Gy, and >71 Gy EQD2 respectively.ConclusionsWhile the incidence of grade 3-4 toxicity was low (8.3% for gastrointestinal toxicity and 1.6% for bladder), the threshold for development of grade 1-2 bladder and rectal toxicity was lower than the doses recommended by the GEC-ESTRO group. By adhering to volume-based prescriptions, there is scope of further reduction in toxicity to organs at risk.



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Physics aspects of the Papillon technique—Five decades later

Publication date: Available online 1 November 2017
Source:Brachytherapy
Author(s): Li Heng Liang, Nada Tomic, Te Vuong, Saad Aldelaijan, Hamed Bekerat, Francois DeBlois, Jan Seuntjens, Slobodan Devic
PurposeThe Papillon technique using 50-kVp soft X-rays to treat rectal adenocarcinomas was developed and clinically implemented in the 1960s. We describe differences between accurate dosimetry and clinical implementation of this technique that is extending from its very inception to date.Methods and MaterialsA renaissance of the Papillon technique occurred with two recently introduced 50-kVp systems: Papillon+ by Ariane and a custom-made rectal applicator (consisting of a surface applicator inserted into a proctoscope) by iCAD's Xoft Axxent Electronic Brachytherapy (eBT) System (iCad, Inc., Sunnyvale, CA). In contrast to the initial design, we investigated the impact of introducing a plastic lid, which would provide more reproducible and more accurate dose delivery across the rectal adenocarcinoma patient population. We use both parallel-plate chamber and radiochromic film dosimeters to determine differences in basic dosimetry characteristics (beam half-value layers, outputs, percent depth doses, and profiles) between the Xoft Electronic Brachytherapy rectal applicator system with and without the plastic lid in place.ResultsCompared to the open-cone applicator, the proposed applicator with the plastic lid produces a slightly harder (more penetrating) beam quality (half-value layer of 1.4 vs. 1.3-mm Al), but with reduced output (by 33%), and a slightly broader beam with flatness not worse than 3% and symmetry not worse than 2%.ConclusionsIn addition to characterizing beam properties modified by the possible introduction of the plastic cap, we also pointed out and addressed misconceptions in the use of radiochromic films for dose measurements at low-energy photon beams.



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Manual vs. automated implantation of seeds in prostate brachytherapy: Oncologic results from a single-center study

Publication date: Available online 1 November 2017
Source:Brachytherapy
Author(s): Laurence Thomas, Antony Chemin, Nicolas Leduc, Sarah Belhomme, Emilie Rich, Olivier Lasbareilles, Antoine Giraud, Edouard Descat, Guilhem Roubaud, Paul Sargos
PurposeThe objective of this study was to study survival and tolerance of prostate cancer patients treated with ¹²⁵I permanent interstitial brachytherapy by automated vs. manual implantation of seeds.Methods and MaterialsBetween 2002 and 2010, 349 selected patients were treated with ¹²⁵I brachytherapy by the same team: from 2002 to April 2005, 65 patients with linked seeds and then 284 patients treated using Nucletron First System automated implantation. We analyzed biochemical recurrence-free survival (bRFS) rates and toxicities (univariate and multivariate analyses).ResultsTwo hundred seventy-seven (79.4%) and 69 patients (19.8%) with low- and intermediate-risk disease were treated, respectively (median follow-up: 64 months). The 5-year bRFS rate was 93.1% (95% confidence interval 89.3–95.6) for the entire cohort. The 5-year bRFS rates were 93.4% and 91.7% for patients with low- and intermediate-risk disease, respectively (p = 0.42). In univariate and multivariate analyses, there was no statistically significant difference in the 5-year bRFS rate depending on the implantation technique (93.1% vs. 91.8%, respectively, for automated and linked seeds; p = 0.53). In univariate analysis, only D90 prostate (dose delivered to 90% of the prostate) <140 Gy (p = 0.01), lack of prostate-specific antigen bounce (p = 0.008), and nadir prostate-specific antigen >0.11 (p = 0.01) were predictive factors for bRFS. We observed Grade 3 urethritis in 7 patients (2%), urinary incontinence in 2 patients (0.7%), and Grade 4 proctitis in 2 patients (0.7%).ConclusionsIn this large single-center series, brachytherapy for selected localized prostate cancer achieved excellent rates of biochemical control at 5 years (93.1%) with an acceptable toxicity profile, irrespective of the implantation technique used.



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The role of 125I interstitial brachytherapy for inoperable parotid gland carcinoma

Publication date: Available online 1 November 2017
Source:Brachytherapy
Author(s): Ming-Wei Huang, Wen-Jie Wu, Xiao-Ming Lv, Guang-Yan Yu, Jian-Guo Zhang
PurposeThe treatment of inoperable parotid gland carcinoma is challenging and controversial. The purpose of this paper was to present our experience in treating this malignancy using ¹²⁵I interstitial brachytherapy.Methods and MaterialsThirteen patients with advanced carcinomas of the parotid gland were included and treated with ¹²⁵I interstitial brachytherapy in Peking University School and Hospital of Stomatology from January 2003 to December 2015. All patients were treated with ¹²⁵I interstitial brachytherapy as a sole modality for the primary tumor. Furthermore, all of them were treated with neck dissection with/without adjunctive external beam radiotherapy for the neck, simultaneously. The prescription dose of interstitial brachytherapy was 140–160 Gy.ResultsMedian followup was 56 months (range: 8–105 months). The 2-year and 5-year local control rates were 91.7% and 58.2%, respectively. The 2-year and 5-year overall survival rates were 100% and 61%, respectively. No cervical lymph node metastasis was observed during the followup. No interstitial brachytherapy-related severe complications occurred. Facial nerve function was preserved well.Conclusions¹²⁵I interstitial brachytherapy is a feasible and effective treatment for inoperable parotid gland carcinomas without severe complications. And neck dissection with/without external beam radiotherapy is necessary for patients with cervical metastasis or at high risk of cervical metastasis.



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Motor cortex excitability in seizure-free STX1B mutation carriers with a history of epilepsy and febrile seizures

Publication date: December 2017
Source:Clinical Neurophysiology, Volume 128, Issue 12
Author(s): Maria-Ioanna Stefanou, Debora Desideri, Justus Marquetand, Paolo Belardinelli, Christoph Zrenner, Holger Lerche, Ulf Ziemann
ObjectiveMutations in STX1B encoding the presynaptic protein syntaxin-1B are associated with febrile seizures with or without epilepsy. It is unclear to what extent these mutations are linked to abnormalities of cortical glutamatergic or GABAergic neurotransmission. We explored this question using single- and paired-pulse transcranial magnetic stimulation (TMS) excitability markers.MethodsWe studied nine currently asymptomatic adult STX1B mutation carriers with history of epilepsy and febrile seizures, who had been seizure-free for at least eight years without antiepileptic drug treatment, and ten healthy age-matched controls. Resting motor threshold (RMT), and input-output curves of motor evoked potential (MEP) amplitude, short-interval intracortical inhibition (SICI, marker of GABAAergic excitability) and intracortical facilitation (ICF, marker of glutamatergic excitability) were tested.ResultsRMT, and input-output curves of MEP amplitude, SICI and ICF revealed no significant differences between STX1B mutation carriers and healthy controls.ConclusionsFindings suggest normal motor cortical GABAAergic and glutamatergic excitability in currently asymptomatic STX1B mutation carriers.SignificanceTMS measures of motor cortical excitability show utility in demonstrating normal excitability in adult STX1B mutation carriers with history of seizures.



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Early corticospinal tract damage in prodromal SCA2 revealed by EEG-EMG and EMG-EMG coherence

Publication date: December 2017
Source:Clinical Neurophysiology, Volume 128, Issue 12
Author(s): Luis Velázquez-Pérez, Johannes Tünnerhoff, Roberto Rodríguez-Labrada, Reidenis Torres-Vega, Yusely Ruiz-Gonzalez, Paolo Belardinelli, Jacqueline Medrano-Montero, Nalia Canales-Ochoa, Yanetza González-Zaldivar, Yaimeé Vazquez-Mojena, Georg Auburger, Ulf Ziemann
ObjectiveClinical data suggest early involvement of the corticospinal tract (CST) in spinocerebellar ataxia type 2 (SCA2). Here we tested if early CST degeneration can be detected in prodromal SCA2 mutation carriers by electrophysiological markers of CST integrity.MethodsCST integrity was tested in 15 prodromal SCA2 mutation carriers, 19 SCA2 patients and 25 age-matched healthy controls, using corticomuscular (EEG-EMG) and intermuscular (EMG-EMG) coherence measures in upper and lower limb muscles.ResultsSignificant reductions of EEG-EMG and EMG-EMG coherences were observed in the SCA2 patients, and to a similar extent in the prodromal SCA2 mutation carriers. In prodromal SCA2, EEG-EMG and EMG-EMG coherences correlated with the predicted time to ataxia onset.ConclusionsFindings indicate early CST neurodegeneration in SCA2. EEG-EMG and EMG-EMG coherence may serve as biomarkers of early CST neurodegeneration in prodromal SCA2 mutation carriers.SignificanceFindings are important for developing preclinical disease markers in the context of currently emerging disease-modifying therapies of neurodegenerative disorders.



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Single-unit activity of the anterior Globus pallidus internus in Tourette patients and posterior Globus pallidus internus in dystonic patients

Publication date: December 2017
Source:Clinical Neurophysiology, Volume 128, Issue 12
Author(s): Andrea Giorni, François Windels, Peter G. Stratton, Raymond Cook, Paul Silberstein, Terrence Coyne, Peter A. Silburn, Pankaj Sah
ObjectivesOur goal was to provide a detailed analysis of neurons' electrophysiological activity recorded in sub-territories of Globus pallidus internus (GPi) used as Deep Brain Stimulation (DBS) targets for these clinical conditions to potentially assist electrode targeting.MethodsWe used intra-operative microelectrode recording during stereotactic neurosurgery to guide implantation of DBS lead.ResultsUnits in the medial anterior part of GPi of 7 Tourette's syndrome patients under general anesthesia were firing at mean and median rate of 32.1 and 21 Hz respectively (n = 101), with 45% of spikes fired during bursts and 21.3 bursts per minute. In the latero-posterior part of GPi of 7 dystonic patients under local anesthesia the mean and median activity were 46.1 and 30.6 Hz respectively (n = 27), and a mean of 21.7 bursts per minute was observed, with 30% of all spikes occurring during these bursts.ConclusionUnits activity pattern – slow-regular, fast-irregular or fast-regular were present in different proportions between the two targets.SignificanceThe electrophysiological characteristics of the medial-anterior part of GPi and its latero-posterior portion can be used to assist DBS electrode targeting and also support the refinement of pathophysiological models of Tourette's syndrome and Dystonia.



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Oxidative stress and cell cycle arrest induced by short-term exposure to dustfall PM 2.5 in A549 cells

Abstract

It was reported that in vitro short-term exposure to PM_2.5 caused different lung diseases through inflammatory response, immune toxicity, oxidative stress, and genetic mutations. However, the complex molecular biological mechanism for its toxicity had not been fully elucidated. Therefore, the present study investigated the cytotoxicity, oxidative damage, mitochondria damage, apoptosis, and cell cycle arrest of NX and QH PM_2.5 in A549 cells. Further, cell cycle arrest-related gene levels in PM_2.5-induced A549 cells were also detected. Our results suggested that PM_2.5 reduced the cell viability in A549 cells. Simultaneously, excessive ROS decreased MMP levels and damaged mitochondrial membrane integrity and induced mitochondrial oxidative damage through the oxygen-dependent killer route, resulting in mitochondrial damage and cell apoptosis. Besides, the results also showed that PM_2.5 induced A549 cell cycle alteration in G2/M phase after co-culture for 24 h. G2/M phase arrest was induced by upregulation of p53 and p21 and downregulation of CDK1 mRNA expression. In addition, lncRNA Sox2ot might play an important role as the specific oncogenes and it participated in G2/M phase arrest by regulating the expression of EZH₂.

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Diurnal and seasonal variations of greenhouse gas emissions from a naturally ventilated dairy barn in a cold region

Publication date: January 2018
Source:Atmospheric Environment, Volume 172
Author(s): Dandan Huang, Huiqing Guo
Carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O) emissions were quantified for a naturally ventilated free-stall dairy barn in the Canadian Prairies climate through continuous measurements for a year from February 2015 to January 2016, with ventilation rate estimated by a CO2 mass balance method. The results were categorized into seasonal emission profiles with monthly data measured on a typical day, and diurnal profiles in cold (January), warm (July), and mild seasons (October) of all three gases. Seasonal CO2, CH4, and N2O concentrations greatly fluctuated within ranges of 593–2433 ppm, 15–152 ppm, and 0.32–0.40 ppm, respectively, with obviously higher concentrations in the cold season. Emission factors of the three gases were summarized: seasonal N2O emission varied between 0.5 and 10 μg s⁻¹ AU⁻¹ with lower emission in the cold season, while seasonal CO2 and CH4 emissions were within narrow ranges of 112–119 mg s⁻¹ AU⁻¹ and 2.5–3.5 mg s⁻¹ AU⁻¹. The result suggested a lower enteric CH4 emission for dairy cows than that estimated by Environment Canada (2014). Significant diurnal effects (P < 0.05) were observed for CH4 emissions in all seasons with higher emissions in the afternoons and evenings. The total greenhouse gas (GHG) emission, which was calculated by summing the three GHG in CO2 equivalent, was mainly contributed by CO2 and CH4 emissions and showed no significant seasonal variations (P > 0.05), but obvious diurnal variations in all seasons. In comparison with previous studies, it was found that the dairy barn in a cold region climate with smaller vent openings had relatively higher indoor CO2 and CH4 concentrations, but comparable CO2 and CH4 emissions to most previous studies. Besides, ventilation rate, temperature, and relative humidity all significantly affected the three gas concentrations with the outdoor temperature being the most relevant factor (P < 0.01); however, they showed less or no statistical relations to emissions.



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