bluuebunny/crossref_metadata_2025_split huggingface dataset:
Host Cell S Phase Restricts
Legionella pneumophila
Intracellular Replication by Destabilizing the Membrane-Bound Replication Compartment
Authors: de Jesús-Díaz Dennise A. , Murphy Connor , Sol Asaf , Dorer Marion , Isberg Ralph R. 
Published: August 2017

ABSTRACT

Legionella pneumophila
grows within cells ranging from environmental amoebae to human macrophages. In spite of this conserved strategy of pathogenesis, identification of host factors that restrict
L. pneumophila
intracellular replication has not been extended outside components of the mammalian innate immune response. We performed a double-stranded RNA (dsRNA) screen against more than 50% of the
Drosophila melanogaster
annotated open reading frames (ORFs) to identify host cell factors that restrict
L. pneumophila
. The majority of analyzed dsRNAs that stimulated
L. pneumophila
intracellular replication were directed against host proteins involved in protein synthesis or cell cycle control. Consistent with disruption of the cell cycle stimulating intracellular replication, proteins involved in translation initiation also resulted in G
1
arrest. Stimulation of replication was dependent on the stage of cell cycle arrest, as dsRNAs causing arrest during S phase had an inhibitory effect on intracellular replication. The inhibitory effects of S phase arrest could be recapitulated in a human cell line, indicating that cell cycle control of
L. pneumophila
replication is evolutionarily conserved. Synchronized HeLa cell populations in S phase and challenged with
L. pneumophila
failed to progress through the cell cycle and were depressed for supporting intracellular replication. Poor bacterial replication in S phase was associated with loss of the vacuole membrane barrier, resulting in exposure of bacteria to the cytosol and their eventual degradation. These results are consistent with the model that S phase is inhibitory for
L. pneumophila
intracellular survival as a consequence of failure to maintain the integrity of the membrane surrounding intracellular bacteria.

IMPORTANCE
Legionella pneumophila
has the ability to replicate within human macrophages and amoebal hosts. Here, we report that the host cell cycle influences
L. pneumophila
intracellular replication. Our data demonstrate that the G
1
and G
2
/M phases of the host cell cycle are permissive for bacterial replication, while S phase is toxic for the bacterium.
L. pneumophila
replicates poorly within host cells present in S phase. The inability of
L. pneumophila
to replicate relies on its failure to control the integrity of its vacuole, leading to cytosolic exposure of the bacteria and eventual degradation. The data presented here argue that growth-arrested host cells that are encountered by
L. pneumophila
in either the environment or within human hosts are ideal targets for intracellular replication because their transit through S phase is blocked.
Excess mortality due to indirect health effects of the 2011 triple disaster in Fukushima, Japan: a retrospective observational study
Authors: Morita Tomohiro , Nomura Shuhei , Tsubokura Masaharu , Leppold Claire , Gilmour Stuart , Ochi Sae , Ozaki Akihiko , Shimada Yuki , Yamamoto Kana , Inoue Manami , Kato Shigeaki , Shibuya Kenji , Kami Masahiro 
Published: August 2017

BackgroundEvidence on the indirect health impacts of disasters is limited. We assessed the excess mortality risk associated with the indirect health impacts of the 2011 triple disaster (earthquake, tsunami and nuclear disaster) in Fukushima, Japan.MethodsThe mortality rates in Soma and Minamisoma cities in Fukushima from 2006 to 2015 were calculated using vital statistics and resident registrations. We investigated the excess mortality risk, defined as the increased mortality risk between postdisaster and predisaster after excluding direct deaths attributed to the physical force of the disaster. Multivariate Poisson regression models were used to estimate the relative risk (RR) of mortality after adjusting for city, age and year.ResultsThere were 6163 and 6125 predisaster and postdisaster deaths, respectively. The postdisaster mortality risk was significantly higher in the first month following the disaster (March 2011) than in the same month during the predisaster period (March 2006–2010). RRs among men and women were 2.64 (95% CI 2.16 to 3.24) and 2.46 (95% CI 1.99 to 3.03), respectively, demonstrating excess mortality risk due to the indirect health effects of the disaster. Age-specific subgroup analyses revealed a significantly higher mortality risk in women aged ≥85 years in the third month of the disaster compared with predisaster baseline, with an RR (95% CI) of 1.73 (1.23 to 2.44).ConclusionsIndirect health impacts are most severe in the first month of the disaster. Early public health support, especially for the elderly, can be an important factor for reducing the indirect health effects of a disaster.
Anti-Inflammatory and Immunostimulatory Activities of Astragalosides
Authors: Qi Yan , Gao Feng , Hou Lifei , Wan Chunping 
Published: August 2017

Astragalus membranaceus (Fisch) Bge (Huang-Qi) is a well-known herbal medicine with tonic property and has been widely used to treat cancer and other immune disorders in China and Southeast Asia for thousands of years. Accumulating evidence suggests that Huang-Qi possesses both immune-boosting and anti-inflammatory/immune-regulatory effects clinically, leaving the mechanism elusive. Recently, we discovered that Astragaloside (ASI), a major active component of Huang-Qi, is able to increase CD45 phosphatase activity. In this paper, we reviewed the recent progress of ASIs in immunoregulatory and anti-inflammatory activities, including the induction of T-cell activation, regulation of effector/regulatory T-cell balance, enhancement of CD45 phosphatase activity, inhibition of pro-inflammatory cytokine and, NF-[Formula: see text]B pathway. Finally, we hypothesized that inducing interferon-[Formula: see text] (IFN-[Formula: see text]) activity by activating CD45 protein tyrosine phosphatase (PTPase) may be involved in the protective role of ASI in two contrary immune-associated diseases. These pharmacological properties highlight the traditional uses of Astragalus and provide a new direction for subsequent research and the clinical application of this traditional herbal.
Functional and molecular plasticity of γ and α1 GABAA receptor subunits in the dorsal motor nucleus of the vagus after experimentally induced diabetes
Authors: Boychuk Carie R. , Smith Katalin C. , Smith Bret N. 
Published: August 2017

Chronic experimentally induced hyperglycemia augments subunit-specific γ-aminobutyric acid A (GABAA) receptor-mediated inhibition of parasympathetic preganglionic motor neurons in the dorsal motor nucleus of the vagus (DMV). However, the contribution of α1 or γ GABAA receptor subunits, which are ubiquitously expressed on central nervous system neurons, to this elevation in inhibitory tone have not been determined. This study investigated the effect of chronic hyperglycemia/hypoinsulinemia on α1- and γ-subunit-specific GABAA receptor-mediated inhibition using electrophysiological recordings in vitro and quantitative RT-PCR. DMV neurons from streptozotocin-treated mice demonstrated enhancement of both phasic and tonic inhibitory currents in response to application of the α1-subunit-selective GABAA receptor-positive allosteric modulator zolpidem. Responses to low concentrations of the GABAA receptor antagonist gabazine suggested an additional increased contribution of γ-subunit-containing receptors to tonic currents in DMV neurons. Consistent with the functional elevation in α1- and γ-subunit-dependent activity, transcription of both the α1- and γ2-subunits was increased in the dorsal vagal complex of streptozotocin-treated mice. Overall, these findings suggest an increased sensitivity to both zolpidem and gabazine after several days of hyperglycemia/hypoinsulinemia, which could contribute to altered parasympathetic output from DMV neurons in diabetes. NEW & NOTEWORTHY Glutamate and GABA signaling in the dorsal vagal complex is elevated after several days of chronic hyperglycemia in a mouse model of type 1 diabetes. We report persistently enhanced GABAA receptor-mediated responses to the somnolescent zolpidem in preganglionic vagal motor neurons. These results imply a broader impact of chronic hyperglycemia on central vagal function than previously appreciated and reinforce the hypothesis that diabetes effects in the brain can impact regulation of metabolic homeostasis.
Role of digit placement control in sensorimotor transformations for dexterous manipulation
Authors: Shibata Daisuke , Santello Marco 
Published: August 2017

Dexterous manipulation relies on the ability to modulate grasp forces to variable digit position. However, the sensorimotor mechanisms underlying such critical ability are not well understood. The present study addressed whether digit force-to-position modulation relies entirely on feedback of digit placement and force, or on the integration of such feedback with motor commands responsible for digit positioning. In two experiments, we asked 25 subjects to estimate the index fingertip position relative to the thumb (perception test) or to grasp and lift an object with an asymmetrical mass distribution while preventing object roll (action test). Both tests were performed after subjects’ digits were placed actively or passively at different distances (active and passive condition, respectively) and without visual feedback. Because motor commands for digit positioning would be integrated with position and force feedback in the active condition, we hypothesized this condition to be characterized by greater accuracy of digit position estimation and digit force-to-position modulation. Surprisingly, discrimination of digit position and force-to-position modulation was statistically indistinguishable in the active and passive conditions. We conclude that voluntary commands for digit positioning are not essential for accurate estimation of finger position or modulation of digit forces to variable digit position. Thus digit force-to-position modulation can be implemented by integrating sensory feedback of digit position and voluntary commands of digit force production following contact. NEW & NOTEWORTHY This study was designed to understand the sensorimotor mechanisms underlying digit force-to-position modulation required for manipulation. Surprisingly, estimation of relative digit position and force-to-position modulation was accurate regardless of whether the digits were passively or actively positioned. Therefore, accurate estimation of digit position does not require an efference copy of active digit positioning, and the hypothesized advantage of active over passive movement on estimation of end-point position appears to be task and effector dependent.
Human Pluripotent Stem Cell–Derived TSC2-Haploinsufficient Smooth Muscle Cells Recapitulate Features of Lymphangioleiomyomatosis
Authors: Julian Lisa M. , Delaney Sean P. , Wang Ying , Goldberg Alexander A. , Doré Carole , Yockell-Lelièvre Julien , Tam Roger Y. , Giannikou Krinio , McMurray Fiona , Shoichet Molly S. , Harper Mary-Ellen , Henske Elizabeth P. , Kwiatkowski David J. , Darling Thomas N. , Moss Joel , Kristof Arnold S. , Stanford William L. 
Published: August 2017

Abstract
Lymphangioleiomyomatosis (LAM) is a progressive destructive neoplasm of the lung associated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes. Cell or animal models that accurately reflect the pathology of LAM have been challenging to develop. Here, we generated a robust human cell model of LAM by reprogramming TSC2 mutation–bearing fibroblasts from a patient with both tuberous sclerosis complex (TSC) and LAM (TSC-LAM) into induced pluripotent stem cells (iPSC), followed by selection of cells that resemble those found in LAM tumors by unbiased in vivo differentiation. We established expandable cell lines under smooth muscle cell (SMC) growth conditions that retained a patient-specific genomic TSC2+/− mutation and recapitulated the molecular and functional characteristics of pulmonary LAM cells. These include multiple indicators of hyperactive mTORC1 signaling, presence of specific neural crest and SMC markers, expression of VEGF-D and female sex hormone receptors, reduced autophagy, and metabolic reprogramming. Intriguingly, the LAM-like features of these cells suggest that haploinsufficiency at the TSC2 locus contributes to LAM pathology, and demonstrated that iPSC reprogramming and SMC lineage differentiation of somatic patient cells with germline mutations was a viable approach to generate LAM-like cells. The patient-derived SMC lines we have developed thus represent a novel cellular model of LAM that can advance our understanding of disease pathogenesis and develop therapeutic strategies against LAM. Cancer Res; 77(20); 5491–502. ©2017 AACR.
Single-Nucleotide Polymorphisms in Vitamin D–Related Genes May Modify Vitamin D–Breast Cancer Associations
Authors: O'Brien Katie M. , Sandler Dale P. , Kinyamu H. Karimi , Taylor Jack A. , Weinberg Clarice R. 
Published: August 2017

AbstractBackground: We previously observed that high serum 25-hydroxyvitamin D (25(OH)D; &gt;38.0 ng/mL) was inversely associated with breast cancer. Here, we examined effect modification by SNPs in vitamin D–related genes.Methods: The Sister Study enrolled 50,884 U.S. women who had a sister with breast cancer, but who had never had breast cancer themselves. Using a case–cohort design, we compared 1,524 women who developed breast cancer within 5 years to 1,810 randomly selected participants. We estimated ratios of HRs (RHRs) for the 25(OH)D–breast cancer association per copy of the minor allele using Cox proportional hazards models. We considered 82 SNPs in 7 vitamin D–related genes (CYP24A1, CYP27B1, CYP2R1, GC, DHCR7/NADSYN1, RXRA, and VDR). We also tested gene-based interactions with 25(OH)D.Results: The SNP with the smallest interaction P value was rs4328262 in VDR (P = 0.0008); the 25(OH)D HR was 0.92 [95% confidence interval (CI), 0.68–1.24] among those homozygous for the common allele, and the minor allele was estimated to decrease the HR by 33% per copy (RHR = 0.67; 95% CI, 0.53–0.85). Five other VDR SNPs showed evidence of interaction at P &lt; 0.05, as did one SNP in CYP2R1 and one in RXRA. As a group, the 82 SNPs showed evidence of multiplicative interaction with 25(OH)D (P = 0.04). In gene-based tests, only VDR showed strong evidence of interaction (P = 0.04).Conclusions: SNPs in vitamin D–related genes may modify the association between serum 25(OH)D and breast cancer.Impact: This work strengthens the evidence for protective effects of vitamin D. Cancer Epidemiol Biomarkers Prev; 26(12); 1761–71. ©2017 AACR.
Deletion of 11q in Neuroblastomas Drives Sensitivity to PARP Inhibition
Authors: Sanmartín Elena , Muñoz Lisandra , Piqueras Marta , Sirerol J. Antoni , Berlanga Pablo , Cañete Adela , Castel Victoria , Font de Mora Jaime 
Published: August 2017

AbstractPurpose: Despite advances in multimodal therapy, neuroblastomas with hemizygous deletion in chromosome 11q (20%–30%) undergo consecutive recurrences with poor outcome. We hypothesized that patients with 11q-loss may share a druggable molecular target(s) that can be exploited for a precision medicine strategy to improve treatment outcome.Experimental Design: SNP arrays were combined with next-generation sequencing (NGS) to precisely define the deleted region in 17 primary 11q-loss neuroblastomas and identify allelic variants in genes relevant for neuroblastoma etiology. We assessed PARP inhibitor olaparib in combination with other chemotherapy medications using both in vitro and in vivo models.Results: We detected that ATM haploinsufficiency and ATM allelic variants are common genetic hallmarks of 11q-loss neuroblastomas. On the basis of the distinct DNA repair pathways triggered by ATM and PARP, we postulated that 11q-loss may define a subgroup of neuroblastomas with higher sensitivity to PARP inhibitors. Noteworthy, concomitant treatment with olaparib and DNA alkylating agent temozolomide potently inhibited growth of cell lines harboring 11q-loss. This drug synergism was less potent when temozolomide was exchanged for cisplatin or irinotecan. Intact 11q cells concomitantly treated with ATM inhibitor displayed growth arrest and enhanced apoptosis, revealing a role for ATM in the mechanism that mediates sensitivity to temozolomide–olaparib. Interestingly, functional TP53 is required for efficacy of this treatment. In an in vivo model, coadministration of temozolomide–olaparib resulted in sustained xenograft regression.Conclusions: Our findings reveal a potent synergism between temozolomide and olaparib in treatment of neuroblastomas with 11q-loss and provide a rationale for further clinical investigation. Clin Cancer Res; 23(22); 6875–87. ©2017 AACR.
Impact of Therapy on Genomics and Transcriptomics in High-Risk Prostate Cancer Treated with Neoadjuvant Docetaxel and Androgen Deprivation Therapy
Authors: Beltran Himisha , Wyatt Alexander W. , Chedgy Edmund C. , Donoghue Adam , Annala Matti , Warner Evan W. , Beja Kevin , Sigouros Michael , Mo Fan , Fazli Ladan , Collins Colin C. , Eastham James , Morris Michael , Taplin Mary-Ellen , Sboner Andrea , Halabi Susan , Gleave Martin E. 
Published: August 2017

Abstract
Purpose: The combination of docetaxel chemotherapy and androgen deprivation therapy (ADT) has become a standard treatment for patients with metastatic prostate cancer. The recently accrued phase III CALGB 90203 trial was designed to investigate the clinical effectiveness of this treatment approach earlier in the disease. Specimens from this trial offer a unique opportunity to interrogate the acute molecular response to docetaxel and ADT and identify potential biomarkers.
Experimental Design: We evaluated baseline clinical data, needle biopsies, and radical prostatectomy (RP) specimens from 52 (of 788) patients enrolled on CALGB 90203 at one high volume center. Pathology review, tumor and germline-targeted DNA sequencing (n = 72 genes), and expression profiling using NanoString platform (n = 163 genes) were performed to explore changes in critical prostate cancer pathways linked to aggression and resistance.
Results: Three of 52 patients had only microfocal residual cancer at prostatectomy. The most common alterations included TMPRSS2-ERG fusion (n = 32), TP53 mutation or deletion (n = 11), PTEN deletion (n = 6), FOXA1 (n = 6), and SPOP (n = 4) mutation, with no significant enrichment in posttreated specimens. We did not observe AR amplification or mutations. The degree of AR signaling suppression varied among treated tumors and there was upregulation of both AR and AR-V7 expression as well as a subset of neuroendocrine and plasticity genes.
Conclusions: These data support the feasibility of targeted and temporal genomic and transcriptome profiling of neoadjuvant-treated prostate cancer with limited formalin-fixed paraffin embedded tissue requirement. Characterization of the heterogeneity of treatment response and molecular outliers that arise posttreatment provides new insight into potential early markers of resistance. Clin Cancer Res; 23(22); 6802–11. ©2017 AACR.
Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells
Authors: Shum Thomas , Omer Bilal , Tashiro Haruko , Kruse Robert L. , Wagner Dimitrios L. , Parikh Kathan , Yi Zhongzhen , Sauer Tim , Liu Daofeng , Parihar Robin , Castillo Paul , Liu Hao , Brenner Malcolm K. , Metelitsa Leonid S. , Gottschalk Stephen , Rooney Cliona M. 
Published: August 2017

Abstract
Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but is associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Coexpressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and antitumor activity during repeated exposure to tumor cells, without T-cell dysfunction or autonomous T-cell growth. Furthermore, C7R-coexpressing CAR T cells were active against metastatic neuroblastoma and orthotopic glioblastoma xenograft models even at cell doses that had been ineffective without C7R support. C7R may thus be able to enhance antigen-specific T-cell therapies against cancer.
Significance: The constitutively signaling C7R system developed here delivers potent IL7 stimulation to CAR T cells, increasing their persistence and antitumor activity against multiple preclinical tumor models, supporting its clinical development. Cancer Discov; 7(11); 1238–47. ©2017 AACR.
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Addressing the Social Needs of Hypertensive Patients
Authors: Schoenthaler Antoinette , Knafl George J. , Fiscella Kevin , Ogedegbe Gbenga 
Published: August 2017

Background—
Poor medication adherence is a pervasive problem in patients with hypertension. Despite research documenting an association between patient–provider communication and medication adherence, there are no empirical data on how the informational and relational aspects of communication affect patient’s actual medication-taking behaviors. The aim of this study was to evaluate the impact of patient–provider communication on medication adherence among a sample of primary care providers and their black and white hypertensive patients.

Methods and Results—
Cohort study included 92 hypertensive patients and 27 providers in 3 safety-net primary care practices in New York City. Patient–provider encounters were audiotaped at baseline and coded using the Medical Interaction Process System. Medication adherence data were collected continuously during the 3-month study with an electronic monitoring device. The majority of patients were black, 58% women, and most were seeing the same provider for at least 1 year. Approximately half of providers were white (56%), 67% women, and have been in practice for an average of 5.8 years. Fifty-eight percent of patients exhibited poor adherence to prescribed antihypertensive medications. Three categories of patient–provider communication predicted poor medication adherence: lower patient centeredness (odds ratio: 3.08; 95% confidence interval: 1.04–9.12), less discussion about patients’ sociodemographic circumstances (living situation, relationship with partner; odds ratio: 6.03; 95% confidence interval: 2.15–17), and about their antihypertensive medications (odds ratio: 6.48; 95% confidence interval: 1.83–23.0). The effect of having less discussion about patients’ sociodemographic circumstances on medication adherence was heightened in black patients (odds ratio: 8.01; 95% confidence interval: 2.80–22.9).

Conclusions—
The odds of poor medication adherence are greater when patient–provider interactions are low in patient centeredness and do not address patients’ sociodemographic circumstances or their medication regimen.