bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Laboratory Response to a Mock Outbreak of Invasive Bacterial Infections: a Preparedness Study
Authors: Olsen Randall J. , Fittipaldi Nahuel , Kachroo Priyanka , Sanson Misu A. , Long S. Wesley , Como-Sabetti Kathryn J. , Valson Chandni , Cantu Concepcion , Lynfield Ruth , Van Beneden Chris , Beres Stephen B. , Musser James M. 
Published: September 2014

ABSTRACT

Large hospital-based clinical laboratories must be prepared to rapidly investigate potential infectious disease outbreaks. To challenge the ability of our
molecular diagnostics laboratory to use whole-genome sequencing in a potential outbreak scenario and identify impediments to these efforts, we studied 84 invasive serotype
emm59
group A streptococcus (GAS) strains collected in the United States. We performed a rapid-response exercise to the mock outbreak scenario using whole-genome sequencing, genome-wide transcript analysis, and mouse virulence studies. The protocol changes installed in response to the lessons learned were tested in a second iteration. The initial investigation was completed in 9 days. Whole-genome sequencing showed that the invasive infections were caused by multiple subclones of epidemic
emm59
GAS strains likely spread to the United States from Canada. The phylogenetic tree showed a strong temporal-spatial structure with diversity in mobile genetic element content, features that are useful for identifying closely related strains and possible transmission events. The genome data informed the epidemiology, identifying multiple patients who likely acquired the organisms through direct person-to-person transmission. Transcriptome analysis unexpectedly revealed significantly altered expression of genes encoding a two-component regulator and the hyaluronic acid capsule virulence factor. Mouse infection studies confirmed a high-virulence capacity of these
emm59
organisms. Whole-genome sequencing, coupled with transcriptome analysis and animal virulence studies, can be rapidly performed in a clinical environment to effectively contribute to patient care decisions and public health maneuvers.
The CD8
+
Memory Stem T Cell (T
SCM
) Subset Is Associated with Improved Prognosis in Chronic HIV-1 Infection
Authors: Ribeiro Susan P. , Milush Jeffrey M. , Cunha-Neto Edecio , Kallas Esper G. , Kalil Jorge , Somsouk Ma , Hunt Peter W. , Deeks Steven G. , Nixon Douglas F. , SenGupta Devi 
Published: September 2014

ABSTRACT

Memory stem T cells (T
SCM
) constitute a long-lived, self-renewing lymphocyte population essential for the maintenance of functional immunity. The hallmarks of HIV-1 pathogenesis are CD4
+
T cell depletion and abnormal cellular activation. We investigated the impact of HIV-1 infection on the T
SCM
compartment, as well as any protective role these cells may have in disease progression, by characterizing this subset in a cohort of 113 subjects with various degrees of viral control on and off highly active antiretroviral therapy (HAART). We observed that the frequency of CD8
+
T
SCM
was decreased in all individuals with chronic, untreated HIV-1 infection and that HAART had a restorative effect on this subset. In contrast, natural controllers of HIV-1 had the highest absolute number of CD4
+
T
SCM
cells among all of the infected groups. The frequency of CD4
+
T
SCM
predicted higher CD8
+
T
SCM
frequencies, consistent with a role for the CD4
+
subset in helping to maintain CD8
+
memory T cells. In addition, T
SCM
appeared to be progenitors for effector T cells (T
EM
), as these two compartments were inversely correlated. Increased frequencies of CD8
+
T
SCM
predicted lower viral loads, higher CD4
+
counts, and less CD8
+
T cell activation. Finally, we found that T
SCM
express the mucosal homing integrin α4β7 and can be identified in gut-associated lymphoid tissue (GALT). The frequency of mucosal CD4
+
T
SCM
was inversely correlated with that in the blood, potentially reflecting the ability of these self-renewing cells to migrate to a crucial site of ongoing viral replication and CD4
+
T cell depletion.

IMPORTANCE
HIV-1 infection leads to profound impairment of the immune system. T
SCM
constitute a recently identified lymphocyte subset with stem cell-like qualities, including the ability to generate other memory T cell subtypes, and are therefore likely to play an important role in controlling viral infection. We investigated the relationship between the size of the CD8
+
T
SCM
compartment and HIV-1 disease progression in a cohort of chronically infected individuals. Our results suggest that HAART restores a normal frequency of CD8
+
T
SCM
and that the natural preservation of this subset in the setting of untreated HIV-1 infection is associated with improved viral control and immunity. Therefore, the CD8
+
T
SCM
population may represent a correlate of protection in chronic HIV-1 infection that is directly relevant to the design of T cell-based vaccines, adoptive immunotherapy approaches, or the pharmacologic induction of T
SCM
.
DnaJA1/Hsp40 Is Co-Opted by Influenza A Virus To Enhance Its Viral RNA Polymerase Activity
Authors: Cao Mengmeng , Wei Candong , Zhao Lili , Wang Jingfeng , Jia Qiannan , Wang Xue , Jin Qi , Deng Tao 
Published: September 2014

ABSTRACT

The RNA-dependent RNA polymerase (RdRp) of influenza A virus is a heterotrimeric complex composed of the PB1, PB2, and PA subunits. The interplay between host factors and the three subunits of the RdRp is critical to enable viral RNA synthesis to occur in the nuclei of infected cells. In this study, we newly identified host factor DnaJA1, a member of the type I DnaJ/Hsp40 family, acting as a positive regulator for influenza virus replication. We found that DnaJA1 associates with the bPB2 and PA subunits and enhances viral RNA synthesis both
in vivo
and
in vitro
. Moreover, DnaJA1 could be translocated from cytoplasm into the nucleus upon influenza virus infection. The translocation of DnaJA1 is specifically accompanied by PB1-PA nuclear import. Interestingly, we observed that the effect of DnaJA1 on viral RNA synthesis is mainly dependent on its C-terminal substrate-binding domain and not on its typical J domain, while the J domain normally mediates the Hsp70-DnaJ interaction required for regulating Hsp70 ATPase activity. Therefore, we propose that DnaJA1 is co-opted by the influenza A virus to enter the nucleus and to enhance its RNA polymerase activity in an Hsp70 cochaperone-independent manner.

IMPORTANCE
The interplay between host factors and influenza virus RNA polymerase plays a critical role in determining virus pathogenicity and host adaptation. In this study, we newly identified a host protein, DnaJA1/Hsp40, that is co-opted by influenza A virus RNA polymerase to enhance its viral RNA synthesis in the nuclei of infected cells. We found that DnaJA1 associates with both PB2 and PA subunits and translocates into the nucleus along with the nuclear import of the PB1-PA dimer during influenza virus replication. Interestingly, the effect of DnaJA1 is mainly dependent on its C-terminal substrate-binding domain and not on its typical J domain, which is required for its Hsp70 cochaperone function. To our knowledge, this is the first report on a member of the Hsp40s that is specifically involved in regulating influenza virus RNA polymerase. Targeting the interactions between polymerase subunits and DnaJA1 may provide a novel strategy to develop antiviral drugs.
Cancer-Associated Adipose Tissue Promotes Breast Cancer Progression by Paracrine Oncostatin M and Jak/STAT3 Signaling
Authors: Lapeire Lore , Hendrix An , Lambein Kathleen , Van Bockstal Mieke , Braems Geert , Van Den Broecke Rudy , Limame Ridha , Mestdagh Pieter , Vandesompele Jo , Vanhove Christian , Maynard Dawn , Lehuédé Camille , Muller Catherine , Valet Philippe , Gespach Christian P. , Bracke Marc , Cocquyt Veronique , Denys Hannelore , De Wever Olivier 
Published: September 2014

Abstract
Increasing evidence supports the critical roles played by adipose tissue in breast cancer progression. Yet, the mediators and mechanisms are poorly understood. Here, we show that breast cancer–associated adipose tissue from freshly isolated tumors promotes F-actin remodeling, cellular scattering, invasiveness, and spheroid reorganization of cultured breast cancer cells. A combination of techniques, including transcriptomics, proteomics, and kinomics enabled us to identify paracrine secretion of oncostatin M (OSM) by cancer-associated adipose tissue. Specifically, OSM, expressed by CD45+ leucocytes in the stromal vascular fraction, induced phosphorylation of STAT3 (pSTAT3-) Y705 and S727 in breast cancer cells and transcription of several STAT3-dependent genes, including S100 family members S100A7, S100A8, and S100A9. Autocrine activation of STAT3 in MCF-7 cells ectopically expressing OSM-induced cellular scattering and peritumoral neovascularization of orthotopic xenografts. Conversely, selective inhibition of OSM by neutralizing antibody and Jak family kinases by tofacitinib inhibited STAT3 signaling, peritumoral angiogenesis, and cellular scattering. Importantly, nuclear staining of pSTAT3-Y705 identified at the tumor invasion front in ductal breast carcinomas correlates with increased lymphovascular invasion. Our work reveals the potential of novel therapeutic strategies targeting the OSM and STAT3 axis in patients with breast cancer harboring nuclear pSTAT3-Y705. Cancer Res; 74(23); 6806–19. ©2014 AACR.
A Recurrent Activating PLCG1 Mutation in Cardiac Angiosarcomas Increases Apoptosis Resistance and Invasiveness of Endothelial Cells
Authors: Kunze Kristin , Spieker Tilmann , Gamerdinger Ulrike , Nau Kerstin , Berger Johannes , Dreyer Thomas , Sindermann Jürgen R. , Hoffmeier Andreas , Gattenlöhner Stefan , Bräuninger Andreas 
Published: September 2014

Abstract
Primary cardiac angiosarcomas are rare tumors with unfavorable prognosis. Pathogenic driver mutations are largely unknown. We therefore analyzed a collection of cases for genomic aberrations using SNP arrays and targeted next-generation sequencing (tNGS) of oncogenes and tumor-suppressor genes. Recurrent gains of chromosome 1q and a small region of chromosome 4 encompassing KDR and KIT were identified by SNP array analysis. Repeatedly mutated genes identified by tNGS were KDR with different nonsynonymous mutations, MLL2 with different nonsense mutations, and PLCG1 with a recurrent nonsynonymous mutation (R707Q) in the highly conserved autoinhibitory SH2 domain in three of 10 cases. PLCγ1 is usually activated by Y783 phosphorylation and activates protein kinase C and Ca2+-dependent second messengers, with effects on cellular proliferation, migration, and invasiveness. Ectopic expression of the PLCγ1-R707Q mutant in endothelial cells revealed reduced PLCγ1-Y783 phosphorylation with concomitant increased c-RAF/MEK/ERK1/2 phosphorylation, increased IP3 amounts, and increased Ca2+-dependent calcineurin activation compared with ectopic expressed PLCγ1-wild-type. Furthermore, cofilin, whose activation is associated with actin skeleton reorganization, showed decreased phosphorylation, and thus activation after expression of PLCγ1-R707Q compared with PLCγ1-wild-type. At the cellular level, expression of PLCγ1-R707Q in endothelial cells had no influence on proliferation rate, but increased apoptosis resistance and migration and invasiveness in in vitro assays. Together, these findings indicate that the PLCγ1-R707Q mutation causes constitutive activation of PLCγ1 and may represent an alternative way of activation of KDR/PLCγ1 signaling besides KDR activation in angiosarcomas, with implications for VEGF/KDR targeted therapies. Cancer Res; 74(21); 6173–83. ©2014 AACR.
Coordinate Hyperactivation of Notch1 and Ras/MAPK Pathways Correlates with Poor Patient Survival: Novel Therapeutic Strategy for Aggressive Breast Cancers
Authors: Mittal Suruchi , Sharma Ankur , Balaji Sai A. , Gowda Manju C. , Dighe Rajan R. , Kumar Rekha V. , Rangarajan Annapoorni 
Published: September 2014

Abstract
Aberrant activation of Notch and Ras pathways has been detected in breast cancers. A synergy between these two pathways has also been shown in breast cell transformation in culture. Yet, the clinical relevance of Notch–Ras cooperation in breast cancer progression remains unexplored. In this study, we show that coordinate hyperactivation of Notch1 and Ras/MAPK pathways in breast cancer patient specimens, as assessed by IHC for cleaved Notch1 and pErk1/2, respectively, correlated with early relapse to vital organs and poor overall survival. Interestingly, majority of such Notch1highErkhigh cases encompassed the highly aggressive triple-negative breast cancers (TNBC), and were enriched in stem cell markers. We further show that combinatorial inhibition of Notch1 and Ras/MAPK pathways, using a novel mAb against Notch1 and a MEK inhibitor, respectively, led to a significant reduction in proliferation and survival of breast cancer cells compared with individual inhibition. Combined inhibition also abrogated sphere-forming potential, and depleted the putative cancer stem-like cell subpopulation. Most importantly, combinatorial inhibition of Notch1 and Ras/MAPK pathways completely blocked tumor growth in a panel of breast cancer xenografts, including the TNBCs. Thus, our study identifies coordinate hyperactivation of Notch1 and Ras/MAPK pathways as novel biomarkers for poor breast cancer outcome. Furthermore, based on our preclinical data, we propose combinatorial targeting of these two pathways as a treatment strategy for highly aggressive breast cancers, particularly the TNBCs that currently lack any targeted therapeutic module. Mol Cancer Ther; 13(12); 3198–209. ©2014 AACR.
Antitumor Effects of a Novel Small Molecule Targeting PCNA Chromatin Association in Prostate Cancer
Authors: Dillehay Kelsey L. , Lu Shan , Dong Zhongyun 
Published: September 2014

AbstractProliferating cell nuclear antigen (PCNA) plays an essential role in DNA replication and repair. Tumor cells express high levels of PCNA, identifying it as a potentially ideal target for cancer therapy. Previously, we identified nine compounds termed PCNA inhibitors (PCNA-Is) that bind directly to PCNA, stabilize PCNA trimer structure, reduce chromatin-associated PCNA, and selectively inhibit tumor cell growth. Of these compounds, PCNA-I1 is most potent. The purposes of this study were to further investigate the effects of targeting PCNA chromatin association on DNA damage and cytotoxicity and to evaluate the therapeutic potential of PCNA-I1 against tumors in mice. Given the important roles of tumor suppressor p53 in regulating sensitivity of tumor cells to chemotherapeutics, we performed studies in two human prostate cancer cell lines differing in p53 expression: LNCaP cells (wild-type p53) and PC-3 cells (p53-null). PCNA-I1 induced DNA damage and apoptosis in both LNCaP and PC-3 cells and enhanced DNA damage and apoptosis triggered by cisplatin. PCNA-I1 also induced autophagy in PC-3 cells. A short-term pretreatment with PCNA-I1 reduced colony formation by 50% in both cell lines. These data suggest that, unlike many other cytotoxic drugs, the effects of PCNA-I1 on tumor cells do not depend on expression of p53. Intravenous administrations of PCNA-I1 significantly retarded growth of LNCaP tumors of in nude mice without causing detectable effects on mouse body weight and hematology profiles. These data provide proof of concept that targeting PCNA chromatin association could be a novel and effective therapeutic approach for treatment of cancer. Mol Cancer Ther; 13(12); 2817–26. ©2014 AACR.
A p53/ARF-Dependent Anticancer Barrier Activates Senescence and Blocks Tumorigenesis without Impacting Apoptosis
Authors: Sinha Vidya C. , Qin Lan , Li Yi 
Published: September 2014

Abstract
In response to oncogene activation and oncogene-induced aberrant proliferation, mammalian cells activate apoptosis and senescence, usually via the p53–ARF tumor-suppressor pathway. Apoptosis is a known barrier to cancer and is usually downregulated before full malignancy, but senescence as an anticancer barrier is controversial due to its presence in the tumor environment. In addition, senescence may aid cancer progression via releasing senescence-associated factors that instigate neighboring tumor cells. Here, it is demonstrated that apoptosis unexpectedly remains robust in ErbB2 (ERBB2/HER2)-initiated mammary early lesions arising in adult mice null for either p53 or ARF. These early lesions, however, downregulate senescence significantly. This diminished senescence response is associated with accelerated progression to cancer in ARF-null mice compared with ARF–wild-type mice. Thus, the ARF–p53 pathway is dispensable for the apoptosis anticancer barrier in the initiation of ErbB2 breast cancer, the apoptosis barrier alone cannot halt mammary tumorigenesis, and senescence is a key barrier against carcinogenesis.
Implications: Findings in this relevant mouse model of HER2-driven breast cancer suggest that effective prevention relies upon preserving both ARF/p53–independent apoptosis and ARF/p53–dependent senescence. Mol Cancer Res; 13(2); 231–8. ©2014 AACR.
PARP1-Driven Poly-ADP-Ribosylation Regulates BRCA1 Function in Homologous Recombination–Mediated DNA Repair
Authors: Hu Yiduo , Petit Sarah A. , Ficarro Scott B. , Toomire Kimberly J. , Xie Anyong , Lim Elgene , Cao Shiliang A. , Park Eunyoung , Eck Michael J. , Scully Ralph , Brown Myles , Marto Jarrod A. , Livingston David M. 
Published: September 2014

Abstract
BRCA1 promotes homologous recombination–mediated DNA repair (HRR). However, HRR must be tightly regulated to prevent illegitimate recombination. We previously found that BRCA1 HRR function is regulated by the RAP80 complex, but the mechanism was unclear. We have now observed that PARP1 interacts with and poly-ADP-ribosylates (aka PARsylates) BRCA1. PARsylation is directed at the BRCA1 DNA binding domain and downmodulates its function. Moreover, RAP80 contains a poly-ADP-ribose–interacting domain that binds PARsylated BRCA1 and helps to maintain the stability of PARP1–BRCA1–RAP80 complexes. BRCA1 PARsylation is a key step in BRCA1 HRR control. When BRCA1 PARsylation is defective, it gives rise to excessive HRR and manifestations of genome instability. BRCA1 PARsylation and/or RAP80 expression is defective in a subset of sporadic breast cancer cell lines and patient-derived tumor xenograft models. These observations are consistent with the possibility that such defects, when chronic, contribute to tumor development in BRCA1+/+ individuals.
Significance: We propose a model that describes how BRCA1 functions to both support and restrict HRR. BRCA1 PARsylation is a key event in this process, failure of which triggers hyper-recombination and chromosome instability. Thus, hyperfunctioning BRCA1 can elicit genomic abnormalities similar to those observed in the absence of certain BRCA1 functions. Cancer Discov; 4(12); 1430–47. ©2014 AACR.
This article is highlighted in the In This Issue feature, p. 1355
Akt protects the heart against ischaemia-reperfusion injury by modulating mitochondrial morphology
Authors: Ong Sang-Bing , Hall Andrew , Dongworth Rachel , Kalkhoran Siavash , Pyakurel Aswin , Scorrano Luca , Hausenloy Derek 
Published: September 2014

SummaryThe mechanism through which the protein kinase Akt (also called PKB), protects the heart against acute ischaemia-reperfusion injury (IRI) is not clear. Here, we investigate whether Akt mediates its cardioprotective effect by modulating mitochondrial morphology. Transfection of HL-1 cardiac cells with constitutively active Akt (caAkt) changed mitochondrial morphology as evidenced by an increase in the proportion of cells displaying predominantly elongated mitochondria (73 ± 5.0 % caAkt vs 49 ± 5.8 % control: N=80 cells/group; p< 0.05). This effect was associated with delayed time taken to induce mitochondrial permeability transition pore (MPTP) opening (by 2.4 ± 0.5 fold; N=80 cells/group: p< 0.05); and reduced cell death following simulated IRI (32.8 ± 1.2 % caAkt vs 63.8 ± 5.6 % control: N=320 cells/group: p< 0.05). Similar effects on mitochondrial morphology, MPTP opening, and cell survival post-IRI, were demonstrated with pharmacological activation of Akt using the known cardioprotective cytokine, erythropoietin (EPO). The effect of Akt on inducing mitochondrial elongation was found to be dependent on the mitochondrial fusion protein, Mitofusin-1 (Mfn1), as ablation of Mfn1 in mouse embryonic fibroblasts (MEFs) abrogated Akt-mediated mitochondrial elongation. Finally, in vivo pre-treatment with EPO reduced myocardial infarct size (as a % of the area at risk) in adult mice subjected to IRI (26.2 ± 2.6 % with EPO vs 46.1 ± 6.5 % in control; N=7/group: p< 0.05), and reduced the proportion of cells displaying myofibrillar disarray and mitochondrial fragmentation observed by electron microscopy in adult murine hearts subjected to ischaemia from 5.8 ± 1.0 % to 2.2 ± 1.0 % (N=5 hearts/group; p< 0.05). In conclusion, we found that either genetic or pharmacological activation of Akt protected the heart against acute ischaemia-reperfusion injury by modulating mitochondrial morphology.
Causes and Implications of Extreme Atmospheric Moisture Demand during the Record-Breaking 2011 Wildfire Season in the Southwestern United States
Authors: Williams A. Park , Seager Richard , Berkelhammer Max , Macalady Alison K. , Crimmins Michael A. , Swetnam Thomas W. , Trugman Anna T. , Buenning Nikolaus , Hryniw Natalia , McDowell Nate G. , Noone David , Mora Claudia I. , Rahn Thom 
Published: September 2014

AbstractIn 2011, exceptionally low atmospheric moisture content combined with moderately high temperatures to produce a record-high vapor pressure deficit (VPD) in the southwestern United States (SW). These conditions combined with record-low cold-season precipitation to cause widespread drought and extreme wildfires. Although interannual VPD variability is generally dominated by temperature, high VPD in 2011 was also driven by a lack of atmospheric moisture. The May–July 2011 dewpoint in the SW was 4.5 standard deviations below the long-term mean. Lack of atmospheric moisture was promoted by already very dry soils and amplified by a strong ocean-to-continent sea level pressure gradient and upper-level convergence that drove dry northerly winds and subsidence upwind of and over the SW. Subsidence drove divergence of rapid and dry surface winds over the SW, suppressing southerly moisture imports and removing moisture from already dry soils. Model projections developed for the fifth phase of the Coupled Model Intercomparison Project (CMIP5) suggest that by the 2050s warming trends will cause mean warm-season VPD to be comparable to the record-high VPD observed in 2011. CMIP5 projections also suggest increased interannual variability of VPD, independent of trends in background mean levels, as a result of increased variability of dewpoint, temperature, vapor pressure, and saturation vapor pressure. Increased variability in VPD translates to increased probability of 2011-type VPD anomalies, which would be superimposed on ever-greater background VPD levels. Although temperature will continue to be the primary driver of interannual VPD variability, 2011 served as an important reminder that atmospheric moisture content can also drive impactful VPD anomalies.