bluuebunny/crossref_metadata_2025_split huggingface dataset:
Within-Host Variations of Human Papillomavirus Reveal APOBEC Signature Mutagenesis in the Viral Genome
Authors: Hirose Yusuke , Onuki Mamiko , Tenjimbayashi Yuri , Mori Seiichiro , Ishii Yoshiyuki , Takeuchi Takamasa , Tasaka Nobutaka , Satoh Toyomi , Morisada Tohru , Iwata Takashi , Miyamoto Shingo , Matsumoto Koji , Sekizawa Akihiko , Kukimoto Iwao 
Published: March 2018

ABSTRACT

Persistent infection with oncogenic human papillomaviruses (HPVs) causes cervical cancer, accompanied by the accumulation of somatic mutations into the host genome. There are concomitant genetic changes in the HPV genome during viral infection; however, their relevance to cervical carcinogenesis is poorly understood. Here, we explored within-host genetic diversity of HPV by performing deep-sequencing analyses of viral whole-genome sequences in clinical specimens. The whole genomes of HPV types 16, 52, and 58 were amplified by type-specific PCR from total cellular DNA of cervical exfoliated cells collected from patients with cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC) and were deep sequenced. After constructing a reference viral genome sequence for each specimen, nucleotide positions showing changes with >0.5% frequencies compared to the reference sequence were determined for individual samples. In total, 1,052 positions of nucleotide variations were detected in HPV genomes from 151 samples (CIN1,
n
= 56; CIN2/3,
n
= 68; ICC,
n
= 27), with various numbers per sample. Overall, C-to-T and C-to-A substitutions were the dominant changes observed across all histological grades. While C-to-T transitions were predominantly detected in CIN1, their prevalence was decreased in CIN2/3 and fell below that of C-to-A transversions in ICC. Analysis of the trinucleotide context encompassing substituted bases revealed that TpCpN, a preferred target sequence for cellular APOBEC cytosine deaminases, was a primary site for C-to-T substitutions in the HPV genome. These results strongly imply that the APOBEC proteins are drivers of HPV genome mutation, particularly in CIN1 lesions.

IMPORTANCE
HPVs exhibit surprisingly high levels of genetic diversity, including a large repertoire of minor genomic variants in each viral genotype. Here, by conducting deep-sequencing analyses, we show for the first time a comprehensive snapshot of the within-host genetic diversity of high-risk HPVs during cervical carcinogenesis. Quasispecies harboring minor nucleotide variations in viral whole-genome sequences were extensively observed across different grades of CIN and cervical cancer. Among the within-host variations, C-to-T transitions, a characteristic change mediated by cellular APOBEC cytosine deaminases, were predominantly detected throughout the whole viral genome, most strikingly in low-grade CIN lesions. The results strongly suggest that within-host variations of the HPV genome are primarily generated through the interaction with host cell DNA-editing enzymes and that such within-host variability is an evolutionary source of the genetic diversity of HPVs.
Kinetic Modeling of Virus Growth in Cells
Authors: Yin John , Redovich Jacob 
Published: March 2018

SUMMARYWhen a virus infects a host cell, it hijacks the biosynthetic capacity of the cell to produce virus progeny, a process that may take less than an hour or more than a week. The overall time required for a virus to reproduce depends collectively on the rates of multiple steps in the infection process, including initial binding of the virus particle to the surface of the cell, virus internalization and release of the viral genome within the cell, decoding of the genome to make viral proteins, replication of the genome, assembly of progeny virus particles, and release of these particles into the extracellular environment. For a large number of virus types, much has been learned about the molecular mechanisms and rates of the various steps. However, in only relatively few cases during the last 50 years has an attempt been made—using mathematical modeling—to account for how the different steps contribute to the overall timing and productivity of the infection cycle in a cell. Here we review the initial case studies, which include studies of the one-step growth behavior of viruses that infect bacteria (Qβ, T7, and M13), human immunodeficiency virus, influenza A virus, poliovirus, vesicular stomatitis virus, baculovirus, hepatitis B and C viruses, and herpes simplex virus. Further, we consider how such models enable one to explore how cellular resources are utilized and how antiviral strategies might be designed to resist escape. Finally, we highlight challenges and opportunities at the frontiers of cell-level modeling of virus infections.
Delineating the trajectories of social and occupational functioning of young people attending early intervention mental health services in Australia: a longitudinal study
Authors: Iorfino Frank , Hermens Daniel F , Cross Shane, PM , Zmicerevska Natalia , Nichles Alissa , Badcock Caro-Anne , Groot Josine , Scott Elizabeth M , Hickie Ian B 
Published: March 2018

ObjectivesMental disorders typically emerge during adolescence and young adulthood and put young people at risk for prolonged socioeconomic difficulties. This study describes the longitudinal course of social and occupational functioning of young people attending primary care-based, early intervention services.DesignA longitudinal study of young people receiving mental healthcare.SettingData were collected between January 2005 and August 2017 from a designated primary care-based mental health service.Participants554 young people (54% women) aged 12–32 years.MeasuresA systematic medical file audit collected clinical and functional information at predetermined time intervals (ie, 3 months to 5+ years) using a clinical pro forma. Group-based trajectory modelling (GBTM) was used to identify distinct trajectories of social and occupational functioning over time (median number of observations per person=4; median follow-up time=23 months).ResultsBetween first clinical contact and time last seen, 15% of young people had reliably deteriorated, 23% improved and 62% did not demonstrate substantive change in function. Of the whole cohort, 69% had functional scores less than 70 at time last seen, indicative of ongoing and substantive impairment. GBTM identified six distinct functional trajectories whereby over 60% had moderate-to-serious functional impairment at entry and remained chronically impaired over time; 7% entered with serious impairment and deteriorated further; a quarter were mildly impaired at entry and functionally recovered and only a small minority (4%) presented with serious impairments and functionally improved over time. Not being in education, employment or training, previous hospitalisation and a younger age at baseline emerged as significant predictors of these functional trajectories.ConclusionYoung people with emerging mental disorders have significant functional impairment at presentation for care, and for the majority, it persists over the course of clinical care. In addition to providing clinical care earlier in the course of illness, these data suggest that more sophisticated and more intensive individual-level and organisational strategies may be required to achieve significant and sustained functional improvements.
Flow cytometric minimal residual disease assessment of peripheral blood in acute lymphoblastic leukaemia patients has potential for early detection of relapsed extramedullary disease
Authors: Keegan Alissa , Charest Karry , Schmidt Ryan , Briggs Debra , Deangelo Daniel J , Li Betty , Morgan Elizabeth A , Pozdnyakova Olga 
Published: March 2018

ObjectivesTo evaluate peripheral blood (PB) for minimal residual disease (MRD) assessment in adults with acute lymphoblastic leukaemia (ALL).MethodsWe analysed 76 matched bone marrow (BM) aspirate and PB specimens independently for the presence of ALL MRD by six-colour flow cytometry (FC).ResultsThe overall rate of BM MRD-positivity was 24% (18/76) and PB was also MRD-positive in 22% (4/18) of BM-positive cases. We identified two cases with evidence of leukaemic cells in PB at the time of the extramedullary relapse that were interpreted as MRD-negative in BM.ConclusionsThe use of PB MRD as a non-invasive method for monitoring of systemic relapse may have added clinical and diagnostic value in patients with high risk of extramedullary disease.
Photodegraded dissolved organic matter from peak freshet river discharge as a substrate for bacterial production in a lake-rich great Arctic delta
Authors: Gareis Jolie A.L. , Lesack Lance F.W. 
Published: March 2018

Lake-rich Arctic river deltas are recharged with terrigenous dissolved organic matter (DOM) during the yearly peak water period corresponding with the solstice (24 h day−1 solar irradiance). Bacteria-free DOM collected during peak Mackenzie River discharge was exposed to sunlight for up to 14 days in June 2010. As solar exposure increased, carbon and lignin concentrations declined (10% and 42%, respectively, after 14 days), as did DOM absorptivity (62% after 14 days), aromaticity, and molecular weight. Photochemical changes were on par with those normally observed in Mackenzie Delta lakes over the entire open-water season. When irradiated freshet DOM was provided as a substrate, no significant differences were observed in community-level metabolism among five bacterial communities from representative delta habitats. However, bacterial abundance was significantly greater when nonirradiated (0 day) rather than irradiated DOM (7 or 14 days) was provided, while cell-specific metabolic measures revealed that per-cell bacterial production and growth efficiency were significantly greater when communities were provided irradiated substrate. This complex response to rapid DOM photodegradation may result from the production of inhibitory reactive oxygen species (ROS), along with shifts in bacterial community composition to species that are better able to tolerate ROS, or metabolize the labile photodegraded DOM.
IκB Kinase α Is Required for Development and Progression of KRAS-Mutant Lung Adenocarcinoma
Authors: Vreka Malamati , Lilis Ioannis , Papageorgopoulou Maria , Giotopoulou Georgia A. , Lianou Marina , Giopanou Ioanna , Kanellakis Nikolaos I. , Spella Magda , Agalioti Theodora , Armenis Vasileios , Goldmann Torsten , Marwitz Sebastian , Yull Fiona E. , Blackwell Timothy S. , Pasparakis Manolis , Marazioti Antonia , Stathopoulos Georgios T. 
Published: March 2018

Abstract
Although oncogenic activation of NFκB has been identified in various tumors, the NFκB–activating kinases (inhibitor of NFκB kinases, IKK) responsible for this are elusive. In this study, we determined the role of IKKα and IKKβ in KRAS-mutant lung adenocarcinomas induced by the carcinogen urethane and by respiratory epithelial expression of oncogenic KRASG12D. Using NFκB reporter mice and conditional deletions of IKKα and IKKβ, we identified two distinct early and late activation phases of NFκB during chemical and genetic lung adenocarcinoma development, which were characterized by nuclear translocation of RelB, IκBβ, and IKKα in tumor-initiated cells. IKKα was a cardinal tumor promoter in chemical and genetic KRAS-mutant lung adenocarcinoma, and respiratory epithelial IKKα-deficient mice were markedly protected from the disease. IKKα specifically cooperated with mutant KRAS for tumor induction in a cell-autonomous fashion, providing mutant cells with a survival advantage in vitro and in vivo. IKKα was highly expressed in human lung adenocarcinoma, and a heat shock protein 90 inhibitor that blocks IKK function delivered superior effects against KRAS-mutant lung adenocarcinoma compared with a specific IKKβ inhibitor. These results demonstrate an actionable requirement for IKKα in KRAS-mutant lung adenocarcinoma, marking the kinase as a therapeutic target against this disease.
Significance: These findings report a novel requirement for IKKα in mutant KRAS lung tumor formation, with potential therapeutic applications. Cancer Res; 78(11); 2939–51. ©2018 AACR.
A G3BP1-Interacting lncRNA Promotes Ferroptosis and Apoptosis in Cancer via Nuclear Sequestration of p53
Authors: Mao Chao , Wang Xiang , Liu Yating , Wang Min , Yan Bin , Jiang Yiqun , Shi Ying , Shen Yi , Liu Xiaoli , Lai Weiwei , Yang Rui , Xiao Desheng , Cheng Yan , Liu Shuang , Zhou Hu , Cao Ya , Yu Weishi , Muegge Kathrin , Yu Herbert , Tao Yongguang 
Published: March 2018

Abstract
Long noncoding RNAs (lncRNA) have been associated with various types of cancer; however, the precise role of many lncRNAs in tumorigenesis remains elusive. Here we demonstrate that the cytosolic lncRNA P53RRA is downregulated in cancers and functions as a tumor suppressor by inhibiting cancer progression. Chromatin remodeling proteins LSH and Cfp1 silenced or increased P53RRA expression, respectively. P53RRA bound Ras GTPase-activating protein-binding protein 1 (G3BP1) using nucleotides 1 and 871 of P53RRA and the RRM interaction domain of G3BP1 (aa 177-466). The cytosolic P53RRA–G3BP1 interaction displaced p53 from a G3BP1 complex, resulting in greater p53 retention in the nucleus, which led to cell-cycle arrest, apoptosis, and ferroptosis. P53RRA promoted ferroptosis and apoptosis by affecting transcription of several metabolic genes. Low P53RRA expression significantly correlated with poor survival in patients with breast and lung cancers harboring wild-type p53. These data show that lncRNAs can directly interact with the functional domain of signaling proteins in the cytoplasm, thus regulating p53 modulators to suppress cancer progression.
Significance: A cytosolic lncRNA functions as a tumor suppressor by activating the p53 pathway. Cancer Res; 78(13); 3484–96. ©2018 AACR.
ONC201 Targets AR and AR-V7 Signaling, Reduces PSA, and Synergizes with Everolimus in Prostate Cancer
Authors: Lev Avital , Lulla Amriti R. , Ross Brian C. , Ralff Marie D. , Makhov Petr B. , Dicker David T. , El-Deiry Wafik S. 
Published: March 2018

Abstract
Androgen receptor (AR) signaling plays a key role in prostate cancer progression, and androgen deprivation therapy (ADT) is a mainstay clinical treatment regimen for patients with advanced disease. Unfortunately, most prostate cancers eventually become androgen-independent and resistant to ADT with patients progressing to metastatic castration-resistant prostate cancer (mCRPC). Constitutively activated AR variants (AR-V) have emerged as mediators of resistance to AR-targeted therapy and the progression of mCRPC, and they represent an important therapeutic target. Out of at least 15 AR-Vs described thus far, AR-V7 is the most abundant, and its expression correlates with ADT resistance. ONC201/TIC10 is the founding member of the imipridone class of small molecules and has shown anticancer activity in a broad range of tumor types. ONC201 is currently being tested in phase I/II clinical trials for advanced solid tumors, including mCRPC, and hematologic malignancies. There has been promising activity observed in patients in early clinical testing. This study demonstrates preclinical single-agent efficacy of ONC201 using in vitro and in vivo models of prostate cancer. ONC201 has potent antiproliferative and proapoptotic effects in both castration-resistant and -sensitive prostate cancer cells. Furthermore, the data demonstrate that ONC201 downregulates the expression of key drivers of prostate cancer such as AR-V7 and downstream target genes including the clinically used biomarker PSA (KLK3). Finally, the data also provide a preclinical rationale for combination of ONC201 with approved therapeutics for prostate cancer such as enzalutamide, everolimus (mTOR inhibitor), or docetaxel.
Implications: The preclinical efficacy of ONC201 as a single agent or in combination, in hormone-sensitive or castration-resistant prostate cancer, suggests the potential for immediate clinical translation. Mol Cancer Res; 16(5); 754–66. ©2018 AACR.
Comparison of Time-to-First Event and Recurrent-Event Methods in Randomized Clinical Trials
Authors: Claggett Brian , Pocock Stuart , Wei L.J. , Pfeffer Marc A. , McMurray John J.V. , Solomon Scott D. 
Published: March 2018

Background:
Most phase-3 trials feature time-to-first event end points for their primary and secondary analyses. In chronic diseases, where a clinical event can occur >1 time, recurrent-event methods have been proposed to more fully capture disease burden and have been assumed to improve statistical precision and power compared with conventional time-to-first methods.

Methods:
To better characterize factors that influence statistical properties of recurrent-event and time-to-first methods in the evaluation of randomized therapy, we repeatedly simulated trials with 1:1 randomization of 4000 patients to active versus control therapy, with true patient-level risk reduction of 20% (ie, relative risk=0.80). For patients who discontinued active therapy after a first event, we assumed their risk reverted subsequently to their original placebo-level risk. Through simulation, we varied the degree of between-patient heterogeneity of risk and the extent of treatment discontinuation. Findings were compared with those from actual randomized clinical trials.

Results:
As the degree of between-patient heterogeneity of risk increased, both time-to-first and recurrent-event methods lost statistical power to detect a true risk reduction and confidence intervals widened. The recurrent-event analyses continued to estimate the true relative risk (0.80) as heterogeneity increased, whereas the Cox model produced attenuated estimates. The power of recurrent-event methods declined as the rate of study drug discontinuation postevent increased. Recurrent-event methods provided greater power than time-to-first methods in scenarios where drug discontinuation was ≤30% after a first event, lesser power with drug discontinuation rates of ≥60%, and comparable power otherwise. We confirmed in several actual trials of chronic heart failure that treatment effect estimates were attenuated when estimated via the Cox model and that increased statistical power from recurrent-event methods was most pronounced in trials with lower treatment discontinuation rates.

Conclusions:
We find that the statistical power of both recurrent-events and time-to-first methods are reduced by increasing heterogeneity of patient risk, a parameter not included in conventional power and sample size formulas. Data from real clinical trials are consistent with simulation studies, confirming that the greatest statistical gains from use of recurrent-events methods occur in the presence of high patient heterogeneity and low rates of study drug discontinuation.
Chinese Medicinal Excrement
Authors: Despeux Catherine 
Published: March 2018

AbstractThe use of medicinal excrement, of which there is some evidence under the Han, increased significantly in the Tang Dynasty. Many recipes, recorded in the Dunhuang manuscripts and in scholarly literature, are based on animal excrement. First, we want to show that this increase is due to the influence of foreign medicines, mainly Āyurvedic medicine and, second, that Buddhism played a key role in this development. By comparing Indian medical sources, Chinese manuscripts from Dunhuang (which was a privileged site for the transfer of knowledge), Chinese texts of scholarly literature, and Buddhist sources, the role of Buddhism in spreading the use of medical excrement can be observed. Buddhism first exerted an ethical influence through the idea of compassion for beings suffering from illness, which then led to the search for first-aid remedies that were cheap and easy to procure, especially in the natural environment, such as the feces of domestic animals. The notion was then conveyed that, beyond the tension between pure and filthy, no remedy is vile and every substance can be a remedy, an idea that can be traced back to Āyurvedic medicine and that is embedded in the story of the model Indian physician, Jīvaka. Finally, the circulation and distribution of animal fecal recipes (here we have taken the example of cow dung) follows the passage of Buddhism from India to China as does the dissemination of such remedies. Thus, we show that Buddhism was a catalyst and a vector for the transmission and transfer of knowledge on medicinal excrement.
Exploring the Source and Potential of Earth–Air Pulsation Using a Closed System
Authors: Li Hongshou 
Published: March 2018

Abstract
Because of Earth’s motion, periodic temperature fluctuations occur in soil on daily and yearly time scales, which inevitably lead to pulsation of the air pressure in the soil. The Earth–air pressure monitoring technique called “hou-qi” is the basis of a calendar formulated by the ancient Chinese. However, the daily/yearly variation of air pressure in the soil is very weak, according to practical monitoring experiments, so hou-qi has long been considered a pseudoscience. To determine the potential maximum change of Earth–air pressure, identify what is causing the underlying Earth–air pressure variation, and reveal the mechanism, we use a closed system, which is a more appropriate system test of the possible validity of hou-qi, to monitor Earth–air pressure variation in this paper. The results show that there are potential air pressure fluctuations of about 120–190 hPa in closed soil over the daily/yearly temperature range of 5°–40°C. This provides ample magnitude for hou-qi. The largest contribution made to Earth–air pressure variation was pressurization due to air warming, with vapor due to water evaporation and desorbed gas having smaller effects. The soil’s water content has a significant effect on Earth–air pressure amplitude. Dry soil contributes almost no water vapor, but the adsorbed gases from dry soil have up to a 38-hPa influence on air pressure. The soil’s salt content also has an important regulating role on Earth–air pressure and can reduce the influence of vapor pressure. This paper provides a scientific basis for the ancient Earth–air monitoring system of hou-qi and also has important significance for hydrometeorology and research on the ancient Chinese civilization.
Physical health problems in people with psychosis: The issue for informal carers
Authors: Onwumere Juliana , Howes Sophia , Shiers David , Gaughran Fiona 
Published: March 2018

Background: Reduced life expectancies are recorded in adults with psychotic disorders. Informal carers play key roles in improving illness outcomes for patients, including significantly reducing rates of relapse and hospitalisation. There is, however, a dearth of literature detailing carers’ perspectives on physical health problems in the relatives they care for and implications for those in the caregiving role. The study sought to explore carers’ subjective experiences of supporting a relative with psychosis and physical health problems. Methods: Carers of adults with psychosis were interviewed individually, or as part of a group, about physical health problems in the relatives they care for. Results: Five key themes were identified from the interviews that reflected (1) ubiquity of physical health problems in psychosis, (2) gaps in service provision for those living with mental and physical health problems, (3) carers’ role in responding to service gaps, (4) difficult conversations and (5) impact on carer health. Conclusion: Service initiatives that are designed to improve patient physical health in psychosis should not overlook the role that informal carers might have in supporting this process. The implications that patient physical health problems present for carer well-being and the quality of the caregiving relationship in psychosis deserve further investigation.