bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of Senescence in Cancer Cells by a Novel Combination of Cucurbitacin B and Withanone: Molecular Mechanism and Therapeutic Potential
Authors: Garg Sukant , Huifu He , Kumari Anjani , Sundar Durai , Kaul Sunil C , Wadhwa Renu 
Published: May 2019

AbstractCancer, an uncontrolled proliferation syndrome, is treated with synthetic chemotherapeutic drugs that are associated with severe adverse effects. Development and application of new natural compounds is warranted to deal with the exponentially increasing incidence of cancer worldwide. Keeping selective toxicity to cancer cells as a priority criterion, we developed a combination of Cucurbitacin B and Withanone, and analyzed its anticancer potential using non-small cell lung cancer cells. We demonstrate that the selective cytotoxicity of the combination, called CucWi-N, to cancer cells is mediated by induction of cellular senescence that was characterized by decrease in Lamin A/C, CDK2, CDK4, Cyclin D, Cyclin E, phosphorylated RB, mortalin and increase in p53 and CARF proteins. It compromised cancer cell migration that was mediated by decrease in mortalin, hnRNP-K, vascular endothelial growth factor, matrix metalloproteinase 2, and fibronectin. We provide in silico, molecular dynamics and experimental data to support that CucWi-N (i) possesses high capability to target mortalin–p53 interaction and hnRNP-K proteins, (ii) triggers replicative senescence and inhibits metastatic potential of the cancer cells, and (iii) inhibits tumor progression and metastasis in vivo. We propose that CucWi-N is a potential natural anticancer drug that warrants further mechanistic and clinical studies.
CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease
Authors: Magg Thomas , Shcherbina Anna , Arslan Duran , Desai Mukesh M , Wall Sarah , Mitsialis Vanessa , Conca Raffaele , Unal Ekrem , Karacabey Neslihan , Mukhina Anna , Rodina Yulia , Taur Prasad D , Illig David , Marquardt Benjamin , Hollizeck Sebastian , Jeske Tim , Gothe Florian , Schober Tilmann , Rohlfs Meino , Koletzko Sibylle , Lurz Eberhard , Muise Aleixo M , Snapper Scott B , Hauck Fabian , Klein Christoph , Kotlarz Daniel 
Published: May 2019

AbstractBackgroundChildren with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes.MethodsTo identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID.ResultsWhole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency.ConclusionOur study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.
Diverse Developmental Responses to Warming Temperatures Underlie Changes in Flowering Phenologies
Authors: Diggle Pamela K , Mulder Christa P H 
Published: May 2019

AbstractClimate change has resulted in increased temperature means across the globe. Many angiosperms flower earlier in response to rising temperature and the phenologies of these species are reasonably well predicted by models that account for spring (early growing season) and winter temperatures. Surprisingly, however, exceptions to the general pattern of precocious flowering are common. Many species either do not appear to respond or even delay flowering in, or following, warm growing seasons. Existing phenological models have not fully addressed such exceptions to the common association of advancing phenologies with warming temperatures. The phenological events that are typically recorded (e.g., onset of flowering) are but one phase in a complex developmental process that often begins one or more years previously, and flowering time may be strongly influenced by temperature over the entire multi-year course of flower development. We propose a series of models that explore effects of growing-season temperature increase on the multiple processes of flower development and how changes in development may impact the timing of anthesis. We focus on temperate forest trees, which are characterized by preformation, the initiation of flower primordia one or more years prior to anthesis. We then synthesize the literature on flower development to evaluate the models. Although fragmentary, the existing data suggest the potential for temperature to affect all aspects of flower development in woody perennials. But, even for relatively well studied taxa, the critical developmental responses that underlie phenological patterns are difficult to identify. Our proposed models explain the seemingly counter-intuitive observations that warmer growing-season temperatures delay flowering in many species. Future research might concentrate on taxa that do not appear to respond to temperature, or delay flowering in response to warm temperatures, to understand what processes contribute to this pattern.
Temporary disengagement and re-engagement in human immunodeficiency virus care in a rural county serving pastoralist communities in Kenya: a retrospective cohort study
Authors: Yonga Paul , Kalya Stephen , Lynen Lutgarde , Decroo Tom 
Published: May 2019

Abstract

Background
Pastoralist communities are known to be hard to reach. The magnitude of temporary disengagement from human immunodeficiency virus (HIV) care is understudied.

Methods
We conducted a retrospective cohort study of temporary disengagement (2 weeks late for a next appointment), virologic response, lost to follow-up (6 months late) and re-engagement in care among patients who started antiretroviral therapy between 2014 and 2016 in Baringo County, Kenya. Predictors of re-engagement after disengagement were estimated using logistic regression.

Results
Of 342 patients, 76.9% disengaged at least once (range 0–7). Of 218 patients with a viral load (VL), 78.0% had a suppressed VL. Those with a history of temporary disengagement from care were less likely to suppress their VL (p=0.002). Six patients had treatment failure (two consecutive VLs &gt;1000 copies/mm3) and all had disengaged at least once. After disengagement from care, male patients (adjusted odds ratio [aOR] 0.3 [95% confidence interval {CI} 0.2 to 0.6]; p&lt;0.001) and patients with World Health Organization stage III–IV (aOR 0.3 [95% CI 0.1 to 0.5; p&lt;0.001) were less likely to re-engage in care.

Conclusions
Temporary disengagement was frequent in this pastoralist setting. This indicator is often overlooked, as most studies only report binary outcomes, such as retention in care. Innovative strategies are required to achieve HIV control in rural settings like this pastoralist setting.
Disruption of TP63-miR-27a* Feedback Loop by Mutant TP53 in Head and Neck Cancer
Authors: Chari Nikhil S , Ivan Cristina , Le Xiandong , Li Jinzhong , Mijiti Ainiwaer , Patel Ameeta A , Osman Abdullah A , Peterson Christine B , Williams Michelle D , Pickering Curtis R , Caulin Carlos , Myers Jeffrey N , Calin George A , Lai Stephen Y 
Published: May 2019

Abstract

Background
Alterations in the epidermal growth factor receptor and PI3K pathways in head and neck squamous cell carcinomas (HNSCCs) are frequent events that promote tumor progression. Ectopic expression of the epidermal growth factor receptor–targeting microRNA (miR), miR-27a* (miR-27a-5p), inhibits tumor growth. We sought to identify mechanisms mediating repression of miR-27a* in HNSCC, which have not been previously identified.

Methods
We quantified miR-27a* in 47 oral cavity squamous cell carcinoma patient samples along with analysis of miR-27a* in 73 oropharyngeal and 66 human papillomavirus–positive (HPV+) samples from The Cancer Genome Atlas. In vivo and in vitro TP53 models engineered to express mutant TP53, along with promoter analysis using chromatin immunoprecipitation and luciferase assays, were used to identify the role of TP53 and TP63 in miR-27a* transcription. An HNSCC cell line engineered to conditionally express miR-27a* was used in vitro to determine effects of miR-27a* on target genes and tumor cells.

Results
miR-27a* expression was repressed in 47 oral cavity tumor samples vs matched normal tissue (mean log2 difference = −0.023, 95% confidence interval = −0.044 to −0.002; two-sided paired t test, P = .03), and low miR-27a* levels were associated with poor survival in HPV+ and oropharyngeal HNSCC samples. Binding of ΔNp63α to the promoter led to an upregulation of miR-27a*. In vitro and in vivo findings showed that mutant TP53 represses the miR-27a* promoter, downregulating miR-27a* levels. ΔNp63α and nucleoporin 62, a protein involved in ΔNP63α transport, were validated as novel targets of miR-27a*.

Conclusion
Our results characterize a negative feedback loop between TP63 and miR-27a*. Genetic alterations in TP53, a frequent event in HNSCC, disrupt this regulatory loop by repressing miR-27a* expression, promoting tumor survival.
Annual Report to the Nation on the Status of Cancer, Featuring Cancer in Men and Women Age 20–49 Years
Authors: Ward Elizabeth M , Sherman Recinda L , Henley S Jane , Jemal Ahmedin , Siegel David A , Feuer Eric J , Firth Albert U , Kohler Betsy A , Scott Susan , Ma Jiemin , Anderson Robert N , Benard Vicki , Cronin Kathleen A 
Published: May 2019

AbstractBackgroundThe American Cancer Society, Centers for Disease Control and Prevention, National Cancer Institute, and North American Association of Central Cancer Registries provide annual updates on cancer occurrence and trends by cancer type, sex, race, ethnicity, and age in the United States. This year’s report highlights the cancer burden among men and women age 20–49 years.MethodsIncidence data for the years 1999 to 2015 from the Centers for Disease Control and Prevention- and National Cancer Institute–funded population-based cancer registry programs compiled by the North American Association of Central Cancer Registries and death data for the years 1999 to 2016 from the National Vital Statistics System were used. Trends in age-standardized incidence and death rates, estimated by joinpoint, were expressed as average annual percent change.ResultsOverall cancer incidence rates (per 100 000) for all ages during 2011–2015 were 494.3 among male patients and 420.5 among female patients; during the same time period, incidence rates decreased 2.1% (95% confidence interval [CI] = −2.6% to −1.6%) per year in men and were stable in females. Overall cancer death rates (per 100 000) for all ages during 2012–2016 were 193.1 among male patients and 137.7 among female patients. During 2012–2016, overall cancer death rates for all ages decreased 1.8% (95% CI = −1.8% to −1.8%) per year in male patients and 1.4% (95% CI = −1.4% to −1.4%) per year in females. Important changes in trends were stabilization of thyroid cancer incidence rates in women and rapid declines in death rates for melanoma of the skin (both sexes). Among adults age 20–49 years, overall cancer incidence rates were substantially lower among men (115.3 per 100 000) than among women (203.3 per 100 000); cancers with the highest incidence rates (per 100 000) among men were colon and rectum (13.1), testis (10.7), and melanoma of the skin (9.8), and among women were breast (73.2), thyroid (28.4), and melanoma of the skin (14.1). During 2011 to 2015, the incidence of all invasive cancers combined among adults age 20–49 years decreased −0.7% (95% CI = −1.0% to −0.4%) among men and increased among women (1.3%, 95% CI = 0.7% to 1.9%). The death rate for (per 100 000) adults age 20–49 years for all cancer sites combined during 2012 to 2016 was 22.8 among men and 27.1 among women; during the same time period, death rates decreased 2.3% (95% CI = −2.4% to −2.2%) per year among men and 1.7% (95% CI = −1.8% to −1.6%) per year among women.ConclusionsAmong people of all ages and ages 20–49 years, favorable as well as unfavorable trends in site-specific cancer incidence were observed, whereas trends in death rates were generally favorable. Characterizing the cancer burden may inform research and cancer-control efforts.
The Hubble Space Telescope UV Legacy Survey of Galactic Globular Clusters – XIX. A chemical tagging of the multiple stellar populations over the chromosome maps
Authors: Marino A F , Milone A P , Renzini A , D’Antona F , Anderson J , Bedin L R , Bellini A , Cordoni G , Lagioia E P , Piotto G , Tailo M 
Published: May 2019

Abstract
The Hubble Space Telescope UV Legacy Survey of Galactic Globular Clusters (GCs) has investigated GCs and their stellar populations. In previous papers of this series we have introduced a pseudo two-colour diagram, or ‘chromosome map’ (ChM) that maximizes the separation between the multiple populations. We have identified two main classes of GCs: Type I, including ∼83 per cent of the objects, and Type II clusters. Both classes host two main groups of stars, referred to in this series as first (1G) and second generation (2G). Type II clusters host more complex ChMs, exhibiting two or more parallel sequences of 1G and 2G stars. We exploit spectroscopic elemental abundances from the literature to assign the chemical composition to the distinct populations as identified on the ChMs of 29 GCs. We find that stars in different regions of the ChM have different compositions: 1G stars share the same light-element content as field stars, while 2G stars are enhanced in N and Na and depleted in O. Stars with enhanced Al, as well as stars with depleted Mg, populate the extreme regions of the ChM. We investigate the intriguing colour spread among 1G stars observed in many Type I GCs, and find no evidence for internal variations in light elements among these stars, whereas either a ∼0.1 dex iron spread or a variation in He among 1G stars remains to be verified. In the attempt of analysing the global properties of the multiple-population phenomenon, we have constructed a universal ChM, which highlights that, though very variegate, the phenomenon has some common pattern among all the analysed GCs. The universal ChM reveals a tight connection with Na abundances, for which we have provided an empirical relation. The additional ChM sequences observed in Type II GCs are enhanced in metallicity and, in some cases, s-process elements. Omega Centauri can be classified as an extreme Type II GC, with a ChM displaying three main extended ‘streams’, each with its own variations in chemical abundances. One of the most noticeable differences is found between the lower and upper streams, with the latter, associated with higher He, being also shifted towards higher Fe and lower Li abundances. We publicly release the ChMs.
Transcriptional supercoiling boosts topoisomerase II-mediated knotting of intracellular DNA
Authors: Valdés Antonio , Coronel Lucia , Martínez-García Belén , Segura Joana , Dyson Sílvia , Díaz-Ingelmo Ofelia , Micheletti Cristian , Roca Joaquim 
Published: May 2019

AbstractRecent studies have revealed that the DNA cross-inversion mechanism of topoisomerase II (topo II) not only removes DNA supercoils and DNA replication intertwines, but also produces small amounts of DNA knots within the clusters of nucleosomes that conform to eukaryotic chromatin. Here, we examine how transcriptional supercoiling of intracellular DNA affects the occurrence of these knots. We show that although (−) supercoiling does not change the basal DNA knotting probability, (+) supercoiling of DNA generated in front of the transcribing complexes increases DNA knot formation over 25-fold. The increase of topo II-mediated DNA knotting occurs both upon accumulation of (+) supercoiling in topoisomerase-deficient cells and during normal transcriptional supercoiling of DNA in TOP1 TOP2 cells. We also show that the high knotting probability (Pkn ≥ 0.5) of (+) supercoiled DNA reflects a 5-fold volume compaction of the nucleosomal fibers in vivo. Our findings indicate that topo II-mediated DNA knotting could be inherent to transcriptional supercoiling of DNA and other chromatin condensation processes and establish, therefore, a new crucial role of topoisomerase II in resetting the knotting–unknotting homeostasis of DNA during chromatin dynamics.
Trust in national health information sources in the United States: comparing predictors and levels of trust across three health domains
Authors: Peterson Emily B , Chou Wen-Ying Sylvia , Kelley Dannielle E , Hesse Brad 
Published: May 2019

AbstractPublic trust in traditional sources of health information is essential for public health agencies and organizations to perform necessary public health functions. Little research has examined levels and predictors of trust in government health agencies and national health organizations. Additionally, few studies have simultaneously analyzed trust in multiple health topics. The major aim of this study was to compare levels and factors associated with trust in national health sources across three health topics: information about tobacco, electronic cigarettes, and general health. Data from two cycles of the National Cancer Institute’s Health Information National Trends Survey collected in 2015 and 2017 were merged and analyzed for this study (n = 5,474). A series of weighted multivariable logistic regression models calculated odds of high trust in government health agencies and health organizations for each health topic. More respondents reported high trust in health organizations than for government health agencies across all topics. More participants reported high trust in these sources tobacco information, as compared to general health or e-cigarette information. Logistic models found that those higher in information seeking confidence were more likely to report high trust across all models. Other demographic variables were inconsistent predictors of trust across topics. This study highlights inconsistent sociodemographic predictors of trust across multiple health topics and national health sources. Researchers, practitioners, and policymakers should consider the unique context of specific health topics in health promotion campaigns, partner with existing community-based organizations, and encourage and enable health information seeking.
Estimating intervention dose of the multilevel multisite children’s healthy living program intervention
Authors: Butel Jean , Braun Kathryn L , Nigg Claudio R , Leon Guerrero Rachael , Fleming Travis , Bersamin Andrea , Coleman Patricia , Novotny Rachel 
Published: May 2019

Abstract
Increased community collective efficacy (CE), defined as social cohesion among neighbors and their willingness to intervene for common good, is associated with improved community health outcomes. However, processes to increase CE and estimate its dose within an intervention are not well understood. The 2 year Children’s Healthy Living (CHL) intervention aimed to improve child behaviors known to affect obesity. We used data from CHL to estimate CE dose and examine its association with a successful outcome from CHL—reduction in children’s recreational screen time. Monthly reports from nine intervention communities were quantified, and CE dose was calculated for each community overall, at 4 time intervals (6, 12, 18, and 24 months), and for each CE building block—social bonding, social bridging, social leveraging, empowerment, and civic engagement. CE dose at each time interval and change in screen time was correlated using Spearman’s rho. Next, communities were categorized as having a high CE dose or a low CE dose, and differences between four high-dose and five low-dose communities were compared using a two-tailed t-test. The correlation between change in screen time and CE dose was significant (rs = 0.83, p = .003). Significantly more activities facilitating empowerment and civic engagement were conducted in high-dose communities, which were more likely to show improvements in screen time, than in low-dose communities. This method of estimating an intervention’s CE dose and examining change over time and effect of CE and its building blocks on intervention outcomes shows promise.
Plant water content integrates hydraulics and carbon depletion to predict drought-induced seedling mortality
Authors: Sapes Gerard , Roskilly Beth , Dobrowski Solomon , Maneta Marco , Anderegg William R L , Martinez-Vilalta Jordi , Sala Anna 
Published: May 2019

Abstract
Widespread drought-induced forest mortality (DIM) is expected to increase with climate change and drought, and is expected to have major impacts on carbon and water cycles. For large-scale assessment and management, it is critical to identify variables that integrate the physiological mechanisms of DIM and signal risk of DIM. We tested whether plant water content, a variable that can be remotely sensed at large scales, is a useful indicator of DIM risk at the population level. We subjected Pinus ponderosa Douglas ex C. Lawson seedlings to experimental drought using a point of no return experimental design. Periodically during the drought, independent sets of seedlings were sampled to measure physiological state (volumetric water content (VWC), percent loss of conductivity (PLC) and non-structural carbohydrates) and to estimate population-level probability of mortality through re-watering. We show that plant VWC is a good predictor of population-level DIM risk and exhibits a threshold-type response that distinguishes plants at no risk from those at increasing risk of mortality. We also show that plant VWC integrates the mechanisms involved in individual tree death: hydraulic failure (PLC), carbon depletion across organs and their interaction. Our results are promising for landscape-level monitoring of DIM risk.
Brexanolone Injection in Postpartum Depression: 2 Multicenter, Double-blind, Randomized, Placebo-controlled Phase 3 Trials
Authors: Meltzer-Brody S. , Colquhoun H. , Riesenberg R. , Epperson C.N. , Deligiannidis K.M. , Rubinow D.R. , Li H. , Sankoh A.J. , Clemson C. , Schacterle A. , Jonas J. , Kanes S. 
Published: May 2019

(Lancet. 2018;392:1058–1070)
Postpartum depression is a common problem, with an overall prevalence in the United States of ∼11.5%. It is associated with impaired mother-infant attachment, increased maternal morbidity and poor outcomes for infants later in life, including lower academic achievement and an increased risk of depression. There is a need for improved pharmacological treatment options for mothers suffering from postpartum depression. Brexanolone is a soluble, intravenous, positive allosteric modulator of y-aminobutyric-acid type A (GABAA) receptors. In a previous phase 2 clinical trial, this medication was found to have rapid and sustained antidepressant effects. The current article reports on 2 randomized double-blind phase 3 studies that aimed to assess the efficacy of brexanolone injection in women with moderate to severe postpartum depression.