bluuebunny/crossref_metadata_2025_split huggingface dataset:
Greater focus on water pools may improve our ability to understand and anticipate drought‐induced mortality in plants
Authors: Martinez‐Vilalta Jordi , Anderegg William R. L. , Sapes Gerard , Sala Anna 
Published: December 2018

SummaryDrought‐induced tree mortality has major impacts on ecosystem carbon and water cycles, and is expected to increase in forests across the globe with climate change. A large body of research in the past decade has advanced our understanding of plant water and carbon relations under drought. However, despite intense research, we still lack generalizable, cross‐scale indicators of mortality risk. In this Viewpoint, we propose that a more explicit consideration of water pools could improve our ability to monitor and anticipate mortality risk. Specifically, we focus on the relative water content (RWC), a classic metric in plant water relations, as a potential indicator of mortality risk that is physiologically relevant and integrates different aspects related to hydraulics, stomatal responses and carbon economy under drought. Measures of plant water content are likely to have a strong mechanistic link with mortality and to be integrative, threshold‐prone and relatively easy to measure and monitor at large spatial scales, and may complement current mortality metrics based on water potential, loss of hydraulic conductivity and nonstructural carbohydrates. We discuss some of the potential advantages and limitations of these metrics to improve our capacity to monitor and predict drought‐induced tree mortality.
Association of maternal allergy with human milk soluble CD14 and fatty acids, and early childhood atopic dermatitis
Authors: Hua Man‐Chin , Su Hui‐Min , Kuo Ming‐Ling , Chen Chien‐Chang , Yao Tsung‐Chieh , Tsai Ming‐Han , Liao Sui‐Ling , Lai Shen‐Hao , Chiu Chih‐Yung , Su Kuan‐Wen , Chen Li‐Chen , Yeh Kuo‐Wei , Huang Jing‐Long 
Published: December 2018

AbstractBackgroundThis study aimed to investigate whether maternal allergy is associated with soluble CD14 (sCD14) and fatty acid composition in different stages of lactation and the onset of atopic dermatitis (AD) in early childhood.MethodsIn total, 443 mother‐child groups (445 children) were enrolled in the Prediction of Allergies in Taiwanese Children birth cohort study. Colostrum and mature milk at 2 months postpartum (2‐month HM) were collected from lactating mothers. Information regarding parental allergy histories and physician‐diagnosed atopic diseases was obtained using age‐specific questionnaires (0‐2 years). We compared sCD14 levels and the composition of 30 fatty acids in the colostrum and 2‐month HM, respectively, between allergic and non‐allergic mothers and between children with and without AD by the age of 2 years.ResultsIn total, 185 (41.8%) mothers presented with allergies, and 154 (34.6%) children had physician‐diagnosed AD by the age of 2 years. Both in the colostrum and 2‐month HM of 289 lactating mothers, sCD14 levels were significantly lower in allergic mothers whose children presented with AD compared with children who did not (P = 0.015 and 0.044, respectively). Among the children with AD who were born to non‐allergic mothers, sCD14 levels were lower. However, the result was not statistically significant (P = 0.376 and 0.264, respectively). Our data revealed the lack of associations between fatty acid composition and AD (P > 0.05).ConclusionDecreased sCD14 levels in the colostrum and 2‐month HM were associated with AD at 2 years of age, particularly among children born to mothers with allergies.
The role of ear environment in postharvest susceptibility of maize to toxigenic Aspergillus flavus
Authors: Mutiga Samuel K. , Chepkwony Nelson , Hoekenga Owens A. , Flint‐Garcia Sherry A. , Nelson Rebecca J. 
Published: December 2018

AbstractA kernel screening assay (KSA) was used to assess the genetic and environmental effects on the vulnerability of maize to aflatoxin accumulation. Kernels of 26 inbred lines that had been grown in seven environments, and 190 lines of the Intermated B73xMo17 (IBM) population grown in one location in the United States, were inoculated with a toxigenic strain of A. flavus and incubated in the dark at 30°C for 6 days. Percent kernel colonization (PKC), sporulation and aflatoxin were influenced by the maize genotypes (G), the location (“ear environment” or E) and the GxE interactions. Overall, low broad‐sense heritabilities were observed for PKC, sporulation and aflatoxin. PKC was significantly correlated with sporulation in all environments. Aflatoxin was positively correlated with colonization for two and with sporulation for all ear environments. Higher grain sulphur or magnesium in IBM was associated with less colonization or aflatoxin. Postharvest susceptibility of maize to aflatoxin is thus influenced by factors that are modulated by the ear environment. In a KSA, sporulation could be a proxy test for aflatoxin accumulation.
Biology of human melanocyte development, Piebaldism, and Waardenburg syndrome
Authors: Saleem Mohammed D. 
Published: December 2018

AbstractMelanocyte development is orchestrated by a complex interconnecting regulatory network of genes and synergistic interactions. Piebaldism and Waardenburg syndrome are neurocristopathies that arise from mutations in genes involved in this complex network. Our understanding of melanocyte development, Piebaldism, and Waardenburg syndrome has improved dramatically over the past decade. The diagnosis and classification of Waardenburg syndrome, first proposed in 1992 and based on phenotype, have expanded over the past three decades to include genotype. This review focuses on the current understanding of human melanocyte development and the evaluation and management of Piebaldism and Waardenburg syndrome. Management is often challenging and requires a multidisciplinary approach.
Molecular phylogenetics and biogeography provide insights into the subgeneric classification of Wiedemannia Zetterstedt (Diptera: Empididae: Clinocerinae)
Authors: Ivković Marija , Wahlberg Emma , Previšić Ana 
Published: December 2018

AbstractThe subgenera of Wiedemannia are poorly defined and, as such, most recently described species are not assigned to a subgenus or have been assigned to a subgenus without explanation. In this study we perform a molecular phylogenetic analysis to elucidate relationships within the genus Wiedemannia. We sequenced two mitochondrial (cytochrome oxidase c subunit I and cytochrome β) and two nuclear (carbomoylphosphate synthase domain of rudimentary and elongation factor‐1α) gene fragments to reconstruct phylogenetic relationships among the subgenera Chamaedipsia, Eucelidia, Philolutra, Pseudowiedemannia, Roederella and Wiedemannia (s.s.) using both Bayesian inference and maximum likelihood approaches. The genus was found to be monophyletic, but most of the subgenera were not. We propose eliminating the present subgeneric division altogether. Molecular dating using a log‐normal clock model and calibration with fossil species indicated that Wiedemannia diversified about 48 Ma, while there was still land connectivity between Europe and Asia with North America. Wiedemannia has a near‐worldwide distribution apart from the Australasian and Neotropical regions and Antarctica, with greatest species richness in the western Palaearctic, especially the Mediterranean region. Molecular phylogenetics support more recent morphological studies. The subgenera of Wiedemannia are invalid and rejected. Biogeographical data suggest potential hotspots, and the current distribution is discussed.
Student‐led community placement in physiotherapy
Authors: O'Connor Anne , Liston Ellen , O'Donnell Marie 
Published: December 2018

SummaryBackgroundService provision and the education of health professionals has diversified with the shift in health care focus to primary care. Current evidence, particularly in physiotherapy education, has identified shortfalls in practical experience and education provided in health promotion. To address this, practice placements in non‐traditional settings have been recommended; however, limited evidence exists to guide this innovation. This study aimed to address this gap by exploring the challenges and facilitators of a community‐based, student‐led placement involving physiotherapy undergraduate students and community‐based groups.MethodsA qualitative descriptive approach was employed. Students (n = 7) and the service users and community facilitators (n = 12) who had engaged in this placement model were invited to participate in focus groups and semi‐structured interviews. Interviews were recorded, transcribed and analysed using thematic analysis.ResultsTwo themes were identified: collaborative learning and embracing change. The acquisition of professional skills, such as leadership, teamwork and adaptability, was perceived to be greater than on traditional placements. Students, service users and community facilitators experienced mutual learning benefits, but also identified challenges with the placement model. These insights informed opinion regarding the sustainability of the model.DiscussionStudent‐led community‐based placements appear to impact positively on the well‐being of community service users. Mutual benefits were acknowledged by all stakeholders. This evaluation highlighted issues related to sustainability, and the need for a balanced representation of student and service user needs. Areas for development were identified, providing an optimistic outlook for the feasibility of this model and its transferability to other health professions.Health professional services have diversified, in both social and health contexts, with a shift in focus from the treatment of ill health to health promotion
Rare occurrence of a huge traumatic extradural haematoma in a patient with an ipsilateral sylvian arachnoid cyst
Authors: Alhillo Haider Tawfeeq , Sadik Hatem Azet , Gheni Teeba N , Hoz Samer S 
Published: December 2018

A man, a teenage victim of an assault to the head, presented to the emergency department, in Baghdad, with a Glasgow Coma Score of 4/15 (E1 M2 V1) and total right-sided paralysis. CT of the brain revealed a large-left sided frontotemporoparietal extradural haematoma with the presence of an ipsilateral sylvian arachnoid cyst deep to the haematoma. Urgent surgical evacuation of the haematoma was performed, leaving the arachnoid cyst intact. The patient improved and gained full consciousness within 4 days.Three years after the initial trauma, the patient has remained well. This case required a thorough discussion of the surgical options, in particular whether to intervene with the associated cyst, and whether any intervention with the cyst should be performed in the same or future operations. This dilemma forms the basis of the discussion in the following report.
The WNT10B Network Is Associated with Survival and Metastases in Chemoresistant Triple-Negative Breast Cancer
Authors: El Ayachi Ikbale , Fatima Iram , Wend Peter , Alva-Ornelas Jackelyn A. , Runke Stephanie , Kuenzinger William L. , Silva Julio , Silva Wendy , Gray Joseph K. , Lehr Stephan , Barch Hilaire C. , Krutilina Raisa I. , White Andrew C. , Cardiff Robert , Yee Lisa D. , Yang Lily , O'Regan Ruth M. , Lowry William E. , Seagroves Tiffany N. , Seewaldt Victoria , Krum Susan A. , Miranda-Carboni Gustavo A. 
Published: December 2018

Abstract

Triple-negative breast cancer (TNBC) commonly develops resistance to chemotherapy, yet markers predictive of chemoresistance in this disease are lacking. Here, we define WNT10B-dependent biomarkers for β-CATENIN/HMGA2/EZH2 signaling predictive of reduced relapse-free survival. Concordant expression of HMGA2 and EZH2 proteins is observed in MMTV-Wnt10bLacZ transgenic mice during metastasis, and Hmga2 haploinsufficiency decreased EZH2 protein expression, repressing lung metastasis. A novel autoregulatory loop interdependent on HMGA2 and EZH2 expression is essential for β-CATENIN/TCF-4/LEF-1 transcription. Mechanistically, both HMGA2 and EZH2 displaced Groucho/TLE1 from TCF-4 and served as gatekeepers for K49 acetylation on β-CATENIN, which is essential for transcription. In addition, we discovered that HMGA2-EZH2 interacts with the PRC2 complex. Absence of HMGA2 or EZH2 expression or chemical inhibition of Wnt signaling in a chemoresistant patient-derived xenograft (PDX) model of TNBC abolished visceral metastasis, repressing AXIN2, MYC, EZH2, and HMGA2 expression in vivo. Combinatorial therapy of a WNT inhibitor with doxorubicin synergistically activated apoptosis in vitro, resensitized PDX-derived cells to doxorubicin, and repressed lung metastasis in vivo. We propose that targeting the WNT10B biomarker network will provide improved outcomes for TNBC.

Significance:
These findings reveal targeting the WNT signaling pathway as a potential therapeutic strategy in triple-negative breast cancer.
Early Loss of Histone H2B Monoubiquitylation Alters Chromatin Accessibility and Activates Key Immune Pathways That Facilitate Progression of Ovarian Cancer
Authors: Hooda Jagmohan , Novak Marián , Salomon Matthew P. , Matsuba Chikako , Ramos Romela I. , MacDuffie Emily , Song Melissa , Hirsch Michelle S. , Lester Jenny , Parkash Vinita , Karlan Beth Y. , Oren Moshe , Hoon Dave S. , Drapkin Ronny 
Published: December 2018

Abstract

Recent insights supporting the fallopian tube epithelium (FTE) and serous tubal intraepithelial carcinomas (STIC) as the tissue of origin and the precursor lesion, respectively, for the majority of high-grade serous ovarian carcinomas (HGSOC) provide the necessary context to study the mechanisms that drive the development and progression of HGSOC. Here, we investigate the role of the E3 ubiquitin ligase RNF20 and histone H2B monoubiquitylation (H2Bub1) in serous tumorigenesis and report that heterozygous loss of RNF20 defines the majority of HGSOC tumors. At the protein level, H2Bub1 was lost or downregulated in a large proportion of STIC and invasive HGSOC tumors, implicating RNF20/H2Bub1 loss as an early event in the development of serous ovarian carcinoma. Knockdown of RNF20, with concomitant loss of H2Bub1, was sufficient to enhance cell migration and clonogenic growth of FTE cells. To investigate the mechanisms underlying these effects, we performed ATAC-seq and RNA-seq in RNF20 knockdown FTE cell lines. Loss of RNF20 and H2Bub1 was associated with a more open chromatin conformation, leading to upregulation of immune signaling pathways, including IL6. IL6 was one of the key cytokines significantly upregulated in RNF20- and H2Bub1-depleted FTE cells and imparted upon these cells an enhanced migratory phenotype. These studies provide mechanistic insight into the observed oncogenic phenotypes triggered by the early loss of H2Bub1.

Significance:
Loss of RNF20 and H2Bub1 contributes to transformation of the fallopian tube epithelium and plays a role in the initiation and progression of high-grade serous ovarian cancer.
Performance of Single-Nucleotide Polymorphisms in Breast Cancer Risk Prediction Models: A Systematic Review and Meta-analysis
Authors: Fung Si Ming , Wong Xin Yi , Lee Shi Xun , Miao Hui , Hartman Mikael , Wee Hwee-Lin 
Published: December 2018

Abstract

Background:
SNP risk information can potentially improve the accuracy of breast cancer risk prediction. We aim to review and assess the performance of SNP-enhanced risk prediction models.

Methods:
Studies that reported area under the ROC curve (AUC) and/or net reclassification improvement (NRI) for both traditional and SNP-enhanced risk models were identified. Meta-analyses were conducted to compare across all models and within similar baseline risk models.

Results:
Twenty-six of 406 studies were included. Pooled estimate of AUC improvement is 0.044 [95% confidence interval (CI), 0.038–0.049] for all 38 models, while estimates by baseline models ranged from 0.033 (95% CI, 0.025–0.041) for BCRAT to 0.053 (95% CI, 0.018–0.087) for partial BCRAT. There was no observable trend between AUC improvement and number of SNPs. One study found that the NRI was significantly larger when only intermediate-risk women were included. Two other studies showed that majority of the risk reclassification occurred in intermediate-risk women.

Conclusions:
Addition of SNP risk information may be more beneficial for women with intermediate risk.

Impact:
Screening could be a two-step process where a questionnaire is first used to identify intermediate-risk individuals, followed by SNP testing for these women only.
Nuclear–Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis
Authors: Yan Dongqing , Pomicter Anthony D. , Tantravahi Srinivas , Mason Clinton C. , Senina Anna V. , Ahmann Jonathan M. , Wang Qiang , Than Hein , Patel Ami B. , Heaton William L. , Eiring Anna M. , Clair Phillip M. , Gantz Kevin C. , Redwine Hannah M. , Swierczek Sabina I. , Halverson Brayden J. , Baloglu Erkan , Shacham Sharon , Khorashad Jamshid S. , Kelley Todd W. , Salama Mohamed E. , Miles Rodney R. , Boucher Kenneth M. , Prchal Josef T. , O'Hare Thomas , Deininger Michael W. 
Published: December 2018

Abstract

Purpose:
Myelofibrosis is a hematopoietic stem cell neoplasm characterized by bone marrow reticulin fibrosis, extramedullary hematopoiesis, and frequent transformation to acute myeloid leukemia. Constitutive activation of JAK/STAT signaling through mutations in JAK2, CALR, or MPL is central to myelofibrosis pathogenesis. JAK inhibitors such as ruxolitinib reduce symptoms and improve quality of life, but are not curative and do not prevent leukemic transformation, defining a need to identify better therapeutic targets in myelofibrosis.

Experimental Design:
A short hairpin RNA library screening was performed on JAK2V617F-mutant HEL cells. Nuclear–cytoplasmic transport (NCT) genes including RAN and RANBP2 were among top candidates. JAK2V617F-mutant cell lines, human primary myelofibrosis CD34+ cells, and a retroviral JAK2V617F-driven myeloproliferative neoplasms mouse model were used to determine the effects of inhibiting NCT with selective inhibitors of nuclear export compounds KPT-330 (selinexor) or KPT-8602 (eltanexor).

Results:
JAK2V617F-mutant HEL, SET-2, and HEL cells resistant to JAK inhibition are exquisitely sensitive to RAN knockdown or pharmacologic inhibition by KPT-330 or KPT-8602. Inhibition of NCT selectively decreased viable cells and colony formation by myelofibrosis compared with cord blood CD34+ cells and enhanced ruxolitinib-mediated growth inhibition and apoptosis, both in newly diagnosed and ruxolitinib-exposed myelofibrosis cells. Inhibition of NCT in myelofibrosis CD34+ cells led to nuclear accumulation of p53. KPT-330 in combination with ruxolitinib-normalized white blood cells, hematocrit, spleen size, and architecture, and selectively reduced JAK2V617F-mutant cells in vivo.

Conclusions:
Our data implicate NCT as a potential therapeutic target in myelofibrosis and provide a rationale for clinical evaluation in ruxolitinib-exposed patients with myelofibrosis.
PRE-surgical Metformin In Uterine Malignancy (PREMIUM): a Multi-Center, Randomized Double-Blind, Placebo-Controlled Phase III Trial
Authors: Kitson Sarah J. , Maskell Zoe , Sivalingam Vanitha N. , Allen Jennifer L. , Ali Saad , Burns Sean , Gilmour Kyle , Latheef Rahamatulla , Slade Richard J. , Pemberton Philip W. , Shaw Joseph , Ryder W. David , Kitchener Henry C. , Crosbie Emma J. 
Published: December 2018

AbstractPurpose:Endometrioid endometrial cancer is strongly associated with obesity and insulin resistance. Metformin, an insulin sensitizer, reduces endometrial tumor growth in vitro. Presurgical window studies allow rapid in vivo assessment of antitumor activity. Previous window studies found metformin reduced endometrial cancer proliferation but these lacked methodological rigor. PREMIUM measured the anti-proliferative effect of metformin in vivo using a robust window study design.Patients and Methods: A multicenter, double-blind, placebo-controlled trial randomized women with atypical hyperplasia or endometrioid endometrial cancer to receive metformin (850 mg daily for 3 days, and twice daily thereafter) or placebo for 1 to 5 weeks until surgery. The primary outcome was posttreatment IHC expression of Ki-67. Secondary outcomes investigated the effect of metformin on markers of the PI3K–Akt–mTOR and insulin signaling pathways and obesity.Results:Eighty-eight women received metformin (n = 45) or placebo (n = 43) and completed treatment. There was no overall difference in posttreatment Ki-67 between the metformin and placebo arms, in an ANCOVA analysis adjusting for baseline Ki-67 expression (mean difference −0.57%; 95% CI, −7.57%–6.42%; P = 0.87). Metformin did not affect expression of markers of the PI3K–Akt–mTOR or insulin signaling pathways, and did not result in weight loss.Conclusions:Short-term treatment with standard diabetic doses of metformin does not reduce tumor proliferation in women with endometrioid endometrial cancer awaiting hysterectomy. This study does not support a biological effect of metformin in endometrial cancer and casts doubt on its potential application in the primary and adjuvant treatment settings.
ER Translocation of the MAPK Pathway Drives Therapy Resistance in BRAF-Mutant Melanoma
Authors: Ojha Rani , Leli Nektaria M. , Onorati Angelique , Piao Shengfu , Verginadis Ioannis I. , Tameire Feven , Rebecca Vito W. , Chude Cynthia I. , Murugan Sengottuvelan , Fennelly Colin , Noguera-Ortega Estela , Chu Charleen T. , Liu Shujing , Xu Xiaowei , Krepler Clemens , Xiao Min , Xu Wei , Wei Zhi , Frederick Dennie T. , Boland Genevieve , Mitchell Tara C. , Karakousis Giorgos C. , Schuchter Lynn M. , Flaherty Keith T. , Zhang Gao , Herlyn Meenhard , Koumenis Constantinos , Amaravadi Ravi K. 
Published: December 2018

Abstract

Resistance to BRAF and MEK inhibitors (BRAFi + MEKi) in BRAF-mutant tumors occurs through heterogeneous mechanisms, including ERK reactivation and autophagy. Little is known about the mechanisms by which ERK reactivation or autophagy is induced by BRAFi + MEKi. Here, we report that in BRAF-mutant melanoma cells, BRAFi + MEKi induced SEC61-dependent endoplasmic reticulum (ER) translocation of the MAPK pathway via GRP78 and KSR2. Inhibition of ER translocation prevented ERK reactivation and autophagy. Following ER translocation, ERK exited the ER and was rephosphorylated by PERK. Reactivated ERK phosphorylated ATF4, which activated cytoprotective autophagy. Upregulation of GRP78 and phosphorylation of ATF4 were detected in tumors of patients resistant to BRAFi + MEKi. ER translocation of the MAPK pathway was demonstrated in therapy-resistant patient-derived xenografts. Expression of a dominant-negative ATF4 mutant conferred sensitivity to BRAFi + MEKi in vivo. This mechanism reconciles two major targeted therapy resistance pathways and identifies druggable targets, whose inhibition would likely enhance the response to BRAFi + MEKi.

Significance:
ERK reactivation and autophagy are considered distinct resistance pathways to BRAF + MEK inhibition (BRAFi + MEKi) in BRAFV600E cancers. Here, we report BRAFi + MEKi–induced ER translocation of the MAPK pathway is necessary for ERK reactivation, which drives autophagy. The ER translocation mechanism is a major druggable driver of resistance to targeted therapy.
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