bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors associated with the referral of children with severe illnesses at primary care level in Ethiopia: a cross-sectional study
Authors: Beyene Habtamu , Kassa Dejene Hailu , Tadele Henok , Persson Lars , Defar Atkure , Berhanu Della 
Published: June 2021

Context and objectiveEthiopia’s primary care has a weak referral system for sick children. We aimed to identify health post and child factors associated with referrals of sick children 0–59 months of age and evaluate the healthcare providers’ adherence to referral guidelines.DesignA cross-sectional facility-based survey.SettingThis study included data from 165 health posts in 52 districts in four Ethiopian regions collected from December 2018 to February 2019. The data included interviews with health extension workers, assessment of health post preparedness, recording of global positioning system (GPS)-coordinates of the health post and the referral health centre, and reviewing registers of sick children treated during the last 3 months at the health posts. We analysed the association between the sick child’s characteristics, health post preparedness and distance to the health centre with referral of sick children by multivariable logistic regressions.Outcome measureReferral to the nearest health centre of sick young infants aged 0–59 days and sick children 2–59 months.ResultsThe health extension workers referred 39/229 (17%) of the sick young infants and 78/1123 (7%) of the older children to the next level of care. Only 18 (37%) sick young infants and 22 (50%) 2–59 months children that deserved urgent referral according to guidelines were referred. The leading causes of referral were possible serious bacterial infection and pneumonia. Those being classified as a severe disease were referred more frequently. The availability of basic amenities (adjusted OR, AOR=0.38, 95% CI 0.15 to 0.96), amoxicillin (AOR=0.41, 95% CI 0.19 to 0.88) and rapid diagnostic test (AOR=0.18, 95% CI 0.07 to 0.46) were associated with less referral in the older age group.ConclusionFew children with severe illness were referred from health posts to health centres. Improving the health posts’ medicine and diagnostic supplies may enhance adherence to referral guidelines and ultimately reduce child mortality.
Adverse childhood experiences and asthma: trajectories in a national cohort
Authors: Pape Kathrine , Cowell Whitney , Sejbaek Camilla Sandal , Andersson Niklas Worm , Svanes Cecilie , Kolstad Henrik Albert , Liu Xiaoqin , Hougaard Karin Sørig , Wright Rosalind J , Schlünssen Vivi 
Published: June 2021

Objective
Research has linked early adverse childhood experiences (ACEs) with asthma development; however, existing studies have generally relied on parent report of exposure and outcome. We aimed to examine the association of early life ACEs with empirically determined trajectories of childhood asthma risk, using independent register information on both exposures and outcome.

Methods
Based on nationwide registries, we established a study cohort of 466 556 children born in Denmark (1997–2004). We obtained information on ACEs during the first 2 years of life (bereavement, parental chronic somatic and/or mental illness) and childhood asthma diagnosis or medication use from birth through age 10 years from the Danish National Patient and Prescription Registries, respectively. We identified asthma phenotypes using group-based trajectory modelling. We then used multinomial logistic regression to examine the association between early ACEs and asthma phenotypes.

Results
We identified four asthma phenotypes: non-asthmatic, early-onset transient, early-onset persistent and late-onset asthma. Girls with early-onset transient asthma (OR 1.13, 95% CI 1.04 to 1.24), early-onset persistent asthma (1.27, 95% CI 1.08 to 1.48) or late-onset asthma (OR 1.28, 95% CI 1.11 to 1.48) vs no asthma were more likely to have early life ACE exposure compared with girls without ACE exposure. Results were similar for boys who also had experienced early life ACEs with ORs of 1.16 (95% CI 1.08 to 1.25), 1.34 (95% CI 1.20 to 1.51) and 1.11 (95% CI 0.98 to 1.25), respectively.

Conclusion
In a nationwide-population study, we identified three childhood onset asthma phenotypes and found that ACEs early in life were associated with increased odds for each of these asthma phenotypes among both girls and boys.
Load transfer mechanism of a load distributive compression anchor installed in weathered rock layer
Authors: Shin Gyu-Beom , Jo Bum-Hee , Baek Sung-Ha , Kim Sung-Ryul , Chung Choong-Ki 
Published: June 2021

The demand for a load distributive compression anchor (LDCA) in construction sites has been increasing, owing to its high bearing capacity and removable steel strands. As an LDCA comprises multiple anchor bodies and unbonded steel strands, the load applied to the strands generates a distributive compressive stress in the grout, preventing high concentration of grout–ground shear stress. Unlike in the conventional anchors, in an LDCA, independent load transfer of each anchor body induces interference effect between adjacent anchor bodies. Therefore, for an efficient design of an LDCA, it is necessary to investigate the load transfer mechanism considering the effect of multiple anchor bodies. In this study, a series of anchor pull-out field tests was conducted for LDCAs consisting of a single anchor body, and double and triple anchor bodies spaced by 1, 2, and 3 m. According to the test results, the LDCA showed a stiffer load–displacement behavior with an increase in the number and spacing of the anchor bodies. The multiple anchor bodies of the LDCA generated an overlapping of the grout axial load and induced its rapid dissipation, increasing the grout–ground shear stress. This interference effect was more clearly observed with a decrease in the anchor body spacing.
Effects of helix angle and feed per knife on cutting forces, noise, and power consumption produced during helical planing of sugar maple wood
Authors: Wellenreiter Paul , Hernández Roger E. , Cáceres Claudia B. , Blais Carl 
Published: June 2021

A conventional straight knife cutterhead and three helical knife cutterheads were tested for planing sugar maple wood (Acer saccharum Marsh.). Effects of helix angle and feed per knife (FK) on maximum cutting forces, sound level, and power consumption were evaluated. A 3-axis dynamometer, an array microphone, and a watt transducer were used to simultaneously record the forces, sound level, and power consumption during machining, respectively. Parallel (FP), positive and negative normal (FNP and FNN), lateral (FL), resultant (FR) forces, and sound level increased as FK increased. Helical tools produced lower FP, FNP, FNN, and FR. Parallel forces tended to decrease as helical angle increased. Differences among helical tools were not significant for normal forces. Helical tools produced higher FL at medium (2.9 mm) and high (4.7 mm) feeds per knife. FR decreased as helix angle increased. The impacts of these cutting forces on the appearance of surface defects and ways to reduce them were discussed. Helical cutterheads considerably generated lower sound pressure level, with a maximum difference of up to 8 dB(A). At low FK (1.3 mm), helical tools required slightly lower cutting power.
Light neutrino masses from gravitational condensation: the Schwinger–Dyson approach
Authors: Barenboim Gabriela , Turner Jessica , Zhou Ye-Ling 
Published: June 2021

AbstractIn this work we demonstrate that non-zero neutrino masses can be generated from gravitational interactions. We solve the Schwinger–Dyson equations to find a non-trivial vacuum thereby determining the neutrino condensate scale and the number of new particle degrees of freedom required for gravitationally induced dynamical chiral symmetry breaking. We show for minimal beyond the Standard Model particle content, the scale of the condensation occurs close to the Planck scale.
Primary Analysis and 4-Year Follow-Up of the Phase III NIBIT-M2 Trial in Melanoma Patients With Brain Metastases
Authors: Di Giacomo Anna Maria , Chiarion-Sileni Vanna , Del Vecchio Michele , Ferrucci Pier Francesco , Guida Michele , Quaglino Pietro , Guidoboni Massimo , Marchetti Paolo , Cutaia Ornella , Amato Giovanni , Covre Alessia , Camerini Roberto , Calabrò Luana , Valente Monica , Giannarelli Diana , Mandalà Mario , Maio Michele 
Published: June 2021

Abstract

Purpose:
Phase II trials have shown encouraging activity with ipilimumab plus fotemustine and ipilimumab plus nivolumab in melanoma brain metastases. We report the primary analysis and 4-year follow-up of the NIBIT-M2 study, the first phase III trial comparing these regimens with fotemustine in patients with melanoma with brain metastases.

Patients and Methods:
This phase III study recruited patients 18 years of age and older with BRAF wild-type or mutant melanoma, and active, untreated, asymptomatic brain metastases from nine centers, randomized (1:1:1) to fotemustine, ipilimumab plus fotemustine, or ipilimumab plus nivolumab. The primary endpoint was overall survival (OS).

Results:
From January, 2013 to September, 2018, 27, 26, and 27 patients received fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab. Median OS was 8.5 months [95% confidence interval (CI), 4.8–12.2] in the fotemustine arm, 8.2 months (95% CI, 2.2–14.3) in the ipilimumab plus fotemustine arm (HR vs. fotemustine, 1.09; 95% CI, 0.59–1.99; P = 0.78), and 29.2 months (95% CI, 0–65.1) in the ipilimumab plus nivolumab arm (HR vs. fotemustine, 0.44; 95% CI, 0.22–0.87; P = 0.017). Four-year survival rate was significantly higher for ipilimumab plus nivolumab than fotemustine [(41.0%; 95% CI, 20.6–61.4) vs. 10.9% (95% CI, 0–24.4; P = 0.015)], and was 10.3% (95% CI, 0–22.6) for ipilimumab plus fotemustine. In the fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab arms, respectively, 11 (48%), 18 (69%), and eight (30%) patients had treatment-related grade 3 or 4 adverse events, without treatment-related deaths.

Conclusions:
Compared with fotemustine, ipilimumab plus nivolumab significantly improved overall and long-term survival of patients with melanoma with asymptomatic brain metastases.
Abstract NT-093: THE N6-METHYLATION OF ADENOSINE (M6A) IN FZD10 MRNA CONTRIBUTES TO RESISTANCE TO PARP INHIBITOR
Authors: Fukumoto Takeshi , Zhu Hengrui , Karakashev Sergey , Nacarelli Timothy , Fatkhutdinov Nail , Wu Shuai , Kossenkov Andrew V. , Showe Louise , Jean Stephanie , Zhang Lin , Zhang Rugang 
Published: June 2021

Abstract
Chemical modifications of RNAs have emerged as a new layer of epigenetic gene regulation. N6-methyladenosine (m6A) is the most abundant chemical modification of messenger RNA. The m6A modification affects RNA fate and functions such as RNA stability. Despite the high initial clinical response rates to PARP inhibitors in BRCA1/2-mutated epithelial ovarian cancers, PARP inhibitor (PARPi) resistance remains a major challenge. The role of m6A modification in PARPi resistance has not previously been explored. Here we show that m6A modification of FZD10 mRNA contributes to PARPi resistance by upregulating the Wnt/β-catenin pathway in BRCA-mutated EOC cells. Global m6A profile reveals a significant increase in m6A modification in FZD10 mRNA. This correlates with an increase in FZD10 mRNA stability and an upregulation of the Wnt/β-catenin pathway in PARPi resistant cells. FZD10 knockdown or inhibition of the Wnt/β-catenin sensitizes the resistant cells to PAPRi. Mechanistically, downregulation of m6A demethylases FTO and ALKBH5 is sufficient to increase FZD10 mRNA m6A modification and reduce PARPi sensitivity. Moreover, PAPRi and Wnt/β-catenin inhibitor showed synergistic suppression of growth of PAPRi resistant cancer both in vitro and in vivo in a xenograft ovarian cancer mouse model. Our results show that m6A contributes to PAPRi resistance in BRCA-deficient EOC cells by upregulating the Wnt/β-catenin pathway through stabilizing FZD10. They also suggest that inhibition of Wnt/β-catenin pathway represents a potential strategy to overcome PARPi resistance.
Citation Format: Takeshi Fukumoto, Hengrui Zhu, Sergey Karakashev, Timothy Nacarelli, Nail Fatkhutdinov, Shuai Wu, Andrew V. Kossenkov, Louise Showe, Stephanie Jean, Lin Zhang, Rugang Zhang. THE N6-METHYLATION OF ADENOSINE (M6A) IN FZD10 MRNA CONTRIBUTES TO RESISTANCE TO PARP INHIBITOR [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-093.
Abstract NT-096: FABCLAVINE, A SECONDARY METABOLITE FROM XENORHABDUS BUDAPESTENSIS AS THERAPY AGAINST OVARIAN CANCER
Authors: Kapur Arvinder K , Kajla Mayur , Paskewitz Susan , Mehta Pooja , Mehta Geeta , Patankar Manish S 
Published: June 2021

Abstract
Ovarian cancer is the fifth most common cause of cancer-related deaths in women in the United States. Most women with ovarian cancer present with advanced disease. Even though initial response to surgery and chemotherapy is generally positive, many patients relapse with chemoresistant disease. We are especially interested in finding natural products that have anti-neoplastic activity against relapsed disease. Here, we report fabclavine, a secondary metabolite from Xenorhabdus budapestensis as novel anti-cancer agent.
Fabclavine was isolated and purified from cell-free supernatants of Xbu cultures. In a two-step procedure, active compounds were first precipitated from the supernatant with acetone and subsequently purified via reverse phase chromatography. Proliferation assays conducted on several ovarian cancer cell lines such as OVCAR3, OVCA433, ID8, IOSE, show that fabclavine inhibits the cancer cell proliferation at nanomolar (250-400 nM) concentration but has no effect on IOSE at that concentration. The ovarian cancer cell line OVCA33 when tested in proliferation assay showed, they are sensitive to fabclavine at a ten-fold lower concentration than cisplatin. Besides proliferation assay in 2D culture, we also tested the effect of fabclavine in 3D culture of ovarian cancer cell lines. The results indicate, fabclavine was equally effective in 3D culture and killed 40-50% of the cells in spheroids. In addition, fabclavine was also tested against cancer stem cells isolated from ovarian cancer patient and grown in 3D culture and it inhibited the growth of stem cells by 45%. Treatment of ovarian cancer cell lines with Fabclavine indicated DNA damage and an increase in cleaved caspase 3 and Annexin V binding, confirming that this agent was killing the OVCAR3, ID8 and OVCA433 cancer cell lines via apoptosis. Further experiments are underway to determine the apoptosis pathway (intrinsic or extrinsic) activated by fabclavine. Here we are describing for the first time a novel agent which is water soluble, active at low concentration and conveniently purified from cell free supernatant of bacterial culture. These properties of fabclavine makes it an excellent molecule to develop as therapy against ovarian tumors.
Citation Format: Arvinder K Kapur, Mayur Kajla, Susan Paskewitz, Pooja Mehta, Geeta Mehta, Manish S Patankar. FABCLAVINE, A SECONDARY METABOLITE FROM XENORHABDUS BUDAPESTENSIS AS THERAPY AGAINST OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-096.
Abstract NT-108: TARGETING BROMODOMAIN PROTEINS AS A THERAPEUTIC STRATEGY FOR CLEAR CELL CARCINOMA OF THE OVARY
Authors: Shigeta Shogo , Shaw Reid , Moser Russell , Gurley Kay , Lui Goldie , Grandori Carla , Kemp Christopher 
Published: June 2021

Abstract
Background and Objectives: Clear cell carcinoma of the ovary (OCCC) is more resistant to platinum-based chemotherapy than high-grade serous ovarian cancer (HGSOC). Also, the indication for PARP inhibitors seems to be limited in OCCC because of the lower frequency of homologous recombination deficiency. As genomic background significantly differs among subtypes, therapeutic strategies should be optimized in response to each subtype or unique gene alterations. This study was designed to find novel therapeutic targets for OCCC by utilizing siRNA screens and unique patient-derived ovarian cancer cells that phenocopy original tumors.
Materials and Methods: Novel patient-derived ovarian cancer cells were established and kindly provided by Dr. Tan Ince at University of Miami. Genomic alterations of these cells were determined by DNA sequencing. siRNA screens targeting 2,172 unique genes were performed with ARID1A-mutated OCCC cell line OCI C5x, and high-grade serous ovarian cancer cell line OCI P5x. Genes inhibition of which significantly suppressed cell proliferation were selected as hits for each subtype independently. The difference of cell viability between OCI C5x and P5x was also compared, and subtype-specific hits were additionally determined. Hits were applied to Gene Ontology (GO) enrichment analysis to comprehend the gene set enrichment. Several prioritized targets for OCCC were validated with additional RNAi experiments and small molecule inhibitors.
Results: 114 and 108 genes were selected as hits specific to OCI C5x and OCI P5x, respectively. GO enrichment analysis revealed OCCC is potentially more vulnerable to epigenetic interventions than HOGSC. The following inspection revealed bromodomain-containing proteins were enriched in the hits for OCI C5x. Among these, we highlighted bromodomain and extra-terminal domain (BET) family proteins BRD2 and BRD3. Subsequent RNAi experiments validated BRD2 and BRD3 are highly potent therapeutic targets for OCCC.
Conclusions: siRNA screening results suggest different approaches are required according to subtypes for the targeted therapy of ovarian cancer. We propose that epigenetic intervention such as BET protein inhibition as a potential therapeutic option for OCCC, 50-60% of which harbor ARID1A mutation.
Citation Format: Shogo Shigeta, Reid Shaw, Russell Moser, Kay Gurley, Goldie Lui, Carla Grandori, Christopher Kemp. TARGETING BROMODOMAIN PROTEINS AS A THERAPEUTIC STRATEGY FOR CLEAR CELL CARCINOMA OF THE OVARY [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-108.
Abstract NT-119: TARGET DISCOVERY OF NATURAL PRODUCT INSPIRED PHYLLANTHUSMINS FOR TREATMENT OF HIGH GRADE SEROUS OVARIAN CANCER
Authors: Young Alexandria N. , Kurina Steven , Huntsman Andrew , Rathnayake Rathnayake A. , Korkmaz Melissa , Kinghorn A. Douglas , Aldrich Leslie , Cologna Stephanie , Fuchs James R. , Burdette Joanna E. 
Published: June 2021

Abstract
BACKGROUND: High grade serous ovarian cancer (HGSOC) is a lethal gynecological malignancy with a need for new therapeutic agents. Many of the most widely used chemotherapeutic drugs are either derived from or are semi-synthetic derivatives of natural products. We developed potent synthetic analogs (PHYs) of the phyllanthusmin class inspired by prior natural product isolated from Phyllanthus poilanei Beille.
MATERIALS & METHODS: HGSOC cell lines, OVCAR3 and OVCAR8, and non-tumorigenic controls, IOSE80 and FT33, were used in this study. Cytotoxicity assays included sulforhodamine B assay, and annexin X/PI staining and Western blotting for confirmation of apoptosis induction. A photo affinity labeling method was used to attach PHY analogs to solid phase support. Targets were isolated using a pulldown technique and mass spectrometry. CRISPR-Cas9 genome editing was used to knockout and confirm putative targets.
RESULTS: The most potent analog, PHY34, has nanomolar potency in HGSOC cell lines in vitro and displayed cytotoxic activity through late-stage autophagy inhibition and activation of apoptosis. PHY34 was readily bioavailable through intraperitoneal administration in vivo where it significantly reduced HGSOC tumor burden. Targets were identified using photo affinity labeling-aided protein pulldown and mass spectrometry, and confirmed by generating knockout cell lines of targets.
CONCLUSIONS: This class of compounds holds promise as a potential, novel chemotherapeutic approach and demonstrates the effectiveness of pleiotropically targeting autophagy and apoptosis as a viable strategy for combating high grade serous ovarian cancer.
Citation Format: Alexandria N. Young, Steven Kurina, Andrew Huntsman, Rathnayake A. Rathnayake, Melissa Korkmaz, A. Douglas Kinghorn, Leslie Aldrich, Stephanie Cologna, James R. Fuchs, Joanna E. Burdette. TARGET DISCOVERY OF NATURAL PRODUCT INSPIRED PHYLLANTHUSMINS FOR TREATMENT OF HIGH GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-119.
Abstract NT-120: KNOCKOUT OF MTF1 RESULTS IN THE INHIBITION OF EMT IN OVARIAN CANCER CELLS
Authors: Zhao Guannan , Yue Lawrence M Pfeffer Junming 
Published: June 2021

Abstract
Due to peritoneal metastasis and frequent recurrence, ovarian cancer has the highest mortality among gynecological cancers. Epithelial to mesenchymal transition (EMT) contributes to ovarian tumor metastasis. In this study, we report for the first time that metal regulatory transcription factor 1 (MTF1) was upregulated in ovarian cancer, and its high expression was associated with poor patient survival and disease relapse. Knockout of MTF1 using lentiviral CRISPR/Cas9 nickase vector-mediated gene editing inhibited EMT by upregulating epithelial cell markers E-cadherin and cytokeratin 7, and downregulating mesenchymal markers Snai2 and β-catenin in ovarian cancer SKOV3 and OVCAR3 cells. Loss of MTF1 reduced cell proliferation, migration, and invasion in both SKOV3 and OVCAR3 cells. Knockout of MTF1 upregulated the expression of the KLF4 transcription factor, and attenuated two cellular survival pathways, ERK1/2 and AKT. Our studies demonstrated that MTF1 plays an oncogenic role and contributes to ovarian tumor metastasis by promoting EMT. MTF1 may be a novel biomarker for early diagnosis as well as a drug target for clinical therapy.
Citation Format: Guannan Zhao, Lawrence M Pfeffer Junming Yue. KNOCKOUT OF MTF1 RESULTS IN THE INHIBITION OF EMT IN OVARIAN CANCER CELLS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-120.