Miracle-dz/UniFAR-FTUs huggingface dataset:
Characterization of Imatinib Resistant CML Leukemic Stem/Initiating Cells and Their Sensitivity to CBP/Catenin Antagonists.

BACKGROUND AND OBJECTIVE The development of the tyrosine kinase inhibitor Imatinib (IM) represents a milestone in CML (Chronic Myeloid Leukemia) treatment. However, it is not curative and patients develop IM resistance. IM resistance has been previously correlated with the emergence of drug-resistant LIC/LSC (Leukemia Initiating Cell/Leukemia Stem Cell) and increased nuclear catenin levels and enhanced Wnt signaling. It has been demonstrated previously that drug resistant CML LIC/LSC can be safely eliminated both in vitro and in vivo via disruption of the CBP/catenin interaction, utilizing the highly biochemically selective small molecule CBP/catenin antagonist ICG- 001. METHODS Here, we utilized an in vitro IM selection of primary CML patients' samples to identify drug-resistant LIC/LSC populations. In this report, we characterized the drug-resistant CML LIC/LSC population using FACS, Smartchip qPCR and colony assays to analyze cell surface markers, transcriptomics and function. RESULTS As opposed to previous characterization of the CML leukemic stem cell population as being either CD34+CD38- or CD34+CD38+, the in vitro selected Imatinib resistant (IM-R) CML LSC population was consistently CD34-CD38-. In Long-Term Culture Initiating Cell assay (LTC-IC, a surrogate assay for long term repopulating stem cells), our results suggest that the CBP/catenin antagonist ICG- 001 sensitizes LIC/LSC to IM treatment by forced differentiative elimination of the CML LIC/LSC population. CONCLUSION In vitro selected IM resistant cells are negative for both CD34 and CD38 by FACS analysis. These cells acquire CD34/CD38 expression after co-culture with stromal cells. CBP/catenin antagonist ICG-001 facilitates IM function in eliminating these cells.
Preference phenotypes to facilitate shared decision-making in rheumatoid arthritis

Objective Implementing treat-to-target (TTT) strategies requires that patients with rheumatoid arthritis (RA) and their rheumatologists decide on how best to escalate care when indicated. The objective of this study was to develop preference phenotypes to facilitate shared decision-making at the point of care for patients failing methotrexate monotherapy. Methods We developed a conjoint analysis survey to measure the preferences of patient with RA for triple therapy, biologics and Janus kinase (JAK) inhibitors. The survey included seven attributes: administration, onset, bothersome side effects, serious infection, very rare side effects, amount of information and cost. Each choice set (n=12) included three hypothetical profiles. Preference phenotypes were identified by applying latent class analysis to the conjoint data. Results 1273 participants completed the survey. A five-group solution was chosen based on progressively lower values of the Akaike and Bayesian information criteria. Members of the largest group (group 3: 38.4%) were most strongly impacted by the cost of the medication. The next largest group (group 1: 25.8%) was most strongly influenced by the risk of bothersome side effects. Members of group 2 (11.2%) were also risk averse, but were most concerned with the risk of very rare side effects. Group 4 (6.6%) strongly preferred oral over parenteral medications. Members of group 5 (18.0%) were most strongly and equally influenced by onset of action and the risk of serious infections. Conclusions Treatment preferences of patients with RA can be measured and represented by distinct phenotypes. Our results underscore the variability in patients’ values and the importance of using a shared decision-making approach to implement TTT.
Towards a (Better) Definition of the Description of Annotated MIR Corpora

Today, annotated MIR corpora are provided by various research labs or companies, each one using its own annotation methodology, concept definitions, and formats. This is not an issue as such. However, the lack of descriptions of the methodology used—how the corpus was actually annotated, and by whom—and of the annotated concepts, i.e. what is actually described, is a problem with respect to the sustainability, usability, and sharing of the corpora. Experience shows that it is essential to define precisely how annotations are supplied and described. We propose here a survey and consolidation report on the nature of the annotated corpora used and shared in MIR, with proposals for the axis against which corpora can be described so to enable effective comparison and the inherent influence this has on tasks performed using them.
Monocyte Chemotactic Protein 1 Promotes Lung Cancer – Induced Bone Resorptive Lesions In Vivo 1

Lung cancer is the leading cause of cancer-related deaths. The morbidity and mortality of lung cancer have markedly increased in the past decade with at least 75% of patients with lung cancer having evidence of metastases at the time of diagnosis. It frequently metastasizes to bone resulting in osteolytic lesions with unknown mechanisms. The aim of this study was to identify factors that mediate lung cancer–induced osteoclast activity in vivo. Using a human cytokine antibody array, we first determined cytokine levels in a conditioned medium collected from non– small cell lung cancer A549 and H1299 cells and the non-neoplastic human bronchial epithelial BEAS2B cells. Both A549 and H1229 cells produced significantly higher amount of several cytokines including monocyte chemotactic protein 1 (MCP-1) and interleukin 8 (IL-8) compared with BEAS2B cells. These findings were confirmed by ELISA. From clinical serum specimens, we also observed that MCP-1 and IL-8 levels were increased in lung cancer patients with bone metastases compared with the patients with localized tumor. Next, we investigated the effects of MCP-1 on osteoclast formation in vitro using murine bone marrow–derived monocytes. A549 conditioned medium induced osteoclast formation that was inhibited by neutralizing antibodies against MCP-1. Finally, A549 cells were stably transfected with MCP-1 short hairpin RNA. The MCP-1 knockdown A549 cells were implanted into the tibia of severe combined immunodeficient mice for 4 weeks. The MCP-1 knockdown significantly diminished A549 cell growth. We conclude that MCP-1 promotes lung cancer–induced osteoclast activity and thus bone resorptive le-
Influence of different resin cements and surface treatments on microshear bond strength of zirconia-based ceramics

Aim: This study aims to evaluate the microshear bond strength of zirconia-based ceramics with different resin cement systems and surface treatments. Materials and Methods: Forty blocks of zirconia-based ceramic were prepared and embedded in polyvinyl chloride (PVC) tubes with acrylic resin. After polishing, the samples were washed in an ultrasonic bath and dried in an oven for 10 min. Half of the samples were subjected to sandblasting with aluminum oxide. Blocks were divided into four groups (n = 10) in which two resin cements were used as follows: (1) RelyX™ U100 with surface-polished zirconia; (2) RelyX™ U100 with surface-blasted zirconia; (3) Multilink with surface-polished zirconia; and 4) Multilink with surface-blasted zirconia. After performing these surface treatments, translucent tubes (n = 30 per group) were placed on the zirconia specimens, and resin cement was injected into them and light cured. The PVC tubes were adapted in a universal testing machine; a stiletto blade, which was bolted to the machine, was positioned on the cementation interface. The microshear test was performed at a speed of 0.5 mm/min. Failure mode was analyzed in an optical microscope and classified as adhesive, cohesive, or mixed. Results: The null hypothesis of this study was rejected because there was a difference found between the resin cement and the surface treatment. There was a statistical difference (P < 0.005) in RelyX™ U100 with surface-blasted zirconia, in relation to the other three groups. For Multilink groups, there was no statistical difference between them. Conclusion: Self-adhesive resin cement showed a more significant tendency toward bond strength in the ceramic-based zirconium oxide grit-blasted surfaces.
Roles of T follicular helper cells in the pathogenesis of adenoidal hypertrophy combined with secretory otitis media

Abstract The aim of this study was to investigate the roles of T follicular helper (Tfh) cells in secretory otitis media (SOM) combined with adenoidal hypertrophy (AH). Patients with AH or AH combined with SOM admitted to the Yancheng No. 1 People's Hospital from December 2012 to December 2014 were included. Fourteen age-matched healthy individuals received physical examinations in the hospital served as control. The venous Tfh was determined using flow cytometry, and CD3 + CD4 + CXCR5 + T lymphocytes were defined as Tfh cells. Serum inflammatory factors including IL-8, IL-1b, IL-6, IL-10, TNF, IL-12p70, IL-21, and IgE were determined using commercial kits. Compared with the AH group, the number of CD4 + CXCR5 + T cells in peripheral blood of the AH combined with SOM group showed significant increase. Statistical differences were noticed in the number of the number of CD4 + CXCR5 + T cells in moderate and severe AH groups compared with that of the control group. Statistical differences were identified in the proportion of CD4 + CXCR5 + T cells in the adenoidal tissues between the AH combined with SOM group and AH group (P < .05). For the CD4 + CXCR5 + T cells in adenoidal tissues, no statistical differences were noticed between the moderate and severe AH groups (P > .05). The number of CD4 + CXCR5 + T cells was positively correlated to the serum IL-21. Nevertheless, no correlation was noticed between CD4 + CXCR5 + T cell and serum IL-8, IL-6, IL-10, and IgE. Tfh is involved in the AH combined with SOM in children. Besides, serum IL-21, IL-8, IL-6, IL-10, and IgE may be involved in the onset of SOM in children.
The mammal-specific Pdx1 Area II enhancer has multiple essential functions in early endocrine cell specification and postnatal β-cell maturation

ABSTRACT The transcription factor Pdx1 is required for multiple aspects of pancreatic organogenesis. It remains unclear to what extent Pdx1 expression and function depend upon trans-activation through 5′ conserved cis-regulatory regions and, in particular, whether the mammal-specific Area II (−2139 to −1958 bp) affects minor or major aspects of organogenesis. We show that Area II is a primary effector of endocrine-selective transcription in epithelial multipotent cells, nascent endocrine progenitors, and differentiating and mature β cells in vivo. Pdx1ΔAREAII/− mice exhibit a massive reduction in endocrine progenitor cells and progeny hormone-producing cells, indicating that Area II activity is fundamental to mounting an effective endocrine lineage-specification program within the multipotent cell population. Creating an Area II-deleted state within already specified Neurog3-expressing endocrine progenitor cells increased the proportion of glucagon+ α relative to insulin+ β cells, associated with the transcriptional and epigenetic derepression of the α-cell-determining Arx gene in endocrine progenitors. There were also glucagon and insulin co-expressing cells, and β cells that were incapable of maturation. Creating the Pdx1ΔAREAII state after cells entered an insulin-expressing stage led to immature and dysfunctional islet β cells carrying abnormal chromatin marking in vital β-cell-associated genes. Therefore, trans-regulatory integration through Area II mediates a surprisingly extensive range of progenitor and β-cell-specific Pdx1 functions. Summary: A crucial enhancer element in the Pdx1 promoter, termed Area II, is required for endocrine progenitor specification, α/β-cell lineage diversification and β-cell maturation in mice.
Factors and misperceptions of routine childhood immunization service uptake in Ethiopia: findings from a nationwide qualitative study

Introduction While the routine childhood immunization program might be affected by several factors, its identification using qualitative evidence of caretakers is generally minimal. This article explores the various factors and misperceptions of routine childhood immunization service uptake in Ethiopia and provides possible recommendations to mitigate them. Methods In this study, we used a qualitative multiple case study design collecting primary data from 63 focus group discussions (FGDs) conducted with a purposefully selected sample of children's caretakers (n = 630). Results According to the results of this study, the use of routine childhood immunization is dependent on four major factors: caretakers' behavior, family characteristics, information and communication and immunization service system. In addition, the participants had some misperceptions about routine childhood immunization. For example, immunization should be taken when the child gets sick and a single dose vaccine is enough for a child. These factors and misperceptions are complex and sometimes context-specific and vary between categories of caretakers. Conclusion Our interpretations suggest that no single factor affects immunization service uptake alone in a unique way. Rather, it is the synergy among the factors that has a collective influence on the childhood immunization system. Therefore, intervention efforts should target these multiple factors simultaneously. Importantly, this study recommends improving the quality of existing childhood immunization services and building awareness among caretakers as crucial components.
Estimated number of off‐target candidate sites for antisense oligonucleotides in human mRNA sequences

Antisense oligonucleotide (ASO) therapeutics are single‐stranded oligonucleotides which bind to RNA through sequence‐specific Watson–Crick base pairings. A unique mechanism of toxicity for ASOs is hybridization‐dependent off‐target effects that can potentially occur due to the binding of ASOs to complementary regions of unintended RNAs. To reduce the off‐target effects of ASOs, it would be useful to know the approximate number of complementary regions of ASOs, or off‐target candidate sites of ASOs, of a given oligonucleotide length and complementarity with their target RNAs. However, the theoretical number of complementary regions with mismatches has not been reported to date. In this study, we estimated the general number of complementary regions of ASOs with mismatches in human mRNA sequences by mathematical calculation and in silico analysis using several thousand hypothetical ASOs. By comparing the theoretical number of complementary regions estimated by mathematical calculation to the actual number obtained by in silico analysis, we found that the number of complementary regions of ASOs could be broadly estimated by the theoretical number calculated mathematically. Our analysis showed that the number of complementary regions increases dramatically as the number of tolerated mismatches increases, highlighting the need for expression analysis of such genes to assess the safety of ASOs.
The Temporal Pole Top‐Down Modulates the Ventral Visual Stream During Social Cognition

Abstract The temporal pole (TP) has been associated with diverse functions of social cognition and emotion processing. Although the underlying mechanism remains elusive, one possibility is that TP acts as domain‐general hub integrating socioemotional information. To test this, 26 participants were presented with 60 empathy‐evoking film clips during fMRI scanning. The film clips were preceded by a linguistic sad or neutral context and half of the clips were accompanied by sad music. In line with its hypothesized role, TP was involved in the processing of sad context and furthermore tracked participants’ empathic concern. To examine the neuromodulatory impact of TP, we applied nonlinear dynamic causal modeling to a multisensory integration network from previous work consisting of superior temporal gyrus (STG), fusiform gyrus (FG), and amygdala, which was extended by an additional node in the TP. Bayesian model comparison revealed a gating of STG and TP on fusiform‐amygdalar coupling and an increase of TP to FG connectivity during the integration of contextual information. Moreover, these backward projections were strengthened by emotional music. The findings indicate that during social cognition, TP integrates information from different modalities and top‐down modulates lower‐level perceptual areas in the ventral visual stream as a function of integration demands.
The Extended Contact Hypothesis: A Meta-Analysis on 20 Years of Research

According to the extended contact hypothesis, knowing that in-group members have cross-group friends improves attitudes toward this out-group. This meta-analysis covers the 20 years of research that currently exists on the extended contact hypothesis, and consists of 248 effect sizes from 115 studies. The aggregate relationship between extended contact and intergroup attitudes was r = . 25, 95% confidence interval (CI) = [. 22, . 27], which reduced to r = . 17, 95% CI = [. 14, . 19] after removing direct friendship’s contribution; these results suggest that extended contact’s hypothesized relationship to intergroup attitudes is small-to-medium and exists independently of direct friendship. This relationship was larger when extended contact was perceived versus actual, highlighting the importance of perception in extended contact. Current results on extended contact mostly resembled their direct friendship counterparts, suggesting similarity between these contact types. These unique insights about extended contact and its relationship with direct friendship should enrich and spur growth within this literature.
Efficacy of Neonatal Release of Ankyloglossia: A Randomized Trial

BACKGROUND: Ankyloglossia has been associated with a variety of infant-feeding problems. Frenotomy commonly is performed for relief of ankyloglossia, but there has been a lack of convincing data to support this practice. OBJECTIVES: Our primary objective was to determine whether frenotomy for infants with ankyloglossia improved maternal nipple pain and ability to breastfeed. A secondary objective was to determine whether frenotomy improved the length of breastfeeding. METHODS: Over a 12-month period, neonates who had difficulty breastfeeding and significant ankyloglossia were enrolled in this randomized, single-blinded, controlled trial and assigned to either a frenotomy (30 infants) or a sham procedure (28 infants). Breastfeeding was assessed by a preintervention and postintervention nipple-pain scale and the Infant Breastfeeding Assessment Tool. The same tools were used at the 2-week follow-up and regularly scheduled follow-ups over a 1-year period. The infants in the sham group were given a frenotomy before or at the 2-week follow-up if it was desired. RESULTS: Both groups demonstrated statistically significantly decreased pain scores after the intervention. The frenotomy group improved significantly more than the sham group (P < .001). Breastfeeding scores significantly improved in the frenotomy group (P = .029) without a significant change in the control group. All but 1 parent in the sham group elected to have the procedure performed when their infant reached 2 weeks of age, which prevented additional comparisons between the 2 groups. CONCLUSIONS: We demonstrated immediate improvement in nipple-pain and breastfeeding scores, despite a placebo effect on nipple pain. This should provide convincing evidence for those seeking a frenotomy for infants with signficant ankyloglossia.
JOURNAL CLUB: The Warthin Tumor Score: A Simple and Reliable Method to Distinguish Warthin Tumors From Pleomorphic Adenomas and Carcinomas.

OBJECTIVE The objective of this article is to propose a Warthin tumor (WT) score to distinguish WTs from other parotid tumors. MATERIALS AND METHODS The study included 78 patients with 92 histologically proven parotid tumors, including 42 WTs, 30 pleomorphic adenomas (PMAs), and 20 carcinomas. Echo-planar DW images were acquired. The WT score, which comprised the mean apparent diffusion coefficient (ADCM) and the SD of the ADC (ADCSD) of tumors, patient age, and patient sex, was used to predict WTs. The diagnostic performance of the WT score was evaluated using ROC analyses. Statistical significance was denoted by p < 0.05. RESULTS With the use of optimized criteria, including an ADCM less than or equal to 1.016 × 10-3 mm2/s (WT score, 1), an ADCSD less than or equal to 0.1171 × 10-3 mm2/s (WT score, 1), patient age older than 49 years (WT score, 1), and male sex (WT score, 1), a WT score greater than 2 had a sensitivity, specificity, positive negative value, negative predictive value, and accuracy of 85.7%, 100.0%, 100.0%, 89.3%, and 93.4%, respectively. CONCLUSION The WT score allows parotid WTs to be distinguished from PMAs and carcinomas with high accuracy.
Vitamin D in prostate cancer

Signaling through the vitamin D receptor has been shown to be biologically active and important in a number of preclinical studies in prostate and other cancers. Epidemiologic data also indicate that vitamin D signaling may be important in the cause and prognosis of prostate and other cancers. These data indicate that perturbation of vitamin D signaling may be a target for the prevention and treatment of prostate cancer. Large studies of vitamin D supplementation will be required to determine whether these observations can be translated into prevention strategies. This paper reviews the available data in the use of vitamin D compounds in the treatment of prostate cancer. Clinical data are limited which support the use of vitamin D compounds in the management of men with prostate cancer. However, clinical trials guided by existing preclinical data are limited.
Deep-sea coral evidence for lower Southern Ocean surface nitrate concentrations during the last ice age

Significance The concentration of atmospheric carbon dioxide (pCO2) varies by 80–100 ppm on glacial–interglacial timescales, with lower pCO2 during the ice ages. In the modern Southern Ocean, the surface nutrients are not fully consumed by phytoplankton, resulting in leakage of deeply sequestered CO2 to the atmosphere. It has been suggested that more complete nutrient consumption in the Southern Ocean would have caused the lower pCO2 during the ice ages. Here, we provide the most spatially comprehensive evidence to date in support of the proposal that the entire Southern Ocean was nutrient-depleted during the last ice age relative to modern conditions. These data are consistent with the hypothesis that Southern Ocean changes contributed to the lower atmospheric pCO2 of the ice ages. The Southern Ocean regulates the ocean’s biological sequestration of CO2 and is widely suspected to underpin much of the ice age decline in atmospheric CO2 concentration, but the specific changes in the region are debated. Although more complete drawdown of surface nutrients by phytoplankton during the ice ages is supported by some sediment core-based measurements, the use of different proxies in different regions has precluded a unified view of Southern Ocean biogeochemical change. Here, we report measurements of the 15N/14N of fossil-bound organic matter in the stony deep-sea coral Desmophyllum dianthus, a tool for reconstructing surface ocean nutrient conditions. The central robust observation is of higher 15N/14N across the Southern Ocean during the Last Glacial Maximum (LGM), 18–25 thousand years ago. These data suggest a reduced summer surface nitrate concentration in both the Antarctic and Subantarctic Zones during the LGM, with little surface nitrate transport between them. After the ice age, the increase in Antarctic surface nitrate occurred through the deglaciation and continued in the Holocene. The rise in Subantarctic surface nitrate appears to have had both early deglacial and late deglacial/Holocene components, preliminarily attributed to the end of Subantarctic iron fertilization and increasing nitrate input from the surface Antarctic Zone, respectively.