Miracle-dz/UniFAR-FTUs huggingface dataset:
Prognostic significance of P2RY8‐CRLF2 and CRLF2 overexpression may vary across risk subgroups of childhood B‐cell acute lymphoblastic leukemia

The cytokine receptor‐like factor 2 (CRLF2) gene plays an important role in early B‐cell development. Aberrations in CRLF2 activate the JAK‐STAT signaling pathway that contributes to B‐cell acute lymphoblastic leukemia (B‐ALL). The prognostic significance of CRLF2 overexpression and P2RY8‐CRLF2 fusion in various B‐ALL risk subgroups has not been well established. Two hundred seventy‐one patients with newly diagnosed childhood B‐ALL were enrolled from a Chinese population. The prevalence of CRLF2 overexpression, CRLF2‐P2RY8 fusion, CRLF2 F232C mutation, and JAK2 and IL7R mutational status were analyzed, and the prognostic impact of CRLF2 overexpression and P2RY8‐CRLF2 on B‐ALL was evaluated by assessing their influence on overall survival and event‐free survival. CRLF2 overexpression and P2RY8‐CRLF2 were found in 19% and 10%, respectively, in the whole cohort. No correlation between CRLF2 overexpression and P2RY8‐CRLF2 was observed. CRLF2 F322C and IL7R mutations were not detected in B‐ALL cases overexpressing CRLF2, and no JAK2 mutations were found in the whole cohort either. The results showed that CRLF2 overexpression and P2RY8‐CRLF2 were associated with a poor outcome in unselected B‐ALL. Moreover, in an intermediate risk B‐ALL subgroup P2RY8‐CRLF2 was correlated with worse survival, whereas in high‐ and low‐risk subgroups, CRLF2 overexpression predicted a poor outcome. Our findings suggest that P2RY8‐CRLF2 is an independent prognostic indicator in intermediate risk B‐ALL, while CRLF2 overexpression is correlated with an inferior outcome in high‐ or low‐risk B‐ALL. Our study demonstrates that the impact of P2RY8‐CRLF2 and CRLF2 overexpression on B‐ALL survival may differ across risk subgroups. © 2016 Wiley Periodicals, Inc.
Polyethylene/Na+-montmorillonite composites prepared by slurry-fed melt intercalation: Response surface analysis of rheological behavior

Water-assisted melt-intercalation process is a relatively new method for nanocomposite production. Technical challenges notwithstanding, this process is capable of bringing forth good results and promising advantages. Having used this process, we produced composites in a twin-screw extruder. The aim of this study was to find, through a designed set of experiments, the conditions that result in producing nanocomposites. In this study, the main focus of our characterization phase was on rheological behavior. We then used mechanical testing, X-ray diffraction, and atomic force microscopy for verification purposes. The results obtained from these techniques were manifold; therefore, we used response surface method to present them intelligibly. After examining different modifiers, we concluded that chain length, packing density, and cation exchange selectivity are important parameters for choosing proper modifier type. Plus, as has been reported by other groups, this process was found to be mainly diffusion-controlled rather than shear-controlled.
PANCREAS METASTASES FROM PAPILLARY THYROID CARCINOMA: A REVIEW OF THE LITERATURE.

OBJECTIVE Although locoregional metastases occur in 5 to 10% of patients with papillary thyroid cancer (PTC), distant metastases are rare, especially to the pancreas. Here we review the literature regarding metastases to the pancreas from PTC and present an illustrative patient. METHODS The literature search was performed through using the PubMed database. The information regarding our illustrative case was obtained from the medical records of our institution. RESULTS Since 1991, 11 cases of pancreas metastases of PTC have been reported. The average age at diagnosis was 55.3 years. There were 8 males and 3 females. Three had classic PTC histology, 2 had tall cell variant, and 2 had follicular variant. Four had T4 tumors, and 2 had T3 tumors. Seven had thyroid cancer spread to regional lymph nodes. One had distant metastasis. Pancreas metastases were diagnosed from 1 month to 13 years after primary PTC was detected; the average was 7 years. Our patient was an 84-year-old female diagnosed with PTC with a BRAFV600E mutation following total thyroidectomy. A whole-body scan after radioactive iodine (RAI) remnant ablation was negative for metastases. A pancreatic tumor was identified 2 years later on a fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan. A biopsy of the tumor was histologically similar to PTC and positive for thyroglobulin, thyroid transcription factor-1, and the BRAFV600E mutation. CONCLUSION The biological reasons why PTCs metastasize to the pancreas remain to be elucidated. Older patients with non-RAI avid, FDG-PET-positive metastases, and symptoms of pancreatitis are at increased risk of this rare entity. ABBREVIATIONS FDG = fluorodeoxyglucose FNA = fine-need aspiration PTC = papillary thyroid cancer RAI = radioactive iodine Tg = thyroglobulin TgAb = antithyroglobulin antibodies TNM = tumor-node-metastasis.
Prognostic value of ductal carcinoma in situ component in invasive ductal carcinoma of the breast: a Surveillance, Epidemiology, and End Results database analysis

Background The prognostic implication of concomitant ductal carcinoma in situ (DCIS) in invasive ductal carcinoma (IDC) remains controversial. Our objective was to investigate whether concomitant DCIS affects survival outcomes in patients with IDC. Materials and methods Patients with nonmetastatic breast cancer who underwent surgery in 2010–2014 were included from the Surveillance, Epidemiology, and End Results program. Statistical analyses were conducted using χ2 test, linear-by-linear association, one-way analysis of variance, Kaplan–Meier method, Cox proportional hazards regression model, and propensity score matching (PSM). Results A total of 61,745 patients were identified, including 44,630 (72.3%), 13,559 (22.0%), and 3,556 (5.7%) patients with no DCIS component reported (No-DCIS), DCIS <25% (L-DCIS), and ≥25% (H-DCIS), respectively. Patients with H-DCIS were more likely to be younger (p<0.001), have smaller tumors (p<0.001), good/moderate differentiation (p<0.001), human epidermal growth factor receptor 2–positive disease (p<0.001), receive mastectomy (p<0.001), and not receive radiotherapy (p<0.001) and chemotherapy (p<0.001). The median follow-up was 27 months, and the 2-year breast cancer-specific survival (BCSS) in patients with No-DCIS, L-DCIS, and H-DCIS was 97.3%, 98.0%, and 98.5%, respectively (p<0.001). Before PSM, H-DCIS was an independent favorable prognostic factor for BCSS; patients with H-DCIS had better BCSS compared to patients with No-DCIS (hazard ratio [HR] 0.674, 95% CI: 0.528–0.861, p=0.002), while the BCSS between No-DCIS and L-DCIS was similar (HR 0.944, 95% CI: 0.840–1.061, p=0.334). However, this survival advantage disappeared after PSM; there was significantly different BCSS between patients with No-DCIS and H-DCIS (HR 0.923, 95% CI: 0.653–1.304, p=0.650). H-DCIS was not associated with BCSS as compared to No-DCIS in the breast-conserving surgery (p=0.295) and mastectomy (p=0.793) groups. Conclusion In breast cancer, patients with H-DCIS have unique clinicopathologic features compared to patients with No-DCIS. Before PSM, H-DCIS was associated with favorable BCSS as compared to No-DCIS. However, the survival advantage disappeared after PSM.
Differential control of renal vs. adrenal sympathetic nerve activity by NTS A2a and P2x purinoceptors.

Activation of adenosine A2a and ATP P2x purinoceptors in the subpostremal nucleus tractus solitarii (NTS) via microinjection of the selective agonists CGS-21680 and α,β-methylene ATP (α,β-MeATP), respectively, elicits large dose-dependent decreases in arterial pressure and heart rate, differential regional vasodilation, and differential inhibition of regional sympathetic outputs. With marked hypotensive hemorrhage, preganglionic adrenal sympathetic nerve activity (pre-ASNA) increases, whereas renal (RSNA) and postganglionic adrenal sympathetic nerve activity (post-ASNA) decrease. In this setting, adenosine levels in the brain stem increase. Therefore, we investigated whether stimulation of specific purinoceptors in the NTS may evoke differential sympathetic responses. RSNA was recorded simultaneously with pre-ASNA or post-ASNA in chloralose-urethan-anesthetized male Sprague-Dawley rats. CGS-21680 (2 and 20 pmol in 50 nl) inhibited RSNA and post-ASNA, whereas pre-ASNA increased markedly. α,β-MeATP (25 and 100 pmol in 50 nl) inhibited all sympathetic outputs. Sinoaortic denervation plus vagotomy markedly prolonged the responses to P2x-purinoceptor stimulation. Glutamate (100 pmol in 50 nl) caused differential inhibition of all sympathetic outputs similar to that evoked by α,β-MeATP. We conclude that NTS A2a-purinoceptor activation evokes differential sympathetic responses similar to those observed during hemorrhage, whereas P2x-purinoceptor and glutamate-receptor activation evokes differential inhibition of sympathetic outputs similar to arterial baroreflex responses.
Distribution and seasonal differences in Pacific Lamprey and Lampetra spp eDNA across 18 Puget Sound watersheds

Lampreys have a worldwide distribution, are functionally important to ecological communities and serve significant roles in many cultures. In Pacific coast drainages of North America, lamprey populations have suffered large declines. However, lamprey population status and trends within many areas of this region are unknown and such information is needed for advancing conservation goals. We developed two quantitative PCR-based, aquatic environmental DNA (eDNA) assays for detection of Pacific Lamprey (Entosphenus tridentatus) and Lampetra spp, using locked nucleic acids (LNAs) in the probe design. We used these assays to characterize the spatial distribution of lamprey in 18 watersheds of Puget Sound, Washington, by collecting water samples in spring and fall. Pacific Lamprey and Lampetra spp were each detected in 14 watersheds and co-occurred in 10 watersheds. Lamprey eDNA detection rates were much higher in spring compared to fall. Specifically, the Pacific Lamprey eDNA detection rate was 3.5 times higher in spring and the Lampetra spp eDNA detection rate was 1.5 times higher in spring even though larval lamprey are present in streams year-round. This significant finding highlights the importance of seasonality on eDNA detection. Higher stream discharge in the fall likely contributed to reduced eDNA detection rates, although seasonal life history events may have also contributed. These eDNA assays differentiate Pacific Lamprey and Lampetra spp across much of their range along the west coast of North America. Sequence analysis indicates the Pacific Lamprey assay also targets other Entosphenus spp and indicates the Lampetra spp assay may have limited or no capability of detecting Lampetra in some locations south of the Columbia River Basin. Nevertheless, these assays will serve as a valuable tool for resource managers and have direct application to lamprey conservation efforts, such as mapping species distributions, occupancy modeling, and monitoring translocations and reintroductions.
Influence of Algae Age and Population on the Response to TiO2 Nanoparticles

This work shows the influence of algae age (at the time of the exposure) and the initial algae population on the response of green algae Raphidocelis subcapitata to titanium dioxide nanoparticles (TiO2 NPs). The different algae age was obtained by changes in flow rate of continually stirred tank reactors prior to NP exposure. Increased algae age led to a decreased growth, variations in chlorophyll content, and an increased lipid peroxidation. Increased initial algae population (0.3−4.2 × 106 cells/mL) at a constant NP concentration (100 mg/L) caused a decline in the growth of algae. With increased initial algae population, the lipid peroxidation and chlorophyll both initially decreased and then increased. Lipid peroxidation had 4× the amount of the control at high and low initial population but, at mid-ranged initial population, had approximately half the control value. Chlorophyll a results also showed a similar trend. These results indicate that the physiological state of the algae is important for the toxicological effect of TiO2 NPs. The condition of algae and exposure regime must be considered in detail when assessing the toxicological response of NPs to algae.
Nicotine stimulates branching and expression of SP-A and SP-C mRNAs in embryonic mouse lung culture.

Although the effects of maternal smoking on fetal growth and viability are overwhelmingly negative, there is a paradoxical enhancement of lung maturation as evidenced, in part, by a lower incidence of respiratory distress syndrome in infants of smoking mothers. Other epidemiologic and experimental evidence further support the view that a tobacco smoke constituent, possibly nicotine, affects the development of the lung in utero. We are studying the direct effects of nicotine on murine lung development using a serumless organ culture system. We have found that embryonic lungs explanted at 11 days gestation showed a 32% increase in branching after 4 days in culture in the presence of 1 μM nicotine and 7- to 15-fold increases in mRNAs encoding surfactant proteins A and C after 11 days. The effect of nicotine exposure on surfactant gene expression is apparently mediated by nicotinic acetylcholine receptors because it was blocked byd-tubocurarine. The nicotine-induced stimulation of surfactant gene expression could, in part, account for the effect of maternal smoking on the incidence of respiratory distress syndrome.
A Role for Mitogen-activated Protein Kinase in the Spindle Assembly Checkpoint in XTC Cells

The spindle assembly checkpoint prevents cells whose spindles are defective or chromosomes are misaligned from initiating anaphase and leaving mitosis. Studies of Xenopus egg extracts have implicated the Erk2 mitogen-activated protein kinase (MAP kinase) in this checkpoint. Other studies have suggested that MAP kinases might be important for normal mitotic progression. Here we have investigated whether MAP kinase function is required for mitotic progression or the spindle assembly checkpoint in vivo in Xenopus tadpole cells (XTC). We determined that Erk1 and/or Erk2 are present in the mitotic spindle during prometaphase and metaphase, consistent with the idea that MAP kinase might regulate or monitor the status of the spindle. Next, we microinjected purified recombinant XCL100, a Xenopus MAP kinase phosphatase, into XTC cells in various stages of mitosis to interfere with MAP kinase activation. We found that mitotic progression was unaffected by the phosphatase. However, XCL100 rendered the cells unable to remain arrested in mitosis after treatment with nocodazole. Cells injected with phosphatase at prometaphase or metaphase exited mitosis in the presence of nocodazole—the chromosomes decondensed and the nuclear envelope re-formed—whereas cells injected with buffer or a catalytically inactive XCL100 mutant protein remained arrested in mitosis. Coinjection of constitutively active MAP kinase kinase-1, which opposes XCL100's effects on MAP kinase, antagonized the effects of XCL100. Since the only known targets of MAP kinase kinase-1 are Erk1 and Erk2, these findings argue that MAP kinase function is required for the spindle assembly checkpoint in XTC cells.
Association of Placebo, Indomethacin, Ibuprofen, and Acetaminophen With Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-analysis

Importance Despite increasing emphasis on conservative management of patent ductus arteriosus (PDA) in preterm infants, different pharmacotherapeutic interventions are used to treat those developing a hemodynamically significant PDA. Objectives To estimate the relative likelihood of hemodynamically significant PDA closure with common pharmacotherapeutic interventions and to compare adverse event rates. Data Sources and Study Selection The databases of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception until August 15, 2015, and updated on December 31, 2017, along with conference proceedings up to December 2017. Randomized clinical trials that enrolled preterm infants with a gestational age younger than 37 weeks treated with intravenous or oral indomethacin, ibuprofen, or acetaminophen vs each other, placebo, or no treatment for a clinically or echocardiographically diagnosed hemodynamically significant PDA. Data Extraction and Synthesis Data were independently extracted in pairs by 6 reviewers and synthesized with Bayesian random-effects network meta-analyses. Main Outcomes and Measures Primary outcome: hemodynamically significant PDA closure; secondary: included surgical closure, mortality, necrotizing enterocolitis, and intraventricular hemorrhage. Results In 68 randomized clinical trials of 4802 infants, 14 different variations of indomethacin, ibuprofen, or acetaminophen were used as treatment modalities. The overall PDA closure rate was 67.4% (2867 of 4256 infants). A high dose of oral ibuprofen was associated with a significantly higher odds of PDA closure vs a standard dose of intravenous ibuprofen (odds ratio [OR], 3.59; 95% credible interval [CrI], 1.64-8.17; absolute risk difference, 199 [95% CrI, 95-258] more per 1000 infants) and a standard dose of intravenous indomethacin (OR, 2.35 [95% CrI, 1.08-5.31]; absolute risk difference, 124 [95% CrI, 14-188] more per 1000 infants). Based on the ranking statistics, a high dose of oral ibuprofen ranked as the best pharmacotherapeutic option for PDA closure (mean surface under the cumulative ranking [SUCRA] curve, 0.89 [SD, 0.12]) and to prevent surgical PDA ligation (mean SUCRA, 0.98 [SD, 0.08]). There was no significant difference in the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities. Conclusions and Relevance A high dose of oral ibuprofen was associated with a higher likelihood of hemodynamically significant PDA closure vs standard doses of intravenous ibuprofen or intravenous indomethacin; placebo or no treatment did not significantly change the likelihood of mortality, necrotizing enterocolitis, or intraventricular hemorrhage. Trial Registration PROSPERO Identifier: CRD42015015797
Differentiation of Promonocytic U937 Cells to Monocytes Is Associated with Reduced Mitochondrial Transport of Ascorbic Acid

Growth of promonocytic U937 cells in the presence of DMSO promotes their differentiation to monocytes. After 4 days of culture in differentiating medium, these cells ceased to proliferate, displayed downregulated ryanodine receptor expression, and responded to specific stimuli with enhanced NADPH-oxidase-derived superoxide formation or cytosolic phospholipase A2-dependent arachidonic acid release. We found that the 4-day differentiation process is also associated with downregulated SVCT2 mRNA expression, in the absence of apparent changes in SVCT2 protein expression and transport rate of ascorbic acid (AA). Interestingly, under the same conditions, these cells accumulated lower amounts of the vitamin in their mitochondria, with an ensuing reduced response to external stimuli sensitive to the mitochondrial fraction of AA. Further analyses demonstrated an unexpected increase in mitochondrial SVCT2 protein expression, however, associated with reduced SVCT2-dependent AA uptake in isolated mitochondria. A decrease in the transporter Vmax, with no change in affinity, was found to account for this response. Differentiation of promonocytic cells to monocytes is therefore characterized by decreased SVCT2 mRNA expression that, even prior to the onset of SVCT2 protein downregulation or apparent changes in plasma membrane transport activity, impacts on the mitochondrial accumulation of the vitamin through a decreased Vmax of the transporter.
Cryo-EM structure of Escherichia coli σ70 RNA polymerase and promoter DNA complex revealed a role of σ non-conserved region during the open complex formation

First step of gene expression is transcribing the genetic information stored in DNA to RNA by the transcription machinery including RNA polymerase (RNAP). In Escherichia coli, a primary σ70 factor forms the RNAP holoenzyme to express housekeeping genes. The σ70 contains a large insertion between the conserved regions 1.2 and 2.1, the σ non-conserved region (σNCR), but its function remains to be elucidated. In this study, we determined the cryo-EM structures of the E. coli RNAP σ70 holoenzyme and its complex with promoter DNA (open complex, RPo) at 4.2 and 5.75 Å resolutions, respectively, to reveal native conformations of RNAP and DNA. The RPo structure presented here found an interaction between the σNCR and promoter DNA just upstream of the −10 element, which was not observed in a previously determined E. coli RNAP transcription initiation complex (RPo plus short RNA) structure by X-ray crystallography because of restraint of crystal packing effects. Disruption of the σNCR and DNA interaction by the amino acid substitutions (R157A/R157E) influences the DNA opening around the transcription start site and therefore decreases the transcription activity of RNAP. We propose that the σNCR and DNA interaction is conserved in proteobacteria, and RNAP in other bacteria replaces its role with a transcription factor.
The Horizon of a Therapy for Rare Genetic Diseases: A “Druggable” Future for Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition characterized by progressive extra-skeletal ossification leading to cumulative and severe disability. FOP has an extremely variable and episodic course and can be induced by trauma, infections, iatrogenic harms, immunization or can occur in an unpredictable way, without any recognizable trigger. The causative gene is ACVR1, encoding the Alk-2 type I receptor for bone morphogenetic proteins (BMPs). The signaling is initiated by BMP binding to a receptor complex consisting of type I and II molecules and can proceed into the cell through two main pathways, a canonical, SMAD-dependent signaling and a p38-mediated cascade. Most FOP patients carry the recurrent R206H substitution in the receptor Glycine-Serine rich (GS) domain, whereas a few other mutations are responsible for a limited number of cases. Mutations cause a dysregulation of the downstream BMP-dependent pathway and make mutated ACVR1 responsive to a non-canonical ligand, Activin A. There is no etiologic treatment for FOP. However, many efforts are currently ongoing to find specific therapies targeting the receptor activity and the downstream aberrant pathway at different levels or targeting cellular components and/or processes that are important in modifying the local environment leading to bone neo-formation.