Miracle-dz/UniFAR-FTUs huggingface dataset:
The impact of ERBB-family germline single nucleotide polymorphisms on survival response to adjuvant trastuzumab treatment in HER2-positive breast cancer

Background Trastuzumab treatment for women with HER2-positive breast cancer (BC) resulted in the significant improvement of both relapse free survival (RFS) and overall survival (OS). However, many women who are classified as HER2-positive do not respond. Many studies have focused on the role of somatic mutations rather than germline polymorphisms in trastuzumab resistance. Results We completed an Agena MassArray screen of 10 ERBB-family single nucleotide polymorphisms (SNPs) in 194 adjuvant trastuzumab treated HER2-positive BC patients. SNPs in EGFR genes have a significant association with RFS and OS. Patients with the minor allele of EGFR N158N had significantly worse OS (hazard ratio (HR) = 4.01, (confidence interval (CI) = 1.53– 10.69), p = 0.05) relative to those with either the heterozygous or wild-type (WT) allele. Patients with the minor allele of EGFR T903T (HR = 3.52, (CI = 1.38– 8.97), p = 0.05) had worse RFS relative to those with either the heterozygous or WT allele. Patients and methods Using next generation sequencing (NGS) we identified ERBB-family (EGFR, HER2, HER3 and HER4) single nucleotide polymorphisms (SNPs) that occurred in 2 or more patients of a 32 HER2-positive BC patient cohort. Agena MassArray analysis confirmed the frequency of these SNPs in 194 women with HER2-positive BC who received trastuzumab in the adjuvant setting. Using Kaplan-Meier estimates and Cox regression analysis we correlated the presence of ERBB-family SNPs with both RFS and OS. Conclusions The presence of germline ERBB-family SNPs may play an important role in how a patient responds to adjuvant trastuzumab, and clinical assessment of these SNPs by targeted genetic screening of patients' blood may be important to stratify patients for treatment.
Polydopamine as a Biocompatible Multifunctional Nanocarrier for Combined Radioisotope Therapy and Chemotherapy of Cancer

Development of biodegradable nanomaterials for drug delivery and cancer theranostics has attracted great attention in recent years. In this work, polydopamine (PDA), a biocompatible polymer, is developed as a promising carrier for loading of both radionuclides and an anticancer drug to realize nuclear‐imaging‐guided combined radioisotope therapy (RIT) and chemotherapy of cancer in one system. It is found that PDA nanoparticles after modification with poly(ethylene glycol) (PEG) can successfully load several different radionuclides such as 99mTc and 131I, as well as an anticancer drug doxorubicin (DOX). While labeling PDA‐PEG with 99mTc (99mTc‐PDA‐PEG) enables in vivo single photon emission computed tomography imaging, nanoparticles co‐loaded with 131I and DOX (131I‐PDA‐PEG/DOX) can be utilized for combined RIT and chemotherapy, which offers effective cancer treatment efficacy in a remarkably synergistic manner, without rendering significant toxicity to the treated animals. Therefore, this study presents an interesting class of biocompatible nanocarriers, which allow the combination of RIT and chemotherapy, the two extensively applied cancer therapeutic strategies, promising for future clinic translations in cancer treatment.
Factor Structure and Measurement Invariance of the Coimbra Neuropsychological Assessment Battery (BANC)

Objective This study aimed to investigate the factor structure of the Coimbra Neuropsychological Assessment Battery (BANC), which is an individually administered battery designed to assess a wide range of neurocognitive functions in children. Method Using the standardization sample of the BANC, a confirmatory factor analysis and a multiple-group analysis were conducted to examine the factor structure and the measurement invariance of three main domains (Memory, Language, and Attention/Executive Functions) in 833 children aged 7-15 years. Results Consistent with the BANC's conceptualization, the three-correlated-factor model demonstrated the most adequate fit to the data. The measurement invariance of the three-correlated-factor model across two age-groups (7-9 years and 10-15 years) was supported (configural, metric, and partial scalar invariance). Conclusion Overall, the BANC shows adequate psychometric properties and provides useful information regarding the children's neuropsychological functioning.
Purification, characterization, and N‐glycosylation of recombinant butyrylcholinesterase from transgenic rice cell suspension cultures

Recombinant butyrylcholinesterase produced in a metabolically regulated transgenic rice cell culture (rrBChE) was purified to produce a highly pure (95%), active form of enzyme. The developed downstream process uses common manufacturing friendly operations including tangential flow filtration, anion‐exchange chromatography, and affinity chromatography to obtain a process recovery of 42% active rrBChE. The purified rrBChE was then characterized to confirm its comparability to the native human form of the molecule (hBChE). The recombinant and native enzyme demonstrated comparable enzymatic behavior and had an identical amino acid sequence. However, rrBChE differs in that it contains plant‐type complex N‐glycans, including an α‐1,3 linked core fucose, and a β‐1,2 xylose, and lacking a terminal sialic acid. Despite this difference, rrBChE is demonstrated to be an effective stoichiometric bioscavenger for five different organophosphorous nerve agents in vitro. Together, the efficient downstream processing scheme and functionality of rrBChE confirm its promise as a cost‐effective alternative to hBChE for prophylactic and therapeutic use.
Insulin resistance in systemic lupus erythematosus patients: contributing factors and relationship with subclinical atherosclerosis.

OBJECTIVES Insulin resistance (IR) plays a role in the increased cardiovascular risk of systemic lupus erythematosus (SLE) patients. This study aimed to determine the potential association of IR with disease activity, drug exposure and subclinical atherosclerosis in patients with SLE. METHODS This cross-sectional study encompassed 87 non-diabetic SLE patients and 82 sex-matched controls. Insulin and C-peptide serum levels, IR indexes by homeostatic model assessment (HOMA2) (both insulin-based: HOMA2-IR, and with C-peptide: HOMA2-IR-C-peptide) and lipid profiles were assessed in patients and controls. Activity (SLEDAI), severity (Katz) and damage (SLICC) index scores, as well as carotid intima-media thickness (cIMT) and carotid plaques, were determined in SLE patients. A multivariable regression analysis, adjusted for classic IR related factors, was performed to evaluate the differences in IR indexes between patients and controls and how IR is associated with disease-related characteristics, including carotid ultrasound results, in SLE patients. RESULTS SLE patients had higher C-peptide serum levels (2.61±1.51 vs. 1.34±0.62 ng/ml, p=0.00) and elevated HOMA2-IRC-peptide index (1.90±1.12 vs. 0.97±0.45, p=0.00) than controls. These differences remained statistically significant after adjusting for classic cardiovascular risk factors and prednisone intake. Traditional IR-related factors, such as body mass index, waist circumference or hypertension, and prednisone intake were significantly associated with HOMA2-IR and HOMA2-IRC-peptide in SLE patients. SLICC damage index was independently associated with HOMA2-IR-C-peptide. The presence of carotid plaques and cIMT values were associated with IR indexes in SLE patients only in the univariate analysis. CONCLUSIONS C-peptide serum levels are independently up-regulated in SLE patients. Although classic IR factors and prednisone are associated with IR, SLE damage over time also contributes to IR in an independent way.
High-Resolution TEM and the Application of Direct and Indirect Aberration Correction

Aberration correction leads to a substantial improvement in the directly interpretable resolution of transmission electron microscopes. Correction of the aberrations has been achieved electron-optically through a hexapole-based corrector and also indirectly by computational analysis of a focal or tilt series of images. These direct and indirect methods are complementary, and a combination of the two offers further advantages. Materials characterization has benefitted from the reduced delocalization and higher resolution in the corrected images. It is now possible, for example, to locate atomic columns at surfaces to higher accuracy and reliability. This article describes the JEM-2200FS in Oxford, which is equipped with correctors for both the image-forming and probe-forming lenses. Examples of the use of this instrument in the characterization of nanocrystalline catalysts are given together with initial results combining direct and indirect methods. The double corrector configuration enables direct imaging of the corrected probe, and a potential confocal imaging mode is described. Finally, modifications to a second generation instrument are outlined.
Human neonatal rotavirus vaccine (RV3-BB) targets rotavirus from birth

Background A strategy of administering a neonatal rotavirus vaccine at birth to target early prevention of rotavirus gastroenteritis may address some of the barriers to global implementation of a rotavirus vaccine. Methods We conducted a randomized, double‐blind, placebo‐controlled trial in Indonesia to evaluate the efficacy of an oral human neonatal rotavirus vaccine (RV3‐BB) in preventing rotavirus gastroenteritis. Healthy newborns received three doses of RV3‐BB, administered according to a neonatal schedule (0 to 5 days, 8 weeks, and 14 weeks of age) or an infant schedule (8 weeks, 14 weeks, and 18 weeks of age), or placebo. The primary analysis was conducted in the per‐protocol population, which included only participants who received all four doses of vaccine or placebo within the visit windows, with secondary analyses performed in the intention‐to‐treat population, which included all participants who underwent randomization. Results Among the 1513 participants in the per‐protocol population, severe rotavirus gastroenteritis occurred up to the age of 18 months in 5.6% of the participants in the placebo group (28 of 504 babies), in 1.4% in the neonatal‐schedule vaccine group (7 of 498), and in 2.7% in the infant‐schedule vaccine group (14 of 511). This resulted in a vaccine efficacy of 75% (95% confidence interval [CI], 44 to 91) in the neonatal‐schedule group (P<0.001), 51% (95% CI, 7 to 76) in the infant‐schedule group (P=0.03), and 63% (95% CI, 34 to 80) in the neonatal‐schedule and infant‐schedule groups combined (combined vaccine group) (P<0.001). Similar results were observed in the intention‐to‐treat analysis (1649 participants); the vaccine efficacy was 68% (95% CI, 35 to 86) in the neonatal‐schedule group (P=0.001), 52% (95% CI, 11 to 76) in the infant‐schedule group (P=0.02), and 60% (95% CI, 31 to 76) in the combined vaccine group (P<0.001). Vaccine response, as evidenced by serum immune response or shedding of RV3‐BB in the stool, occurred in 78 of 83 participants (94%) in the neonatal‐schedule group and in 83 of 84 participants (99%) in the infant‐schedule group. The incidence of adverse events was similar across the groups. No episodes of intussusception occurred within the 21‐day risk period after administration of any dose of vaccine or placebo, and one episode of intussusception occurred 114 days after the third dose of vaccine in the infant‐schedule group. Conclusions RV3‐BB was efficacious in preventing severe rotavirus gastroenteritis when administered according to a neonatal or an infant schedule in Indonesia. (Funded by the Bill and Melinda Gates Foundation and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612001282875.)
Increased expression of nestin and VEGF in endometrial polyps : an immunhistochemical study

Background: Pathogenesis of endometrial polyps have not been fully understood however the increased proliferation of blood vessells and fibrosis may play an important role in the pathogenesis of endometrial polyps. Vascular endothelial growth factor (VEGF) is a a key regulator of angiogenesis and vascular function. Nestin is another molecule which has been reported to be associated with the process of angiogenesis. The aim of this study was to evaluate the expression of Nestin protein and VEGF in pathogenesis of endometrial polyps. Methods: A total of 20 women who had hysteroscopic and histologic confirmation of benign endometrial polyps and their normal endometrial tissue were recruited into the study. Immunohistochemical analysis for VEGF, Nestin and CD34 were performed on formalin fixed, paraffin-embedded tissue using the streptavidin-biotin-peroxidase technique. Angiogenesis was assessed by immunohistochemistry using monoclonal antibody against CD34. Results: Immunostaining of VEGF in glandular epithelial cells and stromal fibroblasts, and immunostaining of Nestin in newly formed vessels were determined. Immunopositivity staining of VEGF in endometrial polyps were significantly stronger than normal endometrium (P<0.05). Nestin expression was observed in vessels which were smaller than that of CD34-positive preexisting large blood vessels. Endometrial polyps demonstrated significantly greater expression of Nestin in proliferating endothelial cells, compared with control endometrium (P<0.05). Conclusion: This study suggests that the increased expression of VEGF and Nestin protein which are may have a role in the pathogenesis of endometrial polyps.
Localization of the Mycoplasma pneumoniae cytadherence-accessory proteins HMW1 and HMW4 in the cytoskeletonlike Triton shell

The location of the cytadherence-accessory high-molecular weight proteins 1 and 4 (HMW1/4) within Mycoplasma pneumoniae cells has been studied by both biochemical and electron microscopic techniques. Peptide mapping studies demonstrated that HMW1/4 share almost identical peptide profiles, suggesting that the two proteins are structurally related. Examination of thin sections of M. pneumoniae with antibodies to HMW1/4 and colloidal gold particles revealed distinct labeling of the filamentous extensions of the mycoplasma cells. Labeling was absent on thin sections of a cytadherence-deficient variant lacking HMW1/4. HMW1/4 partitioned in the detergent-insoluble fraction following Triton X-100 extraction, and analysis by sucrose density gradient centrifugation suggested that HMW1/4 are part of a high-molecular-weight, multiprotein complex. These results were confirmed by immunogold labeling of Triton X-100-extracted M. pneumoniae cells incubated with antibodies to HMW1/4: gold particles bound in specific clusters to detergent-insoluble filaments. Finally, immunogold labeling of whole cells revealed that HMW1/4 are exposed on the cell surface, although to a lesser degree than on the cell interior. These findings indicate that HMW1/4 are membrane proteins associated with the cytoskeletonlike triton shell of M. pneumoniae and localized primarily in the filamentous extensions of the mycoplasma cells.
Unique gene program of rat small resistance mesenteric arteries as revealed by deep RNA sequencing

Deep sequencing of RNA samples from rat small mesenteric arteries (MA) and aorta (AO) identified common and unique features of their gene programs. ~5% of mRNAs were quantitatively differentially expressed in MA versus AO. Unique transcriptional control in MA smooth muscle is suggested by the selective or enriched expression of transcription factors Nkx2‐3, HAND2, and Tcf21 (Capsulin). Enrichment in AO of PPAR transcription factors and their target genes of mitochondrial function, lipid metabolism, and oxidative phosphorylation is consistent with slow (oxidative) tonic smooth muscle. In contrast MA was enriched in contractile and calcium channel mRNAs suggestive of components of fast (glycolytic) phasic smooth muscle. Myosin phosphatase regulatory subunit paralogs Mypt1 and p85 were expressed at similar levels, while smooth muscle MLCK was the only such kinase expressed, suggesting functional redundancy of the former but not the latter in accordance with mouse knockout studies. With regard to vaso‐regulatory signals, purinergic receptors P2rx1 and P2rx5 were reciprocally expressed in MA versus AO, while the olfactory receptor Olr59 was enriched in MA. Alox15, which generates the EDHF HPETE, was enriched in MA while eNOS was equally expressed, consistent with the greater role of EDHF in the smaller arteries. mRNAs that were not expressed at a level consistent with impugned function include skeletal myogenic factors, IKK2, nonmuscle myosin, and Gnb3. This screening analysis of gene expression in the small mesenteric resistance arteries suggests testable hypotheses regarding unique aspects of small artery function in the regional control of blood flow.
Safety and feasibility of transcranial direct current stimulation in amyotrophic lateral sclerosis – a pilot study with a single subject experimental design

ABSTRACT Introduction: Transcranial direct current stimulation (tDCS) has been explored as a neuromodulatory tool to prime motor function in several neurological disorders. Studies using tDCS in amyotrophic lateral sclerosis (ALS) are limited. We investigated the safety, feasibility and effects of long-term tDCS in an individual with ALS. Methods: A 36-year-old male diagnosed with clinically definite ALS received 12 sessions each of anodal, sham, and cathodal tDCS. Outcome measures included disease progression (revised ALS functional rating scale (ALSFRS-R)), clinical measures of endurance and mobility, and corticomotor excitability. Results: No adverse events or change in disease progression were noticed during the study. Small improvement in gait speed (15% increase) was noticed with anodal tDCS only. Conclusions: This case study demonstrates the safety and feasibility of long-term facilitatory and inhibitory tDCS on a single participant with ALS. This study serves as a guideline for implementing tDCS in future ALS trials.
Temporal evolution of stable water isotopologues in cloud droplets in a hill cap cloud in central Europe (HCCT-2010)

Abstract. In this work, we present the first study resolving the temporal evolution of δ 2 H and δ 18 O values in cloud droplets during 13 different cloud events. The cloud events were probed on a 937 m high mountain chain in Germany in the framework of the Hill Cap Cloud Thuringia 2010 campaign (HCCT-2010) in September and October 2010. The δ values of cloud droplets ranged from −77‰ to −15‰ (δ 2 H) and from −12.1‰ to −3.9‰ (δ 18 O) over the whole campaign. The cloud water line of the measured δ values was δ 2 H=7.8×δ 18 O+13×10 −3 , which is of similar slope, but with higher deuterium excess than other Central European Meteoric Water Lines. Decreasing δ values in the course of the campaign agree with seasonal trends observed in rain in central Europe. The deuterium excess was higher in clouds developing after recent precipitation revealing episodes of regional moisture recycling. The variations in δ values during one cloud event could either result from changes in meteorological conditions during condensation or from variations in the δ values of the water vapor feeding the cloud. To test which of both aspects dominated during the investigated cloud events, we modeled the variation in δ values in cloud water using a closed box model. We could show that the variation in δ values of two cloud events was mainly due to changes in local temperature conditions. For the other eleven cloud events, the variation was most likely caused by changes in the isotopic composition of the advected and entrained vapor. Frontal passages during two of the latter cloud events led to the strongest temporal changes in both δ 2 H (≈ 6‰ per hour) and δ 18 O (≈ 0.6‰ per hour). Moreover, a detailed trajectory analysis for the two longest cloud events revealed that variations in the entrained vapor were most likely related to rain out or changes in relative humidity and temperature at the moisture source region or both. This study illustrates the sensitivity of stable isotope composition of cloud water to changes in large scale air mass properties and regional recycling of moisture.
Attribution Strategies and Return on Keyword Investment in Paid Search Advertising

Firms use different attribution strategies such as last-click or first-click attribution to assign conversion credits to search keywords that appear in their consumers’ paths to purchase. These attributed credits impact a firm’s future bidding and budget allocations among keywords and, in turn, determine the overall return-on-investment of search campaigns. In this paper, we model the relationship among the advertiser’s bidding decision for keywords, the search engine’s ranking decision for these keywords, and the consumer’s click-through rate and conversion rate on each keyword, and analyze the impact of the attribution strategy on the overall return-on-investment of paid search advertising.We estimate our simultaneous equations model using a six-month panel data of several hundred keywords from an online jewelry retailer. The data comprises a quasi-experiment as the firm changed attribution strategy from last-click to first-click attribution halfway through the data window. Our results show that returns for keyword investments vary significantly under the different attribution strategies. For the focal firm, first-click attribution leads to lower revenue returns and a more pronounced decrease for more specific keywords. Our policy simulation exercise shows how the firm can increase its overall returns by better attributing the real contribution of keywords. We discuss how an appropriate attribution strategy can help firms to better target customers and lower acquisition costs in the context of paid search advertising.Data, as supplemental material, are available at https://doi.org/10.1287/mksc.2016. 0987 .
Ginsenoside Rg1 Ameliorates Rat Myocardial Ischemia-Reperfusion Injury by Modulating Energy Metabolism Pathways

As a major ingredient of Radix ginseng, ginsenoside Rg1 (Rg1) has been increasingly recognized to benefit the heart condition, however, the rationale behind the role is not fully understood. In vitro study in H9c2 cardiomyocytes has shown the potential of Rg1 to increase ATP content in the cells. We thus speculated that the protective effect of Rg1 on heart ischemia and reperfusion (I/R) injury implicates energy metabolism regulation. The present study was designed to verify this speculation. Male Sprague-Dawley rats were subjected to 30 min of occlusion of left coronary anterior descending artery followed by reperfusion for 90 min. Rg1 (5 mg/kg/h) was continuously administrated intravenously 30 min before occlusion until the end of reperfusion. Myocradial blood flow and heart function were monitored over the period of I/R. Myocardial infarct size, structure and apoptosis, energy metabolism, and change in RhoA signaling pathway were evaluated 90 min after reperfusion. Binding of Rg1 to RhoA was assessed using Surface Plasmon Resonance (SPR). Rg1 prevented I/R-elicited insults in myocardium, including myocardial infarction and apoptosis, decreased myocardial blood flow (MBF) and heart function, and alteration in myocardium structure. Rg1 restored the production of ATP in myocardium after I/R. Rg1 was able to bind to RhoA and down-regulate the activity of RhoA signaling pathway. These results indicated that Rg1 had protective potential against I/R-induced myocardial injury, which may be related to inhibiting myocardial apoptosis and modulating energy metabolism through binding to RhoA.