Miracle-dz/UniFAR-FTUs huggingface dataset:
A Novel Validated Recurrence Risk Score to Guide a Pragmatic Surveillance Strategy After Resection of Pancreatic Neuroendocrine Tumors: An International Study of 1006 Patients.

OBJECTIVE Despite heterogeneous biology, similar surveillance schemas are utilized after resection of all pancreatic neuroendocrine tumors (PanNETs). Given concerns regarding excess radiation exposure and financial burden, our aim was to develop a prognostic score for disease recurrence to guide individually tailored surveillance strategies. METHODS All patients with primary nonfunctioning, nonmetastatic well/moderately differentiated PanNETs who underwent curative-intent resection at 9-institutions from 2000 to 2016 were included (n = 1006). A Recurrence Risk Score (RRS) was developed from a randomly selected derivation cohort comprised of 67% of patients and verified on the validation-cohort comprised of the remaining 33%. RESULTS On multivariable analysis, patients within the derivation cohort (n = 681) with symptomatic tumors (jaundice, pain, bleeding), tumors >2 cm, Ki67 >3%, and lymph node (LN) (+) disease had increased recurrence. Each factor was assigned a score based on their weighted odds ratio that formed a RRS of 0 to 10: symptomatic = 1, tumor >2 cm = 2, Ki67 3% to 20% = 1, Ki67 >20% = 6, LN (+) = 1. Patients were grouped into low- (RRS = 0-2; n = 247), intermediate-(RRS = 3-5; n = 204), or high (RRS = 6-10; n = 9)-risk groups. At 24 months, 33% of high RRS recurred, whereas only 2% of low and 14% of intermediate RRS recurred. This persisted in the validation cohort (n = 325). CONCLUSIONS This international, novel, internally validated RRS accurately stratifies recurrence-free survival for patients with resected PanNETs. Given their unique recurrence patterns, surveillance intervals of 12, 6, and 3 months are proposed for low, intermediate, and high RRS patients, respectively, to minimize radiation exposure and optimize cost/resource utilization.
Examining the Early Period Effect of Nilotinib on Hearing: An Experimental Study

OBJECTIVES Nilotinib has very few side effects, including neutropenia, thrombocytopenia, cardiotoxicity, high pancreatic lipase, ischemia, and vascular occlusion. We aimed to investigate whether short-term administration of nilotinib had ototoxic effects in rats. MATERIALS and METHODS Wistar-albino rats were categorized into three groups: group C (administered 0.25 mL of distilled water, no nilotinib), group N-20 (administered 20 mg/kg/day of nilotinib dissolved in distilled water), and group N-50 (administered 50 mg/kg/day of nilotinib dissolved in distilled water). A single dose was administered once per day, at the same hour, over 21 days. Auditory brainstem response (ABR) thresholds were recorded on day 0 and day 21. RESULTS There were no changes in ABR threshold values obtained on day 0 (baseline) and on day 21 across all three groups. A statistically significant difference was not found in terms of the mean latency of waves V and III, interpeak latency values of waves III–V, and amplitude ratios of waves III–V and V/Va at baseline and on day 21 across all three groups on within-group or between-group evaluation. CONCLUSION Consequently, further studies are needed that involve different drug doses, prolonged administration of drugs, as well as distortion otoacoustic emission test for the evaluation of cochlear activation and ABR. Furthermore, histopathological studies are needed to indicate whether the cochlea is affected to prove that nilotinib has definitively no ototoxic effect.
Endothelial function and T-lymphocyte subsets in patients with overlap syndrome of chronic obstructive pulmonary disease and obstructive sleep apnea

Abstract Background: The coexistence of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) is termed overlap syndrome (OS). COPD and OSA both have increased risks of developing cardiovascular diseases. This study aimed to explore if patients with OS exhibited a higher prevalence of cardiovascular complications, and if patients with OS exhibited vascular endothelial dysfunction and abnormalities in the cellular immune function of T lymphocytes. Methods: Totally 25 patients with stable COPD (COPD group), 25 patients with OSA (OSA group), 25 patients with OS (OS group), and 20 healthy adults (control group) were enrolled between January 2017 and December 2017 from the Respiratory Department of Tianjin Medical University General Hospital. The clinical characteristics of the four groups were collected and the expression levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), tumor necrosis factor-α (TNF-α), and T-lymphocyte subsets were detected. One-way analysis of variance, χ2 test and Pearson correlation were used to manage the data. Results: The prevalence of hypertension and coronary heart disease was significantly higher in the OS group than in the control, OSA, and COPD groups (χ2 = 20.69, P < 0.05 and χ2 = 11.03, P < 0.05, respectively). The levels of sVCAM-1 and TNF-α were significantly higher in the OS group than in other groups (F = 127.40, P < 0.05 and F = 846.77, P < 0.05, respectively). The percentage of CD4+ lymphocytes and CD4+/CD8+ were both significantly lower in the OS group than in any other group (F = 25.40, P < 0.05 and F = 75.08, P < 0.05, respectively). There were significantly negative correlations in the levels of sVCAM-1 and TNF-α with CD4+/CD8+ lymphocytes (r = –0.77, P < 0.05 and r = –0.83, P < 0.05, respectively). Conclusions: The prevalence of hypertension and coronary heart disease was higher in patients with OS than in patients with either OSA or COPD alone. Patients with OS exhibited more severe vascular endothelial injury, stronger inflammatory response, and lower cellular immune function.
Age- and Maturity-Related Variations in Morphology, Body Composition, and Motor Fitness among Young Female Tennis Players

The purpose of this study was to examine the effects of age and maturity on anthropometric and various fitness characteristics in young competitive female tennis players. Sixty-one players, aged 10.4–13.2 years (11.8 ± 0.8) were measured for standing and sitting heights, body mass, skinfolds, grip strength, and agility, and dichotomized into two age (U12 and U14) and maturity (earliest and latest) groups according to their chronological age and maturity status. The results revealed significant age effects for stature, sitting height, leg length, and hand grip in favor of the older players. Girls contrasting in maturation differed significantly for all anthropometric and physical performance variables except for body mass index (BMI), body fat percentage (BF%), and hexagon agility test. The earliest maturing group showed significantly higher values for anthropometric measures and better results in the hand grip test than the latest maturing group. After controlling for chronological age, differences were revealed between contrasting maturity groups in stature, sitting height, BF%, and the hand grip test. The findings highlight the age- and maturity-related trends in body size and muscular strength among young female tennis players in the pubertal period. Nevertheless, the differences in the body composition and agility of the contrasting age and maturity groups were negligible.
Do bilingual children lag behind? A study of morphological encoding using ERPs

Abstract The current study investigates how bilingual children encode and produce morphologically complex words. We employed a silent-production-plus-delayed-vocalization paradigm in which event-related brain potentials (ERPs) were recorded during silent encoding of inflected words which were subsequently cued to be overtly produced. The bilingual children's spoken responses and their ERPs were compared to previous datasets from monolingual children on the same task. We found an enhanced negativity for regular relative to irregular forms during silent production in both bilingual children's languages, replicating the ERP effect previously obtained from monolingual children. Nevertheless, the bilingual children produced more morphological errors (viz. over-regularizations) than monolingual children. We conclude that mechanisms of morphological encoding (as measured by ERPs) are parallel for bilingual and monolingual children, and that the increased over-regularization rates are due to their reduced exposure to each of the two languages (relative to monolingual children).
The Roles of Group Status and Group Membership in the Practice of Hypodescent.

Hypodescent emerged in U.S. history to reinforce racial hierarchy. Research suggests that among contemporary U.S. adults, hypodescent continues to shape social perception. Among U.S. children, however, hypodescent is less likely to be endorsed. Here, we tested for hypodescent by introducing U.S. children (ages 4-9) and adults (N = 273) to hierarchically ordered novel groups (one was high status and another was low status) and then to a child who had one parent from each group. In Study 1, we presented the groups in a third-party context. In Study 2, we randomly assigned participants to the high-status or the low-status group. Across both studies, participants did not reliably endorse hypodescent, raising questions as to what elicits this practice.
pH-Sensitive Chitosan–Heparin Nanoparticles for Effective Delivery of Genetic Drugs into Epithelial Cells

Chitosan has been extensively studied as a genetic drug delivery platform. However, its efficiency is limited by the strength of DNA and RNA binding. Expecting a reduced binding strength of cargo with chitosan, we proposed including heparin as a competing polyanion in the polyplexes. We developed chitosan–heparin nanoparticles by a one-step process for the local delivery of oligonucleotides. The size of the polyplexes was dependent on the mass ratio of polycation to polyanion. The mechanism of oligonucleotide release was pH-dependent and associated with polyplex swelling and collapse of the polysaccharide network. Inclusion of heparin enhanced the oligonucleotide release from the chitosan-based polyplexes. Furthermore, heparin reduced the toxicity of polyplexes in the cultured cells. The cell uptake of chitosan–heparin polyplexes was equal to that of chitosan polyplexes, but heparin increased the transfection efficiency of the polyplexes two-fold. The application of chitosan–heparin small interfering RNA (siRNA) targeted to vascular endothelial growth factor (VEGF) silencing of ARPE-19 cells was 25% higher. Overall, chitosan–heparin polyplexes showed a significant improvement of gene release inside the cells, transfection, and gene silencing efficiency in vitro, suggesting that this fundamental strategy can further improve the transfection efficiency with application of non-viral vectors.
Comprehensive Transcriptome Reveals an Opposite Regulatory Effect of Plant Growth Retardants in Controlling Seedling Overgrowth between Roots and Shoots

Seedling overgrowth always develops in undernourished plants due to biotic or abiotic stresses, which significantly decrease the yield of crops and vegetables. It is known that the plant growth retardants paclobutrazol (PBZ) and chlormequat chloride (CCC) are the most commonly used chemicals in controlling seedling height in plants by regulating the gibberellin (GA) biosynthesis pathway. However, the exact molecular regulation mechanism remains largely unknown. This study performed a comprehensive transcriptome profile to identify significantly differentially expressed genes after adding CCC and PBZ to the water culture seedling raising system for the first time. According to the obviously restrained shoots and roots, the GA biosynthesis genes were significantly decreased, as well as the endogenous GA content being reduced. Intriguingly, the GA signaling pathway genes were affected in opposite ways, increasing in roots but decreasing in shoots, especially regarding the phytochrome interacting factor SlPIF1 and the downstream genes expansins (SlEXPs), which promote cell wall remodeling. Further study found that the most down-regulated genes SlEXPA5 and SlEXPA15 were expressed specifically in shoot tissue, performing the function of repressing elongation, while the up-regulated genes SlEXPB2 and SlEXPB8 were proven to be root-specific expressed genes, which may promote horizontal elongation in roots. This research reported the comprehensive transcriptome profiling of plant growth retardants in controlling seedling overgrowth and restraining GA biosynthesis through the regulation of the GA signaling-related genes SlPIF1 and SlEXPs, with an opposite expression pattern between roots and shoots.
Altered nuclear export signal recognition as a driver of oncogenesis.

Altered expression of XPO1, the main nuclear export receptor in eukaryotic cells, has been observed in cancer and XPO1 has been a focus of anti-cancer drug development. However, mechanistic evidence for cancer-specific alterations in XPO1 function is lacking. Here, genomic analysis of 42,793 cancers identified recurrent and previously unrecognized mutational hotspots in XPO1. XPO1 mutations exhibited striking lineage specificity, with enrichment in a variety of B-cell malignancies, and introduction of single amino acid substitutions in XPO1 initiated clonal, B-cell malignancy in vivo. Proteomic characterization identified that mutant XPO1 altered the nucleo-cytoplasmic distribution of hundreds of proteins in a sequence-specific manner that promoted oncogenesis. XPO1 mutations preferentially sensitized cells to inhibitors of nuclear export, providing a biomarker of response to this family of drugs. These data reveal a new class of oncogenic alteration based on change-of-function mutations in nuclear export signal recognition and identify therapeutic targets based on altered nucleo-cytoplasmic trafficking.
The Contribution of Preschool Meals to the Diet of Finnish Preschoolers

Preschool meals may influence the formation of children’s dietary habits and health. We assessed the contribution of preschool meals to the diet of Finnish children. We used food record data from the cross-sectional DAGIS survey and selected recording days which included all three meals (breakfast, lunch, afternoon snack) at preschool. We analyzed the diet of three- to four-year-olds (n = 324) and five- to six-year-olds (n = 233). Preschool meals accounted for 54% of the weekday’s energy intake in both age groups, and provided ≥60% of total fiber, polyunsaturated fatty acids, and vitamins D and E. More than 60% of fish dishes but only one third of total daily fresh fruit were consumed at preschool. The mean (SD) percentages of energy from protein and fat at preschool were 17% (3%) and 30% (7%) in the younger and 17% (3%) and 31% (6%) in the older age group, respectively. The mean proportions of energy from added sugar at preschool were below 5% in both age groups. On average, salt intake exceeded recommendations and 60% of salt came from preschool food. Tackling high salt intake should be a future goal of guidance for early childhood education and care food services.
Neuropharmacology of the Neuropsychiatric Symptoms of Dementia and Role of Pain: Essential Oil of Bergamot as a Novel Therapeutic Approach

Aging of the population makes of dementia a challenge for health systems worldwide. The cognitive disturbance is a serious but not the only issue in dementia; behavioral and psychological syndromes known as neuropsychiatric symptoms of dementia remarkably reduce the quality of life. The cluster of symptoms includes anxiety, depression, wandering, delusions, hallucinations, misidentifications, agitation and aggression. The pathophysiology of these symptoms implicates all the neurotransmitter systems, with a pivotal role for the glutamatergic neurotransmission. Imbalanced glutamatergic and GABAergic neurotransmissions, over-activation of the extrasynaptic N-methyl-D-aspartate (NMDA) receptors and alterations of the latter have been linked to the development of neuropsychiatric symptoms experienced by almost the entire demented population. Drugs with efficacy and safety for prevention or long term treatment of these disorders are not available yet. Aromatherapy provides the best evidence for positive outcomes in the control of agitation, the most resistant symptom. Demented patients often cannot verbalize pain, resulting in unrelieved symptoms and contributing to agitation. Bergamot essential oil provides extensive preclinical evidence of analgesic properties. Incidentally, the essential oil of bergamot induces anxyolitic-like effects devoid of sedation, typical of benzodiazepines, with a noteworthy advantage for demented patients. These data, together with the reported safety profile, form the rational basis for bergamot as a neurotherapeutic to be trialed for the control of behavioral and psychological symptoms of dementia.
Impact of gestational low protein diet and postnatal bisphenol A exposure on chemically induced mammary carcinogenesis in female offspring rats

This study evaluated the effect of gestational low protein diet (LPD) and/or postnatal bisphenol A (BPA) exposure on mammary gland development and carcinogenesis in female offspring. Pregnant Sprague‐Dawley rats were fed a normal protein diet (NPD, 17% protein) or LPD (6% protein). At weaning, female offspring were distributed in four groups (NPD, LPD, NPD + BPA, and LPD + BPA) and received vehicle or BPA in drinking water (0.1%), during postnatal day (PND) 21 to 51. On PND 51, some female offspring were euthanized or received a single dose of 7,12‐dimethylbenzoanthracene (DMBA, 30 mg/kg, i.g.) and were euthanized on PND 250. On PND 51, neither gestational LPD nor postnatal BPA exposure, individually or in combination, significantly altered the development of mammary gland tree, mean number of terminal structures or estrogen receptor beta (ER‐β), proliferating cell nuclear antigen (PCNA) or caspase‐3 protein expression in the mammary tissue. A significant reduction in mammary epithelial area (%) was observed in both LPD groups and a significant increase in ER‐α protein expression was detected only in LPD group. In LPD + BPA group was observed a significant increase in both fat pad area (%) and in mean number of mammary epithelial cells positive for progesterone receptor (PR). On PND 250, the groups that received BPA presented lower latency and higher tumor incidence and tumor multiplicity and LPD + BPA group more aggressive tumors. These findings suggest that postnatal BPA exposure associated with gestational LPD is able to induce morphological changes in the mammary gland and increase susceptibility to mammary carcinogenesis.
General Criminality as a Marker of Heterogeneity in Domestically Violent Men: Differences in Trauma History, Psychopathology, Neurocognitive Functioning, and Psychophysiology

This study examined whether involvement in general criminal behavior was a useful marker of critical historic, psychological, and cognitive aspects of heterogeneity in domestically violent men. Two subgroups of domestically violent men, those with (n = 56) and without (n = 54) a history of criminal involvement, were compared with a group of nonviolent men (n = 82) on internalizing psychopathology, substance abuse, maltreatment in the family of origin, cognitive and executive functioning, and psychophysiological factors. Results found that domestically violent criminal men scored higher than the other two groups on a number of measures including history of childhood violence exposure, childhood externalizing behavior, and adult internalizing psychopathology. No differences were found on their psychophysiological reactivity and cognitive performance. The domestically violent noncriminal group and the comparison group were largely similar on study variables with the exception of education and substance use. Results suggest that general theories of antisocial behavior may be relevant and helpful for understanding domestically violent and criminally involved batterers, whereas social and family violence theories may be of greater relevance to noncriminally involved batterers. Implications of these results for intervention are considered.
DNA-dependent protein kinase: effect on DSB repair, G2/M checkpoint and mode of cell death in NSCLC cell lines

Abstract Purpose: To evaluate the effect of NU7026, a specific inhibitor of DNA-PKcs, on DNA-double strand break (DSB) repair in a cell cycle specific manner, on the G2/M checkpoint, mitotic progression, apoptosis and clonogenic survival in non-small-cell lung carcinoma (NSCLC) cell lines with different p53 status. Material and methods: Cell cycle progression, and hyperploidy were evaluated using flow cytometry. Polynucleation as a measure for mitotic catastrophe (MC) was evaluated by fluorescence microscopy. DSB induction and repair were measured by constant-gel electrophoresis and γH2AX assay. The efficiency of DSB rejoining during the cell cycle was assessed by distinguishing G1 and G2/M phase cells on the basis of the DNA content in flow cytometry. The overall effect on cell death was determined by apoptosis and the surviving fraction after irradiation with 2 Gy (SF2) assessed by clonogenic survival. Results: DSB signaling upon treatment with NU7026, as measured by γH2AX signaling, was differently affected in G1 and G2/M cells. The background level of γH2AX was significantly higher in G2/M compared to G1 cells, whereas NU7026 had no effect on the background level. The steepness of the initial dose effect relation at 1 h after irradiation was less pronounced in G2/M compared to G1 cells. NU7026 had no significant effect on the initial dose-effect relation of γH2AX signaling. In comparison, NU7026 significantly slowed down the repair kinetics and increased the residual γH2AX signal at 24 h after irradiation in the G1 phase of all cell lines, but was less effective in G2/M cells. NU7026 significantly increased the fraction of G2/M phase cells upon irradiation. Moreover, NU7026 significantly increased mitotic catastrophe and hyperploidy, as a measure for mitotic failure after low irradiation doses of about 4 Gy, but decreased both at higher doses of 20 Gy. In addition, radiation induced apoptosis increased in A549, H520 and H460 but decreased in H661 upon NU7026 treatment, with a significant reduction of SF2 in all NSCLC cell lines. Conclusion: Overall, NU7026 significantly influences the cell cycle progression through the G2- and M-phases and thereby determines the fate of cells. The impairment of DNA-PK upon treatment with NU7026 affects the efficiency of the NHEJ system in a cell cycle dependent manner, which may be of relevance for a clinical application of DNA-PK inhibitors in tumor therapy.
Inhibition of miR-223 expression using a sponge strategy decreases restenosis in rat injured carotids.

OBJECTIVE Restenosis is a frequent complication of angioplasty. It consists of a neointimal hyperplasia resulting from progression and migration of vascular smooth muscle cells (VSMC) into the vessel lumen. The microRNA miR-223 was recently shown to be involved in cardiovascular diseases including atherosclerosis, vascular calcification and arterial thrombosis. In this study, our aim was to assess the impact of miR-223 modulation on restenosis in a rat model of carotid artery after balloon injury. METHODS The over and down-expression of miR-223 were induced by adenoviral vectors, containing either a pre-miR-223 sequence allowing artificial miR-223 expression or a sponge sequence, trapping the native microRNA, respectively. Restenosis was quantified on stained rat carotid sections. RESULTS In vitro, three mRNA (Myocyte Enhancer Factor 2C (MEF2C), Ras homolog gene family, member B (RhoB) and Nuclear factor 1 A-type (NFIA)) reported as miR-223 direct targets and known to be implicated in VSMC differentiation and contractility were studied by RT-qPCR. Our findings showed that down-expression of miR-223 significantly reduced neointimal hyperplasia by 44% in carotids, and was associated with a 2-3-fold overexpression of MEF2C, RhoB and NFIA in a murine monocyte macrophage cell line, RAW 264.7 cells. CONCLUSIONS Down-regulating miR-223 could be a potential therapeutic approach to prevent restenosis after angioplasty.