Miracle-dz/UniFAR-FTUs huggingface dataset:
Follicle-Stimulating Hormone Receptor Is Expressed by Most Ovarian Cancer Subtypes and Is a Safe and Effective Immunotherapeutic Target

Purpose: To define the safety and effectiveness of T cells redirected against follicle-stimulating hormone receptor (FSHR)-expressing ovarian cancer cells. Experimental Design: FSHR expression was determined by Western blotting, immunohistochemistry, and qPCR in 77 human ovarian cancer specimens from 6 different histologic subtypes and 20 human healthy tissues. The effectiveness of human T cells targeted with full-length FSH in vivo was determined against a panel of patient-derived xenografts. Safety and effectiveness were confirmed in immunocompetent tumor-bearing mice, using constructs targeting murine FSHR and syngeneic T cells. Results: FSHR is expressed in gynecologic malignancies of different histologic types but not in nonovarian healthy tissues. Accordingly, T cells expressing full-length FSHR-redirected chimeric receptors mediate significant therapeutic effects (including tumor rejection) against a panel of patient-derived tumors in vivo. In immunocompetent mice growing syngeneic, orthotopic, and aggressive ovarian tumors, fully murine FSHR-targeted T cells also increased survival without any measurable toxicity. Notably, chimeric receptors enhanced the ability of endogenous tumor-reactive T cells to abrogate malignant progression upon adoptive transfer into naïve recipients subsequently challenged with the same tumor. Interestingly, FSHR-targeted T cells persisted as memory lymphocytes without noticeable PD-1–dependent exhaustion during end-stage disease, in the absence of tumor cell immunoediting. However, exosomes in advanced tumor ascites diverted the effector activity of this and other chimeric receptor–transduced T cells away from targeted tumor cells. Conclusions: T cells redirected against FSHR+ tumor cells with full-length FSH represent a promising therapeutic alternative against a broad range of ovarian malignancies, with negligible toxicity even in the presence of cognate targets in tumor-free ovaries. Clin Cancer Res; 23(2); 441–53. ©2016 AACR.
The Influence of Varying Cost Formats on Preferences

Background. Numerous studies have found that cost strongly influences patients’ decision making. The objective of this study was to explore the impact of varying cost formats on patients’ preferences. Methods. Mechanical Turk workers completed a choice-based conjoint (CBC) survey. The CBC survey was designed to examine stated preferences for the use of second-line agents to treat diabetes across 5 attributes: route of administration, efficacy, risk of low blood sugar, frequency of checking blood sugar levels, and cost. We developed 7 versions of the CBC survey that were identical except for the cost attribute. We described cost in terms of: Affordability, Monthly Co-pay, Dollar Sign Rating, How Expensive, or How Cheap compared with other medications, Working Hours Equivalent (per mo) and Percent of Monthly Income. The resulting part-worth utilities were used to calculate the relative importance of cost and to estimate treatment preferences for exenatide, a sulfonylurea, and insulin. Results. The relative impact of cost varied significantly across the 7 formats. Cost had the greatest influence on participants’ decisions when framed in terms of Affordability [mean (SD) relative importance, 37.3 (0.9)] and the lowest influence when framed in terms of How Cheap (compared with other drugs) [12.1 (0.9)]. A sulfonylurea was strongly preferred across 4 of the 7 formats. Preference for insulin, the most effective, albeit riskiest, option was low across all cost formats. Conclusions. The format used to describe cost affects how the attribute impacts patients’ preferences. Individuals are most cost-sensitive when cost is framed in terms of affordability and least cost-sensitive when cost is described in terms of how cheap the medication is compared with others.
A model to investigate xerostomia-related dental caries.

The aim of this study was to develop an in vivo model in which onset, progression, and prevention of xerostomia-related dental caries can be studied. The progress of the caries process was investigated on ground and polished human enamel blocks placed in the lower denture of 7 edentulous subjects suffering from xerostomia. During a period of 6 weeks the samples were analyzed at weekly intervals by means of scanning optical monitoring, scanning longitudinal microradiography, scanning electron microscopy, and hardness measurements. Although the indentation length increased significantly within 2 weeks, no demineralization could be yet observed with scanning optical monitoring, longitudinal microradiography, and electron microscopy in most samples. Starting from the 3rd week a progressive demineralization could be observed by all methods. The mineral loss (hydroxyapatite) in the 3rd week was 0.0126 kg.m-2 (median) which increased to 0.0761 kg.m-2 after 6 weeks. Scanning electron microscopy showed a destruction which resembled that of natural xerostomia-related dental caries. From this study it may be concluded that the in vivo model developed is suitable for studying onset, progression, and prevention of xerostomia-related dental caries.
CDK1-dependent Inhibition of the E3 Ubiquitin Ligase CRL4CDT2 Ensures Robust Transition from S Phase to Mitosis*

Background: CRL4CDT2 mediates replication-coupled destruction during S phase. CRL4CDT2 substrates reaccumulate by an unexplored mechanism. Results: CDK1 activity blocks CRL4CDT2 by preventing chromatin recruitment of the substrate receptor, CDT2. Conclusion: CDK1 activity facilitates CRL4CDT2 substrate reaccumulation upon S phase exit; several of these substrates are then required for normal mitotic progression. Significance: We provide the first evidence that CDK1 regulates the activity of CRL4CDT2. Replication-coupled destruction of a cohort of cell cycle proteins ensures efficient and precise genome duplication. Three proteins destroyed during replication via the CRL4CDT2 ubiquitin E3 ligase, CDT1, p21, and SET8 (PR-SET7), are also essential or important during mitosis, making their reaccumulation after S phase a critical cell cycle event. During early and mid-S phase and during DNA repair, proliferating cell nuclear antigen (PCNA) loading onto DNA (PCNADNA) triggers the interaction between CRL4CDT2 and its substrates, resulting in their degradation. We have discovered that, beginning in late S phase, PCNADNA is no longer sufficient to trigger CRL4CDT2-mediated degradation. A CDK1-dependent mechanism that blocks CRL4CDT2 activity by interfering with CDT2 recruitment to chromatin actively protects CRL4CDT2 substrates. We postulate that deliberate override of replication-coupled destruction allows anticipatory accumulation in late S phase. We further show that (as for CDT1) de novo SET8 reaccumulation is important for normal mitotic progression. In this manner, CDK1-dependent CRL4CDT2 inactivation contributes to efficient transition from S phase to mitosis.
LEARN: Learned Experts’ Assessment-Based Reconstruction Network for Sparse-Data CT

Compressive sensing (CS) has proved effective for tomographic reconstruction from sparsely collected data or under-sampled measurements, which are practically important for few-view computed tomography (CT), tomosynthesis, interior tomography, and so on. To perform sparse-data CT, the iterative reconstruction commonly uses regularizers in the CS framework. Currently, how to choose the parameters adaptively for regularization is a major open problem. In this paper, inspired by the idea of machine learning especially deep learning, we unfold the state-of-the-art “fields of experts”-based iterative reconstruction scheme up to a number of iterations for data-driven training, construct a learned experts’ assessment-based reconstruction network (LEARN) for sparse-data CT, and demonstrate the feasibility and merits of our LEARN network. The experimental results with our proposed LEARN network produces a superior performance with the well-known Mayo Clinic low-dose challenge data set relative to the several state-of-the-art methods, in terms of artifact reduction, feature preservation, and computational speed. This is consistent to our insight that because all the regularization terms and parameters used in the iterative reconstruction are now learned from the training data, our LEARN network utilizes application-oriented knowledge more effectively and recovers underlying images more favorably than competing algorithms. Also, the number of layers in the LEARN network is only 50, reducing the computational complexity of typical iterative algorithms by orders of magnitude.
Trajectory tracking control of ball on plate system using weighted Artificial Fish Swarm Algorithm based PID

This paper uses weighted Artificial Fish Swarm Algorithm to optimally tune the parameters of a PID controller. The PID is applied to trajectory tracking control of a ball on plate system and its good control performance is verified by simulation examples. The inherent challenges associated with this system render it suitable for testing various control schemes. In this paper, Euler-Lagrange technique was adopted for obtaining the model of the system. Then, the optimal PID controllers in dual feedback loop were used for controlling the system. Simulation of the system was achieved in MATLAB 2015, and unit step response of the system along x-Axis shows a good performance. Also, the ball was able to track a reference circular trajectory however, with a tracking error of 0.0132 m.
ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis

Background: Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years. There is a need for a reference tool compiling current data to aid professionals in treatment decisions. Objectives: To develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS. Methods: This guideline has been developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology and following the updated EAN recommendations. Clinical questions were formulated in Patients–Intervention–Comparator–Outcome (PICO) format and outcomes were prioritized. The quality of evidence was rated into four categories according to the risk of bias. The recommendations with assigned strength (strong and weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panelists was reached by use of the modified nominal group technique. Results: A total of 10 questions were agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency (EMA) at the time of publication. A total of 21 recommendations were agreed by the guideline working group after three rounds of consensus. Conclusion: The present guideline will enable homogeneity of treatment decisions across Europe.
The complex genetics of human insulin-like growth factor 2 are not reflected in public databases

Recent advances in genetics present unique opportunities for enhancing knowledge about human physiology and disease susceptibility. Understanding this information at the individual gene level is challenging and requires extracting, collating, and interpreting data from a variety of public gene repositories. Here, I illustrate this challenge by analyzing the gene for human insulin-like growth factor 2 (IGF2) through the lens of several databases. IGF2, a 67-amino acid secreted peptide, is essential for normal prenatal growth and is involved in other physiological and pathophysiological processes in humans. Surprisingly, none of the genetic databases accurately described or completely delineated human IGF2 gene structure or transcript expression, even though all relevant information could be found in the published literature. Although IGF2 shares multiple features with the mouse Igf2 gene, it has several unique properties, including transcription from five promoters. Both genes undergo parental imprinting, with IGF2/Igf2 being expressed primarily from the paternal chromosome and the adjacent H19 gene from the maternal chromosome. Unlike mouse Igf2, whose expression declines after birth, human IGF2 remains active throughout life. This characteristic has been attributed to a unique human gene promoter that escapes imprinting, but as shown here, it involves several different promoters with distinct tissue-specific expression patterns. Because new testable hypotheses could lead to critical insights into IGF2 actions in human physiology and disease, it is incumbent that our fundamental understanding is accurate. Similar challenges affecting knowledge of other human genes should promote attempts to critically evaluate, interpret, and correct human genetic data in publicly available databases.
Islet transplantation to the renal subcapsular space improves late complications in streptozotocin-diabetic rats.

Transplantation of isolated islets is a promising approach in the treatment of diabetes. We have examined the long-term effects on the late complications of islet transplantation in an experimental diabetes model in the rat. Diabetes was induced by streptozotocin (70 mg/kg i.v.) and the rats were treated with either insulin (daily injection of 40 U) or transplantation of 1,000 freshly isolated, hand-picked, islets into the left renal subcapsular space. Both islet transplantation and insulin treatment completely normalized the increased levels of blood glucose, urine volume and water intake that were observed in the diabetic rats. The decreased growth rate of the diabetic rats was almost normalized by both treatment protocols. As for late complications, after 3 months, all untreated diabetic rats had cataract. They also had swelling and vacuolation of renal tubular cells, and, consistent with this, very high levels of urinary beta 2-microglobulin excretion. Both islet transplantation and insulin treatment completely prevented these late complications. Thus, islet transplantation to the renal subcapsular space is in this experimental model as good as insulin treatment in treating the clinical signs of diabetes and in preventing diabetic complications in the eye and kidney.
Multiple aspects of high school students’ strategic processing on reading outcomes: The role of quantity, quality, and conjunctive strategy use

BACKGROUND While the literature on strategy use is relatively mature, measures of strategy use overwhelmingly measure only one aspect of that use, frequency, when relating that strategy use to performance outcomes. While this might be one important attribute of strategy use, there is increasing evidence that quality and conditional use of cognitive and metacognitive strategies may also be important. AIMS This study examines how multiple aspects of strategy use, namely frequency, quality, and conjunctive use of strategies, influence task performance on both well- and ill-structured task outcomes in addition to other concomitant variables that may interact with strategic processing during reading. SAMPLE The sample consisted of 21 high school students enrolled in an upper-level biology class in a suburban school in the north-eastern United States. METHODS These participants completed measures of prior knowledge and interest, then read either an expository or persuasive text while thinking aloud. They then completed a passage recall and open-ended response following passage completion. RESULTS In general, quantity was not positively related to the study outcomes and was negatively related to one of them. Quality of strategy use, on the other hand, was consistently related to positive reading outcomes. The influence of knowledge and interest in terms of strategies is also discussed as well as six cases which illustrate the relation of aspects of strategy use and the other concomitant variables. CONCLUSIONS Evaluating strategy use by solely examining the frequency of strategy use did not explain differences in task performance as well as evaluating the quality and conjunctive use of strategies. Further, important relations between prior knowledge, interest, and the task outcomes appeared to be mediated and moderated by the aspects of strategy use investigated.
Genetic Polymorphism of the MxA Gene Promoter and Interferon Responsiveness of Hepatitis C Patients: Revisited by Analyzing Two SNP Sites (–123 and –88) in vivo and in vitro

We have previously reported a single nucleotide polymorphism (SNP) at nucleotide (nt) position –88 (G or T) within an interferon-stimulated response element-like sequence in the promoter region of the MxA gene, which correlated with responsiveness of hepatitis C patients to interferon. Upstream of it, we then identified another SNP (C or A at nt –123) and investigated whether this SNP also correlates with interferon responsiveness. The two SNPs showed a high linkage to each other: all the individuals having G at –88 had C at –123, and 73% of those having T at –88 had A at –123. As was expected from this observation, the SNP at –123 also exhibited a correlation with interferon responsiveness (C/C homozygotes were more frequent among nonresponders than among responders: 65% of 107 vs. 40% of 52, p = 0.0028). These in vivo data from patients were further supported by results from in vitro experiments. The MxA promoter sequence with A at –123 and T at –88 showed about 4-fold higher activity of upregulating the downstream reporter gene than that with C at –123 and G at –88, in a luciferase reporter assay.
Chronic Melatonin Treatment Counteracts Glucocorticoid-Induced Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis in the Rat

Transient exposure of rats to high doses of dexamethasone (DEX; 500 µg/day for 5 days) produced a host of symptoms that are indicative of hypothalamic-pituitary-adrenal (HPA) axis dysregulation, such as increased adrenocortical secretion over 24 h, blunted and prolonged secretory response to emotional stress, refractoriness of adrenocorticotropin in vitro release to stimulation with the secretagogues corticotropin-releasing hormone (CRH) and vasopressin, decreased levels of mRNA encoding type II corticosteroid receptors in the hippocampus and increased numbers of transcripts encoding CRH in the paraventricular nucleus. Daily administration of melatonin (MEL; 80 µg/kg) concomitantly with, and for 5 days after discontinuation of, glucocorticoid treatment ‘normalized’ most of the symptoms of impaired HPA regulation caused by the exposure to DEX. While none of the treatments used caused major shifts in circadian patterns of corticosterone secretion, MEL administration was associated with diminished overall corticosterone secretion and increased sensitivity to glucocorticoid feedback. Taken together, these findings indicate that chronic MEL treatment may protect several regulatory components of the HPA axis from glucocorticoid-induced deterioration.
Clinical Usefulness of Maternal Odor in Newborns: Soothing and Feeding Preparatory Responses

This study assessed the responsiveness of newborn breast- and bottle-fed infants to presentations of maternal odor. Maternal odor was presented for 1 min to crying, sleeping or awake newborns. The odors were: (1) own mother’s odor – presentation of a hospital gown worn by the baby’s mother, (2) other mother’s odor – presentation of a hospital gown of another newborn baby’s mother, (3) clean gown – presentation of a clean hospital gown and (4) no gown – no gown presented. The results indicated that crying babies stopped crying when either own mother or other mother odor was presented. Awake babies responded specifically to their own mother’s odor by increasing mouthing. These results suggest that the practice of presenting the mother’s odor to a distressed infant is of clinical usefulness since it was capable of attenuating crying. The results also characterized a role for maternal odor with respect to feeding since presentation of the infant’s own mother odor increased mouthing. Thus, presentation of maternal odor may also be useful in enhancing nipple acceptance and feeding in newborns.
Optimal time of tumour response evaluation and effectiveness of hypofractionated proton beam therapy for inoperable or recurrent hepatocellular carcinoma

Objective To evaluate the optimal time of tumour response and effectiveness of hypofractionated proton beam therapy (PBT) for hepatocellular carcinoma (HCC). Results Overall, treatment was well tolerated with no grade toxicity ≥3. Of 71 patients, 66 patients (93%) eventually reached complete response (CR) after PBT: 93.9% (62 of 66) of patients who reached CR within 12 months, and the remaining 4 patients (6.1%) reached CR at 12.5, 16.2, 19.1 and 21.7 months, respectively. The three-year local progression-free survival (LPFS), relapse-free survival (RFS) and OS rates were 89.9%, 26.8%, and 74.4%, respectively. Multivariate analysis revealed that the tumour response was an independent prognostic factor for LPFS, RFS, and OS. Conclusion Most CR was achieved within 1 year after PBT and further salvage treatments in PBT field might be postponed up to approximately 18–24 months. Hypofractionated PBT could be good alternative for HCC patients who are unsuitable for surgical or invasive treatments with curative intent. Materials and Methods Seventy-one inoperable or recurrent HCC patients underwent hypofractionated PBT using 66 GyE in 10 fractions. The tumour responses were defined as the maximal tumour response observed during the follow-up period using the modified Response Evaluation Criteria in Solid Tumors criteria.
English Word Stress in the Post-Nuclear Position

Abstract Stress oppositions between words like import ≠ import are audible in the nucleus of intonation contours where they are distinguished by fundamental frequency. In the post-nuclear position the opposition is neutralized; the two stresses are identical in terms of fundamental frequency, but measurably different in terms of intensity and duration. Listeners’ reactions are not random, though: those syllables which fit into a regular sequence of stressed and unstressed syllables are interpreted as stressed and unstressed, respectively. Speech production is also influenced by sentence rhythm: syllables which correspond to the general rhythmic pattern have greater duration and intensity. But listeners do not perceive these modifications.
Recombinant rabies virus with the glycoprotein fused with a DC-binding peptide is an efficacious rabies vaccine

Our previous studies demonstrated that recruiting and/or activating dendritic cells (DCs) enhanced the immunogenicity of recombinant rabies viruses (rRABV). In this study, rRABV LBNSE with a small DC-binding peptide (designated as rLBNSE-DCBp) or a negative control peptide (designated as rLBNSE-DCCp) fused to the glycoprotein (G) was constructed and rescued. As expected, significantly more activated DCs were detected in rLBNSE-DCBp-immunized mice than those immunized with rLBNSE or rLBNSE-DCCp. Subsequently, significantly more generation of TFH and GC B cells were observed in rLBNSE-DCBp immunized mice than those in rLBNSE or rLBNSE-DCCp-immunized mice. In addition, significantly higher levels of virus neutralizing antibodies (VNAs) were observed in mice immunized with rLBNSE-DCBp than those immunized with rLBNSE or rLBNSE-DCCp, resulting in a better protection of rLBNSE-DCBp immunized mice against the lethal challenge. Taken together, our results suggest that rRABV with G fused with DCBp is a promising rabies vaccine candidate.