Miracle-dz/UniFAR-FTUs huggingface dataset:
Clinical Use of Cinacalcet in MEN1 Hyperparathyroidism

Background. Management of multiple-endocrine neoplasia type 1- (MEN1-) associated hyperparathyroidism is associated with high recurrence rates and high surgical morbidity due to multiple neck explorations. Cinacalcet, a calcimimetic agent licensed for the treatment of secondary hyperparathyroidism and parathyroid carcinoma, may provide a medical alternative for the management of these complex patients. Methods. A prospective audit was performed of eight patients; three males and five females, aged 20–38 at diagnosis. Two patients commenced cinacalcet as primary treatment and six had previous surgery. Six patients had complications of hyperparathyroidism: renal calculi, renal dysfunction, and reduced bone mineral density. All were commenced on cinacalcet 30 mg bd for MEN1 associated hyperparathyroidism; doses were subsequently reduced to 30 mg od in four patients. Results. Significant reductions were observed in serum calcium and PTH measurements. Serum calcium reduced by a median of 0.35 mmol/L (P = .012 Wilcoxon Signed Rank). Serum PTH levels decreased by a median of 5.05 pmol/L (P = .012). There was no change in urine calcium. Duration ranged from 10–35 months with maintenance of control. Cinacalcet was well tolerated by six patients; one experienced nausea and one experienced diarrhoea. Conclusion. Cinacalcet is an effective and well-tolerated medical treatment for the management of complex primary hyperparathyroidism.
The TOPCONS web server for consensus prediction of membrane protein topology and signal peptides

TOPCONS (http://topcons.net/) is a widely used web server for consensus prediction of membrane protein topology. We hereby present a major update to the server, with some substantial improvements, including the following: (i) TOPCONS can now efficiently separate signal peptides from transmembrane regions. (ii) The server can now differentiate more successfully between globular and membrane proteins. (iii) The server now is even slightly faster, although a much larger database is used to generate the multiple sequence alignments. For most proteins, the final prediction is produced in a matter of seconds. (iv) The user-friendly interface is retained, with the additional feature of submitting batch files and accessing the server programmatically using standard interfaces, making it thus ideal for proteome-wide analyses. Indicatively, the user can now scan the entire human proteome in a few days. (v) For proteins with homology to a known 3D structure, the homology-inferred topology is also displayed. (vi) Finally, the combination of methods currently implemented achieves an overall increase in performance by 4% as compared to the currently available best-scoring methods and TOPCONS is the only method that can identify signal peptides and still maintain a state-of-the-art performance in topology predictions.
Density and distribution of primordial follicles in single pieces of cortex from 21 patients and in individual pieces of cortex from three entire human ovaries.

BACKGROUND At the time of cryopreservation of ovarian tissue for fertility preservation a small biopsy of ovarian cortex is usually taken for histological evaluation of the follicular reserve. The purpose of this study was to evaluate the distribution and density of primordial follicles in single pieces of cortex from individual patients and in pieces of cortex comprising entire ovaries, all prepared for cryopreservation. METHODS Cortical biopsies from 21 patients and the whole cortex of one ovary were evaluated histologically prior to cryopreservation. In addition, the cortex of two whole ovaries was cryopreserved before histological evaluation. The volume of each cortical fragment was measured, all follicles counted and the follicular density calculated. RESULTS In individual pieces of cortex follicular density showed a significant inverse linear correlation with age. The follicular density per cortical fragment prepared from each of the three entire ovaries varied from 1.8 to 166, 0.007 to 140 and 0.04 to 4.48 follicles/mm(3) cortical tissue. CONCLUSION The density of primordial follicles varied more than two orders of magnitude in cortical fragments from each of the three ovaries. Primordial follicles were very unevenly distributed throughout the cortex of these ovaries, although a significant linear correlation between age and follicular density was found.
Detection of epidermal growth factor receptor mutations in lung adenocarcinoma cytological specimens by immunocytochemistry

Tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR) improve the survival of patients with lung adenocarcinoma, and determine the EGFR mutation status before treatment is necessary. In contrast to biopsy samples, cytological specimens are obtained less invasively and are useful for EGFR mutation analyses. Recently, novel antibodies against two major EGFR mutations were developed: SP111, which is specific for the E746-A750 deletion in exon 19; and SP125, which is specific for the L858R mutation. To the best of our knowledge, no study has evaluated cytological specimens using the two novel antibodies, thus their specificity and sensitivity were examined in surgical resection, and cytological lung adenocarcinoma samples in the present study. Previous screening for EGFR mutation status by molecular testing identified delE746-A750 in 3 cases and the L858R mutation in 7 cases; the other cases did not have the L858R or the delE746-A750 mutation. Using a four-grade scoring system (score 0 to 3+), the immunohistochemistry (IHC) and immunocytochemistry (ICC) results were compared with those of molecular testing. Using a score of ≥2 as positive, IHC and ICC using SP111 demonstrated sensitivities of 100 and 33.3%, and specificities of 100 and 100%, respectively. IHC and ICC using SP125 revealed sensitivities of 100 and 71.4%, and specificities of 100 and 100%, respectively. Therefore, screening for EGFR mutations by ICC may facilitate therapeutic decision-making, particularly in medical centers that are unable to perform molecular testing.
Acinar‐to‐ductal metaplasia accompanies c‐myc‐induced exocrine pancreatic cancer progression in transgenic rodents

Several important characteristics of exocrine pancreatic tumor pathogenesis remain incompletely defined, including identification of the cell of origin. Most human pancreatic neoplasms are ductal adenocarcinomas. However, acinar cells have been proposed as the source of some ductal neoplasms through a process of acinar‐to‐ductal metaplasia. The oncogenic transcription factor c‐myc is associated with human pancreatic neoplasms. Transgenic mice overexpressing c‐myc under control of acinar cell‐specific elastase (Ela) gene regulatory elements not only develop acinar cell carcinomas but also mixed neoplasms that display both acinar‐like neoplastic cells and duct‐like neoplastic cells. In this report, we demonstrate that, first, c‐myc is sufficient to induce acinar hyperplasia, though neoplastic lesions develop focally. Second, cell proliferation remains elevated in the neoplastic duct cell compartment of mixed neoplasms. Third, the proliferation/apoptosis ratio in cells from all lesion types remains constant, suggesting that differential regulation of these processes is not a feature of cancer progression in this model. Fourth, before the development of mixed neoplasms, there is transcriptional activation of the duct cell‐specific cytokeratin‐19 gene promoter in multicellular foci of amylase‐positive acinar neoplasms. This observation provides direct evidence for metaplasia as the mechanism underlying development of ductal neoplastic cells within the context of an acinar neoplasm and suggests that the stimulus for this transformation acts over a multicellular domain or field within a neoplasm. Finally, focal ductal elements develop in some acinar cell carcinomas in Ela‐c‐myc transgenic rats, indicating that myc‐associated acinar‐to‐ductal metaplasia is not restricted to the mouse.
Lineage-Specific Expansion of IFIT Gene Family: An Insight into Coevolution with IFN Gene Family

In mammals, IFIT (Interferon [IFN]-induced proteins with Tetratricopeptide Repeat [TPR] motifs) family genes are involved in many cellular and viral processes, which are tightly related to mammalian IFN response. However, little is known about non-mammalian IFIT genes. In the present study, IFIT genes are identified in the genome databases from the jawed vertebrates including the cartilaginous elephant shark but not from non-vertebrates such as lancelet, sea squirt and acorn worm, suggesting that IFIT gene family originates from a vertebrate ancestor about 450 million years ago. IFIT family genes show conserved gene structure and gene arrangements. Phylogenetic analyses reveal that this gene family has expanded through lineage-specific and species-specific gene duplication. Interestingly, IFN gene family seem to share a common ancestor and a similar evolutionary mechanism; the function link of IFIT genes to IFN response is present early since the origin of both gene families, as evidenced by the finding that zebrafish IFIT genes are upregulated by fish IFNs, poly(I:C) and two transcription factors IRF3/IRF7, likely via the IFN-stimulated response elements (ISRE) within the promoters of vertebrate IFIT family genes. These coevolution features creates functional association of both family genes to fulfill a common biological process, which is likely selected by viral infection during evolution of vertebrates. Our results are helpful for understanding of evolution of vertebrate IFN system.
The social and cultural impact of the car in interwar Britain

This study argues that society's choices between possible technological developments are highly reflective of patterns of political, social, and economic power. Employing insights from recent historical and sociological work on class, gender, consumption and technology the processes by which social relations shaped the design, marketing and uses of the car are explained. In turn, it is argued that the legal and physical infrastructure which developed in the car's wake were extremely expressive of class and gender relations. The interwar years are studied because it was during this period, when the car as a technology was still open to contestation, that the British car culture was defined. This was so because it was during the 1920s and 1930s that car ownership became a reality for millions of middle-class Britons. An analysis of the symbolic, as well as the utilitarian, benefits of ownership is offered and reveals the car's role in the expression of social and gender identity. The extent to which these factors impinged upon the actions of car manufacturers and motor dealers is also related. This perspective and the use of oral evidence has unearthed significant new evidence about the composition of the motoring community. The process through which influential sections of opinion reached a concordance with the car is explained. As it became increasingly useful for them, the professional and commercial middle-classes swung against significant restrictions on car use. Pre-1914 they were often outraged by the danger and inconvenience that were inevitable side effects of rising car ownership. However, once owners themselves they were increasingly attracted to new ideas about road safety which placed more and more emphasis on the education and segregation of other road users. The influential pro-motoring lobby manipulated these developments, a factor which is investigated here for the first time.
Can Observers Predict Trustworthiness?

Abstract We investigate whether experimental subjects can predict behavior in a prisoner's dilemma played on a TV show. Subjects report probabilistic beliefs that a player cooperates, before and after the players communicate. Subjects correctly predict that women and players who make a voluntary promise are more likely to cooperate. They are able to distinguish truth from lies when a player is asked about her intentions by the host. Subjects are to some extent able to predict behavior; their beliefs are 7~percentage points higher for cooperators than for defectors. We also study their Bayesian updating. Beliefs do not satisfy the martingale property and display mean reversion.
Polymorphisms of FAS and FAS Ligand Genes Involved in the Death Pathway and Risk and Progression of Squamous Cell Carcinoma of the Head and Neck

Purpose: Alteration of the FAS/FAS ligand (FASLG) pathway regulating cell death may lead to cancer development, but the effects of functional promoter polymorphisms of the FAS and FASLG genes on risk of squamous cell carcinoma of the head and neck (SCCHN) are unknown. Design: We genotyped the FAS −1377 G>A, FAS −670 A>G, FASLG −844 C>T, and FASLG IVS2nt −124 A>G polymorphisms in 721 case patients with SCCHN and 1,234 cancer-free non–Hispanic White control subjects frequency-matched by age and sex. Multivariate logistic regression was used to assess the adjusted odds ratios (OR) and 95% confidence intervals (CI). Results: Compared with the FAS −1377 GG and −670 AA genotypes, the FAS −1377 AA and −670 (GG + AG) genotypes were associated with an increased risk of SCCHN (OR, 2.23; 95% CI, 1.07-4.64 and OR, 1.24; 95% CI, 1.01-1.52, respectively), whereas no risk of SCCHN was associated with any of the FASLG genotypes. When we used the combined FAS −1377 (GG + AG)/−670 AA genotypes as the reference, we found that the individuals carrying the FAS −1377 AA/−670 (GG + AG) had the highest risk (OR, 2.69; 95% CI, 1.24-5.83), whereas individuals carrying genotypes other than FAS −1377 (GG + AG)/−670 AA had a higher risk of SCCHN (OR, 1.24; 95% CI, 1.01-1.52). Furthermore, the elevated risk was particularly evident for pharyngeal cancer with the larger tumors without regional lymph metastasis (OR, 1.77; 95% CI, 1.07-2.94). Conclusions: The FAS (but not FASLG) polymorphisms seem to contribute to risk of developing SCCHN, particularly the pharyngeal cancer in non–Hispanic Whites. However, potential selection bias warrants future population-based studies to verify the findings.
Examining new phylogenetic markers to uncover the evolutionary history of early-diverging fungi: comparing MCM7, TSR1 and rRNA genes for single- and multi-gene analyses of the Kickxellomycotina

The recently recognised protein-coding genes MCM7 and TSR1 have shown significant promise for phylogenetic resolution within the Ascomycota and Basidiomycota, but have remained unexamined within other fungal groups (except for Mucorales). We designed and tested primers to amplify these genes across early-diverging fungal clades, with emphasis on the Kickxellomycotina, zygomycetous fungi with characteristic flared septal walls forming pores with lenticular plugs. Phylogenetic tree resolution and congruence with MCM7 and TSR1 were compared against those inferred with nuclear small (SSU) and large subunit (LSU) rRNA genes. We also combined MCM7 and TSR1 data with the rDNA data to create 3- and 4-gene trees of the Kickxellomycotina that help to resolve evolutionary relationships among and within the core clades of this subphylum. Phylogenetic inference suggests that Barbatospora, Orphella, Ramicandelaber and Spiromyces may represent unique lineages. It is suggested that these markers may be more broadly useful for phylogenetic studies among other groups of early-diverging fungi.
Diabetes specialist nurse as main care provider for patients with type 2 diabetes.

BACKGROUND The objective of this study was to determine whether the management of type 2 diabetes (DM2) can be transferred from an internist to a nurse specialised in diabetes (NSD). METHODS Ninety-three patients with DM2 referred by their general practitioner were randomised; 84 patients completed the study. The intervention group received care from an NSD who treated glycaemia, blood pressure and lipid profile by protocol. The control group received care from an internist. The primary endpoint was the main decrease in HbA1c. Secondary endpoints included blood pressure, lipid profile, healthcare costs, QOL , and patient satisfaction. RESULTS HbA1c, total cholesterol, LDL cholesterol and cholesterol/HDL ratio decreased significantly in both study populations after a follow-up time of 12 months. Cholesterol/HDL ratio decreased by 0.4 and 0.9 in the NSD and control group respectively (p=0.034 for the difference between groups). The decreases (95% confidence interval) in systolic blood pressure were 8.6 mmHg (2.6, 14.7) in the NSD group and 4.0 mmHg (-0.9, 8.9) in the control group, without a significant difference between groups. After one year, 33.3% of the patients in the NSD group achieved an HbA1c level. <7% compared with 2.2%at baseline (p=0.002). Healthcare costs were less and patient satisfaction with the NSD s was significantly better(p<0.001), while maintaining the same QOL . CONCLUSION NSD s using treatment protocols are able to provide effective care for patients with DM 2, comparable with the care provided by an internist, with respect to clinical parameters, and superior with respect to healthcare costs and patient satisfaction.
Use of immuno-LCM to identify the in situ expression profile of cellular constituents of the tumor microenvironment

Expression profiling using microarrays has become an essential tool for interrogating tumor biology. However, profiling of whole tumor RNA reflects both tumor and host cells, making it difficult to dissect molecular events within specific cellular compartments in the tumor microenvironment. We developed and optimized a simple, rapid technique combining immunohistochemistry and laser-capture microdissection (immuno-LCM) to purify specific cell populations from the tumor microenvironment followed by RNA isolation and amplification for microarray analysis. Using this methodology, we were able to elucidate the in situ expression profile of pure tumor cells and tumor endothelial cells from ovarian tumors with brisk immune infiltrates. This technique not only increased the specificity of profiling isolated cell populations, eliminating genes expressed by surrounding cells, but also increased the sensitivity of analysis, allowing for the detection of low expression genes that were not detected in whole tumor arrays. Pathway analysis of tumor cells in situ identified distinct activation of signaling pathways converging on NF-κB, as compared to pathways identified in cultured tumor cell lines, which were primarily metabolic. Profiling of tumor vascular endothelial cells revealed most known panendothelial and tumor endothelial-specific markers, and unveiled genes specific to the myeloid-monocytic lineage. We propose that immuno-LCM coupled with transcriptional profiling is a convenient tool to dissecting molecular and cellular events in complex biological systems such as the tumor microenvironment.
Salicylic Acid 1s a Systemic Signal and an lnducer of Pathogenesis-Related Proteins in Virus-lnfected TÕbacco

Systemic induction of pathogenesis-related (PR) proteins in tobacco, which occurs during the hypersensitive response to tobacco mosaic virus (TMV), may be caused by a minimum 10-fold systemic increase in endogenous levels of salicylic acid (SA). This rise in SA parallels PR-1 protein induction and occurs in TMV-resistant Xanthi-nc tobacco carrying the N gene, but not in TMV-susceptible (nn) tobacco. By feeding SA to excised leaves of Xanthi-nc (NN) tobacco, we have shown that the observed increase in endogenous SA levels is sufficient for the systemic induction of PR-1 proteins. TMV infection became systemic and Xanthi-nc plants failed to accumulate PR-1 proteins at 32OC. This loss of hypersensitive response at high temperature was associated with an inability to accumulate SA. However, spraying leaves with SA induced PR-1 proteins at both 24 and 32OC. SA is most likely exported from the primary site of infection to the uninfected tissues. A computer model predicts that SA should move rapidly in phloem. When leaves of Xanthi-nc tobacco were excised 24 hr after TMV inoculation and exudates from the cut petioles were collected, the increase in endogenous SA in TMV-inoculated leaves paralleled SA levels in exudates. Exudation and leaf accumulation of SA were proportional to TMV concentration and were higher in light than in darkness. Different components of TMV were compared for their ability to induce SA accumulation and exudation: three different aggregation states of coat protein failed to induce SAI but unencapsidated vira1 RNA elicited SA accumulation in leaves and phloem. These results further support the hypothesis that SA acts as an endogenous signal that triggers local and systemic induction of PR-1 proteins and, possibly, some components of systemic acquired resistance in NN tobacco.
Short‐Term Risk of Bleeding During Heparin Bridging at Initiation of Vitamin K Antagonist Therapy in More Than 90 000 Patients With Nonvalvular Atrial Fibrillation Managed in Outpatient Care

Background Several studies have recently examined the risks of bleeding and of ischemic stroke and systemic embolism associated with perioperative heparin bridging anticoagulation in patients with nonvalvular atrial fibrillation. However, few studies have investigated bridging risks during vitamin K antagonist initiation in outpatient settings. Methods and Results A retrospective cohort study was conducted on individuals starting oral anticoagulation between January 2010 and November 2014 for nonvalvular atrial fibrillation managed in outpatient care and identified from French healthcare insurance. Bleeding and ischemic stroke and systemic embolism events were identified from the hospitalization database. Adjusted hazard ratios with 95% CI were estimated using Cox models during the first and 2 following months of anticoagulation. Of 90 826 individuals, 30% had bridging therapy. A total of 318 (0.35%) cases of bleeding and 151 (0.17%) ischemic stroke and systemic embolism cases were identified during the first month of follow‐up and 231 (0.31%) and 122 (0.16%) during the 2 following months, respectively. At 1 month of follow‐up, the incidence of bleeding was higher in the bridged group compared with the nonbridged group (0.47% versus 0.30%; P<0.001), and this increased risk persisted after adjustment for covariates (hazard ratio=1.60; 95% CI, 1.28–2.01). This difference disappeared after the first month of treatment (0.93; 0.70–1.23). No significant difference in the occurrence of ischemic stroke and systemic embolism was observed either at 1 month of follow‐up or later. Conclusions At vitamin K antagonist initiation for nonvalvular atrial fibrillation managed in ambulatory settings, bridging therapy is associated with a higher risk of bleeding and a similar risk of arterial thromboembolism compared with no bridging therapy.
MODELS AND ALGORITHMS FOR TRACKING USING VARIABLE DIMENSION PARTICLE FILTERS

In this paper we discuss modifications to tracking models, and sequential Monte Carlo algorithms for their estimation from sequential and batch data. New models for tracking are proposed which involve a dynamical model on both the hidden state value and its arrival times. In this way we aim to have a more flexible and parsimonious representation of time-varying state characteristics which is more amenable to estimation using Bayesian filtering. In order to perform inference in this scenario new particle filters and smoothers are proposed for cases where the state process arrives at unknown times that are generally different from the observation arrival times.