Miracle-dz/UniFAR-FTUs huggingface dataset:
Circulating Tumour Cell Biomarkers in Head and Neck Cancer: Current Progress and Future Prospects

Head and neck cancer (HNC) continues to carry a significant burden of disease both for patients and health services. Facilitating biomarker-led treatment decisions is critical to improve outcomes in this group and deliver therapy tailored to the individual tumour biological profile. One solution to develop such biomarkers is a liquid biopsy analysing circulating tumour cells (CTCs)—providing a non-invasive and dynamic assessment of tumour specific alterations in ‘real-time’. A major obstacle to implementing such a test is the standardisation of CTC isolation methods and subsequent down-stream analysis. Several options are available, with a recent shift in vogue from positive-selection marker-dependent isolation systems to marker-independent negative-selection techniques. HNC single-CTC characterisation, including single-cell sequencing, to identify actionable mutations and gene-expression signatures has the potential to both guide the understanding of patient tumour heterogeneity and support the adoption of personalised medicine strategies. Microfluidic approaches for isolating CTCs and cell clusters are emerging as novel technologies which can be incorporated with computational platforms to complement current diagnostic and prognostic strategies. We review the current literature to assess progress regarding CTC biomarkers in HNC and potential avenues for future translational research and clinical implementation.
The more you get, the more you give: Positive cascading effects shape the evolutionary potential of prenatal maternal investment

Maternal effects are prevalent in nature and significantly contribute to variation in phenotypic trait expression. However, little attention has been paid to the factors shaping variation in the traits mediating these effects (maternal effectors). Specific maternal effectors are often not identified, and typically they are assumed to be inherited in an additive genetic and autosomal manner. Given that these effectors can cause long‐lasting effects on offspring phenotype, it is likely that they may also affect themselves in the next generation. Although the existence of such cascading maternal effects has been discussed and modeled, empirical examples of such effects are rare, let alone quantitative estimates of their strength and evolutionary consequences. Here, we demonstrate that the investment a mother makes in her eggs positively affects the egg investment of her daughters. Through reciprocally crossing artificially selected lines for divergent prenatal maternal investment in Japanese quail (Coturnix japonica), we demonstrate that the size of eggs daughters lay resembles the egg size of their maternal line significantly more than that of their paternal line, highlighting that egg size is in part maternally inherited. Correspondingly, we find that variation in the daughters' egg size is in part determined by maternal identity, in addition to substantial additive genetic effects. Furthermore, this maternal variance in offspring egg size is fully explained by maternal egg size, demonstrating the presence of a positive cascading effect of maternal egg size on offspring egg size. Finally, we use an evolutionary model to quantify the consequences of covariance between cascading maternal and additive genetic effects for both maternal effector and offspring body mass evolution. Our study demonstrates that by amplifying the amount of variation available for selection to act on, positive cascading maternal effects can significantly enhance the evolutionary potential of maternal effectors and the offspring traits that they affect.
IL-38: A New Player in Inflammatory Autoimmune Disorders

Interleukin (IL)-38, a newly discovered IL-1 family cytokine, is expressed in several tissues and secreted by various cells. IL-38 has recently been reported to exert an anti-inflammatory function by binding to several receptors, including interleukin-36 receptor (IL-36R), interleukin-1 receptor accessory protein-like 1 (IL-1RAPL1), and interleukin-1 receptor 1 (IL-1R1) to block binding with other pro-inflammatory cytokines and inhibit subsequent signaling pathways; thereby regulating the differentiation and function of T cells, peripheral blood mononuclear cells, macrophages, and dendritic cells. Inflammatory autoimmune diseases, which are common immune-mediated inflammatory syndromes, are characterized by an imbalance between T helper cells (Ths), especially Th1s and Th17s, and regulatory T cells (Tregs). Recent findings have shown that abnormal expression of IL-38 in inflammatory autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, primary Sjogren’s syndrome, psoriasis, inflammatory bowel disease, hidradenitis suppurativa, ankylosing spondylitis, and glaucoma, involves Th1s, Th17s, and Tregs. In this review, the expression, regulation, and biological function of IL-38 are discussed, as are the roles of IL-38 in various inflammatory autoimmune disorders. Current data support that the IL-38/IL-36R and/or IL-38/IL-1RAPL1 axis primarily play an anti-inflammatory role in the development and resolution of inflammatory autoimmune diseases and indicate a possible therapeutic benefit of IL-38 in these diseases.
Phase II Trial of Cediranib in Combination With Cisplatin and Pemetrexed in Chemotherapy-Naïve Patients With Unresectable Malignant Pleural Mesothelioma (SWOG S0905).

PURPOSE Antiangiogenic agents combined with chemotherapy have efficacy in the treatment of unresectable malignant pleural mesothelioma (MPM). Cediranib (AstraZeneca, Cheshire, United Kingdom), a vascular endothelial growth factor receptor and platelet-derived growth factor receptor inhibitor, demonstrated therapeutic potential in a prior phase I trial. We evaluated a phase II trial for efficacy. PATIENTS AND METHODS SWOG S0905 (ClinicalTrials.gov identifier: NCT01064648) randomly assigned cediranib or placebo with platinum-pemetrexed for six cycles followed by maintenance cediranib or placebo in unresectable chemotherapy-naïve patients with MPM of any histologic subtype. Primary end point was Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 progression-free survival (PFS). Secondary end points included overall survival, PFS by modified RECIST v1.1, response (modified RECIST and RECIST v1.1), disease control, and safety/toxicity. The trial was designed to detect a difference in RECIST v1.1 PFS at the one-sided 0.1 level using a stratified log-rank test. RESULTS Ninety-two eligible patients were enrolled (75% epithelioid and 25% biphasic or sarcomatoid). The cediranib arm had more grade 3 and 4 diarrhea, dehydration, hypertension, and weight loss. Cediranib improved PFS by RECIST v1.1 (hazard ratio, 0.71; 80% CI, 0.54 to 0.95; P = .062; 7.2 months v 5.6 months) and increased modified RECIST v1.1 response (50% v 20%; P = .006). By modified RECIST v1.1, cediranib numerically increased PFS (hazard ratio, 0.77; 80% CI, 0.59 to 1.02; P = .12; median, 6.9 months v 5.6 months). No significant difference in overall survival was observed. CONCLUSION The addition of cediranib to platinum-pemetrexed improved PFS by RECIST v1.1 and response rate by modified RECIST in patients with unresectable MPM. Whereas adding antiangiogenics to chemotherapy has been a successful strategy for some patients, the cediranib toxicity profile and small incremental survival benefit precludes additional development in MPM.
(Inverse) Agonists of Retinoic Acid-Related Orphan Receptor γ: Regulation of Immune Responses, Inflammation, and Autoimmune Disease.

Retinoic acid-related orphan receptor γt (RORγt) functions as a ligand-dependent transcription factor that regulates multiple proinflammatory genes and plays a critical role in several inflammatory and autoimmune diseases. Various endogenous and synthetic RORγ (inverse) agonists have been identified that regulate RORγ transcriptional activity, including many cholesterol intermediates and oxysterols. Changes in cholesterol biosynthesis and metabolism can therefore have a significant impact on the generation of oxysterol RORγ ligands and, consequently, can control RORγt activity and inflammation. These observations contribute to a growing literature that connects cholesterol metabolism to the regulation of immune responses and autoimmune disease. Loss of RORγ function in knockout mice and in mice treated with RORγ inverse agonists results in reduced production of proinflammatory cytokines, such as IL-17A/F, and increased resistance to autoimmune disease in several experimental rodent models. Thus, RORγt inverse agonists might provide an attractive therapeutic approach to treat a variety of autoimmune diseases.Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Rotator Cuff Degeneration: The Role of Genetics

Background: The literature is certain regarding the multifactorial etiology of rotator cuff degeneration. However, it remains unclear if rotator cuff degeneration exclusively depends on intrinsic and extrinsic factors or if it is also genetically determined. We compared the health status of cuff tendons, evaluated with a magnetic resonance imaging (MRI) study, between elderly monozygotic and dizygotic twins with the aim of separating the contributions of genetics from shared and unique environments. Methods: The rotator cuff tendon status was assessed using the Sugaya classification by MRI. Heritability, defined as the proportion of total variance of a specific characteristic in a particular population due to a genetic cause, was calculated as twice the difference between the intraclass correlation coefficients for monozygotic and dizygotic pairs. The influence of shared environment, which contributes to twin and sibling similarity, was calculated as the difference between the monozygotic correlation coefficient and the heritability index. Results: We identified 33 pairs of elderly twins: 17 monozygotic pairs and 16 dizygotic pairs, with a mean age (and standard deviation) of 64.62 ± 3.32 years. The polychoric correlation was 0.62 in monozygotic twins and 0.53 in dizygotic twins. The calculated heritability index was 0.18 (18%), and the contribution was 0.44 (44%) for the shared environment and 0.38 (38%) for the unique environment. Conclusions: The role of genetics in rotator cuff degeneration is quantified by our study on elderly monozygotic and dizygotic twins; however, it is only partial with respect to the contribution of shared and unique environments.
Development and Validation of Risk Nomogram Model Predicting Coronary Microvascular Obstruction in Patients with ST-Segment Elevation Myocardial Infarction (STEMI) Undergoing Primary Percutaneous Catheterization

Background Coronary microvascular functional and structural obstruction (CMVO) remains a major complication in patients with ST-segment elevation myocardial infarction (STEMI). This study was designed to develop and validate a nomogram model to predict CMVO risk during primary percutaneous catheterization procedure. Material/Methods Starting January 2014 to December 2016, a cohort of eligible candidates were enrolled and divided into a training or a validation database. Each database was divided into MO or NMO subgroups based on TIMI myocardial perfusion grade results after recanalization. Independent factors were identified by multivariate logistic regression, from which the nomogram was plotted. The echocardiography measurement of the left ventricular ejection fraction (LVEF) was arranged within 7 days after the procedure. Results A nomogram was built for CMVO risk prediction for the first time. There were 446 participants in the training database with 319 cases in the NMO subgroup and 127 participants in the MO subgroup. The validation database included 99 participants with 25 cases in the NMO subgroup and 74 in the MO subgroup. The risk model was developed by 6 independently significant factors: age, symptom onset to balloon time, Killip classification, admission activated clotting time, neutrophil/lymphocyte ratio, and glucose value. Internal receiver operating characteristic displayed favorable performance with concordance index of 0.925, while external validation area under curve was 0.939. There were significant differences in LVEF values during hospitalization between the subgroups of each database (both P<0.001). Conclusions The nomogram model consisting of 6 factors could predict CMVO risk accurately for STEMI patients undergoing primary percutaneous catheterization.
Endothelial dysfunction assessed by digital tonometry and discrepancy between fraction flow reserve and instantaneous wave free ratio

Abstract Background: We tested whether the level of endothelial dysfunction assessed by digital tonometry, and expressed as reactive hyperemia index (RHI), is related to occurrences of a discrepancy between fractional flow reserve (FFR) and the instantaneous wave free ratio (iFR) (ClinicalTrials.gov identifier: NCT03033810). Methods: We examined patients with coronary stenosis in the range of 40–70%, assessed by both FFR and iFR (system Philips-Volcano) for stable angina. We included consecutive patients with FFR and iFR in one native coronary artery, and who had had no previous intervention. Results: We included 138 patients. Out of those, 24 patients (17.4%) had a negative FFR (with an FFR value >0.8) and positive iFR (with a iFR value ≤0.89) – designated the FFRn/iFRp discrepancy group, and 22 patients (15.9%) had a positive FFR (≤0.8) and negative iFR (>0.89) – designated the FFRp/iFRn discrepancy. RHI was higher in the discrepancy groups compared the group without discrepancy (1.73 ± 0.79 vs. 1.48 ± 0.50, p = 0.025). However, this finding was not confirmed in multivariant logistic regression analyses. Patients with any type of discrepancy differed from the agreement group by having a higher occurrence of diabetes mellitus [9 patients (21.4%) vs. 36 patients (39.6%), p = 0.029], active smoking (23 patients or 54.8% vs. 26 patients or 28.6%, p = 0.003) and lower use of calcium channel blockers (9 patients, 21.4%, vs. 43 patients, 46.7%, p = 0.004). Conclusion: The presence of endothelial dysfunction can be associated with a discrepancy in FFR/iFR. However, RHI correlated with risk factors of atherosclerosis, not with FFR or iFR.
A fully Synthetic Heparan Sulfate-Based Neural Tissue Construct that Maintains the Undifferentiated State of Neural Stem Cells.

Heparin and heparan sulfate (HS) are attractive components for constructing biomaterials due to their ability to recruit and regulate the activity of growth factors. The structural and functional heterogeneity of naturally derived heparin and HS is, however, an impediment for the preparation of biomaterials for regenerative medicine. To address this problem, we have prepared hydrogels modified by well-defined synthetic HS-derived disaccharides. Human induced pluripotent cell-derived neural stem cells (HIP™-NSCs) encapsulated in a polyethylene glycol-based hydrogel modified by a pendent HS-disaccharide that is a known ligand for fibroblast growth factor-2 (FGF-2), exhibited significant increase in proliferation and self-renewal. This observation is important because evidence is emerging that undifferentiated stems cells can yield significant therapeutic benefits via their paracrine signaling mechanisms. Our data indicate that the HS disaccharide protects FGF-2, which has a very short biological half-live, from degradation. It is anticipated that by careful selection of a synthetic HS-oligosaccharide, it will be possible to control retention and release of specific growth factor, which in turn will provide control over cell fate.
Tuning of the enzyme ratio in a neutral redox convergent cascade: A key approach for an efficient one‐pot/two‐step biocatalytic whole‐cell system

The efficiency of a versatile in vivo cascade involving a promiscuous alcohol dehydrogenase, obtained from a biodiversity search, and a Baeyer–Villiger monooxygenase was enhanced by the independent control of the production level of each enzyme to produce ε‐caprolactone and 3,4‐dihydrocoumarin. This goal was achieved by adjusting the copy number per cell of Escherichia coli plasmids. We started from the observation that this number generally correlates with the amount of produced enzyme and demonstrated that an in vivo multi‐enzymatic system can be improved by the judicious choice of plasmid, the lower activity of the enzyme that drives the limiting step being counter‐balanced by a higher concentration. Using a preconception‐free approach to the choice of the plasmid type, we observed positive and negative synergetic effects, sometimes unexpected and depending on the enzyme and plasmid combinations. Experimental optimization of the culture conditions allowed us to obtain the complete conversion of cyclohexanol (16 mM) and 1‐indanol (7.5 mM) at a 0.5‐L scale. The yield for the conversion of cyclohexanol was 80% (0.7 g ε‐caprolactone, for the productivity of 244 mg·L −1·h −1) and that for 1‐indanol 60% (0.3 g 3,4‐dihydrocoumarin, for the productivity of 140 mg·L −1·h −1).
Spatiotemporal characterization of dynamic epithelial filopodia during zebrafish epiboly

During zebrafish epiboly, the embryonic cell mass, or blastoderm, spreads to enclose the yolk cell. The blastoderm consists of an outer epithelial sheet, the enveloping layer (EVL), and the underlying deep cell layer (DEL). Studies have provided insights into the mechanisms of EVL and deep cell epiboly, but little is known about the interactions between the two cell layers and what role they may play during epiboly.
Correlation between broth microdilution, E-test and disk diffusion methods for testing antifungal susceptibility of Candida species isolated from Thai blood samples

Abstract Background Broth microdilution (BMD) is a standard assay for susceptibility of Candida to antifungals, but complexity limits its routine application. E-test (ET) and disk diffusion (DD) assays are attractive alternatives because of their simplicity and reproducibility. Objectives To determine the correlation between BMD, and ET and DD assay results for Candida isolates. Methods We tested 63 Candida isolates for their susceptibility to fluconazole and voriconazole using BMD, ET, and DD, and recorded minimum inhibitory concentrations (MIC) and inhibitory zone diameters (ZD). Spearman correlations were determined and the Clinical and Laboratory Standards Institute recommendations were used to assess major and minor errors in test results. Results The isolates included 32 (51%) C. albicans, 14 (22%) C. tropicalis, 12 (19%) C. parapsilosis, 4 (6%) C. glabrata, and 1 (2%) C. guilliermondii. The BMD-MIC and ET-MIC had good correlation for fluconazole (r = 0.94; P < 0.001) and voriconazole (r = 0.95; P < 0.001). The BMD-MIC for both antifungals were significantly correlated with the ZD of the DD assays (r = −0.47; P < 0.001; r = −0.75; P < 0.001, respectively). Agreement between the BMD and the ET and DD results exceeded 90%. No major errors were identified in any comparisons. Conclusions C. albicans were predominant among the isolates and were susceptible to fluconazole and voriconazole. The BMD results were well correlated with ET and DD assay results, and therefore ET and DD assays can be recommended as initial screening tools in resource-limited hospitals because of their relatively low cost.
On the Sum of Powers of Two k-Fibonacci Numbers which Belongs to the Sequence of k-Lucas Numbers

Abstract Let k ≥ 1 and denote (Fk,n)n≥0, the k-Fibonacci sequence whose terms satisfy the recurrence relation Fk,n = kFk,n−1 +Fk,n−2, with initial conditions Fk,0 = 0 and Fk,1 = 1. In the same way, the k-Lucas sequence (Lk,n)n≥0 is defined by satisfying the same recurrence relation with initial values Lk,0 = 2 and Lk,1 = k. These sequences were introduced by Falcon and Plaza, who showed many of their properties, too. In particular, they proved that Fk,n+1 + Fk,n−1 = Lk,n, for all k ≥ 1 and n ≥ 0. In this paper, we shall prove that if k ≥ 1 and Fk,n+1s+Fk,n−1s∈(Lk,m)m≥1 $F_{k,n + 1}^s + F_{k,n - 1}^s \in \left( {L_{k,m} } \right)_{m \ge 1} $ for infinitely many positive integers n, then s =1.
BULGARIAN ACADEMY OF SCIENCES

The following article presents an overview of the use of artificial neural networks for the task of Word Sense Disambiguation (WSD). More specifically, it surveys the advances in neural language models in recent years that have resulted in methods for the effective distributed representation of linguistic units. Such representations – word embeddings, context embeddings, sense embeddings – can be effectively applied for WSD purposes, as they encode rich semantic information, especially in conjunction with recurrent neural networks, which are able to capture long-distance relations encoded in word order, syntax, information structuring.
Crystal structure of N′-(4-methoxybenzylidene)-5-phenyl-1H-pyrazole-3-carbohydrazide, C18H16N4O2

Abstract C18H16N4O2, triclinic, P1̅ (no. 2), a = 10.9734(4) Å, b = 11.8835(5) Å, c = 13.0996(5) Å, α = 78.581(2)°, β = 78.542(1)°, γ = 83.725(2)°, V = 1636.68(11) Å3, Z = 4, Rgt(F) = 0.0439, wRref(F2) = 0.1182, T = 100 K.
Engineering small-caliber vascular grafts from collagen filaments and nanofibers with comparable mechanical properties to native vessels

At the present time, there is no successful synthetic, off-the-shelf small-caliber vascular graft (<6 mm) for the repair or bypass of the coronary or carotid arteries. This stimulates on-going investigations to fabricate an artificial vascular graft that has both sufficient mechanical properties as well as superior biological performance. Collagen has long been considered as a viable material to encourage cell recruitment, tissue regeneration, and revascularization, but its use has been limited by its inferior mechanical properties. In this study, novel electrochemically aligned collagen filaments were used to engineer a bilayer small-caliber vascular graft, by circular knitting the collagen filaments and electrospinning collagen nanofibers. The collagen prototype grafts showed significantly greater bursting strength under dry and hydrated conditions to that of autografts such as the human internal mammary artery and the saphenous vein (SV). The suture retention strength was sufficient under dry condition, but that under hydrated condition needs to be further improved. The radial dynamic compliance of the collagen grafts was similar to that of the human SV. During in vitro cell culture assays with human umbilical vein endothelial cells, the prototype collagen grafts also encouraged cell adhesion and promoted cell proliferation compared to the synthetic poly(lactic acid) grafts. In conclusion, this study demonstrated the feasibility of the use of novel collagen filaments for fabricating small caliber tissue-engineered vascular grafts that provide both sufficient mechanical properties and superior biological performance.
The EU General Data Protection Regulation’s Impact on Website Operators and eCommerce

The technology relies on an assumption that it is very secure because records would be almost impossible to decrypt. However, with the continued development of quantum computing, this may not always be the case. There are other security concerns, for example, that it could be possible to trace or deduce a party’s identity from transactions or through access to a party that has permission to decrypt the data. In theory, at least, a ledger might also be “captured” if someone were able to control the majority of participating computers.