Miracle-dz/UniFAR-FTUs huggingface dataset:
Bone-targeting agents in major solid tumour metastases: a multinational cohort study

Objective To describe the epidemiology, clinical characteristics and utilisation patterns of bone-targeting agents (BTAs) in patients with bone metastases from breast, prostate and lung cancer. Methods This is a multinational retrospective cohort study including patients with three major solid tumours (breast, prostate and lung cancer) and newly initiated on BTAs (ie, denosumab, zoledronic acid and pamidronate). Records were retrieved from nationwide health databases from Hong Kong and Taiwan (HK and TW: 2013–2017) and Korea (KR: 2012–2016). Descriptive analyses included the annual incidence rates of bone metastases and the cumulative incidence curves of BTA initiation. We used Sankey diagrams to visualise the dynamic BTA utilisation patterns. Results The annual incidence rate of bone metastases ranged from 3.5% to 4.5% in TW, from 9.6% to 10.3% in HK and from 2.9% to 3.8% in KR. We identified 14.1% (5127), 9.3% (883) and 9.4% (4800) of patients with bone metastases newly initiated on BTAs in TW, HK and KR, respectively. The most frequently used BTA in TW (67.1%) and HK (51.9%) was denosumab, while in KR (84.8%) it was zoledronic acid. Sankey diagrams indicated the proportion of patients remaining on denosumab was highest in TW and HK, while it was zoledronic acid in KR. Specifically, in TW, patients who were on bisphosphonates or had discontinued treatment frequently switched to or reinitiated denosumab. Conclusions We found the rate of BTA utilisation remained low across all sites and tumour types in recent years. The dynamic utilisation patterns of BTAs provide better understanding of the treatment landscape for future evaluation of associated outcomes of patients.
Segmental Motion of Cervical Arthroplasty Leads to Decreased Adjacent-Level Degeneration: Analysis of the 7-Year Postoperative Results of a Multicenter Randomized Controlled Trial

Background Cervical artificial disc replacement (C-ADR) has become a common and accepted surgical treatment for many patients with cervical disc degeneration/herniation and radiculopathy who have failed nonoperative treatment. Midterm follow-up studies of the original investigational device exemption trials comparing C-ADR to traditional anterior cervical discectomy and fusion (ACDF) have revealed C-ADR patients have less adjacent-level disease and fewer reoperations at 5 to 7 years. The purpose of this study was to examine the relationship of radiographic adjacent-level disease (R-ALD) with the amount of index-level segmental range of motion (ROM) in C-ADR patients using the long-term follow-up data from the ProDisc-C investigational device exemption trial. Methods This was a post hoc analysis of a 1:1 randomized controlled trial. The initial previously described Food and Drug Administration–approved 2-year study was extended, and consenting patients in the original study were followed at annual intervals up to 7 years. Logistic regression was used to assess any progression in adjacent-level disease (ALD). Ordinal logistic regression was also used to assess the relationship between any progressive R-ALD and final flexion extension (F/E) ROM in C-ADR patients. Spearman’s rank-order correlation was used when R-ALD was kept as an ordinal variable to assess the same relationship. Results At the last follow-up visit, the rate of progressive R-ALD was significantly higher in ACDF patients than in C-ADR patients. When C-ADR patients were divided into 3 groups based on final F/E ROM, those with 0° to 3° (n = 19), 4° to 6° (n = 15), and 7° (n = 42) of segmental motion at the index procedure level, the rate of progressive R-ALD trended significantly with final ROM (P = 0.01). Conclusions C-ADR leads to a significant decrease in R-ALD compared to ACDF. The difference in R-ALD is related to the preservation of motion at the index level and resultant preservation of kinematics and forces across the adjacent disc space. Level of Evidence 4.
Hybrid Technique in SCALE for Fission Source Convergence Applied to Used Nuclear Fuel Analysis

The new hybrid SOURCE ConveRgence accelERator (SOURCERER) sequence in SCALE deterministically computes a fission distribution and uses it as the starting source in a Monte Carlo eigenvalue criticality calculation. In addition to taking the guesswork out of defining an appropriate, problem-dependent starting source, the more accurate starting source provided by the deterministic calculation decreases the probability of producing inaccurate tally estimates associated with undersampling problems caused by inadequate source convergence. Furthermore, SOURCERER can increase the efficiency of the overall simulation by decreasing the number of cycles that has to be skipped before the keff accumulation. SOURCERER was applied to a representative example for a used nuclear fuel cask utilized at the Maine Yankee storage site {Scaglione and Ilas}. Because of the time constraints of the Used Fuel Research, Development, and Demonstration project, it was found that using more than 30,000 neutrons per cycle will lead to inaccurate Monte Carlo calculation of keff due to the inevitable decrease in the number of skipped and active cycles used with this problem. For a fixed uncertainty objective and by using 30,000 neutron per cycle, the use of SOURCERER increased the efficiency of the keff calculation by 60%compared to a Monte Carlo calculation thatmore » used a starting source distributed uniformly in fissionable regions, even with the inclusion of the extra computational time required by the deterministic calculation. Additionally, the use of SOURCERER increased the reliability of keff calculation using any number of skipped cycles below 350. « less
Interpretation of P16 expression as a marker of HPV in colorectal cancer.

BACKGROUND Colorectal cancer is one of the most prevalent types of tumors worldwide. P16ᴵᴺᴷ⁴ᵃ is a widely used immunohistochemical marker for high-risk HPV infection. The purpose of this study is to explore the relationship between P16 expression as an indicator of HPV infection and colorectal cancer in Egyptian patients, as well as its association with histopathological characteristics. MATERIAL AND METHODS The study was performed on 59 cases of colorectal carcinoma cases and 30 specimens of normal colonic mucosa. RESULTS p16 protein was detected in 22% (13 of 59) of patients with colorectal carcinoma. No evidence of P16 expression in all 30 cases of non-neoplastic colonic mucosa was found. More frequent expression of P16 was seen in distal carcinomas. CONCLUSION our study demonstrated that P16 protein is expressed in a reasonable percent of colorectal carcinoma cases, suggesting a role of HPV in colorectal carcinogenesis. The present study highlights the role of p16 protein expression which is important in the pathogenesis in colorectal carcinoma, especially regarding distal tumors.
How Essential is Kratom Availability and Use during Covid-19? Use Pattern Analysis Based on Survey and Social Media Data

Background: Kratom, a tree native to Southeast Asia, is increasingly used in Western countries for self-treatment of pain, psychiatric disorders, and mitigation of withdrawal symptoms from drugs of abuse. Because kratom is solely supplied from its native locations, supply shortages during the COVID-19 pandemic may impact the availability of preparations and hence force consumers to change their patterns of use. The aim of this study was to understand if and how COVID-19 was influencing kratom purchasing and use. Methods: Additional questions specific to kratom availability and changes in use during COVID-19 were added to an international online survey with responses collected between January and July 2020. During the same period, kratom-related social media posts to Twitter, Reddit, and Bluelight were analyzed for themes similar to the survey questions. Results: The survey results indicated no changes in kratom use patterns although the sample size was relatively small (n = 70) with younger consumers reporting a potential issue in obtaining their desired products from their usual sources. The survey respondents identified primarily as non-Hispanic whites (87.1%). Social media themes revolved primarily around quitting kratom during COVID-19, misinformation about the effects of kratom on COVID-19, and other non-COVID-related discussions. While some consumers may increase their kratom dose because of additional stress, a majority of discussions centered around reducing or rationing kratom due to COVID-19 or a perceived dependence. Access to quality kratom products was also a major discussion topic on social media. Conclusions: Kratom use patterns did not change due to COVID-19 but consumers were concerned about potential product shortages and resulting quality issues. Clinicians and public health officials need to be informed and educated about kratom use as a potential mitigation strategy for substance use disorders and for self-treatment of pain.
Somatic Genomic Testing in Patients With Metastatic or Advanced Cancer: ASCO Provisional Clinical Opinion.

PURPOSE An ASCO provisional clinical opinion offers timely clinical direction to ASCO's membership following publication or presentation of potentially practice-changing data from major studies. This provisional clinical opinion addresses the appropriate use of tumor genomic testing in patients with metastatic or advanced solid tumors. CLINICAL CONTEXT An increasing number of therapies are approved to treat cancers harboring specific genomic biomarkers. However, there is a lack of clarity as to when tumor genomic sequencing should be ordered, what type of assays should be performed, and how to interpret the results for treatment selection. PROVISIONAL CLINICAL OPINION Patients with metastatic or advanced cancer should undergo genomic sequencing in a certified laboratory if the presence of one or more specific genomic alterations has regulatory approval as biomarkers to guide the use of or exclusion from certain treatments for their disease. Multigene panel-based assays should be used if more than one biomarker-linked therapy is approved for the patient's disease. Site-agnostic approvals for any cancer with a high tumor mutation burden, mismatch repair deficiency, or neurotrophic tyrosine receptor kinase (NTRK) fusions provide a rationale for genomic testing for all solid tumors. Multigene testing may also assist in treatment selection by identifying additional targets when there are few or no genotype-based therapy approvals for the patient's disease. For treatment planning, the clinician should consider the functional impact of the targeted alteration and expected efficacy of genomic biomarker-linked options relative to other approved or investigational treatments.Additional information is available at www.asco. org/assays-and-predictive-markers-guidelines.
Disruptions of the Meshed Architecture in Autism Spectrum Disorder

ABSTRACT We take a wide view of social cognition to include embodied and situated processes of intersubjective interaction, which include, for example, nonverbal cues, joint attention and joint action, social affordances and direct enactive perception of intentions and affective states. In this article we propose a model that can help to capture and organize the many different factors involved in social cognition, and we evaluate how this model may inform research on Autism Spectrum Disorder (ASD). Specifically, we propose that social interaction can be viewed as a form of embodied-situated performance. In this respect the model of a meshed architecture, borrowed from performance studies, can provide some insight into social cognition, and specifically into social cognitive problems in ASD. As currently understood this model integrates cognitive and embodied motoric processes. We have developed a more enhanced model of a meshed architecture that applies more generally to situated cognition, and we apply this enhanced model to studies on social cognition and ASD.
“Who Cares?”: Young Adolescents’ Perceived Barriers to Civic Action

Abstract While civic participation is a crucial component of healthy and sustainable democracies, young adolescents may perceive or experience barriers that limit their civic action. This study draws from focus groups and surveys during a week-long summer civics camp to explore ways in which 47 young adolescents entering Grades 6–9 described barriers they perceive to civic action in their schools and communities. Findings reveal that participants entered camp believing they were capable of making a difference in their communities. Their ideas for youth civic action in schools and broader communities typically represented personally responsible and participatory notions of citizenship. Key obstacles to civic activities included partnerships with peers/adults, peers’ reluctance to exercise civic duty, social-emotional factors, and lack of resources.
Work-Based Learning, Technology-Enhanced Learning And Reflection: The Case Of Open University Students

The research reported in this thesis investigates the attitudes of Open University (OU) students towards work-based learning (WBL) and reflection in learning and practice. It also seeks to evaluate the potential of educational technologies to support work-based learning and reflection. The research was carried out using a mixed methods approach, which yielded data amenable to both quantitative and qualitative analysis. The methods used to collect data consisted of an electronic survey sent to 788 OU work-based learners and follow-up telephone interviews conducted with 10 learners selected from amongst the 200 who responded to the survey. The paradigm of pragmatism informed the research design, data collection and analysis. The findings of the research suggested that: • OU students derive motivation by participating in WBL and could see its relevance and benefits to their personal, academic and career development. • OU students had an understanding of the key concepts associated with reflection, although this understanding tended to focus on the dimension of reflection concerned with looking back at experience and learning from it rather than on surfacing tacit knowledge. • Most work-based learners saw the value of using reflective techniques to help them to integrate work and study and to improve performance. • Although the more established technologies of email and online discussion forums were the predominant for both work and study purposes, it was found that ‘Web 2.0’ technologies were used by many students for leisure purposes. Provisional conclusions include the suggestion that, although there is evidence of a latent demand for using new technologies to engage in informal reflective activity, simply making these technologies available without sufficient thought being given to the pedagogical efficacy of doing so may lead to sub-optimal results; in particular, when considering the use such tools for reflective activity as part of a formal assessment. The research also indicates that the demography, attitudes and behaviours of OU students also need to be taken in to account when integrating new technologies. There are several aspects to this, including the willingness and ability of students to use new technologies effectively for study purposes and whether the OU prescribes the technology or allows some student choice.
Exploring Current Challenges and Perspectives for Automatic Reconstruction of Clonal Evolution

Background/Aim: In the field of cancer research, reconstructing clonal evolution is of major interest. The technique provides new insights for analysis and prediction of tumor development. However, reconstruction based on mutational data is characterized by several challenges. Materials and Methods: By performing extensive literature research, we identified 51 currently available tools for reconstructing clonal evolution. By analyzing two cancer data sets (n=21), we investigated the applicability and performance of each tool. Results: Seventeen out of 51 tools could be applied to our data. Correct clustering of variants can be observed for 4 patients in the presence of ≤3 clusters and ≥5 time points. Correct phylogenetic trees are determined for 10 patients. Accurate visualization is possible, by applying adjustments to the original algorithms. Conclusion: Despite bearing considerable potential, automatic reconstruction of clonal evolution remains challenging. To replace tedious manual reconstruction, further research including systematic error analyses using simulation tools needs to be conducted.
The control of central nervous system myelination and the phenotypic characterisation of a novel zebrafish mutant, akineto(u45)

Part 1 of this thesis addresses the control of myelination in the central nervous system (CNS). We have a sound knowledge of myelin structure, particularly the molecules and cells involved in its make-up. However, our understanding of the control of myelin formation is scanty. Myelination of CNS tracts during development follows a strictly ordered schedule suggesting local control by axons. Here I present evidence that CNS axons need to form synaptic connections before they can be myelinated. I have used myelin renewal during regeneration of the fish optic nerve as a model system: the axons withstand target deprivation and their behaviour in these circumstances is well characterised from earlier studies of synaptic plasticity. Depriving the regenerating optic nerve of its primary target, the contralateral optic tectum, delays myelination until the regenerating axons find the intact ipsilateral tectum and form synapses there. Facilitating this process hastens the onset of myelination and denying the axons of any opportunity to form synapses abolishes it. I investigated possible mechanisms by which the synaptogenesis-timed signal is mediated and also compared myelination during regeneration and development. Part 2 describes the phenotypic characterisation of a novel zebrafish mutant: akineto (aknu45). Aknu45 mutant embryos cannot contract their skeletal muscles. Here I show that this is caused by incomplete sarcomere assembly. Myofibrils of mutants lack properly assembled thick filaments. Our understanding of the process of myofibrillogenesis, particularly relating to thick filament assembly, is mostly speculative at present. Although the aknu45 gene is unidentified so far, I am currently engaged in efforts to identify it. Subsequently the aknu45 mutation may become a useful tool to further unravel the process of myofibrillogenesis.
Reduction of Aflatoxin M1 Content during Manufacture and Storage of Egyptian Domaiti Cheese

Elevated levels of aflatoxin M 1 (AFM 1) in milk and milk products is considered to pose certain hygienic risks for human health. The maximum level of AFM 1 allowable in Egyptian milk is 50 ng/L and while a previous study found the majority of milk was below this level, some milk contained up to 250 ng/L. The aim was to determine what proportion of initial AFM 1 in milk is retained after manufacture into Domiati cheese and remains during 90 d storage. Milk was spiked with 1µg/kg AFM 1 then pasteurized at 63oC for 30 min and made into Domiati cheese using salt additions of 6%, 8% and 10% (wt/wt). Cheese making was performed on 3 separate occasions. The AFM 1 levels in milk, cheese and whey were determined using an ELISA test kit. Pasteurization of milk caused ≤10% loss of AFM 1. About 60%, 58%, and 56% of total AFM 1 remained in cheese curd made using 6%, 8% and 10% salt respectively, with the residual being lost in the whey. After 2 wk storage at 20 oC, all of the cheeses had a 17% reduction in AFM 1 compared to their levels after manufacture. With continued storage through 90 d the losses of AFM 1 were significantly different ( P < 0.05) with reduction in AFM 1 or 20.5%, 21.4%, 22.0% for cheeses made using 6%, 8% and 10% salt respectively. Thus, including pasteurization of milk, conversion of milk into Domiati cheese and its subsequent storage period for 3 mo produced an overall 64% reduction of AFM 1. In conclusion, as well as avoiding contamination of milk with AFM 1 there is a lower health risk to the population from the presence of AFM 1 in milk when the milk is pasteurized and converted into Domiati cheese that is then stored for the customary 3 mo.
Ultra-high phase transition amplitude of Fe-doped high-performance VO2 films manufactured by DC-magnetron sputtering for modulation application

In the field of electronic modulation, vanadium dioxide (VO2) is a potential material owing to its function of automatic insulator-to-metal transition (MIT) which can induce rapid changes in electrical resistivity through MIT. Nevertheless, the application of modulator based on VO2 is limited by some performance shortcomings, including wide hysteresis loop width (ΔH), high phase transition temperature (Tc) as well as low phase transition amplitude (AMIT). In this work, by DC (DirectCurrent)-magnetron sputtering with doping Fe3+ into VO2 films, narrowed ΔH and decreased Tc are observed. Interestingly, the Fe doped VO2 films show ultra-high phase transition amplitude despite the low Tc due to the influence of Fe dopants. Specifically, the 0.5% Fe-doped VO2 film shows the best MIT characteristics with ultra-high phase transition amplitude of 104, narrow ΔH decreased to 9.8° and low Tc around 60.02°C, which is considered to be the first time to highly heighten the electrical MIT properties by Fe doping. In addition, we also comprehensively studied the influences of doping with Fe element on the MIT properties and microstructures based on characterization such as SEM, XRD, Raman shift and XPS results. These results show that our unique preparation method can manufacture VO2 thin films with excellent MIT properties, which will be beneficial to the popularization and publicity of VO2 based electrical modulator.
Development and Evaluation of Competitive Inhibitors of Trastuzumab-HER2 Binding to Bypass the Binding-Site Barrier

Our group has developed and experimentally validated a strategy to increase antibody penetration in solid tumors through transient inhibition of antibody-antigen binding. In prior work, we demonstrated that 1HE, an anti-trastuzumab single domain antibody that transiently inhibits trastuzumab binding to HER2, increased the penetration of trastuzumab and increased the efficacy of ado-trastuzumab emtansine (T-DM1) in HER2+ xenograft bearing mice. In the present work, 1HE variants were developed using random mutagenesis and phage display to enable optimization of tumor penetration and efficacy of trastuzumab-based therapeutics. To guide the rational selection of a particular 1HE mutant for a specific trastuzumab-therapy, we developed a mechanistic pharmacokinetic (PK) model to predict within-tumor exposure of trastuzumab/T-DM1. A pharmacodynamic (PD) component was added to the model to predict the relationship between intratumor exposure to T-DM1 and the corresponding therapeutic effect in HER2+ xenografts. To demonstrate the utility of the competitive inhibition approach for immunotoxins, PK parameters specific for a recombinant immunotoxin were incorporated into the model structure. Dissociation half-lives for variants ranged from 1.1 h (for variant LG11) to 107.9 h (for variant HE10). Simulations predicted that 1HE co-administration can increase the tumor penetration of T-DM1, with inhibitors with longer trastuzumab binding half-lives relative to 1HE (15.5 h) further increasing T-DM1 penetration at the expense of total tumor uptake of T-DM1. The PK/PD model accurately predicted the response of NCI-N87 xenografts to treatment with T-DM1 or T-DM1 co-administered with 1HE. Model predictions indicate that the 1HE mutant HF9, with a trastuzumab binding half-life of 51.1 h, would be the optimal inhibitor for increasing T-DM1 efficacy with a modest extension in the median survival time relative to T-DM1 with 1HE. Model simulations predict that LG11 co-administration will dramatically increase immunotoxin penetration within all tumor regions. We expect that the mechanistic model structure and the wide range of inhibitors developed in this work will enable optimization of trastuzumab-cytotoxin penetration and efficacy in solid tumors.