Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeted therapy and immunotherapy: Emerging biomarkers in metastatic melanoma

Targeted therapy directed against oncogenic BRAF mutations and immune checkpoint inhibitors have transformed melanoma therapy over the past decade and prominently improved patient outcomes. However, not all patients will respond to targeted therapy or immunotherapy and many relapse after initially responding to treatment. This unmet need presents two major challenges. First, can we elucidate novel oncogenic drivers to provide new therapeutic targets? Second, can we identify patients who are most likely to respond to current therapeutic strategies in order to both more accurately select populations and avoid undue drug exposure in patients unlikely to respond? In an effort to evaluate the current state of the field with respect to these questions, we provide an overview of some common oncogenic mutations in patients with metastatic melanoma and ongoing efforts to therapeutically target these populations, as well as a discussion of biomarkers for response to immune checkpoint inhibitors—including tumor programmed death ligand 1 expression and the future use of neoantigens as a means of truly personalized therapy. This information is becoming important in treatment decision making and provides the framework for a treatment algorithm based on the current landscape in metastatic melanoma.
Design and explanation of organizational excellence model in home appliances industry

Article history: Received March 1, 2011 Received in Revised form July, 14, 2011 Accepted 15 July 2011 Available online 17 July 2011 Home appliances are considered as one of low margin and competitive industry in the world. This industry often needs significant amount of investment and resources and it often faces with some challenges during economic crises. In this paper, we present a framework for organizational excellence to detect any possible problems in home appliances industry. The proposed framework of this paper is used for a real-world case study of Iranian home appliances. The results of our survey indicate that there are four major dimensions involved with this industry including facilities, knowledge and skills, environment and vision. There are three criteria associated with facilities with 30 indexes, 14 criteria associated with knowledge and skills with 144 indexes, three criteria involved with environment with 33 indexes and five criteria linked with vision with 53 indexes. Therefore, home appliances in our case study needs 4 dimensions for achieving the organizational excellence. © 2012 Growing Science Ltd. All rights reserved.
HIV-1 integrase inhibitors targeting various DDE transposases: Retroviral integration versus RAG-mediated recombination

Transposases are ubiquitous mobile genetic elements responsible for genome development, driving rearrangements, such as insertions, deletions and translocations. Across species evolution, some transposases are tamed by their host and are made part of complex cellular systems. The proliferation of retroviruses is also dependent on transposase related enzymes termed integrases. Recombination-activating gene protein (RAG)1 and metnase are just two examples of transposase domestication and together with retroviral integrases (INs), they belong to the DDE polynucleotidyl transferases superfamily. They share mechanistic and structural features linked to the RNase H-like fold, harboring a DDE(D) metal dependent catalytic motif. Recent antiretroviral compounds target the catalytic domain of integrase, but they also have the potential of inhibiting other related enzymes. In this review, we report the activity of different classes of integrase inhibitors on various DDE transposases. Computational simulations are useful to predict the extent of off-target activity and have been employed to study the interactions between RAG1 recombinase and compounds from three different pharmacologic classes. We demonstrate that strand-transfer inhibitors display a higher affinity towards the RAG1 RNase H domain, as suggested by experimental data compared to allosteric inhibitors. While interference with RAG1 and 2 recombination is associated with a negative impact on immune function, the inhibition of metnase or HTLV-1 integrase opens the way for the development of novel therapies for refractory cancers.
Are Awe-Prone People More Curious? The Relationship Between Dispositional Awe, Curiosity, and Academic outcomes.

OBJECTIVE Guided by a functional account of awe, we aimed to test the hypothesis that people who often feel awe are also more curious (Studies 1 and 2), and that this relationship in turn related to academic outcomes (Study 3). METHOD In Study 1 (n = 1,005), we used a self-report approach to test the relationship between dispositional awe and curiosity. In Study 2 (n = 100), we used a peer-report approach to test if participants' dispositional awe related to how curious they were rated by their friends. In Study 3, in a sample of 447 high school adolescents we tested if dispositional awe predicted academic outcomes via curiosity. RESULTS We found that dispositional awe was positively related to people's self-rated curiosity (Study 1) and how curious they were rated by their friends (Study 2). In Study 3, we found that dispositional awe was related to academic outcomes via curiosity. CONCLUSIONS We conclude that among the seven positive emotion dispositions tested, awe was related to unique variance in curiosity, and this link in turn predicted academic outcomes. This work further characterizes awe as an epistemic emotion and suggests that activities that inspire awe may improve academic outcomes.
Arabic Handwritten Documents Segmentation into Text-Lines and Words using Deep Learning

One of the most important steps in a handwriting recognition system is text-line and word segmentation. But, this step is made difficult by the differences in handwriting styles, problems of skewness, overlapping and touching of text and the fluctuations of text-lines. It is even more difficult for ancient and calligraphic writings, as in Arabic manuscripts, due to the cursive connection in Arabic text, the erroneous position of diacritic marks, the presence of ascending and descending letters, etc. In this work, we propose an effective segmentation of Arabic handwritten text into text-lines and words, using deep learning. For text-line segmentation, we used an RU-net which allows a pixel-wise classification to separate text-lines pixels from the background ones. For word segmentation, we resorted to the text-line transcription, as we have not got a ground truth at word level. A BLSTM-CTC (Bidirectional Long Short Term Memory followed by a Connectionist Temporal Classification) is then used to perform the mapping between the transcription and text-line image, avoiding the need of the input segmentation. A CNN (Convolutional Neural Network) precedes the BLST-CTC to extract the features and to feed the BLSTM with the essential of the text-line image. Tested on the standard KHATT Arabic database, the experimental results confirm a segmentation success rate of no less than 96.7% for text-lines and 80.1% for words.
Awareness, Usage and Discovery of Swipe-revealed Hidden Widgets in iOS

Revealing a hidden widget with a dedicated sliding gesture is a common interaction design in today's handheld devices. Such "Swhidgets" (for swipe-revealed hidden widgets) provide a fast (and sometime unique) access to some commands. Interestingly, swhidgets do not follow conventional design guidelines in that they have no explicit signifiers, and users have to discover their existence before being able to use them. In this paper, we discuss the benefits of this signifierless design and investigate how iOS users deal with this type of widgets. We report on the results of a laboratory study and an online survey, investigating iOS users' experience with swhidgets. Our results suggest that swhidgets~are moderately but unevenly known by participants, yet the awareness and the discovery issues of this design is worthy of further discussion.
Verifying the Security of Enclaved Execution Against Interrupt-based Side-channel Attacks

Computing platforms sometimes provide hardware support for enclaves or trusted execution environments. On such platforms, security critical code can execute in an enclave or secure world, isolated from all other software on the platform. But the past few years, several successful side-channel attacks have been developed that break, or at least significantly weaken the isolation that these mechanisms offer. Particularly dangerous are software-based side-channels, as they can be launched even without physical access to the computing platform. These attacks often exploit architectural or micro-architectural features of the platform, like caches, paging, speculative execution, or interrupts. Extending a platform with new features, brings a risk of introducing new such side-channel attacks. In this talk, we will discuss an approach to formally prove the security of platform extensions against these side-channel attacks, and instantiate that approach in a simple setting. More specifically, we will consider the concrete case of extending a microprocessor that supports enclaved execution with support for securely interrupting these enclaves. The base platform we start from is the Sancus system. We show how making enclaves interruptible can lead to new side-channel attacks that weaken the isolation properties of enclaves. We then discuss how to formalize security against such attacks, and discuss the design and implementation of an interrupt handling mechanism for Sancus that is provably secure in the sense that it does not introduce new side-channel attacks.
How significant are export subsidies to agricultural trade? Trade and welfare implications of global reforms

We analyze the impacts of removing export subsidies with or without reforms to domestic support and tariffs using a multi-country trade model. Model simulations are designed to assess both the magnitude and the direction of trade in the absence of export subsidies in connection with other domestic distortions and import barriers. Results show that the impacts of export subsidy removal, while significant for some countries and products, are comparatively smaller and are dominated by the much larger trade and welfare distortions imposed by import barriers. Hence, the removal of domestic subsidies, including export subsidies, by themselves may not be sufficient to improve global welfare and expand trade since the welfare gains by the net exporters are far outweighed by the losses of net importers. One implication from these simulations is that export subsidy reform must be combined with market access liberalization in order to benefit exporters and importers and to attract the widest support among WTO members.
The experiences of dealing with consequences of an avalanche – surviving soldiers’ perspectives

ABSTRACT Purpose: The aim of the study was to explore and describe experiences of daily life after having experienced an avalanche three decades ago. Method: This paper presents a qualitative study of 12 male survivors of an avalanche during their military service, interviewed 30 years post-disaster. Findings: A comprehensive understanding of the categories led to the latent theme “Finding my own way of managing and dealing with life”. Findings revealed three categories describing experiences of daily living: (i) A comfortable life; (ii) A challenging, yet accomplished life; (iii) A demanding life. The first category represents a greater degree of using adaptive coping strategies for managing everyday life compared to the other two categories. The third category represents the group having the most challenging consequences. Among the three, the latter category conveys the most maladaptive coping strategies. Conclusions:The participants had different experiences with regards to their health and how they coped with their everyday life after the avalanche disaster. Insights into coping strategies may provide a guide for appropriate interventions for survivors dealing with traumatic events.
Carbon Nanotube and Graphene Based Polyamide Electrospun Nanocomposites

Electrospinning is a unique and versatile technique to produce nanofibres; the facility to incorporate fillers has expanded its range of applications. This review gives a brief description of the process and the different polymers employed for obtaining nanofibres. Owing to the ability of fibrillation of polyamides, these polymers have resulted in a wide variety of interesting results obtained when using this technique; therefore these features are summarised. Additionally, because of the feasibility of incorporating carbon nanotubes and graphene in these nanofibres and the growing interest on these nanomaterials, this review focuses in the most common methods employed for their incorporation in electrospun polyamides. Several equipment setups used for the electrospinning of the nanofibres are explained. The outstanding electrical, optical, crystallinity, and mechanical properties obtained by a number of research groups are discussed. The potential applications of the resulting nanocomposites have also been explored.
Enhanced Therapeutic Potential of the Secretome Released from Adipose-Derived Stem Cells by PGC-1α-Driven Upregulation of Mitochondrial Proliferation

Peroxisome proliferator activated receptor λ coactivator 1α (PGC-1α) is a potent regulator of mitochondrial biogenesis and energy metabolism. In this study, we investigated the therapeutic potential of the secretome released from the adipose-derived stem cells (ASCs) transfected with PGC-1α (PGC-secretome). We first generated PGC-1α-overexpressing ASCs by transfecting ASCs with the plasmids harboring the gene encoding PGC-1α. Secretory materials released from PGC-1α-overexpressing ASCs were collected and their therapeutic potential was determined using in vitro (thioacetamide (TAA)-treated AML12 cells) and in vivo (70% partial hepatectomized mice) models of liver injury. In the TAA-treated AML12 cells, the PGC-secretome significantly increased cell viability, promoted expression of proliferation-related markers, such as PCNA and p-STAT, and significantly reduced the levels of reactive oxygen species (ROS). In the mice, PGC-secretome injections significantly increased liver tissue expression of proliferation-related markers more than normal secretome injections did (p < 0.05). We demonstrated that the PGC-secretome does not only have higher antioxidant and anti-inflammatory properties, but also has the potential of significantly enhancing liver regeneration in both in vivo and in vitro models of liver injury. Thus, reinforcing the mitochondrial antioxidant potential by transfecting ASCs with PGC-1α could be one of the effective strategies to enhance the therapeutic potential of ASCs.
Early Signs of Inflammation With Mild Oxidative Stress in Mixed Martial Arts Athletes After Simulated Combat

Abstract Gomes-Santos, JAF, Lambertucci, RH, Vardaris, CV, Passos, MEP, Silva-Junior, EP, Hatanaka, E, Gorjão, R, McAnulty, SR, Souza-Junior, TP, and Barros, MP. Early signs of inflammation with mild oxidative stress in Mixed Martial Arts athletes after simulated combat. J Strength Cond Res 36(1): 180–186, 2022—Combat sports involve a combination of strenuous physical activity, usually at the anaerobic threshold, followed by intermittent low-intensity recovery periods for energy re-establishment. Oxidative stress and inflammation are inevitable exercise-related processes that could drastically affect athletic performance and practitioners' health, unless efficiently controlled during and after physical activities. This study aims to measure oxidative stress and inflammation biomarkers in the plasma of 12 top ranked professional Mixed Martial Arts (MMAs) athletes before and after simulated combats under official rules (pre-post study). Our results show that the athletes exhibited mild oxidative imbalances in plasma, evidenced by significant (p < 0.01) higher contents of both reduced (+7.3%) and oxidized glutathione (+28%), uric acid (+21%), and “free” iron (+21%) after combat, whereas variation tendencies (0.05 < p < 0.01) were observed in the antioxidant capacity in plasma (−40%), and SOD (−27%) or GPX (+20%) antioxidant activities in erythrocytes. However, a clear pro-inflammatory state was detected by increases in circulating cytokines IL-6 (+6,020%), IL-1β (+4,357%), and tumor necrosis factor alpha (+63%), and by an abrupt drop of the anti-inflammatory cytokine IL-10 (−98%). A significant correlation was observed between pre-post variations of IL-6 and GSH/GSSG ratio in plasma (p < 0.0001), which reinforces the integration between oxidative stress and inflammation during MMA combats. Considering metabolic and mechanical stresses (imposed by combat techniques, e.g., punches and joint locks), this study indicates pre-existing inflammation, although minor oxidative stress, in MMA professionals after combat.
Conditional Reprogramming for Patient-Derived Cancer Models and Next-Generation Living Biobanks

Traditional cancer models including cell lines and animal models have limited applications in both basic and clinical cancer research. Genomics-based precision oncology only help 2–20% patients with solid cancer. Functional diagnostics and patient-derived cancer models are needed for precision cancer biology. In this review, we will summarize applications of conditional cell reprogramming (CR) in cancer research and next generation living biobanks (NGLB). Together with organoids, CR has been cited in two NCI (National Cancer Institute, USA) programs (PDMR: patient-derived cancer model repository; HCMI: human cancer model initiatives. HCMI will be distributed through ATCC). Briefly, the CR method is a simple co-culture technology with a Rho kinase inhibitor, Y-27632, in combination with fibroblast feeder cells, which allows us to rapidly expand both normal and malignant epithelial cells from diverse anatomic sites and mammalian species and does not require transfection with exogenous viral or cellular genes. Establishment of CR cells from both normal and tumor tissue is highly efficient. The robust nature of the technique is exemplified by the ability to produce 2 × 106 cells in five days from a core biopsy of tumor tissue. Normal CR cell cultures retain a normal karyotype and differentiation potential and CR cells derived from tumors retain their tumorigenic phenotype. CR also allows us to enrich cancer cells from urine (for bladder cancer), blood (for prostate cancer), and pleural effusion (for non-small cell lung carcinoma). The ability to produce inexhaustible cell populations using CR technology from small biopsies and cryopreserved specimens has the potential to transform biobanking repositories (NGLB: next-generation living biobank) and current pathology practice by enabling genetic, biochemical, metabolomic, proteomic, and biological assays, including chemosensitivity testing as a functional diagnostics tool for precision cancer medicine. We discussed analyses of patient-derived matched normal and tumor models using a case with tongue squamous cell carcinoma as an example. Last, we summarized applications in cancer research, disease modeling, drug discovery, and regenerative medicine of CR-based NGLB.
Guidance for Design and Endpoints of Clinical Trials in Chronic Hepatitis B—Report From the 2019 EASL‐AASLD HBV Treatment Endpoints Conference

Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic hepatitis B virus (HBV) treatment endpoints to guide clinical trials aiming to “cure” HBV. Agreement among the conference participants was reached on some key points. “Functional” but not sterilising cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post‐treatment. The primary endpoint of phase III trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity for the prediction of sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg‐positive or negative chronic hepatitis, who are treatment‐naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV “functional cure”, the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.
MEchanical DIlatation of the Cervix in a Scarred uterus (MEDICS): the study protocol of a randomised controlled trial comparing a single cervical catheter balloon and prostaglandin PGE2 for cervical ripening and labour induction following caesarean delivery

Introduction Labour induction in women with a previous caesarean delivery currently uses vaginal prostaglandin E2 (PGE2), which carries the risks of uterine hyperstimulation and scar rupture. We aim to compare the efficacy of mechanical labour induction using a transcervically applied Foley catheter balloon (FCB) with PGE2 in affected women attempting trial of labour after caesarean (TOLAC). Methods and analysis This single-centre non-inferiority prospective, randomised, open, blinded-endpoint study conducted at an academic maternity unit in Singapore will recruit a total of 100 women with one previous uncomplicated caesarean section and no contraindications to vaginal delivery. Eligible consented participants with term singleton pregnancies and unfavourable cervical scores (≤5) requiring labour induction undergo stratified randomisation based on parity and are assigned either FCB (n=50) or PGE2 (n=50). Treatments are applied for up to 12 hours with serial monitoring of the mother and the fetus and serial assessment for improved cervical scores. If the cervix is still unfavourable, participants are allowed a further 12 hours’ observation for cervical ripening. Active labour is initiated by amniotomy at cervical scores of ≥6. The primary outcome is the rate of change in the cervical score, and secondary outcomes include active labour within 24 hours of induction, vaginal delivery, time-to-delivery interval and uterine hyperstimulation. All analyses will be intention-to-treat. The data generated in this trial may guide a change in practice towards mechanical labour induction if this proves efficient and safer for women attempting TOLAC compared with PGE2, to improve labour management in this high-risk population. Ethics and dissemination Ethical approval is granted by the Domain Specific Review Board (Domain D) of the National Healthcare Group, Singapore. All adverse events will be reported within 24 hours of notification for assessment of causality. Data will be published and will be available for future meta-analyses. Trial registration number NCT03471858; Pre-results.