Miracle-dz/UniFAR-FTUs huggingface dataset:
Short-Term Incidence of Sequelae of HCV Infection Among Medicaid Beneficiaries in Oregon

Objectives: Given the known high morbidity and mortality of hepatitis C virus (HCV) infection in Oregon, we sought to develop a practical method of estimating the severe sequelae of HCV infection among Medicaid beneficiaries in Oregon. Methods: We assembled a retrospective cohort that identified all Oregon Medicaid beneficiaries with HCV infection enrolled for at least 1 year during 2009-2013. We linked this cohort to 3 data sets to identify HCV-related deaths, cases of hepatocellular carcinoma (HCC), and first hospitalizations for advanced liver disease (ALD). We calculated incidence density rates and used multivariable Cox regression modeling to calculate adjusted hazard ratios (aHRs) to evaluate the association between demographic characteristics (birth year, sex, race, ethnicity) and these 3 outcomes. Results: Of 11 790 Oregon Medicaid beneficiaries with HCV infection, 474 (4.0%) had an HCV-related death, 156 (1.3%) had HCC, and 596 (5.1%) had a first hospitalization for ALD. Adjusted hazard ratios for deaths were 2.2 (95% confidence interval [CI], 1.6-2.8) among persons born in 1945 through 1965 (vs persons born after 1965), 2.1 (95% CI, 1.7-2.5) among males (vs females), and 1.9 (95% CI, 1.2-2.9) among Asian/Pacific Islanders and 2.2 (95% CI, 1.5-3.2) among American Indian/Alaska Natives (vs white persons). The same risk groups had significant aHRs for first hospitalizations for ALD. Persons born before 1945 (aHR = 17.0; 95% CI, 5.2-55.8) and in 1945 through 1965 (aHR = 12.8; 95% CI, 4.1-40.3) vs born after 1965, males (aHR = 3.3; 95% CI, 2.3-4.8) vs females, and Asian/Pacific Islanders (aHR = 3.9; 95% CI, 2.3-6.7) vs white persons had higher risks for HCC. Conclusions: Continued assessments using the methods piloted in this study will allow Oregon to monitor trends in severe sequelae of HCV infection over time.
SCOPe: classification of large macromolecular structures in the structural classification of proteins—extended database

Abstract The SCOPe (Structural Classification of Proteins—extended, https://scop.berkeley.edu) database hierarchically classifies domains from the majority of proteins of known structure according to their structural and evolutionary relationships. SCOPe also incorporates and updates the ASTRAL compendium, which provides multiple databases and tools to aid in the analysis of the sequences and structures of proteins classified in SCOPe. Protein structures are classified using a combination of manual curation and highly precise automated methods. In the current release of SCOPe, 2.07, we have focused our manual curation efforts on larger protein structures, including the spliceosome, proteasome and RNA polymerase I, as well as many other Pfam families that had not previously been classified. Domains from these large protein complexes are distinctive in several ways: novel non-globular folds are more common, and domains from previously observed protein families often have N- or C-terminal extensions that were disordered or not present in previous structures. The current monthly release update, SCOPe 2.07–2018-10–18, classifies 90 992 PDB entries (about two thirds of PDB entries).
Effective control of acute myeloid leukaemia and acute lymphoblastic leukaemia progression by telomerase specific adoptive T-cell therapy

Telomerase (TERT) is a ribonucleoprotein enzyme that preserves the molecular organization at the ends of eukaryotic chromosomes. Since TERT deregulation is a common step in leukaemia, treatments targeting telomerase might be useful for the therapy of hematologic malignancies. Despite a large spectrum of potential drugs, their bench-to-bedside translation is quite limited, with only a therapeutic vaccine in the clinic and a telomerase inhibitor at late stage of preclinical validation. We recently demonstrated that the adoptive transfer of T cell transduced with an HLA-A2-restricted T-cell receptor (TCR), which recognize human TERT with high avidity, controls human B-cell chronic lymphocytic leukaemia (B-CLL) progression without severe side-effects in humanized mice. In the present report, we show the ability of our approach to limit the progression of more aggressive leukemic pathologies, such as acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL). Together, our findings demonstrate that TERT-based adoptive cell therapy is a concrete platform of T cell-mediated immunotherapy for leukaemia treatment.
Genetic variations in human papillomavirus and cervical cancer outcomes

Cervical cancer is driven by persistent infection of human papillomavirus (HPV), which is influenced by HPV type and intratypic variants, yet the impact of HPV type and intratypic variants on patient outcomes is far less understood. Here, we examined the association of cervical cancer stage and survival with HPV type, clade, lineage, and intratypic variants within the HPV E6 locus. Of 1,028 HPV‐positive cases recruited through the CerGE study, 301 were in‐situ and 727 were invasive cervical cancer (ICC), with an average post‐diagnosis follow‐up of 4.8 years. HPV sequencing was performed using tumor‐isolated DNA to assign HPV type, HPV 16 lineage, clade, and intratypic variants within the HPV 16 E6 locus, of which nonsynonomous variants were functionally annotated by molecular modeling. HPV 18‐related types were more prevalent in ICC compared to in‐situ disease and associated with significantly worse recurrence‐free survival (RFS) compared to HPV 16‐related types. The HPV 16 Asian American lineage D3 and Asian lineage A4 associated more frequently with ICC than with in situ disease and women with an intratypic HPV 16 lineage B exhibited a trend toward worse RFS than those with A, C, or D lineages. Participants with intratypic E6 variants predicted to stabilize the E6–E6AP–p53 complex had worse RFS. Variants within the highly immunogenic HPV 16 E6 region (E14–I34) were enriched in ICC compared to in‐situ lesions but were not associated with survival. Collectively, our results suggest that cervical cancer outcome is associated with HPV variants that affect virus‐host interactions.
MicroRNA-221 sensitizes chronic myeloid leukemia cells to imatinib by targeting STAT5

Abstract MicroRNAs (miRNAs) are involved in various processes from the development to drug resistance of tumors, including chronic myeloid leukemia (CML). In this study, we examined the STAT5-related miRNA-expression profile in CML cell lines (K562 and imatinib-resistant K562/G) by quantitative real-time reverse-transcriptase polymerase chain reactions. MiR-221 expression was markedly decreased in K562/G cells and peripheral blood mononuclear cells from patients with treatment failure, when compared to imatinib-sensitive CML cells and patients with optimal responses respectively. We also observed the expression of STAT5 inversely correlated with miR-221 expression in K562 and KBM5 cells. Additionally, STAT5 was validated as a direct target of miR-221 in dual-luciferase reporter vector assays. MiR-221 restoration and STAT5 knockdown in K562/G cells increased the sensitivity of CML cells to imatinib by reducing the Bcl2: Bax ratio. Collectively, our data suggested that miR-221–STAT5 axis played crucial roles in controlling the sensitivity of CML cells to imatinib.
A Machine Learning Approach to Indian Native Language Identification

NLI (Native Language Identification) determines the native language of the non-native users using their writings in a foreign language. It has several applications namely forensic and security, author profiling and identification, and educational applications. English is a most common language used in social media by many non-English people in the world to share their thoughts and ideas. They blend English with their native language for their posts and comments. Identifying the native language from the short text in English is still a challenging task. In this paper, we present a language agnostic approach without any language specific processing and employed machine learning approach with and without feature selection to identify the native language of a Indian speaker using their comments and posts in social network. The bag of word features are extracted from the text posted by the user and the feature vectors are constructed using TF-IDF score for the training data. We have used a statistical feature selection methodology to select the features that are significantly contributing to NLI task. The classifier with highest cross validation accuracy was used for predicting the native language of the user. Our approaches are evaluated using INLI@FIRE2018 shared task data set.
Comparison of sterol and fatty acid profiles of chytrids and their hosts reveals trophic upgrading of nutritionally inadequate phytoplankton by fungal parasites

Chytrids are ubiquitous fungal parasites in aquatic ecosystems, infecting representatives of all major phytoplankton groups. They repack carbon from inedible phytoplankton hosts into easily ingested chytrid propagules (zoospores), rendering this carbon accessible to zooplankton. Grazing on zoospores may circumvent bottlenecks in carbon transfer imposed by the dominance of inedible or poorly nutritious phytoplankton (mycoloop). We explored qualitative aspects of the mycoloop by analysing lipid profiles (fatty acids, sterols) of two chytrids infecting two major bloom-forming phytoplankton taxa of contrasting nutritional value: the diatom Asterionella formosa and the filamentous cyanobacterium Planktothrix agardhii. The polyunsaturated fatty acid composition of chytrids largely reflected that of their hosts, highlighting their role as conveyors of otherwise inaccessible essential lipids to higher trophic levels. We also showed that chytrids are capable of synthesizing sterols, thus providing a source of these essential nutrients for grazers even when sterols are absent in their phytoplankton hosts. Our findings reveal novel qualitative facets of the mycoloop, showing that parasitic chytrids, in addition to making carbon and essential lipids available from inedible sources, also upgrade their host's biochemical composition by producing sterols de novo, thereby enhancing carbon and energy fluxes in aquatic food webs.
Quantitative CT assessment of lung injury after successful cardiopulmonary resuscitation in a porcine cardiac arrest model of different downtimes.

Background Utilize quantitative computed tomography (QCT) to detect and evaluate the severity of lung injury after successful cardiopulmonary resuscitation (CPR) in a porcine cardiac arrest (CA) model with different downtimes. Methods Twenty-one male domestic pigs weighing 38±3 kg were randomized into 3 groups: the sham group (n=5), the ventricular fibrillation (VF) 5 min (VF5) group (n=8), and the VF 10 min (VF10) group (n=8). VF was induced and untreated for 5 (VF5 group) or 10 (VF10 group) min before the commencement of manual CPR. Eight animals (8/8, 100%) in VF5 and 6 (6/8, 75%) in VF10 were successfully resuscitated. Chest QCT scans and arterial blood gas tests were performed at baseline and 6 h post-resuscitation. The QCT score, volume, and weight of ground-glass opacification (GGO), which was defined as poorly aerated regions with a CT value ranging from -500 Hounsfield units (HU) to -100 HU, and intense parenchymal opacification (IPO), which was defined as a non-aerated area with a CT value greater than -100 HU, were quantitatively measured. Results Significantly shorter durations of CPR and fewer defibrillations were observed in the VF5 group compared with the VF10 group [duration of CPR: VF5 (6±0 minutes) versus VF10 (8.3±1.5 minutes), P<0.05; numbers of defibrillation: VF5 (1±0) versus VF10 (2.2±0.8), P<0.05]. Compared with the baseline or sham animals, declining gas exchanges (end-tidal CO2, PO2, oxygen index) were observed in both VF groups; however, there were no significant differences in gas exchanges between the VF groups. Compared with the VF5 group, the GGO QCT score, volume, and weight were significantly greater in the VF10 group (P=0.002, 0.001, and 0.002 respectively), while no significant differences were found in the IPO QCT score, volume, or weight between two the VF groups (P=0.354, 0.447, and 0.512 respectively). Conclusions QCT analysis enables unique non-invasive assessments of different lung injuries (IPO and GGO lesions) that can clearly distinguish heterogeneous lesions and allow for early detection and quantitative monitoring of the severity of lung injury following CPR. QCT could provide a basis for clinical early ventilation strategy management after CPR.
MicroRNA-149* suppresses hepatic inflammatory response through antagonizing STAT3 signaling pathway

Chronic inflammation is increasingly recognized as an important component of tumorigenesis and metabolic diseases. The roles of microRNA149* (miRNA149*) in inflammation remain poorly understood. Here, we demonstrate that miR-149* is a suppressor of STAT3-mediated inflammation. MiR-149*−/− mice were generated with CRISPR/CAS9 technique. In a lipopolysaccharide (LPS)-induced inflammation model, miR-149*−/− mice show more severe liver injury and inflammation, compared with wild-type (WT) mice. MiR-149*−/− mice also displayed elevated messenger RNA (mRNA) levels of interleukin (IL)-6, inducible nitric oxide synthase (iNOS), complement C3 (C3) and IL-4 in response to LPS. Then miR-149* agomir administration is largely able to alleviate the LPS-induced some inflammatory gene expression in WT mouse liver. In vitro, miR-149* mimics inhibited expression of STAT3-meidated inflammatory mediators induced by LPS and suppresses the phosphorylation of STAT3 and its transcription activity in HepG2 cells. These findings identify miR-149* as a negative mediator of inflammation that may serve as an attractive therapeutic tool for immune and inflammatory liver diseases.
Comparison of Legionella pneumophila, L. micdadei, L. bozemanii, and L. dumoffii by transmission electron microscopy

Clinical isolates of Legionella pneumophila, L. micdadei, L. bozemanii, and L. dumoffii were grown on charcoal-yeast extract agar from a living-medium inoculum and prepared for transmission electron microscopy by three different methods. Cells of all four Legionella species possessed cytoplasmic vacuoles, a gram-negative type of cell envelope with a dense peptidoglycan-like layer, a ruthenium red-positive polysaccharide capsule, and a single subpolar flagellum. The dense polysaccharide capsule seen on cells of L. micdadei was separated from the outer membrane by an extra layer of electron-lucent material that was not present on cells of the other species examined.
Design and formulation of functional pluripotent stem cell-derived cardiac microtissues

Significance Robust and predictive in vitro models of human cardiac tissue function could have transformative impact on our ability to test new drugs and understand cardiac disease. Despite significant effort, the generation of high-fidelity adult-like human cardiac tissue analogs remains challenging. In this paper, we systematically explore the design criteria for pluripotent stem cell-derived engineered cardiac tissue. Parameters such as biomechanical stress during tissue remodeling, input-cell composition, electrical stimulation, and tissue geometry are evaluated. Our results suggest that a specified combination of a 3D matrix-based microenvironment, uniaxial mechanical stress, and mixtures of cardiomyocytes and fibroblasts improves the performance and maturation state of in vitro engineered cardiac tissue. Access to robust and information-rich human cardiac tissue models would accelerate drug-based strategies for treating heart disease. Despite significant effort, the generation of high-fidelity adult-like human cardiac tissue analogs remains challenging. We used computational modeling of tissue contraction and assembly mechanics in conjunction with microfabricated constraints to guide the design of aligned and functional 3D human pluripotent stem cell (hPSC)-derived cardiac microtissues that we term cardiac microwires (CMWs). Miniaturization of the platform circumvented the need for tissue vascularization and enabled higher-throughput image-based analysis of CMW drug responsiveness. CMW tissue properties could be tuned using electromechanical stimuli and cell composition. Specifically, controlling self-assembly of 3D tissues in aligned collagen, and pacing with point stimulation electrodes, were found to promote cardiac maturation-associated gene expression and in vivo-like electrical signal propagation. Furthermore, screening a range of hPSC-derived cardiac cell ratios identified that 75% NKX2 Homeobox 5 (NKX2-5)+ cardiomyocytes and 25% Cluster of Differentiation 90 OR (CD90)+ nonmyocytes optimized tissue remodeling dynamics and yielded enhanced structural and functional properties. Finally, we demonstrate the utility of the optimized platform in a tachycardic model of arrhythmogenesis, an aspect of cardiac electrophysiology not previously recapitulated in 3D in vitro hPSC-derived cardiac microtissue models. The design criteria identified with our CMW platform should accelerate the development of predictive in vitro assays of human heart tissue function.
MMP14 empowers tumor‐initiating breast cancer cells under hypoxic nutrient‐depleted conditions

Tumor‐initiating cells (TICs) existing in breast cancer are thought to be involved in initiation, progression, and relapse of tumors. In these processes, the epithelial‐to‐mesenchymal transition (EMT) and proteases are crucial factors that also dependent on the tumor milieu, including hypoxic nutrient‐deprived, as well as normoxic nutrient‐rich, environments. Therefore, we investigated EMT and proteases in TICs and their response to different environments by means of a newly generated immortalized TIC (iTIC) line. With the use of primary CD24+CD90+CD45− TICs from the mouse mammary tumor virus‐polyoma middle T mouse breast cancer model, iTICs were generated by single cell‐initiated sphere and subsequent 2‐dimensional monolayer culture. Our data demonstrate the possibility to generate iTICs that are highly tumorigenic in culture and in mouse mammary fat pad. Contrasting environmental conditions provide these cells with a phenotypic and molecular plasticity that has a growth‐promoting character in nutrient‐rich normoxia and a motile character in nutrient‐deprived hypoxia. Expression profiling revealed partial and dynamically changing EMT states, as well as a significantly up‐regulated proteolytic signature, including many metalloproteinases, such as matrix metalloproteinase 14 (Mmp14). Inhibitor treatment of metalloproteinases, as well as short hairpin RNA‐mediated knockdown of Mmp14 strongly impacted TIC characteristics, including tumor initiation, cell growth, migration, and invasion, especially in starved environments. We conclude that metalloproteinases empower TICs to adapt to changing environments. —Hillebrand, L. E. , Wickberg, S. M. , Gomez‐Auli, A. , Folio, M. , Maurer, J., Busch, H. , Boerries, M. , Reinheckel, T. MMP14 empowers tumor‐initiating breast cancer cells under hypoxic nutrient‐depleted conditions. FASEB J. 33, 4124–4140 (2019). www.fasebj. org
Drug–drug interaction between levetiracetam and non-vitamin K antagonist anticoagulants

In the updated guide on NOAC use in patients with non-valvular atrial fibrillation, the European Heart Rhythm Association recommends against the use of the antiepileptic drug, levetiracetam, due to potential P-glycoprotein-mediated drug–drug interaction (DDI). While the summary of product characteristics of apixaban, and edoxaban list phenytoin, carbamazepine, and phenobarbital, and dabigatran’s lists phenytoin and carbamazepine, none lists levetiracetam as a P-gp inducer. In a Phase I trial, healthy volunteers received concomitant levetiracetam and digoxin, a P-gp substrate. Administration of a P-gp inducer with digoxin would be expected to decrease digoxin plasma concentrations; however, repeated levetiracetam exposure had no effect on digoxin steady-state pharmacokinetics. Absence of effect on digoxin pharmacodynamics, as measured by ECG parameters, supports this lack of interaction. Pgp and CYP450 enzyme expression induction by xenobiotics is primarily mediated by the pregnane X receptor (PXR). Since levetiracetam does not induce CYP450 enzyme expression, as supported by clinical data, it is unlikely to activate PXR, and therefore, induce P-gp expression. Finally, levetiracetam has no effect on the expression, or function of the products of the ABC transporter genes, ABCB1 (coding for P-gp), ABCC1, ABCC2, and ABCG2, in human cell lines. Importantly, P-gp function is species-specific; levetiracetam is a substrate of mouse, but not of rat or human P-gp. Data obtained in nonhuman models may not be relevant to humans. The recommendation appears to be solely based on results from in vivo animal models. However, clinical data, which supersede animal model data, demonstrate that levetiracetam is not a P-gp inducer. Evidence presented here support the absence of any clinically relevant DDI between levetiracetam and NOACs. The recommendation could potentially constitute a serious safety risk for patients treated concomitantly with levetiracetam and a NOAC, if levetiracetam is substituted.
Imaging in evaluation of response to neoadjuvant breast cancer treatment benefits of MRI.

PURPOSE To compare the value of conventional imaging modalities and MRI for determination of response to neoadjuvant chemotherapy for breast cancer. MATERIAL AND METHODS Sixty tumors (53 ductal carcinomas, seven invasive lobular carcinomas) in 51 patients were evaluated by physical examination, mammography, ultrasound, and MRI at baseline before therapy, after three courses of chemotherapy, and after six courses prior to surgery. Data from physical examination and imaging studies were compared to histopathological findings. RESULTS (i) MRI was the most reliable technique for evaluation of residual tumor size; this parameter was correctly estimated in 63% of cases by MRI versus, respectively 52, 38, and 43% by physical examination, mammography, and ultrasound, (ii) MRI correctly identified the response to chemotherapy in all cases of complete response (five cases), and in 45/55 cases of partial response (43 cases) or no response (12 cases), and (iii) among the 32 patients who underwent a mastectomy, MRI correctly revealed the multifocal nature of the disease for 12/15 multifocal lesions found at histological examination; both mammography and sonography were accurate in only six of the 15 cases. CONCLUSION MRI appears to be a valuable technique for assessment of response to chemotherapy and identification of multifocal disease prior to surgery.