Miracle-dz/UniFAR-FTUs huggingface dataset:
Ibrutinib for mantle cell lymphoma at first relapse: a United Kingdom real‐world analysis of outcomes in 211 patients

Ibrutinib is an established treatment for relapsed/refractory (R/R) mantle cell lymphoma (MCL) and clinical trial data supports use at second line compared to later relapse. We aimed to investigate outcomes and tolerability for ibrutinib when given second line in a real‐world setting. Our multicentre retrospective analysis included 211 R/R MCL patients, median age 73 years, receiving ibrutinib second‐line within the United Kingdom’s National Health Service. Overall response to ibrutinib was 69% (complete response 27%). The median progression‐free survival (PFS) was 17·8 months (95% CI 13·1–22·2) and median overall survival (OS) 23·9 months (95% CI 15·0–32·8). Drug‐related adverse event led to dose reduction in 10% of patients and discontinuation in 5%. In patients with progressive disease, accounting for 100 of 152 patients stopping ibrutinib, 43% received further systemic therapy. Post‐ibrutinib rituximab, bendamustine and cytarabine (R‐BAC) showed a trend toward improved survival compared to alternative systemic treatments (post‐ibrutinib median OS 14·0 months, 95% CI 8·1–19·8, vs. 3·6 months, 95% CI 2·6–4·5, P = 0·06). Our study confirms the clinical benefit and good tolerability of ibrutinib at first relapse in a real‐world population. Patients progressing on ibrutinib had limited survival but outcomes with R‐BAC in select patients were promising.
Independent component analysis based gene co-expression network inference (ICAnet) to decipher functional modules for better single-cell clustering and batch integration

Abstract With the tremendous increase of publicly available single-cell RNA-sequencing (scRNA-seq) datasets, bioinformatics methods based on gene co-expression network are becoming efficient tools for analyzing scRNA-seq data, improving cell type prediction accuracy and in turn facilitating biological discovery. However, the current methods are mainly based on overall co-expression correlation and overlook co-expression that exists in only a subset of cells, thus fail to discover certain rare cell types and sensitive to batch effect. Here, we developed independent component analysis-based gene co-expression network inference (ICAnet) that decomposed scRNA-seq data into a series of independent gene expression components and inferred co-expression modules, which improved cell clustering and rare cell-type discovery. ICAnet showed efficient performance for cell clustering and batch integration using scRNA-seq datasets spanning multiple cells/tissues/donors/library types. It works stably on datasets produced by different library construction strategies and with different sequencing depths and cell numbers. We demonstrated the capability of ICAnet to discover rare cell types in multiple independent scRNA-seq datasets from different sources. Importantly, the identified modules activated in acute myeloid leukemia scRNA-seq datasets have the potential to serve as new diagnostic markers. Thus, ICAnet is a competitive tool for cell clustering and biological interpretations of single-cell RNA-seq data analysis.
Divided attention at encoding or retrieval interferes with emotionally enhanced memory for words

ABSTRACT Emotional information is typically better remembered than neutral information. We asked whether emotional, compared to neutral, words were less vulnerable to the detrimental effects of divided attention. In two experiments, undergraduate students intentionally encoded words of intermixed valence (neutral, negative, or positive) and arousal (neutral, high, or low). Following a filled delay, memory was assessed with a free recall test. In Experiment 1, participants encoded visually-presented words under either full attention (FA; no distracting task) or divided attention (DA; concurrently making animacy decisions to auditorily-presented distractor words) in a counterbalanced, within-subjects design. As expected following FA at encoding, recall was significantly enhanced for negative compared to neutral words. Following DA at encoding, recall was significantly impaired across all valences. Critically, DA at encoding also eliminated the memory benefit for negative information: recall of negative words was no longer significantly different from neutral or positive words. In Experiment 2, we manipulated attention at retrieval rather than encoding. Remarkably, results from Experiment 1 were replicated: DA eliminated the well-known emotionality boost for negative words. In both experiments, memory for positive words did not significantly differ from neutral. Findings suggest that DA during either encoding or retrieval can interfere with the specific mechanisms by which negative emotion typically improves memory.
Melanocortin 5 Receptor Expression and Recovery of Ocular Immune Privilege after Uveitis

ABSTRACT Purpose The therapeutic use of the RPE-neuropeptide α-MSH suppresses experimental autoimmune uveitis (EAU). This suppression is partially through the α-MSH melanocortin 5 receptor (MC5r). Therefore, we examined the possible role of MC5r-expression in the recovery of RPE suppression of phagolysosome-activation in macrophages following α-MSH-treatment of EAU Methods The conditioned media of cultured in situ RPE-eyecup from α-MSH-treated EAU wild-type and MC5r(-/-) mice were used to treat macrophages to assay for phagolysosome activation. Results MC5r(-/-) mice treated with α-MSH recovered from EAU, but with greater retinal damage, and the RPE suppressed phagolysosome activation in wild type but not in MC5r(-/-) macrophages. In addition, α-MSH did not suppress phagolysosome activation in MC5r(-/-) macrophages, and resting-MC5r(-/-) macrophages had augmented phagocytic activity. Conclusion α-MSH treatment of EAU mediates a MC5r-dependent recovery of RPE suppression of phagolysosome activation in macrophages possibly altering antigen processing and presentation. Also, MC5r-expression helps protect the retina from inflammatory damage. In addition, MC5r-expression is important in the homeostatic maintenance of phagosome-maturation within macrophages.
A TNFR2–hnRNPK Axis Promotes Primary Liver Cancer Development via Activation of YAP Signaling in Hepatic Progenitor Cells

This work defines how hnRNPK links TNFα signaling and Hippo pathway transcription coactivator YAP in hepatic progenitor cells during primary liver tumorigenesis. Most primary liver cancer (PLC) cases progress mainly due to underlying chronic liver inflammation, yet the underlying mechanisms of inflammation-mediated PLC remain unclear. Here we uncover a TNF receptor II (TNFR2)–hnRNPK–YAP signaling axis in hepatic progenitor cells (HPC) essential for PLC development. TNFR2, but not TNF receptor I (TNFR1), was required for TNFα-induced activation of YAP during malignant transformation of HPCs and liver tumorigenesis. Mechanistically, heterogeneous nuclear ribonuclear protein K (hnRNPK) acted downstream of TNFα–TNFR2 signaling to directly interact with and stabilize YAP on target gene promoters genome-wide, therefore coregulating the expression of YAP target genes. Single-cell RNA sequencing confirmed the association of TNFR2–hnRNPK with YAP expression and the pathologic importance of HPC. Accordingly, expressions of TNFR2, hnRNPK, and YAP were all upregulated in PLC tissues and were strongly associated with poor prognosis of PLC including patient survival. Collectively, this study clarifies the differential roles of TNFRs in HPC-mediated tumorigenesis, uncovering a TNFR2–hnRNPK–centered mechanistic link between the TNFα-mediated inflammatory milieu and YAP activation in HPCs during PLC development. Significance: This work defines how hnRNPK links TNFα signaling and Hippo pathway transcription coactivator YAP in hepatic progenitor cells during primary liver tumorigenesis.
Diagnosis and Treatment of Multiple Sclerosis: A Review.

Importance Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disease of the central nervous system characterized by inflammatory demyelination with axonal transection. MS affects an estimated 900 000 people in the US. MS typically presents in young adults (mean age of onset, 20-30 years) and can lead to physical disability, cognitive impairment, and decreased quality of life. This review summarizes current evidence regarding diagnosis and treatment of MS. Observations MS typically presents in young adults aged 20 to 30 years with unilateral optic neuritis, partial myelitis, sensory disturbances, or brainstem syndromes such as internuclear ophthalmoplegia developing over several days. The prevalence of MS worldwide ranges from 5 to 300 per 100 000 people and increases at higher latitudes. Overall life expectancy is less than in the general population (75.9 vs 83.4 years), and MS more commonly affects women (female to male sex distribution of nearly 3:1). Diagnosis is made based on a combination of signs and symptoms, radiographic findings (eg, magnetic resonance imaging [MRI] T2 lesions), and laboratory findings (eg, cerebrospinal fluid-specific oligoclonal bands), which are components of the 2017 McDonald Criteria. Nine classes of disease-modifying therapies (DMTs), with varying mechanisms of action and routes of administration, are available for relapsing-remitting MS, defined as relapses at onset with stable neurologic disability between episodes, and secondary progressive MS with activity, defined as steadily increasing neurologic disability following a relapsing course with evidence of ongoing inflammatory activity. These drugs include interferons, glatiramer acetate, teriflunomide, sphingosine 1-phosphate receptor modulators, fumarates, cladribine, and 3 types of monoclonal antibodies. One additional DMT, ocrelizumab, is approved for primary progressive MS. These DMTs reduce clinical relapses and MRI lesions (new T2 lesions, gadolinium-enhancing lesions). Efficacy rates of current DMTs, defined by reduction in annualized relapse rates compared with placebo or active comparators, range from 29%-68%. Adverse effects include infections, bradycardia, heart blocks, macular edema, infusion reactions, injection-site reactions, and secondary autoimmune adverse effects, such as autoimmune thyroid disease. Conclusions and Relevance MS is characterized by physical disability, cognitive impairment, and other symptoms that affect quality of life. Treatment with DMT can reduce the annual relapse rate by 29% to 68% compared with placebo or active comparator.
Long-term exercise effects after cardiac telerehabilitation in patients with coronary artery disease: 1-year follow-up results of the randomized study.

BACKGROUND Home-based cardiac telerehabilitation (HBCT) is a feasible and effective alternative to traditional center-based cardiac rehabilitation (CBCR). Currently, there are only limited studies focusing on a long-term effect of HBCT, which means it is essential to do more research in this study field. AIM This study aimed at investigating a 1-year effect of a randomized controlled study using Cardiac Rehabilitation through the Global Position System (CR-GPS) compared to outpatient cardiac rehabilitation. Study focused on cardiorespiratory fitness (CRF) and health-related quality of life (HRQL) in patients with coronary heart disease (CAD). DESIGN A long-term follow-up of a randomized study. SETTING Patients were enrolled, and the intervention was performed in an outpatient or homebased model. The results were obtained and evaluated in a hospital. POPULATION Patients who participated in the CR-GPS study were diagnosed with CAD with low to moderate cardiovascular risk. METHODS Patients enrolled in the study were eligible participants who had previously completed a 12-week HBCT program using a wrist heart rate (HR) monitor or attended a traditional CBCR. Primary outcome was the change in CRF expressed in peak oxygen uptake (pVO2), and the secondary outcomes were self-reported HRQL, objectively measured anthropometric characteristics, and mortality and hospitalization rates. RESULTS 44 patients (76%) completed the long-term follow-up. The average peak of pVO2 was higher after 1-year follow-up in the telerehabilitation group (HBCT 25.5 ml / kg / min compared to the active control group CBCR 23.6 ml / kg / min p = 0.047). No statistically significant difference between the two groups was found after long-term follow-up for the parameter HRQL. For both groups, there was a significant improvement in the range of perceptions of general health. There was no death case and no difference in hospitalization rate between the groups. CONCLUSIONS This study supports the HBCT model. It has been demonstrated that it induces satisfactory long-term effects in pVO2, exercise performance, and perceived general health in CAD patients with low to moderate cardiovascular risk. CLINICAL REHABILITATION IMPACT Cardiovascular telerehabilitation using wrist HR monitors is a feasible and effective rehabilitation method that can help patients eliminate barriers that prevent them from using CBCR programs. Especially in the current global situation with the COVID-19 pandemic, this topic is becoming increasingly important.
The human tRNA taurine modification enzyme GTPBP3 is an active GTPase linked to mitochondrial diseases

Abstract GTPBP3 and MTO1 cooperatively catalyze 5-taurinomethyluridine (τm5U) biosynthesis at the 34th wobble position of mitochondrial tRNAs. Mutations in tRNAs, GTPBP3 or MTO1, causing τm5U hypomodification, lead to various diseases. However, efficient in vitro reconstitution and mechanistic study of τm5U modification have been challenging, in part due to the lack of pure and active enzymes. A previous study reported that purified human GTPBP3 (hGTPBP3) is inactive in GTP hydrolysis. Here, we identified the mature form of hGTPBP3 and showed that hGTPBP3 is an active GTPase in vitro that is critical for tRNA modification in vivo. Unexpectedly, the isolated G domain and a mutant with the N-terminal domain truncated catalyzed GTP hydrolysis to only a limited extent, exhibiting high Km values compared with that of the mature enzyme. We further described several important pathogenic mutations of hGTPBP3, associated with alterations in hGTPBP3 localization, structure and/or function in vitro and in vivo. Moreover, we discovered a novel cytoplasm-localized isoform of hGTPBP3, indicating an unknown potential noncanonical function of hGTPBP3. Together, our findings established, for the first time, the GTP hydrolysis mechanism of hGTPBP3 and laid a solid foundation for clarifying the τm5U modification mechanism and etiology of τm5U deficiency-related diseases.
Trends of pulmonary fungal infections from 2013 to 2019: an AI-based real-world observational study in Guangzhou, China

ABSTRACT Recently, the prevalence trend of pulmonary fungal infection (PFI) has rapidly increased. Changes in the risk factors for, distributions of underlying diseases associated with and clinical characteristics of some individual PFIs have been reported in the past decade. However, data regarding PFIs remain uncertain. This study reports the epidemiological characteristics and trends of PFIs over time in recent years. We applied an automated natural language processing (NLP) system to extract clinically relevant information from the electronic health records (EHRs) of PFI patients at the First Affiliated Hospital of Guangzhou Medical University. Then, a trend analysis was performed. From January 1, 2013, to December 31, 2019, 40,504 inpatients and 219,414 outpatients with respiratory diseases were screened, in which 1368 inpatients and 1313 outpatients with PFI were identified. These patients were from throughout the country, but most patients were from southern China. Upward trends in PFIs were observed in both hospitalized patients and outpatients (P<0.05). The stratification by age showed that the incidence of hospitalized patients aged 14–30 years exhibited the most obvious upward trend, increasing from 9.5 per 1000 patients in 2013 to 88.3 per 1000 patients in 2019. Aspergillosis (56.69%) was the most common PFI, but notably, the incidence rates of Talaromyces marneffei, which used to be considered uncommon, exhibited the most rapid increases. In younger PFI patients, the incidence and trend of PFIs have increased. Infection by previously uncommon pathogens has also gradually increased. Increased attention should be paid to young PFI patients and uncommon PFI pathogen infections.
Developmental Anatomy of the Eustachian Tube: Implications for Balloon Dilation

Objective To describe the developmental anatomy of the eustachian tube (ET) and its relationship to surrounding structures on computed tomography. Study Design Case series with chart review. Setting A tertiary care hospital. Methods ET anatomy was assessed with reformatted high-resolution computed tomography scans from 2010 to 2018. Scans (n = 78) were randomly selected from the following age groups: <4, 5 to 7, 8 to 18, and >18 years. The following were measured and compared between groups: ET length, angles, and relationship between its bony cartilaginous junction and the internal carotid artery and between its nasopharyngeal opening and the nasal floor. Results The distance between the bony cartilaginous junction and internal carotid artery decreased with age between the <4-year-olds (2.4 ± 0.6 mm) and the 5- to 7-year-olds (2.0 ± 0.3 mm, P = .001). The ET length increased among the <4-year-olds (32 mm), 5- to 7-year-olds (36 mm), and 8- to 18-year-olds (41 mm, P < .0001). The cartilaginous ET increased among the <4-year-olds (20 mm), 5- to 7-year-olds (25 mm), and 8- to 18-year-olds (28 mm, P < .0001). The ET horizontal angle increased among the <4-year-olds (17°), 5- to 7-year-olds (21°), and 8- to 18-year-olds (23°, P≤ .003), but the ET sagittal angle did not statistically change after 5 years of age. The height difference between the nasopharyngeal opening of the ET and the nasal floor increased among the <4-year-olds (4 mm), 5- to 7-year-olds (7 mm), and 8- to 18-year-olds (11 mm, P < .0001). Conclusion The ET elongates with age, and its angles and relationship to the nasal floor increase. Although some parameters mature faster, more than half of the ET growth occurs by 8 years of age, and adult morphology is achieved by early adolescence.
Unfolded and intermediate states of PrP play a key role in the mechanism of action of an antiprion chaperone

Significance Many diseases involve the propagation of misfolded proteins as in prion diseases. Compounds that can inhibit conversion into misfolded conformers exist, but their mechanism of action remains poorly understood. By observing the effects of the polymeric antiprion pharmacological chaperone pentosan polysulfate on the folding of single prion protein molecules, we find that interactions with partially and fully unfolded states play an important role. A comparison to previous results for a chaperone with very different chemical properties suggests that antiprion agents help to prevent conversion by interacting with the protein when it unfolds from the native structure during the conversion process. Unfolded states may, therefore, be fruitful targets for developing more effective therapeutic inhibitors of prion and prion-like conversion. Prion and prion-like diseases involve the propagation of misfolded protein conformers. Small-molecule pharmacological chaperones can inhibit propagated misfolding, but how they interact with disease-related proteins to prevent misfolding is often unclear. We investigated how pentosan polysulfate (PPS), a polyanion with antiprion activity in vitro and in vivo, interacts with mammalian prion protein (PrP) to alter its folding. Calorimetry showed that PPS binds two sites on natively folded PrP, but one PPS molecule can bind multiple PrP molecules. Force spectroscopy measurements of single PrP molecules showed PPS stabilizes not only the native fold of PrP but also many different partially folded intermediates that are not observed in the absence of PPS. PPS also bound tightly to unfolded segments of PrP, delaying refolding. These observations imply that PPS can act through multiple possible modes, inhibiting misfolding not only by stabilizing the native fold or sequestering natively folded PrP into aggregates, as proposed previously, but also by binding to partially or fully unfolded states that play key roles in mediating misfolding. These results underline the likely importance of unfolded states as critical intermediates on the prion conversion pathway.
Measuring attitudes of those caring for people living with dementia: A quantitative survey

Background: The prevalence of dementia is increasing with more healthcare workers being required to care for people living with this progressive neurological disorder. The knowledge level and attitude of healthcare workers caring for those living with dementia need to be assessed and resources targeted effectively to ensure best quality care is provided. Healthcare workers for the purpose of this paper include anyone employed to care for those living with dementia. Aim: To investigate the attitudes of healthcare workers towards people living with dementia. Methods: A survey of 110 healthcare workers was undertaken between October 2016 and December 2017, using the Dementia Attitude Scale to measure attitudes towards people living with dementia. Demographic data were collected by a survey to explore whether a person’s age; cultural background; qualification level; or experience level had an impact on their attitude towards people living with dementia. Results: The full survey was completed by n = 85 healthcare workers with the majority having strongly positive views about people living with dementia, with an average score of 88.31/100. However, a large number reported being afraid of people living with dementia (n = 76, 89.4%) and would avoid people with dementia who were agitated (n = 51, 61.4%). While 100% (n = 85) agreed or strongly agreed that it was possible to enjoy interacting with people living with dementia, they were more ambivalent with n = 26 (31.6%) strongly agreeing with the statement that working with people living with dementia is rewarding. A significant difference in attitude was found using one-way analysis of variance within groups due to age (p < .000) and cultural background (p < .035). Conclusions: Healthcare workers within this study had mainly positive attitudes towards people with dementia as demonstrated by the high attitude scores. However, this paper has shown that healthcare workers may require further education to improve attitude and care towards those living with dementia.