Miracle-dz/UniFAR-FTUs huggingface dataset:
KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma.

BACKGROUND Patients with relapsed or refractory mantle-cell lymphoma who have disease progression during or after the receipt of Bruton's tyrosine kinase (BTK) inhibitor therapy have a poor prognosis. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, may have benefit in patients with relapsed or refractory mantle-cell lymphoma. METHODS In a multicenter, phase 2 trial, we evaluated KTE-X19 in patients with relapsed or refractory mantle-cell lymphoma. Patients had disease that had relapsed or was refractory after the receipt of up to five previous therapies; all patients had to have received BTK inhibitor therapy previously. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2×106 CAR T cells per kilogram of body weight. The primary end point was the percentage of patients with an objective response (complete or partial response) as assessed by an independent radiologic review committee according to the Lugano classification. Per the protocol, the primary efficacy analysis was to be conducted after 60 patients had been treated and followed for 7 months. RESULTS A total of 74 patients were enrolled. KTE-X19 was manufactured for 71 patients and administered to 68. The primary efficacy analysis showed that 93% (95% confidence interval [CI], 84 to 98) of the 60 patients in the primary efficacy analysis had an objective response; 67% (95% CI, 53 to 78) had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the patients) and infections (in 32%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively; none were fatal. Two grade 5 infectious adverse events occurred. CONCLUSIONS KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma. The therapy led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies. (Funded by Kite, a Gilead company; ZUMA-2 ClinicalTrials.gov number, NCT02601313.).
Purification and crystal structure of human ODA16: Implications for ciliary import of outer dynein arms by the intraflagellar transport machinery

Motile cilia protrude from cell surfaces and are necessary to create movement of cells and fluids in the body. At the molecular level, cilia contain several dynein molecular motor complexes including outer dynein arms (ODAs) that are attached periodically to the ciliary axoneme, where they hydrolyse ATP to create the force required for bending and motility of the cilium. ODAs are preassembled in the cytoplasm and subsequently trafficked into the cilium by the intraflagellar transport (IFT) system. In the case of the green alga Chlamydomonas reinhardtii, the adaptor protein ODA16 binds to ODAs and directly to the IFT complex component IFT46 to facilitate the ciliary import of ODAs. Here, we purified recombinant human IFT46 and ODA16, determined the high‐resolution crystal structure of the ODA16 protein, and carried out direct interaction studies of IFT46 and ODA16. The human ODA16 C‐terminal 320 residues adopt the fold of an eight‐bladed β‐propeller with high overall structural similarity to the Chlamydomonas ODA16. However, the small 80 residue N‐terminal domain, which in Chlamydomonas ODA16 is located on top of the β‐propeller and is required to form the binding cleft for IFT46, has no visible electron density in case of the human ODA16 structure. Furthermore, size exclusion chromatography and pull‐down experiments failed to detect a direct interaction between human ODA16 and IFT46. These data suggest that additional factors may be required for the ciliary import of ODAs in human cells with motile cilia.
Respiratory Severity Score with Regard to Birthweight during the Early Days of Life for Predicting Pulmonary Hypertension in Preterm Infants.

OBJECTIVE The respiratory severity score (RSS) has been demonstrated to be associated with the oxygenation index in intubated newborn infants. We aimed to evaluate the usefulness of RSS with regard to birthweight (BW) in preterm infants for predicting an association with future pulmonary hypertension (PH). METHODS Preterm infants with <30 weeks' gestation and <1250 g BW were reviewed and grouped into two (PH vs. no PH). Basic perinatal characteristics, comorbidities and parameters reflecting lung condition, including duration of invasive mechanical ventilator care, were compared. Respiratory support parameters (FiO2, RSS and RSS/kg) during the first 5 days of birth (0-120 h) were compared between the groups, and receiver operating characteristics curves were produced to evaluate the association with PH. RESULTS RSS/kg, of the three respiratory support parameters, demonstrated significantly higher values in the PH group in the early days of life. Particularly, RSS/kg at day 2 of life had the greatest area under the curve [0.762, 95% confidence interval (CI) 0.655-0.869, p < 0.001] and maintained statistical significance [odds ratio (OR) 1.352, 95% CI 1.055-1.732, p = 0.017] in the multivariable analysis for a potential association with PH, along with gestational age (OR 0.996, 95% CI 0.993-0.999, p = 0.015) and preterm premature rupture of membrane >18 h (OR 4.907, 95% CI 1.436-16.765, p = 0.011). CONCLUSION RSS/kg is a potential marker associated with the development of PH. Future studies could verify its usefulness as a reliable surrogate for predicting respiratory morbidity in clinical settings.
Advances in disease-modifying pharmacotherapies for the treatment of amyotrophic lateral sclerosis

ABSTRACT Introduction To date, riluzole and edaravone are the only two drugs that have successfully passed clinical trials for the treatment of Amyotrophic Lateral Sclerosis (ALS). Unfortunately, both drugs exhibit very modest effects. Most other drugs have failed at phase III to show significant effects in phase III when tested in larger cohorts. This pattern necessitates improvements in the approach to ALS pharmacotherapy. Areas covered The authors discuss the two approved drugs, as well as several examples of drug candidates whose clinical trials did not demonstrate efficacy in phase III. Post-hoc analyses reveal that future clinical trials should include disease-staging procedures, longer-term trials to correctly assess survival, genetic studies of participants to aid in stratification, and more similarity between the protocols on preclinical models and clinical trials. Finally, they discuss the trials in process that demonstrate some of these suggestions and improvements. Expert opinion The approval of riluzole and edaravone was essentially a desperate attempt to provide urgent pharmacotherapy to the ALS community. To evolve toward more efficient therapies, we must conduct clinical trials with optimal stratification based on rapid/slow progressors and cognitive decline. Pharmaco-metabolomics should allow for the identification of biomarkers that are adapted for a given drug.
Near visual acuity and patient-reported outcomes in presbyopic patients after bilateral multifocal aspheric LASIK excimer laser surgery.

PURPOSE To determine improvement of near visual acuity by bilateral multifocal aspheric LASIK treatments in presbyopic patients. SETTING Goethe-University, Frankfurt, Germany. DESIGN Prospective, non-randomized trial. METHODS Thirty presbyopic patients underwent laser in situ keratomileusis (LASIK) treatment with a multifocal aspheric ablation profile using an excimer laser (PresbyMAX). The first 15 patients received a multifocal aspheric ablation profile combined with micro-monovision. For the consecutive 15 patients, less depth of focus (DOF) was included on the distance eye (hybrid). OUTCOME PARAMETERS Uncorrected (UDVA) and corrected distance visual acuity (CDVA), uncorrected (UIVA) and distance-corrected intermediate visual acuity (DCIVA), and uncorrected (UNVA) and distance-corrected (DCNVA) near visual acuity; manifest refraction spherical equivalent (MRSE); subjective quality of vision; and spectacle independence RESULTS:: Binocular CDVA changed from -0.16±0.10 logarithm of the minimum angle of resolution (logMAR) preoperatively to 0.05±0.20 logMAR UDVA and -0.06±0.14 logMAR CDVA (p = 0.000, p = 0.001) 1 year postoperatively. Near visual acuity improved from 0.47±0.13 logMAR (DCNVA) and 0.48±0.26 logMAR (UNVA) to 0.19±0.19 logMAR (DCNVA, p<0.001) and 0.05±0.15 logMAR (UNVA, p<0.001). The hybrid- and the µ-monovision group did not differ statistically except for a better DCNVA in the µ-monovision patients (0.21±0.15 logMAR vs 0.34±0.17 logMAR, p=0.034). Of the hybrid- and µ-monovision patients, 21 (72%) and 12 (41%) had a binocular CDVA and UDVA of 20/20 or better, 8 (28%) patients lost 1 line of CDVA, 3 (10%) lost 2 lines, 4 (14%) lost 3, and 2 (7%) lost 4 lines of CDVA. CONCLUSIONS The PresbyMAX laser seemed to satisfy most of the patients even though they experienced a loss of CDVA. The gain of near visual acuity and therefore reported less need of spectacles appeared to compensate for this loss.
Analysis of the influencing factors of the unsafe driving behaviors of online car-hailing drivers in china

Online car-hailing drivers are a special group between professional drivers and private car drivers. The paper built the unsafe driving behavior model of online car-hailing drivers based on the theory of planned behavior (TPB), explored the socio-psychological factors underlying drivers’ motivation for unsafe driving behavior and examined how these factors predict their behaviors. 239 online car-hailing drivers were surveyed with a self-reported questionnaire. Factors analysis proved the TPB questionnaire to be valid and reliable. Structural equation modeling showed that attitude to behavior (0.18), subjective norm(0.39) significantly influenced drivers' behavioral intention, perceived behavioral control (0.27) could both affected drivers' behavioral intention (0.27) and behavior(0.21),behavioral intention was the most direct and important predictor of behavior. This study provided a valuable contribution to designing more effective interventions to improve driving safety of online car-hailing drivers.
LUF7244 plus Dofetilide Rescues Aberrant Kv11.1 Trafficking and Produces Functional IKv11.1

Voltage-gated potassium 11.1 (Kv11.1) channels play a critical role in repolarization of cardiomyocytes during the cardiac action potential (AP). Drug-mediated Kv11.1 blockade results in AP prolongation, which poses an increased risk of sudden cardiac death. Many drugs, like pentamidine, interfere with normal Kv11.1 forward trafficking and thus reduce functional Kv11.1 channel densities. Although class III antiarrhythmics, e.g., dofetilide, rescue congenital and acquired forward trafficking defects, this is of little use because of their simultaneous acute channel blocking effect. We aimed to test the ability of a combination of dofetilide plus LUF7244, a Kv11.1 allosteric modulator/activator, to rescue Kv11.1 trafficking and produce functional Kv11.1 current. LUF7244 treatment by itself did not disturb or rescue wild type (WT) or G601S-Kv11.1 trafficking, as shown by Western blot and immunofluorescence microcopy analysis. Pentamidine-decreased maturation of WT Kv11.1 levels was rescued by 10 μM dofetilide or 10 μM dofetilide + 5 μM LUF7244. In trafficking defective G601S-Kv11.1 cells, dofetilide (10 μM) or dofetilide + LUF7244 (10 + 5 μM) also restored Kv11.1 trafficking, as demonstrated by Western blot and immunofluorescence microscopy. LUF7244 (10 μM) increased IKv11.1 despite the presence of dofetilide (1 μM) in WT Kv11.1 cells. In G601S-expressing cells, long-term treatment (24–48 hour) with LUF7244 (10 μM) and dofetilide (1 μM) increased IKv11.1 compared with nontreated or acutely treated cells. We conclude that dofetilide plus LUF7244 rescues Kv11.1 trafficking and produces functional IKv11.1. Thus, combined administration of LUF7244 and an IKv11.1 trafficking corrector could serve as a new pharmacological therapy of both congenital and drug-induced Kv11.1 trafficking defects. SIGNIFICANCE STATEMENT Decreased levels of functional Kv11.1 potassium channel at the plasma membrane of cardiomyocytes prolongs action potential repolarization, which associates with cardiac arrhythmia. Defective forward trafficking of Kv11.1 channel protein is an important factor in acquired and congenital long QT syndrome. LUF7244 as a negative allosteric modulator/activator in combination with dofetilide corrected both congenital and acquired Kv11.1 trafficking defects, resulting in functional Kv11.1 current.
Long noncoding RNA SNHG14 promotes the aggressiveness of retinoblastoma by sponging microRNA-124 and thereby upregulating STAT3

A long noncoding RNA called small nucleolar RNA host gene 14 (SNHG14) has been validated as a key regulator of cellular processes in multiple types of human cancer. However, to the best of our knowledge, the expression status and specific roles of SNHG14 in retinoblastoma (RB) have not been studied. The aims of the present study were to determine the expression status of SNHG14 in RB, assess the effects of SNHG14 on malignant characteristics of RB cells and investigate the mechanisms of action of SNHG14 in RB. SNHG14 expression levels in RB tissue samples and cell lines were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell proliferation, apoptosis, migration and invasion in vitro, and tumor growth in vivo were quantitated by the Cell Counting Kit-8 assay, flow cytometry, migration and invasion assays, and mouse tumor xenograft experiments, respectively. The target microRNA (miRNA) of SNHG14 was predicted by bioinformatics analysis and was subsequently validated by a luciferase reporter assay, RNA immunoprecipitation (RIP) assay, RT-qPCR, and western blot analysis. SNHG14 was identified to be significantly overexpressed in RB tissues and cell lines. SNHG14 overexpression was markedly associated with the intraocular international retinoblastoma classification stage, optic nerve invasion, and differentiation grade among patients with RB. The patients in the SNHG14 high-expression group exhibited shorter overall survival compared with the SNHG14 low-expression group. Functional analysis revealed that SNHG14 silencing inhibited cell proliferation, migration and invasion, and increased apoptosis in vitro, and decreased tumor growth in vivo. SNHG14 directly interacted with, and functioned as a competing endogenous RNA (ceRNA) of, miR-124, consequently upregulating signal transducer and activator of transcription 3 (STAT3). miR-124 inhibition and STAT3 expression recovery attenuated the effects of the SNHG14 silencing on RB cells. In conclusion, SNHG14 served as a ceRNA to upregulate STAT3 by sponging miR-124. Therefore, targeting the SNHG14/miR-124/STAT3 pathway may be an effective therapeutic strategy against RB.
Development and initial psychometric assessment of the race-related attitudes and multiculturalism scale in Australia

Aim The present study aims to develop the Race-related Attitudes and Multiculturalism Scale (RRAMS), as well as to perform an initial psychometric assessment of this instrument in a national sample of Australian adults. Methods The sample comprised 2,714 Australian adults who took part in the 2013 National Dental Telephone Interview Survey (NDTIS), which includes a telephone-based interview and a follow-up postal questionnaire. We used Exploratory Factor Analysis (EFA) to evaluate the RRAMS’ factorial structure (n = 271) and then proceeded with Confirmatory Factor Analysis (CFA) to confirm the proposed structure in an independent sample (n = 2,443). Measurement invariance was evaluated according to sex, age and educational attainment. Construct validity was assessed through known-groups comparisons. Internal consistency was assessed with McDonald’s ΩH and ordinal α. Multiple imputation by chained equations was adopted to handle missing data. Results EFA indicated that, after excluding 4 out of the 12 items, a two-factor structure provided a good fit to the data. This configural structure was then confirmed in an independent sample by means of CFA (χ2(19) = 341.070, p<0.001, CFI = 0.974, RMSEA = 0.083; 90% CI [0.076, 0.091]). Measurement invariance analyses suggested that the RRAMS items can be used to compare men/women, respondents with/without tertiary education and young/older participants. The “Anglo-centric/Assimilationist attitudes” (ΩH = 0.83, αORDINAL = 0.85) and “Inclusive/Pluralistic attitudes” subscales (ΩH = 0.77, αORDINAL = 0.79) showed adequate reliability. Men and participants with low education had higher Anglo-centric/assimilationist attitudes and lower inclusive/pluralistic attitudes, suggesting construct validity. Conclusions The RRAMS appears to be a valid and reliable measure to evaluate multiculturalist attitudes in the Australian context. The instrument may be useful in the assessment and monitoring of interventions aiming to promote multiculturalist inclusive attitudes and to increase social cohesion in Australia.
Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction

Background: The pleomorphic clinical presentation makes the diagnosis of desminopathy difficult. We aimed to describe the prevalence, phenotypic expression, and mitochondrial function of individuals with putative disease-causing desmin (DES) variants identified in patients with an unexplained etiology of cardiomyopathy. Methods: A total of 327 Czech patients underwent whole exome sequencing and detailed phenotyping in probands harboring DES variants. Results: Rare, conserved, and possibly pathogenic DES variants were identified in six (1.8%) probands. Two DES variants previously classified as variants of uncertain significance (p.(K43E), p.(S57L)), one novel DES variant (p.(A210D)), and two known pathogenic DES variants (p.(R406W), p.(R454W)) were associated with characteristic desmin-immunoreactive aggregates in myocardial and/or skeletal biopsy samples. The individual with the novel DES variant p.(Q364H) had a decreased myocardial expression of desmin with absent desmin aggregates in myocardial/skeletal muscle biopsy and presented with familial left ventricular non-compaction cardiomyopathy (LVNC), a relatively novel phenotype associated with desminopathy. An assessment of the mitochondrial function in four probands heterozygous for a disease-causing DES variant confirmed a decreased metabolic capacity of mitochondrial respiratory chain complexes in myocardial/skeletal muscle specimens, which was in case of myocardial succinate respiration more profound than in other cardiomyopathies. Conclusions: The presence of desminopathy should also be considered in individuals with LVNC, and in the differential diagnosis of mitochondrial diseases.
A New Paroxetine-Based GRK2 Inhibitor Reduces Internalization of the μ-Opioid Receptor

G protein-coupled receptor (GPCR) kinases (GRKs) play a key role in terminating signals initiated by agonist-bound GPCRs. However, chronic stimulation of GPCRs, such as that which occurs during heart failure, leads to the overexpression of GRKs and maladaptive downregulation of GPCRs on the cell surface. We previously reported the discovery of potent and selective families of GRK inhibitors based on either the paroxetine or GSK180736A scaffold. A new inhibitor, CCG258747, which is based on paroxetine, demonstrates increased potency against the GRK2 subfamily and favorable pharmacokinetic parameters in mice. CCG258747 and the closely related compound CCG258208 also showed high selectivity for the GRK2 subfamily in a kinome panel of 104 kinases. We developed a cell-based assay to screen the ability of CCG258747 and 10 other inhibitors with different GRK subfamily selectivities and with either the paroxetine or GSK180736A scaffold to block internalization of the μ-opioid receptor (MOR). CCG258747 showed the best efficacy in blocking MOR internalization among the compounds tested. Furthermore, we show that compounds based on paroxetine had much better cell permeability than those based on GSK180736A, which explains why GSK180736A-based inhibitors, although being potent in vitro, do not always show efficacy in cell-based assays. This study validates the paroxetine scaffold as the most effective for GRK inhibition in living cells, confirming that GRK2 predominantly drives internalization of MOR in the cell lines we tested and underscores the utility of high-resolution cell-based assays for assessment of compound efficacy. SIGNIFICANCE STATEMENT G protein–coupled receptor kinases (GRKs) are attractive targets for developing therapeutics for heart failure. We have synthesized a new GRK2 subfamily–selective inhibitor, CCG258747, which has nanomolar potency against GRK2 and excellent selectivity over other kinases. A live-cell receptor internalization assay was used to test the ability of GRK2 inhibitors to impart efficacy on a GRK-dependent process in cells. Our data indicate that CCG258747 blocked the internalization of the μ-opioid receptor most efficaciously because it has the ability to cross cell membranes.
Two Synthetic 18-Way Outcrossed Populations of Diploid Budding Yeast with Utility for Complex Trait Dissection

Advanced-generation multiparent populations (MPPs) are a valuable tool for dissecting complex traits, having more power than genome-wide association studies to detect rare variants and higher resolution than F2 linkage mapping. To extend the advantages of MPPs in budding yeast, we describe the creation and characterization of two outbred MPPs derived from 18 genetically diverse founding strains. We carried out de novo assemblies of the genomes of the 18 founder strains, such that virtually all variation segregating between these strains is known, and represented those assemblies as Santa Cruz Genome Browser tracks. We discovered complex patterns of structural variation segregating among the founders, including a large deletion within the vacuolar ATPase VMA1, several different deletions within the osmosensor MSB2, a series of deletions and insertions at PRM7 and the adjacent BSC1, as well as copy number variation at the dehydrogenase ALD2. Resequenced haploid recombinant clones from the two MPPs have a median unrecombined block size of 66 kb, demonstrating that the population is highly recombined. We pool-sequenced the two MPPs to 3270× and 2226× coverage and demonstrated that we can accurately estimate local haplotype frequencies using pooled data. We further downsampled the pool-sequenced data to ∼20–40× and showed that local haplotype frequency estimates remained accurate, with median error rates 0.8 and 0.6% at 20× and 40×, respectively. Haplotypes frequencies are estimated much more accurately than SNP frequencies obtained directly from the same data. Deep sequencing of the two populations revealed that 10 or more founders are present at a detectable frequency for > 98% of the genome, validating the utility of this resource for the exploration of the role of standing variation in the architecture of complex traits.