Miracle-dz/UniFAR-FTUs huggingface dataset:
Combining selective inhibitors of nuclear export (SINEs) with chimeric antigen receptor (CAR) T cells for CD19-positive malignancies

Chimeric antigen receptor (CAR) T cells directed against CD19 (CD19.CAR T cells) have yielded impressive clinical responses in the treatment of patients with lymphoid malignancies. However, resistance and/or relapse can limit treatment outcome. Risk of tumor escape can be reduced by combining treatment strategies. Selective inhibitors of nuclear export (SINEs) directed against nuclear exportin-1 (XPO1) have demonstrated anti-tumor efficacy in several hematological malignancies. The aim of the present study was to evaluate the combination of CAR T cells with the SINE compounds eltanexor and selinexor. As expected, eltanexor and selinexor were toxic to CD19-positive malignant cells and the sensitivity of cells towards SINEs correlated with the levels of XPO1-expression in ALL cell lines. When SINEs and CAR T cells were simultaneously combined, SINEs exerted toxicity towards CAR T cells and impaired their function affecting cytotoxicity and cytokine release ability. Flow cytometry and western blot analysis revealed that eltanexor decreased the cytoplasmic concentration of the transcription factor phosphorylated-STAT3 in CAR T cells. Due to CAR T-cell toxicity, sequential use of SINEs and CAR T cells was evaluated: Cytotoxicity of CAR T cells increased significantly when target cells were pre-treated with the SINE compound eltanexor. In addition, exhaustion of CAR T cells decreased when target cells were pre-treated with eltanexor. In summary, whereas the concomitant use of SINEs and CAR T cells does not seem advisable, sequential use of SINEs and CAR T cells might improve the anti-tumor efficacy of CAR T cells.
Functional results of total-knee arthroplasty versus medial unicompartmental arthroplasty: two-year results of a randomised, assessor-blinded multicentre trial

Objective The primary objective of the trial was to assess the clinical effectiveness of medial unicompartmental knee arthroplasty versus total knee arthroplasty in patients with isolated medial osteoarthritis of the knee. Design Prospective, randomised, 2 years, assessor-blind, multicentre, superiority trial. Setting The patients were enrolled between December 2015 and May 2018 from the outpatient clinics of three public high-volume arthroplasty hospitals (Finland). Participants We recruited 143 patients with symptomatic-isolated medial osteoarthritis of the knee needing an arthroplasty procedure. All the patients were suitable for both unicompartmental and total knee arthroplasties. Population was selected as the end-stage-isolated medial osteoarthritis. Interventions All patients, randomized 1:1, received a medial unicompartmental arthroplasty or a total knee arthroplasty through a similar midline skin incision. Patients were blinded to the type of arthroplasty for the whole 2 years of follow-up. Main outcome measures Primary outcome measure was between-group differences in the Oxford Knee Score (OKS) and secondary outcome Knee injury and Osteoarthritis Score (KOOS) at 2 years postoperatively. The changes within and between the groups were analysed with analysis of variance for repeated measurements. Results The primary outcome was comparable for medial unicompartmental arthroplasty and total knee arthroplasty at 2 years. The mean difference in the OKS between the groups was 1.6 points (95% CI −0.7 to 3.9). In the KOOS subscales, the mean difference between the groups was 0.1 points (95% CI −4.8 to 5.0) for pain, 7.8 points (95% CI 1.5 to 14.0) for symptoms, 4.3 points (95% CI −0.6 to 9.2) for function in daily living, 4.3 points (95% CI −3.0 to 11.6) for function in sports, and 2.1 points (95% CI −4.8 to 9.1) for knee-related quality of life. Conclusions The recovery after unicompartmental knee arthroplasty was faster compared with total knee arthroplasty, but unicompartmental arthroplasty did not provide a better patient-reported outcome at 2 years. Trial registration number NCT02481427.
Unifying Phylogenetic Birth–Death Models in Epidemiology and Macroevolution

Abstract Birth–death stochastic processes are the foundations of many phylogenetic models and are widely used to make inferences about epidemiological and macroevolutionary dynamics. There are a large number of birth–death model variants that have been developed; these impose different assumptions about the temporal dynamics of the parameters and about the sampling process. As each of these variants was individually derived, it has been difficult to understand the relationships between them as well as their precise biological and mathematical assumptions. Without a common mathematical foundation, deriving new models is nontrivial. Here, we unify these models into a single framework, prove that many previously developed epidemiological and macroevolutionary models are all special cases of a more general model, and illustrate the connections between these variants. This unification includes both models where the process is the same for all lineages and those in which it varies across types. We also outline a straightforward procedure for deriving likelihood functions for arbitrarily complex birth–death(-sampling) models that will hopefully allow researchers to explore a wider array of scenarios than was previously possible. By rederiving existing single-type birth–death sampling models, we clarify and synthesize the range of explicit and implicit assumptions made by these models. [Birth–death processes; epidemiology; macroevolution; phylogenetics; statistical inference. ]
The liver X receptor agonist LXR 623 restricts flavivirus replication

ABSTRACT The vector-borne flaviviruses (VBFVs) are well known for causing great misery and death in humans worldwide. The VBFVs include those transmitted by mosquitos, such as Zika virus (ZIKV), dengue virus; and those transmitted by ticks including the tick-borne flavivirus serocomplex and Powassan virus (POWV). Two of our recent reports showed that intracranial POWV infection in the reservoir host, Peromyscus leucopus, was restricted and caused no overt clinical disease. Several modes of analyses suggested activation of the LXR pathway. Activation of the LXR pathway leads to increased efflux of cholesterol from cells and consequent disturbances in membrane biogenesis. Because VBFV replication is dependent on membrane biogenesis, we evaluated the effect of an LXR agonist (LXR623) on POWV and ZIKV infection and observed that the compound impaired permissive replication of both viruses in a human neuroblastoma SK-N-SH cell line. The LXR agonist resulted in failure of the viruses to induce ER expansion and elaborate vesicle formation, suggesting that the efflux of cholesterol was part of the antiviral mechanism. We also observed that the LXR agonist contributed to the mechanism of virus suppression by increased expression of mRNAs encoding for the antiviral cytokines CXCL10, RANTES and IFN1β. In sharp contrast, a LXR antagonist (GSK2033) had no significant effect on VBFV replication. We conclude that LXR623 impairs flavivirus replication by stimulating cellular antiviral factors.
Remediation of chromium- and fluoride-contaminated groundwater by immobilized Citrobacter sp. on a nano-ZrO2 hybrid material

To effectively address excessive SO42-, Cr(VI), total chromium and F- in the groundwater of acidic mining areas, a facultative anaerobic bacterium, Citrobacter, with sulfate-reducing properties, tolerance to hexavalent chromium and the ability to reduce Cr(VI) to Cr(III) was isolated and domesticated. Based on microbial immobilization technology, a nano-ZrO2 polyacrylamide hybrid material was prepared as an embedding agent to form nano-ZrO2 polyacrylamide Citrobacter (ZPC) particles. ZPC was microscopically characterized, and the removal performance and mechanism of ZPC for SO42-, Cr(VI), total chromium and F- in groundwater were analyzed. The results of single-factor tests showed that the optimal reaction conditions included a reaction temperature of 35°C, Citrobacter dosage of 35% (volume ratio) in the particles and hybrid material dosage of 300 mL; under these conditions, the removal rates of SO42-, Cr(VI), total chromium and F- were 70.5%, 100%, 100% and 93.3%, respectively, and the pH value increased from 4.6 to 8.07. On this basis, the effects of the reaction layer type, influent hydraulic load and influent concentration on the removal efficiency of polluted groundwater were studied through dynamic experiments. The experimental results showed that ZPC particles were better than Citrobacter as a reaction layer; the optimal influent hydraulic load was 3.0 m3/(m2·d); the selectivity of ZPC particles to anions and anionic groups was different; and the order of adsorption selectivity was F- > Cr(VI) > SO42-.
Nuclear IGF1R interacts with NuMA and regulates 53BP1-dependent DNA double-strand break repair in colorectal cancer

Nuclear insulin-like growth factor 1 receptor (nIGF1R) has been associated with poor overall survival and chemotherapy resistance in various types of cancer; however, the underlying mechanism remains unclear. In the present study, immunoprecipitation-coupled mass spectrometry was performed in an IGF1R-overexpressing SW480-OE colorectal cancer cell line to identify the nIGF1R interactome. Network analysis revealed 197 proteins of interest which were involved in several biological pathways, including RNA processing, DNA double-strand break (DSB) repair and SUMOylation pathways. Nuclear mitotic apparatus protein (NuMA) was identified as one of nIGF1R's colocalizing partners. Proximity ligation assay (PLA) revealed different levels of p53-binding protein 1 (53BP1)-NuMA colocalization between IGF1R-positive (R+) and IGF1R-negative (R−) mouse embryonic fibroblasts following exposure to ionizing radiation (IR). 53BP1 was retained by NuMA in the R− cells during IR-induced DNA damage. By contrast, the level of NuMA-53BP1 was markedly lower in R+ cells compared with R− cells. The present data suggested a regulatory role of nIGF1R in 53BP1-dependent DSB repair through its interaction with NuMA. Bright-field PLA analysis on a paraffin-embedded tissue microarray from patients with colorectal cancer revealed a significant association between increased nuclear colocalizing signals of NuMA-53BP1 and a shorter overall survival. These results indicate that nIGF1R plays a role in facilitating 53BP1-dependent DDR by regulating the NuMA-53BP1 interaction, which in turn might affect the clinical outcome of patients with colorectal cancer.
Dehydrocrenatidine extracted from Picrasma quassioides induces the apoptosis of nasopharyngeal carcinoma cells through the JNK and ERK signaling pathways

Nasopharyngeal carcinoma (NPC) is an indicator disease in Asia due to its unique geographical and ethnic distribution. Dehydrocrenatidine (DC) is a β-carboline alkaloid abundantly present in Picrasma quassioides (D. Don) Benn, a deciduous shrub or small tree native to temperate regions of southern Asia, and β-carboline alkaloids play anti-inflammatory and antiproliferative roles in various cancers. However, the mechanism and function of DC in human NPC cells remain only partially explored. The present study aimed to examine the cytotoxicity and biochemical role of DC in human NPC cells. The MTT method, cell cycle analysis, DAPI determination, Annexin V/PI double staining, and mitochondrial membrane potential examination were performed to evaluate the effects of DC treatment on human NPC cell lines. In addition, western blotting analysis was used to explore the effect of DC on apoptosis and signaling pathways in related proteins. The analysis results confirmed that DC significantly reduced the viability of NPC cell lines in a dose- and time-dependent manner and induced apoptosis through internal and external apoptotic pathways (including cell cycle arrest, altered mitochondrial membrane potential, and activated death receptors). Western blot analysis illustrated that DC's effect on related proteins in the mitogen-activated protein kinase pathway can induce apoptosis by enhancing ERK phosphorylation and inhibiting Janus kinase (JNK) phosphorylation. Notably, DC induced apoptosis by affecting the phosphorylation of JNK and ERK, and DC and inhibitors (SP600125 and U0126) in combination restored the overexpression of p-JNK and p-ERK. To date, this is the first study to confirm the apoptosis pathway induced by DC phosphorylation of p-JNK and p-REK in human NPC. On the basis of evidence obtained from this study, DC targeting the inhibition of NPC cell lines may be a promising future strategy for NPC treatment.
What Surrogates Understand (and Don’t Understand) About Patients’ Wishes After Engaging Advance Care Planning: A Qualitative Analysis

Background: The goal of advance care planning (ACP) is to improve end-of-life decision-making for patients and their spokespersons, but multiple studies have failed to show substantial or consistent benefit from ACP. Understanding how and why ACP under-performs in the setting of complex medical decision-making is key to optimizing current, or designing new, ACP interventions. Aim: To explore how ACP did or did not contribute to a spokespersons’ understanding of patient wishes after engaging in ACP. Design: Thematic analysis of 200 purposively sampled interviews from a randomized control trial of an ACP decision aid. Setting/Participants: 200 dyads consisting of patients 18 years or older with advanced serious illness and their spokesperson at 2 tertiary care centers in Hershey, PA and Boston, MA. Participants were interviewed 1 month after completing ACP. Results: ACP helped participants: 1) express clear end-of-life wishes, 2) clarify values, and 3) recognize challenges associated with applying those wishes in complex situations. Shortcomings of ACP included 1) unknown prognostic information or quality-of-life outcomes to inform decision-making, 2) skepticism about patients’ wishes, and 3) complicated emotions impacting end-of-life discussions. Conclusions: Helping patients and their spokespersons better anticipate decision-making in the face of prognostic and informational uncertainty as well as the emotional complexities of making medical decisions may improve the efficacy of ACP interventions.
Natural history of Waldenström macroglobulinemia following acquired resistance to ibrutinib monotherapy

Ibrutinib is highly active and produces long-term responses in patients with Waldenström macroglobulinemia (WM), but acquired resistance can occur with prolonged treatment. We therefore evaluated the natural history and treatment outcomes in 51 WM patients with acquired resistance to ibrutinib monotherapy. The median time between ibrutinib initiation and discontinuation was 2 years (range, 0.4-6.5 years). Following discontinuation of ibrutinib, a rapid increase in serum immunoglobulin M level was observed in 60% (29/48) of evaluable patients, of whom ten acutely developed symptomatic hyperviscosity. Forty-eight patients (94%) received salvage therapy after ibrutinib. The median time to salvage therapy after ibrutinib cessation was 18 days (95% confidence interval [CI]: 13-27). The overall and major response rates to salvage therapy were 56% and 44%, respectively, and the median duration of response was 48 months (95% CI: 34-not reached). Quadruple-class (rituximab, alkylator, proteasome inhibitor, ibrutinib) exposed disease (odds ratio [OR] 0.20, 95% CI: 0.05-0.73) and salvage therapy ≤7 days after discontinuing ibrutinib (OR 4.12, 95% CI: 1.07-18.9) were identified as independent predictors of a response to salvage therapy. The 5-year overall survival (OS) following discontinuation of ibrutinib was 44% (95% CI: 26-75). Response to salvage therapy was associated with better OS after ibrutinib (hazard ratio 0.08, 95% CI: 0.02-0.38). TP53 mutations were associated with shorter OS, while acquired BTK C481S mutations had no impact. Our findings reveal that continuation of ibrutinib until subsequent treatment is associated with improved disease control and clinical outcomes.
Assessment of occupational exposure from shielded and unshielded syringes for clinically relevant positron emission tomography (PET) isotopes—a Monte Carlo approach using EGSnrc

18F has been the most widely used radionuclide in positron emission tomography (PET) facilities over the last few decades. However, increased interest in novel PET tracers, theranostics and immuno-PET has led to significant growth in clinically used positron-emitting radionuclides. The decay schemes of each of these radioisotopes are markedly different from 18F, with different endpoint energies for the emitted positrons and, in some cases, additional high energy gamma radiation. This has implications for the occupational exposure of personnel involved in the manipulation and dispensing of PET radiopharmaceuticals. The EGSnrc Monte Carlo simulation software was used to estimate the doses to extremities in contact with unshielded and shielded syringes containing 64Cu, 18F, 11C, 13N, 15O, 68Ga and 89Zr, respectively. Dose rates at various distances from the syringe were also modelled, with dose rates reported in terms of eye (Hp(3)), skin equivalent (Hp(0.07)) and deep (Hp(10)) doses. The composition and geometry of the simulated syringe shields were based on a selection of commercially available PET shields. Experimental dose rate measurements were performed for validation purposes where possible. Contact skin dose rates for all isotopes, except for 64Cu, were found to be higher than 18F for the unshielded syringe. The addition of a shield resulted in approximately equal contact skin dose rates for nearly all isotopes, for each shield type, with the exception of 89Zr which was notably higher. Dose rate constants (µGy/MBq.hr) for a range of PET isotopes and shields are presented and their significance discussed.
Hidden fraction of Polish population immune to SARS-CoV-2 in May 2021

Population immunity to SARS-CoV-2 derives from two well-defined and controlled sources: vaccinations or diagnosed and registered cases of the disease. It may however also result from asymptomatic, oligosymptomatic, or even full-blown but undiagnosed and unregistered cases from which patients recovered at home. Here we present a population screening for SARS-CoV-2 specific IgG and IgA antibodies in Polish citizens (healthy adults, N=501) who had never been positively diagnosed with or vaccinated against SARS-CoV-2. Blood samples were collected in Wrocaw (Lower Silesia) on 15th and 22nd May 2021. Sera from COVID-19 patients with a severe course (hospitalized) (N=43) or had been vaccinated (N=14) served as a positive control. The patients were tested with Microblot-Array COVID-19 IgG and IgA (quantitative) that contain specific SARS-CoV-2 antigens: NCP, RBD, Spike S2, E, ACE2, PLPro protein, as well as antigens for exclusion cross-reactivity with other coronaviruses: MERS-CoV, SARS-CoV, HCoV 229E Np, HCoV NL63 Np. Within the investigated population of healthy adults who had never been positively diagnosed with or vaccinated against SARS-CoV-2, we found that 35.5% (178 out of 501) were positive for SARS-CoV-2-specific IgG and 52.5% (263 out of 501) were positive for SARS-CoV-2-specific IgA; 21.6% of the investigated population developed virus-specific IgG or IgA while being asymptomatic. Anti-RBD IgG, which represents virus-neutralizing potential, was found in 25.6% of individuals (128 out of 501). These patients, though positive for anti-SARS-CoV-2 antibodies, cannot be identified in the public health system as convalescents due to undiagnosed infections, and they are considered unaffected by SARS-CoV-2. Their contribution to population immunity against COVID-19 should however be considered in predictions and modeling of the COVID-19 pandemic. Of note, the majority of the investigated population still lacked anti-RBD IgG protection (74.4%); thus the positive fraction is not sufficient for effective population immunity, and vaccination against COVID-19 is still of the most importance for controlling the pandemic.
Linalool Inhibits MCF-7 Tumor Growth in a Xenograft Model by Apoptosis Induction and Immune Modulation

In this study, the anti-cancer activity of linalool was investigated in MCF-7 breast cancer-bearing mice. Natural killer (NK) and B cell populations in peripheral blood were studied by flow cytometry. The expressions of proliferating cell nuclear antigen (PCNA) and Ki-67 in xenograft tumors were evaluated by immunohistochemistry. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed to investigate apoptosis induction in an in vivo model. The results indicated that linalool possesses an inhibitory effect on breast cancer growth in the xenograft model. Linalool reduced B cell counts, but increased NK cell counts in mice peripheral blood. The immunosignals of PCNA and Ki-67 were significantly lower in the linalool treatment group than those of the control group. The TUNEL assay showed that linalool significantly induced apoptosis compared to the control group. The findings of this study provide insight and evidence on the antiproliferative activity of linalool on human breast cancer.
Essentiality of Manganese for Bone Health: An Overview and Update

The evidence regarding a deficiency of manganese (Mn) in humans is scarce. So the aim of this narrative review was to consider the state of the art on the relation between manganese and bone health in humans and the effectiveness of manganese supplementation (alone or with other micronutrients) on bone mineralization. This review included 4 eligible studies. All the literature published is in agreement in showing that osteoporotic women have lower serum Mn levels than women with normal bone mineral density, thus confirming the essential role of manganese in the synthesis of cartilage and bone collagen, as well as in bone mineralization and confirming the studies on the animal model. Considering the human studies that evaluated the effectiveness of an oral Mn supplement for a long period (2 years) on the bone mineral density of menopausal women, both of the clinical trials showed that bone loss was significantly greater in the placebo group than in the group taking supplementation, equal to 5.0 mg Mn/day in the study by Strause, and equal to 2.5 mg Mn/day in the study by Saltman, considering, however, that supplementation was represented by a set of microelements (Mn, copper, and zinc) and by calcium.
Reliabilities of WMS–IV Discrepancy Score Comparisons for Subtests, Indexes, and Selected WAIS–IV Composites

This investigation provides internal consistency reliabilities for the Wechsler Memory Scale–Fourth Edition (WMS–IV) subtest and index discrepancy scores using the standardization samples of the Adult and Older Adult batteries. Subtest reliabilities ranged from . 00 to . 93 for Adults and . 25 to . 94 for Older Adults. Three of 91 Adult coefficients and three of 24 Older Adult coefficients reached the recommended level (≥ .90). Index reliabilities ranged from . 46 to . 94 for 100 Adult Battery comparisons and . 19 to 93 for 36 Older Adult Battery comparisons. Each battery had 10 coefficients ≥ . 90. Ability–memory discrepancies were reported using WAIS–IV VCI, PRI, WMI, and GAI as intelligence standards. Ability–memory comparisons for the Adult Battery ranged from . 82 to . 93 with 12 of 20 comparisons ≥ . 90; Older Adult Battery reliabilities ranged from . 85 to . 94 with six of 16 comparisons ≥ . 90. In terms of discrepancy score reliabilities, the WMS–IV represents a marked improvement over the WMS–III.