Purpose
To demonstrate accurate MR image reconstruction from undersampled k‐space data using cross‐domain convolutional neural networks (CNNs)
Methods
Cross‐domain CNNs consist of 3 components: (1) a ...deep CNN operating on the k‐space (KCNN), (2) a deep CNN operating on an image domain (ICNN), and (3) an interleaved data consistency operations. These components are alternately applied, and each CNN is trained to minimize the loss between the reconstructed and corresponding fully sampled k‐spaces. The final reconstructed image is obtained by forward‐propagating the undersampled k‐space data through the entire network.
Results
Performances of K‐net (KCNN with inverse Fourier transform), I‐net (ICNN with interleaved data consistency), and various combinations of the 2 different networks were tested. The test results indicated that K‐net and I‐net have different advantages/disadvantages in terms of tissue‐structure restoration. Consequently, the combination of K‐net and I‐net is superior to single‐domain CNNs. Three MR data sets, the T2 fluid‐attenuated inversion recovery (T2 FLAIR) set from the Alzheimer's Disease Neuroimaging Initiative and 2 data sets acquired at our local institute (T2 FLAIR and T1 weighted), were used to evaluate the performance of 7 conventional reconstruction algorithms and the proposed cross‐domain CNNs, which hereafter is referred to as KIKI‐net. KIKI‐net outperforms conventional algorithms with mean improvements of 2.29 dB in peak SNR and 0.031 in structure similarity.
Conclusion
KIKI‐net exhibits superior performance over state‐of‐the‐art conventional algorithms in terms of restoring tissue structures and removing aliasing artifacts. The results demonstrate that KIKI‐net is applicable up to a reduction factor of 3 to 4 based on variable‐density Cartesian undersampling.
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•Pluripotent stem cell (PSC)-derived expandable human hepatocyte-like liver organoids were generated.•PSC-derived human hepatic organoids are capable of long-term expansion with ...competent liver functionality.•PSC-derived human hepatic organoids provide a robust hepatic model for toxicity prediction and drug screening.
The development of hepatic models capable of long-term expansion with competent liver functionality is technically challenging in a personalized setting. Stem cell-based organoid technologies can provide an alternative source of patient-derived primary hepatocytes. However, self-renewing and functionally competent human pluripotent stem cell (PSC)-derived hepatic organoids have not been developed.
We developed a novel method to efficiently and reproducibly generate functionally mature human hepatic organoids derived from PSCs, including human embryonic stem cells and induced PSCs. The maturity of the organoids was validated by a detailed transcriptome analysis and functional performance assays. The organoids were applied to screening platforms for the prediction of toxicity and the evaluation of drugs that target hepatic steatosis through real-time monitoring of cellular bioenergetics and high-content analyses.
Our organoids were morphologically indistinguishable from adult liver tissue-derived epithelial organoids and exhibited self-renewal. With further maturation, their molecular features approximated those of liver tissue, although these features were lacking in 2D differentiated hepatocytes. Our organoids preserved mature liver properties, including serum protein production, drug metabolism and detoxifying functions, active mitochondrial bioenergetics, and regenerative and inflammatory responses. The organoids exhibited significant toxic responses to clinically relevant concentrations of drugs that had been withdrawn from the market due to hepatotoxicity and recapitulated human disease phenotypes such as hepatic steatosis.
Our organoids exhibit self-renewal (expandable and further able to differentiate) while maintaining their mature hepatic characteristics over long-term culture. These organoids may provide a versatile and valuable platform for physiologically and pathologically relevant hepatic models in the context of personalized medicine.
A functionally mature, human cell-based liver model exhibiting human responses in toxicity prediction and drug evaluation is urgently needed for pre-clinical drug development. Here, we develop a novel human pluripotent stem cell-derived hepatocyte-like liver organoid that is critically advanced in terms of its generation method, functional performance, and application technologies. Our organoids can contribute to the better understanding of liver development and regeneration, and provide insights for metabolic studies and disease modeling, as well as toxicity assessments and drug screening for personalized medicine.
Recent research has led to contradictory notions regarding the conventional theory that apoptotic cell death can evoke inflammatory or immunogenic responses orchestrated by released damage-associated ...patterns (DAMPs). By inducing IL-1β from bone marrow-derived macrophages in an effort to determine the inflammatory mediators released from apoptotic cells, we found that exosomal fractions called “apoptotic exosome-like vesicles” (AEVs) prepared from apoptotic-conditioned medium were the main inflammatory factors. These AEVs showed characteristics of exosomes in their size, density, morphology, and protein expression but had unique marker proteins, sphingosine-1-phosphate receptors 1 and 3 (S1PR1 and 3). Their biogenesis was completely dependent on cellular sphingosine-1-phosphate (S1P)/S1PRs signaling from multiple fine spindles of plasma membrane accompanied by F-actin, S1PR1, S1PR3, and CD63 at the early apoptotic phase and progressing to the maturation of F-actin–guided multivesicular endosomes mediated by Gβγ subunits of S1PRs downstream. S1P-loaded S1PRs on AEVs were critical factors for inducing IL-1β via NF-κB transcriptional factor and p38 MAPK, possibly through the RHOA/NOD2 axis, in differentiating macrophages. The AEVs induced genes of proinflammatory cytokines, chemokines, and mediators in both in vitro and in vivo models. In conclusion, AEVs could be key inflammatory mediators, acting as DAMPs that could explain the pathogeneses of various chronic inflammations, autoimmune diseases, or cancers in the future.
and
are strong genetic determinants of thiopurine toxicity in pediatric acute lymphoblastic leukemia (ALL) patients. Since patients with
or
deficiency suffer severe adverse drug reactions, star (*) ...allele-based haplotypes have been used to predict an optimal 6-mercaptopurine (6-MP) dosing. However, star allele haplotyping suffers from insufficient, inconsistent, and even conflicting designations with uncertain and/or unknown functional alleles. Gene-wise variant burden (GVB) scoring enables us to utilize next-generation sequencing (NGS) data to predict 6-MP intolerance in children with ALL. Whole exome sequencing was performed for 244 pediatric ALL patients under 6-MP treatments. We assigned star alleles with PharmGKB haplotype set translational table. GVB for
and
was computed by aggregating
deleteriousness scores of multiple coding variants for each gene. Poor last-cycle dose intensity percent (DIP < 25%) was considered as 6-MP intolerance, resulting therapeutic failure of ALL. DIPs showed significant differences (
< 0.05) among
poor (PM,
= 1), intermediate (IM,
= 48), and normal (NM,
= 195) metabolizers.
exhibited no PM and only seven IMs. GVB showed significant differences among the different haplotype groups of both
and
(
< 0.05). Kruskal-Wallis test for DIP values showed statistical significances for the seven different GVB score bins of
. GVB
outperformed the star allele-based haplotypes in predicting patients with reduced last-cycle DIPs at all DIP threshold levels (i.e., 5%, 10%, 15%, and 25%). In
-and-
combined interaction analyses, GVB
outperformed star alleles area under the receiver operating curve (AUROC) = 0.677 vs. 0.645 in specificity (0.813 vs. 0.796), sensitivity (0.526 vs. 0.474), and positive (0.192 vs. 0.164) and negative (0.953 vs. 0.947) predictive values. Overall, GVB correctly classified five more patients (i.e., one into
and four into
groups) than did star allele haplotypes. GVB analysis demonstrated that 6-MP intolerance in pediatric ALL can be reliably predicted by aggregating NGS-based common, rare, and novel variants together without hampering the predictive power of the conventional haplotype analysis.
Virtual reality (VR)-based rehabilitation has been reported to have beneficial effects on upper extremity function in stroke survivors; however, there is limited information about its effects on ...distal upper extremity function and health-related quality of life (HRQoL). The purpose of the present study was to examine the effects of VR-based rehabilitation combined with standard occupational therapy on distal upper extremity function and HRQoL, and compare the findings to those of amount-matched conventional rehabilitation in stroke survivors.
The present study was a single-blinded, randomized controlled trial. The study included 46 stroke survivors who were randomized to a Smart Glove (SG) group or a conventional intervention (CON) group. In both groups, the interventions were targeted to the distal upper extremity and standard occupational therapy was administered. The primary outcome was the change in the Fugl-Meyer assessment (FM) scores, and the secondary outcomes were the changes in the Jebsen-Taylor hand function test (JTT), Purdue pegboard test, and Stroke Impact Scale (SIS) version 3.0 scores. The outcomes were assessed before the intervention, in the middle of the intervention, immediately after the intervention, and 1 month after the intervention.
The improvements in the FM (FM-total, FM-prox, and FM-dist), JTT (JTT-total and JTT-gross), and SIS (composite and overall SIS, SIS-social participation, and SIS-mobility) scores were significantly greater in the SG group than in the CON group.
VR-based rehabilitation combined with standard occupational therapy might be more effective than amount-matched conventional rehabilitation for improving distal upper extremity function and HRQoL.
This study is registered under the title "Effects of Novel Game Rehabilitation System on Upper Extremity Function of Patients With Stroke" and can be located in https://clinicaltrials.gov with the study identifier NCT02029651 .
End-effector (EE) and exoskeleton (Exo) robots have not been directly compared previously. The present study aimed to directly compare EE and Exo robots in chronic stroke patients with ...moderate-to-severe upper limb impairment. This single-blinded, randomised controlled trial included 38 patients with stroke who were admitted to the rehabilitation hospital. The patients were equally divided into EE and Exo groups. Baseline characteristics, including sex, age, stroke type, brain lesion side (left/right), stroke duration, Fugl-Meyer Assessment (FMA)-Upper Extremity score, and Wolf Motor Function Test (WMFT) score, were assessed. Additionally, impairment level (FMA, motor status score), activity (WMFT), and participation (stroke impact scale SIS) were evaluated. There were no significant differences in baseline characteristics between the groups. After the intervention, improvements were significantly better in the EE group with regard to activity and participation (WMFT-Functional ability rating scale, WMFT-Time, and SIS-Participation). There was no intervention-related adverse event. The EE robot intervention is better than the Exo robot intervention with regard to activity and participation among chronic stroke patients with moderate-to-severe upper limb impairment. Further research is needed to confirm this novel finding.
Recent studies have shown that metabolic tumor volume (MTV) by positron emission tomography/computed tomography (PET/CT) is an important prognostic parameter in patients with non‐Hodgkin's lymphoma. ...However, it is unknown whether doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) alone in early stage Hodgkin's lymphoma would lead to similar disease control as combined modality therapy (CMT) using MTV by PET/CT. One hundred and twenty‐seven patients with early stage Hodgkin's lymphoma who underwent PET/CT at diagnosis were enrolled. The MTV was delineated on PET/CT by the area ≥SUVmax, 2.5 (standardized uptake value SUV). Sixty‐six patients received six cycles of ABVD only. The other 61 patients received CMT (involved‐field radiotherapy after 4–6 cycles of ABVD). The calculated MTV cut‐off value was 198 cm3. Clinical outcomes were compared according to several prognostic factors (i.e. age ≥50 years, male, performance status ≥2, stage II, B symptoms, ≥4 involved sites, extranodal site, large mediastinal mass, CMT, elevated erythrocyte sedimentation rate and high MTV). Older age (progression‐free survival PFS, P = 0.003; overall survival OS, P = 0.007), B symptoms (PFS, P = 0.006; OS, P = 0.036) and high MTV (PFS, P = 0.008; OS, P = 0.007) were significant independent prognostic factors. Survival of two high MTV groups treated with ABVD only and CMT were lower than the low MTV groups (PFS, P < 0.012; OS, P < 0.045). ABVD alone was sufficient to control disease in those with low MTV status. However, survival was poor, even if the CMT was assigned a high MTV status. The MTV would be helpful for deciding the therapeutic modality in patients with early stage Hodgkin's lymphoma.
Aims
To evaluate whether sodium‐glucose cotransporter‐2 (SGLT2) inhibition reduces cellular senescence in the kidney and to investigate the molecular pathways involved in the renoprotective effect.
...Materials and methods
Dapagliflozin (1 mg/kg), glimepiride (2.5 mg/kg) or vehicle was administered daily via oral gavage for 8 weeks in db/db mice. Expression levels of ageing marker genes (p21, p16, and p53) and oxidative stress were measured in the kidney using real‐time RT‐PCR, immunohistochemistry, and Western blot analysis. For in vitro analysis, HK‐2 cells, a human renal tubular epithelial cell line, were pretreated with H2O2 to induce cellular senescence, and the levels of ageing markers were measured after treatment with β‐hydroxybutyrate (β‐HB) or NRF2‐specific siRNA.
Results
Expression levels of ageing marker genes (p21, p16 and p53) and senescence‐associated secretory phenotypes of the kidney were increased in the vehicle‐treated db/db (db/db + vehicle) group compared with the db/+ group, and this increase was markedly reversed in the dapagliflozin‐treated db/db (db/db + SGLT2 inhibitor) group, but not in the glimepiride‐treated db/db (db/db + sulphonylurea SU) group. In the kidneys of mice in the db/db + SGLT2 inhibitor group, oxidative stress and DNA damage were also reduced compared with those of mice in the db/db + vehicle and db/db + SU groups. Dapagliflozin increased plasma β‐HB, which reduced H2O2‐induced DNA damage and senescence in HK‐2 cells. β‐HB‐induced NRF2 nuclear translocation mediated anti‐senescent effects by inducing antioxidant pathways.
Conclusions
Dapagliflozin prevented the progression of diabetic kidney disease by inhibiting cellular senescence and oxidative stress via ketone‐induced NRF2 activation.
•A total of 129 coffee samples were analyzed by ICP-OES, ICP-MS and DMA.•Elemental profiling of 45 elements was used to authenticate the geographical origin.•Statistical analyses such as ANOVA, CA, ...LDA and PCA were performed.•The order of macro elements was; K>P>Mg>Ca>S>Na>Fe.•The concentrations of toxic trace elements were lower than the PTWI values.
This study was aimed to establish the elemental profiling and provenance of coffee samples collected from eleven major coffee producing regions of Ethiopia. A total of 129 samples were analyzed for forty-five elements using inductively coupled plasma (ICP)-optical emission spectroscopy (OES), ICP-mass spectrometry (MS) and direct mercury analyzer (DMA). Among the macro elements, K showed the highest levels whereas Fe was found to have the lowest concentration values. In all the samples, Ca, K, Mg, P and S contents were statistically significant (p<0.05). Micro elements showed the concentrations order of: Mn>Cu>Sr>Zn>Rb>Ni>B. Contents of the trace elements were lower than the permissible standard values. Inter-regions differentiation by cluster analysis (CA), linear discriminant analysis (LDA) and principal component analysis (PCA) showed that micro and trace elements are the best chemical descriptors of the analyzed coffee samples.
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