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Purpose: Identifying the palliative care needs of patients with advanced cancer is important for maintaining quality of life and timely transition to palliative care. We aimed to validate the Korean Sheffield Profile for Assessment and Referral for Care (K-SPARC) in such patients and establish its psychometric properties, including reliability, validity, and responsiveness to change., Materials and Methods: We used the forward-back translated version of SPARC, which was verified through a pilot study, to assess the palliative care needs of patients with advanced cancer. Reliability was evaluated by internal consistency using Cronbach's alpha coefficients and test-retest reliability. Criterion validity was analyzed against other questionnaires, including the Korean versions of the Functional Assessment of Cancer Therapy-General (FACT-G Korean) and Korean versions of the Edmonton Symptom Assessment System (K-ESAS). Factor analysis was used to assess construct validity., Results: Two hundred fifty-nine patients were included from 2019 to 2022. Forty-nine percent of all patients were women, and the median age was 63 years. Cronbach's alpha coefficient (range, 0.642-0.903) and test-retest reliability (range, 0.574-0.749) indicated acceptable reliability. The correlation coefficients between K-SPARC and FACT-G Korean suggested significant criterion validity. The correlation coefficients for the physical, social, emotional, and functional domains were 0.701, 0.249, 0.718, and 0.511, respectively (p-value <0.001, all). Factor analysis demonstrated satisfactory construct validity of the tool., Conclusion: This study demonstrated the utility of K-SPARC as an evaluation tool for providing palliative care to patients with advanced cancer through psychometric validation; the tool had good internal consistency, reliability, and acceptable validity.

In observational studies, there has been an association found between spleen volume and Crohn disease. We conducted a two-way, two-sample Mendelian randomization analysis to determine whether these associations have a causal relationship. Single nucleotide polymorphisms (P < 5 × 10-8) were used as instrumental variables for spleen volume and Crohn disease. Estimates of the genetic associations between spleen volume and Crohn disease were obtained from the Integrative Epidemiology Unit, European Bioinformatics Institute, UK Biobank, and FinnGen databases. Analysis was performed using MR-Egger regression, weighted median estimator, inverse variance weighted, simple model, and weighted model. Genetically predicted spleen volume was found to be associated with Crohn disease. In the IEU database, the odds ratios (ORs) for Crohn disease caused by spleen volume were 1.237 (95% CI, 1.056-1.417, P = .021), and the ORs for spleen volume caused by Crohn disease were 1.015 (95% CI, 0.985-1.044; P = .049). In the EBI database, the ORs for Crohn disease caused by spleen volume were 1.292 (95% CI, 1.120-1.463, P = .003), and the ORs for spleen volume caused by Crohn disease were 1.026 (95% CI, 1.005-1.046; P = .013). Results from the UKB and FinnGen databases showed no causal relationship between the two. The summary results showed that Crohn disease caused an increase in spleen volume, with ORs of 1.009 (95% CI, 1.000-1.018; P = .047). This study provides evidence for a mutual causal relationship between spleen volume and an increased risk of Crohn disease., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP-43 aggregates. Recent evidence has been indicated that phosphorylated TDP-43 (pTDP-43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP-43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP-43 detectable in routine biopsied muscles? (ii) Can detection of pTDP-43 aggregation discriminate between ALS and non-ALS patients? (iii) Can pTDP-43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non-ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP-43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP-43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non-ALS controls (16/54; p < 0.001). The pTDP-43 aggregates were mainly close to the sarcolemma. Using a semi-quantified pTDP-43 aggregates score, we applied a cut-off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP-43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof-of-concept for the detection of pTDP-43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS., (© 2024 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Quantum dots have diverse biomedical applications, from constructing biological infrastructures like medical imaging to advancing pharmaceutical research. However, concerns about human health arise due to the toxic potential of quantum dots based on heavy metals. Therefore, research on quantum dots has predominantly focused on oxidative stress, cell death, and other broader bodily toxicities. This study investigated the toxicity and cellular responses of mouse embryonic stem cells (mESCs) and mouse adult stem cells (mASCs) to nitrogen-doped carbon quantum dots (NCQDs) made of non-metallic materials. Cells were exposed to NCQDs, and we utilized a fluorescent ubiquitination-based cell system to verify whether NCQDs induce cytotoxicity. Furthermore, we validated the differentiation-inducing impact of NCQDs by utilizing embryonic stem cells equipped with the Oct4 enhancer-GFP reporter system. By analyzing gene expression including Crebzf, Chop, and ATF6, we also observed that NCQDs robustly elicited endoplasmic reticulum (ER) stress. We confirmed that NCQDs induced cytotoxicity and abnormal differentiation. Interestingly, we also confirmed that low concentrations of NCQDs stimulated cell proliferation in both mESCs and mASCs. In conclusion, NCQDs modulate cell death, proliferation, and differentiation in a concentration-dependent manner. Indiscriminate biological applications of NCQDs have the potential to cause cancer development by affecting normal cell division or to fail to induce normal differentiation by affecting embryonic development during pregnancy. Therefore, we propose that future biomedical applications of NCQDs necessitate comprehensive and diverse biological studies., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Multiple sclerosis (MS) is an autoimmune-mediated chronic inflammatory demyelinating disease of the central nervous system (CNS) that poses significant treatment challenges. Currently, it is believed that inflammatory and neuroprotective reactive astrocytes, along with other resident CNS cells and immune cells, contribute to the pathophysiology of MS. In our study, we found that isoliquiritigenin (ILG), a bioactive chalcone compound, significantly reduces the clinical scores of experimental autoimmune encephalomyelitis (EAE) by 44 % (P < 0.05). Additionally, ILG significantly decreases the pathological scores of spinal cord inflammation and demyelination by 61 % and 65 %, respectively (both P < 0.0001). Furthermore, ILG affects the populations of CD4, Th1, Th17, and Treg cells in vivo. More importantly, ILG significantly promotes the activation of astrocytes in EAE (P < 0.0001). Additionally, ILG treatment indirectly inhibits inflammatory reactive astrocytes and promotes neuroprotective reactive astrocytes. It reduces spleen levels of TNFα, IL1α, C1qa, IL1β, and IL17A by 95 % (P < 0.001), 98 % (P < 0.01), 46 % (P < 0.05), 97 % (P < 0.001), and 60 % (P < 0.001), respectively. It also decreases CNS levels of TNFα, IL1α, C1qa, IL1β, and IL17A by 53 % (P < 0.05), 88 % (P < 0.05), 64 % (P < 0.01), 57 % (P < 0.05), and 60 % (P < 0.001), respectively. These results indicate that ILG exerts an immunoregulatory effect by inhibiting the secretion of pro-inflammatory cytokines. Consequently, ILG inhibits inflammatory reactive astrocytes, promotes neuroprotective reactive astrocytes, alleviates inflammation and improves EAE. These findings provide a theoretical basis and support for the application of ILG in the prevention and treatment of MS., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interests. This manuscript is new and is not being considered for publication elsewhere, and there are no any papers in submission or recent publications with potential overlap., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Gastric cancer remains a leading cause of cancer-related mortality globally. Traditional open surgery for gastric cancer is often associated with significant morbidity and prolonged recovery., Aim: To evaluate the effectiveness of laparoscopic minimally invasive surgery as an alternative to traditional open surgery for gastric cancer, focusing on its potential to reduce trauma, accelerate recovery, and achieve comparable oncological outcomes., Methods: This study retrospectively analyzed 203 patients with gastric cancer who underwent surgery at the Shanghai Health Medical College Affiliated Chongming Hospital from January 2020 to December 2023. The patients were divided into two groups: Minimally invasive surgery group ( n = 102), who underwent laparoscopic gastrectomy, and open surgery group ( n = 101), who underwent traditional open gastrectomy. We compared surgical indicators (surgical incision size, intraoperative blood loss, surgical duration, and number of lymph nodes dissected), recovery parameters (time to first flatus, time to start eating, time to ambulation, and length of hospital stay), immune function (levels of IgA, IgG, and IgM), intestinal barrier function (levels of D-lactic acid and diamine oxidase), and stress response (levels of C-reactive protein, interleukin-6, and procalcitonin)., Results: The minimally invasive surgery group demonstrated significantly better outcomes in terms of surgical indicators, including smaller incisions, less blood loss, shorter surgery time, and more lymph nodes dissected ( P < 0.05 for all). Recovery was also faster in the minimally invasive surgery group, with earlier return of bowel function, earlier initiation of diet, quicker mobilization, and shorter hospital stays ( P < 0.05 for all). Furthermore, patients in the minimally invasive surgery group had better preserved immune function, superior intestinal barrier function, and a less pronounced stress response postoperatively ( P < 0.05 for all)., Conclusion: Laparoscopic minimally invasive surgery for gastric cancer not only provides superior surgical indicators and faster recovery but also offers advantages in preserving immune function, protecting intestinal barrier function, and mitigating the stress response compared to traditional open surgery. These findings support the broader adoption of laparoscopic techniques in the management of gastric cancer., Competing Interests: Conflict-of-interest statement: The authors declare that they have no competing interests to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

A standardized protocol for the isolation of cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) is lacking. Therefore, we established a cfDNA isolation protocol optimized for clinical CSF specimens, integrating acceptable modifications and using artificial CSF generated from remnant CSF spiked with reference cell-free tumor DNA (ctDNA). We compared the isolation yields of in vitro diagnostic (IVD)-certified column-based (CB) and magnetic bead-based (MB) isolation. Furthermore, we modified both methods, including pre- and post-elution steps. To confirm ctDNA integrity and quantify the variant allele frequency after isolation, we performed droplet digital PCR (ddPCR) targeting IDH1 R132C in the reference ctDNA. MB isolation had a higher yield than CB isolation ( P <0.0001), and post-isolation vacuum increased the final concentration in both methods, with little effect on cfDNA integrity. Our study provides a protocol to maximize CSF-ctDNA concentrations in IVD testing and future studies.

During the ultraintense laser interaction with solids (overdense plasmas), the competition between two possible quantum electrodynamics (QED) mechanisms responsible for e^{±} pair production, i.e., linear and nonlinear Breit-Wheeler (BW) processes, remains to be studied. Here, we have implemented the linear BW process via a Monte Carlo algorithm into the QED particle-in-cell (PIC) code yunic, enabling us to self-consistently investigate both pair production mechanisms in the plasma environment. By a series of two-dimensional QED-PIC simulations, the transition from the linear to the nonlinear BW process is observed with the increase of laser intensities in the typical configuration of a linearly polarized laser interaction with solid targets. A critical normalized laser amplitude about a&#95;{0}∼400-500 is found under a large range of preplasma scale lengths, below which the linear BW process dominates over the nonlinear BW process. This work provides a practicable technique to model linear QED processes via integrated QED-PIC simulations. Moreover, it calls for more attention to be paid to linear BW pair production in near future 10-PW-class laser-solid interactions.

Background: Reverse transcription real-time PCR (rRT-PCR) has been a gold-standard method to detect SARS-CoV-2, for which quality assessment of nucleic acids (NAs) is not needed. In order to prepare for future use, we evaluated NA quality from archived SARS-CoV-2 rRT-PCR samples., Methods: NA samples were collected in February 2021 and extracted using the QIAamp DSP Virus Spin Kit, (53 SARS-CoV-2-positive and 100 SARS-CoV-2-negative). Quality, quantity, and purity of NA were measured spectrophotometrically or fluorescently. Droplet digital PCR was used to characterize the double strand DNA (dsDNA) origin and composition by quantifying 16S rDNA and RPP30., Results: The RIN and purity were not significantly different between groups (p = 0.3828). RNA quantity was significantly higher than dsDNA in both groups (p < 0.0001); both dsDNA and RNA quantity were significantly higher in positive samples (dsDNA, RNA p = 0.021). For dsDNA, 16S rDNA copies were significantly greater than RPP30 in both groups (p < 0.0001), and RPP30 were significantly higher in positive samples (p < 0.0001)., Conclusions: Archived NA quality after SARS-CoV-2 rRT-PCR was guaranteed for subsequent molecular research using human or bacterial DNA, especially for short targets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: In this paper, we present a comprehensive overview of our experience in establishing and leading distinct extracorporeal cardiopulmonary resuscitation (ECPR)-related teams to independently handle ECPR in the early stages in the emergency department., Methods: A retrospective analysis was conducted on the clinical data of 29 patients who underwent ECPR treatment in the emergency room between May 2018 and April 2022. A control group, consisting of 10 patients treated between May 2018 and September 2019 was managed using a standard rescue coordination mode. The 19 patients who received ECPR between October 2019 and April 2022 were treated by members of the department's 24-h extracorporeal life support team. We compared the implementation and operational challenges faced by the two groups, including item preparation, circuit setup, and ECPR initiation times, among other factors., Results: Gender, age, cardiac arrest risk factors, and other baseline data did not significantly differ between the two groups. Extracorporeal membrane oxygenation (ECMO) pipeline prefilling time (from 35.27±10.34 to 13.46±5.32), ECPR establishment time (from 62.35±29.61 to 30.98±13.41), and item preparation time (from 16.42±9.78 to 3.19±1.49) all considerably decreased when compared to the control group. The rate of return of spontaneous circulation recovery rose from 37.50 % to 77.78 % (P < 0.05). The consequences of gastrointestinal and pulmonary bleeding were greatly reduced while ECPR was being used, and the difference was statistically significant (P < 0.05). Significant improvements were made in the ECPR weaning rate (from 25.00 % to 38.89 %) and survival rate (from 20.0 % to 36.8 %)., Conclusion: The establishment of a 24-h extracorporeal life support team significantly reduced the time needed for rescue during the early stage of independent setup of ECPR in the emergency department and serves as a guide for effective care of critically ill patients., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Objective: Haemophilia A (HA) is associated with high clinical and healthcare burden. We developed an Excel-based model comparing current practice to improved management in severe HA patients currently managed on demand (OD). Outcomes included short- and long-term bleed events. Expected annual bleeds were estimated based on locally-derived OD annualised bleed rate (ABR), adjusted by relative prophylaxis-related ABRs (published literature). The objective of our study was to explore the impact of improving HA prophylaxis in target countries with limited published data (Algeria, Argentina, Chile, India, Malaysia, Mexico, Taiwan and Thailand). Bleed-related healthcare resource use (HCRU) and costs were estimated as a function of bleed type, with inputs obtained from local expert estimates. Clotting factor concentrates (CFC) consumption related to treatment and prophylaxis was estimated based on locally relevant dosing. CFC costs were not included., Results: When 20% of OD patients were switched to prophylaxis, projected reduction in bleeds was estimated between 3% (Taiwan) through 14% (Algeria and India); projected reductions in hospitalisations ranged from 3% (Taiwan) through 15% (India). Projected HCRU-related annual cost savings were estimated at USD 0.45 m (Algeria), 0.77 m (Argentina), 0.28 m (Chile), 0.13 m (India), 0.29 m (Malaysia), 2.79 m (Mexico), 0.15 m (Taiwan) and 0.78 m (Thailand). Net change in annual CFC consumption ranged from a 0.05% reduction (Thailand) to an overall 5.4% increase (Algeria). Our model provides a flexible framework to estimate the clinical and cost offsets of improved prophylaxis. Modest increase in CFC consumption may be an acceptable offset for improvements in health and healthcare capacity in resource constrained economies., (© 2023. The Author(s).)

The low intrinsic growth capacity of neurons and an injury-induced inhibitory milieu are major contributors to the failure of sensory and motor functional recovery following spinal cord injury. Heat shock transcription factor 1 (HSF1), a master regulator of the heat shock response, plays neurogenetic and neuroprotective roles in the damaged or diseased central nervous system. However, the underlying mechanism has not been fully elucidated. In the present study, we used a gecko model of spontaneous nerve regeneration to investigate the potential roles of gecko HSF1 (gHSF1) in the regulation of neurite outgrowth and inflammatory inhibition of macrophages following spinal cord injury. gHSF1 expression in neurons and microglia at the lesion site increased dramatically immediately after tail amputation. gHSF1 overexpression in gecko primary neurons significantly promoted axonal growth by suppressing the expression of suppressor of cytokine signaling-3, and facilitated neuronal survival via activation of the mitogen-activated extracellular signal-regulated kinase/extracellular regulated protein kinases and phosphatidylinositol 3-kinase/protein kinase B pathways. Furthermore, gHSF1 efficiently inhibited the macrophage-mediated inflammatory response by inactivating IkappaB-alpha/NF-kappaB signaling. Our findings show that HSF1 plays dual roles in promoting axonal regrowth and inhibiting leukocyte inflammation, and provide new avenues of investigation for promoting spinal cord injury repair in mammals., Competing Interests: None

SPG30 is a newly categorized type of HSP caused by variants in the kinesin family member 1A gene (KIF1A). Advances in next-generation sequencing have resulted in a limited number of studies describing the clinical, electrophysiological, and radiological features of HSP, with variable manifestations. Most known pathogenic KIF1A variants affect the motor domain, although some rare pathogenic variants have been identified that affect the non-motor domain. Here, we report a Korean family with a rare homozygous autosomal-recessive form of SPG30. A 59-year-old man and his father presented with an uncomplicated, mild SPG30 phenotype, characterized by a progressive, spastic gait. Familial co-segregation analysis revealed a pathogenic c.2751&#95;2753delGGA KIF1A variant that affects the non-motor domain. Our case broadens the genetic and clinical variability of SPG30, warranting similar studies to consolidate the pathogenicity of SPG30., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Scope: Continuous ultraviolet (UV) exposure causes skin photoaging, wrinkle formation, and skin barrier damage. In this study, the protective effect of mixed probiotics (MP) against photoaging in UVB-irradiated Hs68 fibroblasts and SKH-1 hairless mice is investigated., Methods and Results: The mice are irradiated with UVB for 8 weeks to induce photoaging, and MP (15 and 50 mg day -1 ) is orally administered once a day. Skin parameters are measured in the dorsal skin and wrinkle formation factors are analyzed in skin replicas. To evaluate the mitogen-activated protein kinase (MAPK) signaling pathway, western blotting and qRT-PCR are performed. MP (50 mg day -1 ) significantly improves skin moisture, transepidermal water loss, erythema, and skin thickness. MP also effectively suppresses wrinkle formation by regulating the transcriptional expression of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs. MP also reduces inflammatory cytokine levels and phosphorylation of extracellular signaling regulatory kinase, Jun N-terminal kinase, and p38 protein. Furthermore, the intestinal microbiome of the MP groups is significantly different compared with that of the UVB group, and the relative abundance of Lactobacillus and Akkermansia is significantly increased., Conclusion: Collectively, these findings suggest that MP modulates the gut microbiome and ameliorates UVB-induced photoaging by downregulating the MAPK pathway., (© 2023 Wiley-VCH GmbH.)

Some quantum critical states cannot be smoothly deformed into each other without either crossing some multicritical points or explicitly breaking certain symmetries even if they belong to the same universality class. This brings up the notion of "symmetry-enriched" quantum criticality. While recent works in the literature focused on critical states with robust degenerate edge modes, we propose that the conformal boundary condition (B.C.) is a more generic characteristic of such quantum critical states. We show that in two families of quantum spin chains, which generalize the Ising and the three-state Potts models, the quantum critical point between a symmetry-protected topological phase and a symmetry-breaking order realizes a conformal B.C. distinct from the simple Ising and Potts chains. Furthermore, we argue that the conformal B.C. can be derived from the bulk effective field theory, which realizes a novel bulk-boundary correspondence in symmetry-enriched quantum critical states.

The aim of this paper was to perform an analysis of the state-of-the-art solutions of the permissioned blockchain compliance with the General Data Protection Regulation (GDPR), including the implementation of one of the analyzed methods and the own solution. This paper covers the subject of GDPR and its impact on already existing blockchain databases to determine the domain of the problem, including the necessity to introduce mutability in the data structure to comply with the "right to be forgotten". The performed analysis made it possible to discuss current research in technical terms as well as in the regulation itself. In the experimental part, attempts were made to research and implement the Reference-based Tree Structure (RBTS), including the performance tests. The proposed solution is efficient and easily reproducible. The deletion of unwanted content is quick and requires consent only from the owner of personal data; therefore, eliminating the dependency on the other blockchain network participants., (© 2022. The Author(s).)

Many works have shown that dense positrons can be effectively generated from laser-solid interactions in the strong-field quantum electrodynamics (QED) regime. Whether these positrons are polarized has not yet been reported, limiting their potential applications. Here, by polarized QED particle-in-cell simulations including electron-positron spin and photon polarization effects, we investigate a typical laser-solid setup that an ultraintense linearly polarized laser irradiates a foil target with micrometer-scale-length preplasmas. We find that once the positron yield becomes appreciable with the laser intensity exceeding 10^{24}  W/cm^{2}, the positrons are obviously polarized. Around 30 nC positrons can acquire >30% polarization degree with a flux of 10^{12}  sr^{-1}. The angle-dependent polarization is attributed to the asymmetrical laser fields that positrons undergo near the skin layer of overdense plasmas, where radiative spin flip and radiation reaction play significant roles. The polarization mechanism is robust and could generally appear in future 100-PW-class laser-solid experiments.

Purpose: Various types of trauma can cause retinal hemorrhages in children, including accidental and nonaccidental head trauma. We used animal eyes and a finite element model of the eye to examine stress patterns produced during purely linear and angular accelerations, along with stresses attained during simulated repetitive shaking of an infant., Methods: Using sheep and primate eyes, sclerotomy windows were created by removing the sclera, choroid, and retinal pigment epithelium to expose the retina. A nanofiber square was glued to a 5 mm2 area of retina. The square was pulled and separated from vitreous while force was measured. A finite element model of the pediatric eye was used to computationally measure tension stresses during shaking., Results: In both sheep and primate eyes, tension stress required for separation of retina from vitreous range from 1 to 5 kPa. Tension stress generated at the vitreoretinal interface predicted by the computer simulation ranged from 3 to 16 kPa during a cycle of shaking. Linear acceleration generated lower tension stress than angular acceleration. Angular acceleration generated maximal tension stress along the retinal vasculature. Linear acceleration produced more diffuse force distribution centered at the poster pole., Conclusions: The finite element model predicted that tension stress attained at the retina during forcible shaking of an eye can exceed the minimum threshold needed to produce vitreoretinal separation as measured in animal eyes. Furthermore, the results show that movements that involve significant angular acceleration produce strong stresses localized along the vasculature, whereas linear acceleration produces weaker, more diffuse stress centered towards the posterior pole of the eye.

Purpurin-18 (P18) is one of the essential photosensitizers used in photodynamic therapy (PDT), but its hydrophobicity causes easy coalescence and poor bioavailability. This study aimed to synthesize P18 and design P18-loaded solid lipid nanoparticles (SLNs) to improve its bioavailability. The characteristics of the synthesized P18 and SLNs were evaluated by particle characteristics and release studies. The effects of P18 were evaluated using the 1,3-diphenylisobenzofuran (DPBF) assay as a nonbiological assay and a phototoxicity assay against HeLa and A549 cell lines as a biological assay. The mean particle size and zeta potential of the SLNs were 164.70-762.53 nm and -16.77-25.54 mV, respectively. These results indicate that P18-loaded SLNs are suitable for an enhanced permeability and retention effect as a passive targeting anti-cancer strategy. The formulations exhibited a burst and sustained release based on their stability. The DPBF assay indicated that the PDT effect of P18 improved when it was entrapped in the SLNs. The photocytotoxicity assay indicated that P18-loaded SLNs possessed light cytotoxicity but no dark cytotoxicity. In addition, the PDT activity of the formulations was cell type- and size-dependent. These results suggest that the designed P18-loaded SLNs are a promising tool for anticancer treatment using PDT.

Background: The germline mutations of DDX41, also known as DEAD box RNA helicase 41, have been found in about 1.5% of myeloid neoplasms (MNs). Development of MDS/AML is relatively common in germline DDX41 mutations. However, a variety of hematological malignancies (HMs) have been reported., Case Presentation: We report a novel case of bi-alleleic DDX41 mutations in B-cell lymphoblastic leukemia (B-ALL), with unusual location of DDX41 mutations. The gene expression profile (GEP) of Ph + B-ALL with bi-alleleic DDX41 mutations showed heterogeneously transitional GEP and altered gene expression levels of genes involved in the process essential for red blood cells and myeloid cell differentiation were noted., Conclusions: We report that DDX41 mutations are unusual but can be an underlying event in Ph + B-ALL and screening DDX41 mutations can be also informative for patients awaiting for haploidentical stem cell transplantation and choosing the therapy., (© 2022. The Author(s).)

Genetic differences may be associated with the response to tyrosine kinase inhibitor (TKI) in patients with chronic myeloid leukemia (CML). In this study, we identified genetic alterations between rapid and slow responders (BCR/ABL1 International Scale at 6 months: ≤0.1 % vs. > 0.1 %) of TKI treatment in chronic phase CML patients. Our analyses involved single nucleotide polymorphism (SNP), a Genome Wide Association Study and a Network-wide Association Study (NetWAS). Seventy-two patients from 16 institutions were enrolled and treated with a TKI, nilotinib. Gene Set Analysis identified genetic alterations in pathways related to the differentiation, proliferation, and activity of various innate immune cells. The NetWAS analysis found that genes associated with natural killer (NK) cells (PTPRCAP, BLNK, HCK, ARHGEF11, GPR183, TRPV2, SHKBP1, CD2) showed significant differences between rapid and slow responders of nilotinib. However, we found no significantly different genetic alterations according to the response in the SNP analysis. In conclusion, we found that rapidity of response to TKI was associated with pathway-associated genetic alterations in immune cells, particularly with respect to NK cell activity. These results suggested that the innate immune system at initial diagnosis had an important role in treatment response in patients with CML., (Copyright © 2022. Published by Elsevier Ltd.)

Background: It is well known that obstructive jaundice could affect the pharmacodynamics of some anesthetics, and the sensitivity of some anesthetics would increase among icteric patients. Remimazolam is a new ultra-short-acting intravenous benzodiazepine sedative/anesthetic, which is a high-selective and affinity ligand for the benzodiazepine site on the GABAA receptor. However, no study has reported the pharmacodynamics of remimazolam in patients with obstructive jaundice. We hypothesize that obstructive jaundice affects the pharmacodynamics of remimazolam, and the sensitivity of remimazolam increases among icteric patients., Methods/design: The study will be performed as a prospective, controlled, multicenter trial. The study design is a comparison of remimazolam requirements to reach a bispectral index of 50 in patients with obstructive jaundice versus non-jaundiced patients with chronic cholecystitisor intrahepatic bile duct stones. Remimazolam was infused at 6 mg/kg/h until this endpoint was reached., Discussion: Remimazolam could be suitable for anesthesia of patients with obstructive jaundice, because remimazolam is not biotransformed in the liver. Hyperbilirubinemia has been well-described to have toxic effects on the brain, which causes the increasing of sensitivity to some anesthetics, such as desflurane, isoflurane, and etomidate. Furthermore, remimazolam and etomidate have the same mechanism of action when exerting an anesthetic effect. We aim to demonstrate that obstructive jaundice affects the pharmacodynamics of remimazolam, and the dose of remimazolam when administered to patients with obstructive jaundice should be modified., Trial Registration: Chinese Clinical Trial Registry ChiCTR2100043585 . Registered on 23 February 2021., (© 2022. The Author(s).)

Ultra-deep sequencing detects low-frequency genetic mutations with high sensitivity. We used this approach to prospectively examine mutations in the BCR/ABL1 tyrosine kinase from patients with newly diagnosed, chronic-phase chronic myeloid leukemia (CML) treated with the tyrosine kinase inhibitor nilotinib. Between May 2013 and November 2014, 50 patients from 18 institutions were enrolled in the study. We screened 103 somatic mutations and found that mutations in the P-loop domain were the most frequent (173/454 mutations in the P-loop) and noted the presence of the V299 L mutation (dasatinib-resistant/nilotinib-sensitive) in 98 % of patients (49/50). No patients had Y253H, E255 V, or F359 V/C/I mutations, which would recommend dasatinib rather than nilotinib treatment. The S417Y mutation was associated with lower achievement of a major molecular response (MMR) at 6 months, and the V371A mutation was associated with reduced MMR and MR 4.5 durations (MMR for 2 years: 100 % for no mutation vs. 75 % for mutation, P=0.039; MR 4.5 for 15 months: 94.1 % vs. 25 %, P=0.002). Patients with known nilotinib-resistant mutations had lower rates of MR 4.5 achievement. In conclusion, ultra-deep sequencing is a sensitive method for genetic-based treatment decisions. Based on the results of these mutational analyses, nilotinib treatment is a promising option for Korean patients with CML., (Copyright © 2021. Published by Elsevier Ltd.)

Calcium deficiency usually causes accelerated quality deterioration in postharvest fruit, whereas the underlining mechanism is still unclear. Here, we report that calcium deficiency induced the development of bitter pit on the surface of apple peels compared with the healthy appearance in control apples during postharvest storage. Physiological analysis indicates that calcium-deficient peels contained higher levels of superoxide anion (O 2 •- ), malondialdehyde (MDA), total phenol, flavonoid contents and polyphenol oxidase (PPO) activity, and reduced calcium, H 2 S production, anthocyanin, soluble protein content, and peroxidase (POD) activity compared with those in calcium-sufficient peels. The principal component analysis (PCA) results show that calcium content, ROS, and H 2 S production were the main factors between calcium-deficient and calcium-sufficient apple peels. Transcriptome data indicated that four calmodulin-like proteins (CMLs), seven AP2/ERFs, and three bHLHs transcripts were significantly differentially expressed in calcium-deficient apple peels. RT-qPCR and correlation analyses further revealed that CML5 expression was significantly positively correlated with the expression of ERF2/17 , bHLH2, and H 2 S production related genes. In addition, transcriptional co-activation of CML5 by ERF2 and bHLH2 was demonstrated by apple transient expression assays and dual-luciferase reporter system experiments. Therefore, these findings provide a basis for studying the molecular mechanism of postharvest quality decline in calcium-deficient apples and the potential interaction between Ca 2+ and endogenous H 2 S.