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Simple Summary: Imiquimod (IMQ) is clinically used in the treatment of various skin malignancies. We previously showed that IMQ-induced apoptosis and autophagic cell death in skin cancer cells are ROS-dependent. Additionally, IMQ-induced apoptosis is associated with a decrease in Mcl-1 levels. However, the exact role of Mcl-1 in IMQ-induced apoptosis, including its protective mechanisms and physiological function in cancer cells, remains unclear. This study demonstrated that the overexpression of Mcl-1 or IL-6-induced Mcl-1 upregulation reversed mitochondrial dysfunction, mitochondrial fission, and mitophagy in IMQ-treated cancer cells and protected them from IMQ-induced apoptosis. These results provide significant insights supporting the role of Mcl-1 in mitochondria and suggest that it may be a potential target for cancer research and therapy. Mitochondria, vital organelles that generate ATP, determine cell fate. Dysfunctional and damaged mitochondria are fragmented and removed through mitophagy, a mitochondrial quality control mechanism. The FDA-approved drug IMQ, a synthetic agonist of Toll-like receptor 7, exhibits antitumor activity against various skin malignancies. We previously reported that IMQ promptly reduced the level of the antiapoptotic Mcl-1 protein and that Mcl-1 overexpression attenuated IMQ-triggered apoptosis in skin cancer cells. Furthermore, IMQ profoundly disrupted mitochondrial function, promoted mitochondrial fragmentation, induced mitophagy, and caused cell death by generating high levels of ROS. However, whether Mcl-1 protects mitochondria from IMQ treatment is still unknown. In this study, we demonstrated that Mcl-1 overexpression induced resistance to IMQ-induced apoptosis and reduced both IMQ-induced ROS generation and oxidative stress in cancer cells. Mcl-1 overexpression maintained mitochondrial function and integrity and prevented mitophagy in IMQ-treated cancer cells. Furthermore, IL-6 protected against IMQ-induced apoptosis by increasing Mcl-1 expression and attenuating IMQ-induced mitochondrial fragmentation. Mcl-1 overexpression ameliorates IMQ-induced ROS generation and mitochondrial fragmentation, thereby increasing mitochondrial stability and ultimately attenuating IMQ-induced cell death. Investigating the roles of Mcl-1 in mitochondria is a potential strategy for cancer therapy development. [ABSTRACT FROM AUTHOR]

Background and Objectives: As the global aging population grows, the incidence of thyroidectomy in elderly patients is increasing. This study aimed to evaluate the surgical outcomes of thyroidectomy in patients aged 80 years and older. Materials and Methods: All patients aged 80 years and older who underwent thyroidectomies at our hospital between January 2015 and December 2022 were reviewed in this retrospective cohort study. Collected data consisted of patients' clinical characteristics, functional status, compression symptoms, preoperative assessments, perioperative outcomes, postoperative complications (such as bleeding events, recurrent laryngeal nerve injury, hypocalcemia), pathological findings, readmission, and follow-up outcomes. Results: Seventeen patients were included in this study, with female predominance (82.4%). The mean age was 85.6 ± 4.8 years. Fourteen patients (82.4%) exhibited compression-related symptoms as surgical indications. Based on pathological reports, patients were categorized into benign (12/17, 70.6%) and malignancy (5/17, 29.4%) groups. The benign group had a shorter operation time compared with the malignancy group (164.3 ± 32.0 min vs. 231.0 ± 79.1 min, p = 0.048). No major postoperative complications developed. The median postoperative follow-up duration was 28 months (range: 2–91 months). Thirteen patients (76.5%) were alive at the end of the study period. Conclusions: Despite potential age-related risks, thyroidectomy is feasible for carefully selected patients aged 80 years and older. It provides benefits not only in terms of oncological curative treatment but also in improving the quality of life, such as compressive symptoms and wound condition. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphorylation plays a critical role in initiating upstream cellular signaling transduction. However, the challenge in biological samples is the variability in relative concentrations (0.1%) of site‐specific tyrosine phosphorylation on proteins. To navigate these fluctuations and accurately quantify the absolute levels of tyrosine phosphosites among different samples, we reported a hybrid data‐independent acquisition‐parallel reaction monitoring (DIA‐PRM) MS technique for the robust identification and quantification of the phosphoproteome, the establishment of a comprehensive library of tyrosine phosphosites, and the specific assessment of changes in tyrosine phosphorylation. In our model study on non‐small cell lung cancer cells, our PRM strategy accomplished by a spiked‐in synthetic heavy phosphopeptide demonstrated reliable targeted quantification of the pY1197 on EGFR, revealing levels of 2.5, 4.9, and 5.3 fmol in pervanadate (PV)‐treated cells at 0, 15, and 30 min, respectively. Additionally, DIA‐extensive phosphoproteomic analysis provided 2765 tyrosine phosphosites within 14,961 global phosphosites corresponding to 1536 phosphoproteins, contributing to the phospho‐library establishment and relative quantification of phosphorylation level, especially in the PV‐treated time‐dependent increase of ErbB signaling pathway. This hybrid DIA‐PRM approach will advance the application of precise measurement of changes in multiple phosphotyrosine residues and enhance our understanding of phosphoproteomic dynamics in drug‐resistant cascades. [ABSTRACT FROM AUTHOR]

Glossogyne tenuifolia (Labill.) Cass. ex Cass (Compositae) is a herbaceous plant that is endemic to Taiwan. Traditional Chinese Medicine has utilized it as a treatment for fever, inflammation, and liver preservation. Recent research has unveiled its bioactivities, including anti-inflammation, anti-cancer, antiviral, antioxidant, anti-fatigue, hepatoprotection, and immune modulation elements. Nevertheless, its effect on skin health remains to be investigated. Thus, we investigated the impact of G. tenuifolia essential oil (GTEO) on forskolin (FRK)-induced melanin biosynthesis and its mechanisms in B16-F10 murine melanoma in vitro. Treatment of GTEO resulted in a substantial decrease in FRK-induced melanin production, accompanied by a significant decrease in tyrosinase mRNA and protein expression levels. Additionally, our data demonstrated that the decrease in tyrosinase expression resulted from the suppression of MITF, as indicated by the reduced movement of MITF into the cell nucleus. Moreover, GTEO prompted a prolonged ERK1/2 activation, leading to the decline of MITF through proteasomal degradation, and it was verified that GTEO had no inhibitory impact on MITF activity in ERK1/2 inhibitor-treated cells. Additional studies demonstrated that α-pinene and D-limonene, which are the primary components in GTEO, showed strong melanin and tyrosinase inhibitory effects, indicating that α-pinene and D-limonene may contribute to its anti-melanogenic effects. Collectively, these data presented compelling proof that GTEO, along with its primary components α-pinene and D-limonene, show great potential as natural sources for developing innovative skin-whitening agents in the field of cosmetics. [ABSTRACT FROM AUTHOR]

Semiconductor manufacturing employs per- and polyfluoroalkyl substances (PFAS) as fluoroasurfactants to enhance the quality of photolithography lines. Our research, employing a fragment-based approach to investigate nontarget PFAS, overcomes conventional homologous series limitations. In a mixture of PFAS standards used as a quality control sample, 92% (36 out of 39 compounds spanning 11 compound classes) were detectable through the fragment-based nontarget procedure. This indicates the effectiveness of this approach in identifying the hydrophobic and hydrophilic characteristics of various fluorosurfactants. Eighty-three PFAS were detected in wastewater and effluent samples from semiconductor industry, including 29 newly discovered compounds, categorized into three groups. First, besides detecting perfluorobutane sulfonamido ethanol (FBSE), various fluoroalkyl chain structures of FBSE derivatives were initially identified in wastewater. These include perfluorobutyl ether sulfonamido ethanol, unsaturated FBSE, and hydrogen-substituted FBSE. These derivatives were also detected in trace amounts in commercial authentic standards of FBSE. To quantify their presence, we analyzed the FBSE derivatives from the authentic standard, and the relative proportions of these derivatives contribute to approximately 0.5%. This suggests that the FBSE derivative series detected in wastewater may arise from byproducts of chemical formulations used in the manufacturing of semiconductors. Second, transformation products from FBSE during oxidation, including the first identified intermediate transformation compounds, perfluorobutane sulfonamido acetaldehyde and its hydrate, were discovered. Third, diverse reaction products are generated from the intricate processes of semiconductor manufacturing, which utilize strong acids, bases, and solvents under UV light or heated conditions. These processes include the formation of PFAS-related compounds through hydration, sulfonation, oxidation, and nitrification. This study revealed 25 isomeric PFAS, encompassing headgroup isomers and functional tail group isomers. These findings underscore the importance of comprehending diverse reactions and the overall emission compositions of PFAS in semiconductor wastewater, highlighting its complexity and presenting challenges for subsequent wastewater treatment. [ABSTRACT FROM AUTHOR]

In recent times, there has been growing attention towards exploring the nutritional and functional aspects of potato protein, along with its diverse applications. In the present study, we examined the anti‐osteoclast properties of potato protein hydrolysate (PP902) in vitro. Murine macrophages (RAW264.7) were differentiated into osteoclasts by receptor activator of nuclear factor‐κB ligand (RANKL), and PP902 was examined for its inhibitory effect. Initially, treatment with PP902 was found to significantly prevent RANKL‐induced morphological changes in macrophage cells, as determined by tartrate‐resistant acid phosphatase (TRAP) staining analysis. This notion was further supported by F‐actin analysis using a confocal microscope. Furthermore, PP902 treatment effectively and dose‐dependently down‐regulated the expression of RANKL‐induced osteoclastogenic marker genes, including TRAP, CTR, RANK, NFATc1, OC‐STAMP, and c‐Fos. These inhibitory effects were associated with suppressing NF‐κB transcriptional activation and subsequent reduced nuclear translocation. The decrease in NF‐κB activity resulted from reduced activation of its upstream kinases, including I‐κBα and IKKα. Moreover, PP902 significantly inhibited RANKL‐induced p38MAPK and ERK1/2 activities. Nevertheless, PP902 treatment prevents RANKL‐induced intracellular reactive oxygen species generation via increased HO‐1 activity. The combined antioxidant and anti‐inflammatory effects of PP902 resulted in significant suppression of osteoclastogenesis, suggesting its potential as an adjuvant therapy for osteoclast‐related diseases. [ABSTRACT FROM AUTHOR]

Background: Entrustable Professional Activities (EPA)-based assessment is easily and intuitively used in evaluating the learning outcomes of competency-based medical education (CBME). This study aimed to develop an EPA for occupational therapy focused on providing health education and consultation (TP-EPA3) and examine its validity. Methods: Nineteen occupational therapists who had completed online training on the EQual rubric evaluation participated in this study. An expert committee identified six core EPAs for pediatric occupational therapy. TP-EPA3 was developed following the EPA template and refined through consensus meetings. The EQual rubric, a 14-item, five-point criterion-based anchor system, encompassing discrete units of work (DU), entrustable, essential, and important tasks of the profession (EEIT), and curricular role (CR), was used to evaluate the quality of TP-EPA3. Overall scores below 4.07, or scores for DU, EEIT, and CR domains below 4.17. 4.00, and 4.00, respectively, indicate the need for modifications. Results: The TP-EPA3 demonstrated good validity, surpassing the required cut-off score with an average overall EQual score of 4.21 (SD = 0.41). Specific domain scores for DU, EEIT, and CR were 3.90 (SD = 0.69), 4.46 (SD = 0.44), and 4.42 (SD = 0.45), respectively. Subsequent revisions clarified observation contexts, enhancing specificity and focus. Further validation of the revised TP-EPA3 and a thorough examination of its reliability and validity are needed. Conclusion: The successful validation of TP-EPA3 suggests its potential as a valid assessment tool in occupational therapy education, offering a structured approach for developing competency in providing health education and consultation. This process model for EPA development and validation can guide occupational therapists in creating tailored EPAs for diverse specialties and settings. [ABSTRACT FROM AUTHOR]

Disparities in data underlying clinical genomic interpretation is an acknowledged problem, but there is a paucity of data demonstrating it. The All of Us Research Program is collecting data including whole-genome sequences, health records, and surveys for at least a million participants with diverse ancestry and access to healthcare, representing one of the largest biomedical research repositories of its kind. Here, we examine pathogenic and likely pathogenic variants that were identified in the All of Us cohort. The European ancestry subgroup showed the highest overall rate of pathogenic variation, with 2.26% of participants having a pathogenic variant. Other ancestry groups had lower rates of pathogenic variation, including 1.62% for the African ancestry group and 1.32% in the Latino/Admixed American ancestry group. Pathogenic variants were most frequently observed in genes related to Breast/Ovarian Cancer or Hypercholesterolemia. Variant frequencies in many genes were consistent with the data from the public gnomAD database, with some notable exceptions resolved using gnomAD subsets. Differences in pathogenic variant frequency observed between ancestral groups generally indicate biases of ascertainment of knowledge about those variants, but some deviations may be indicative of differences in disease prevalence. This work will allow targeted precision medicine efforts at revealed disparities. A comparison of the frequency of pathogenic mutations in 73 genes in the All of Us cohort highlights the differences in pathogenic variation attributed to ancestry. [ABSTRACT FROM AUTHOR]

Objectives To compare the risk of PsA in psoriasis (PsO) patients treated with acitretin vs DMARDs. Methods This retrospective study used Taiwan's National Health Insurance Research Database from 1997 to 2013. Adult PsO patients without PsA prescribed acitretin or DMARDs for ≥30 days within a year were assigned to the acitretin cohort or DMARDs cohort, respectively. Patients in the acitretin cohort prescribed DMARDs for >7 days, or in the DMARDs cohort prescribed acitretin for >7 days, were excluded. Cumulative incidence of PsA were determined within both cohorts using the Kaplan–Meier method. The hazard ratio (HR) comparing acitretin to DMARDs was calculated with Cox regression models, adjusting for demographic and clinical covariates including the use of NSAIDs and comorbidities. Results The study included 1948 patients in each cohort. The 5-year cumulative incidence of PsA in the acitretin cohort was lower than that in the reference cohort (7.52% vs 9.93%; P  = 0.005), with a more pronounced difference in the subpopulation receiving NSAIDs treatment. However, in subpopulations without NSAIDs treatment, the 5-year cumulative incidence of PsA in the acitretin cohort was comparable to the DMARDs cohort (5.26% vs 6.98%; P  = 0.106). Acitretin was not associated with PsA development in PsO (HR 0.83, 95% confidence interval 0.65–1.05). This risk remained consistent regardless of adjustments for NSAID treatment and comorbidities. Other independent risk factors for PsA included female and NSAIDs treatment. Conclusion Compared with DMARDs, acitretin was not associated with increased PsA risk in PsO patients. [ABSTRACT FROM AUTHOR]

Background and Objectives: The pancreatic solid pseudopapillary neoplasm (SPN), a rare tumor predominantly affecting young women, has seen an increased incidence due to improved imaging and epidemiological knowledge. This study aimed to understand the outcomes of different interventions, possible complications, and associated risk factors. Materials and Methods: This study retrospectively analyzed 24 patients who underwent pancreatic surgery for SPNs between September 1998 and July 2020. Results: Surgical intervention, typically required for symptomatic cases or pathological confirmation, yielded favorable outcomes with a 5-year survival rate of up to 97%. Despite challenges in standardizing preoperative evaluation and follow-up protocols, aggressive complete resection showed promising long-term survival and good oncological outcomes. Notably, no significant differences were found between conventional and minimally invasive (MI) surgery in perioperative outcomes. Histopathological correlations were lacking in prognosis and locations. Among the patients, one developed diffuse liver metastases 41 months postoperatively but responded well to chemotherapy and transcatheter arterial chemoembolization, with disease stability observed at 159 postoperative months. Another patient developed nonalcoholic steatohepatitis after surgery and underwent liver transplantation, succumbing to poor medication adherence 115 months after surgery. Conclusions: These findings underscore the importance of surgical intervention in managing SPNs and suggest the MI approach as a viable option with comparable outcomes to conventional surgery. [ABSTRACT FROM AUTHOR]

Ago2 differentially regulates oncogenic and tumor-suppressive miRNAs in cancer cells. This discrepancy suggests a secondary event regulating Ago2/miRNA action in a context-dependent manner. We show here that a positive charge of Ago2 K212, that is preserved by SIR2-mediated Ago2 deacetylation in cancer cells, is responsible for the direct interaction between Ago2 and Caveolin-1 (CAV1). Through this interaction, CAV1 sequesters Ago2 on the plasma membranes and regulates miRNA-mediated translational repression in a compartment-dependent manner. Ago2/CAV1 interaction plays a role in miRNA-mediated mRNA suppression and in miRNA release via extracellular vesicles (EVs) from tumors into the circulation, which can be used as a biomarker of tumor progression. Increased Ago2/CAV1 interaction with tumor progression promotes aggressive cancer behaviors, including metastasis. Ago2/CAV1 interaction acts as a secondary event in miRNA-mediated suppression and increases the complexity of miRNA actions in cancer. Synopsis: A direct interaction between Ago2 and CAV1, mediated by the positive charge of Ago2 K212, increases the complexity of miRNA actions and modulates exosomal cargo sorting of metastatic tumors. Ago2 directly binds to the CSD of CAV1 through W199FGFHQSVRPSLWK212, the CBM of Ago2 in cancer cells. The positive charge of Ago2 lysine 212, which is preserved by SIRT-2-mediated deacetylation in cancer cells, in the CBM is required for Ago2/CAV1 interaction. Elevated Ago2/CAV1 interaction in metastatic tumors increases the plasma membrane-association of Ago2, complexity of miRNA-mediated mRNA expression, and Ago2/miRNA release via exosomes. A direct interaction between Ago2 and CAV1, mediated by the positive charge of Ago2 K212, increases the complexity of miRNA actions and modulates exosomal cargo sorting of metastatic tumors. [ABSTRACT FROM AUTHOR]

Background In the era of biologic therapy, phototherapy and methotrexate (MTX) are still commonly used for treatment in patients with moderate-to-severe psoriasis. However, the skin cancer risk following a combination of MTX and narrowband ultraviolet B (NB-UVB) has rarely been explored. Objectives To investigate whether MTX plus NB-UVB increases skin cancer risk in patients with psoriasis. Methods We conducted a retrospective cohort study of data in the Taiwan National Health Insurance Research Database from 1997 to 2013. Cumulative incidences and multivariate analysis were investigated using a competing risk regression model, comparing skin cancer risk between cohorts of people having combination therapy and those using NB-UVB alone, matched for relative confounders. We further conducted a sensitivity analysis for those receiving a higher MTX dose. Standardized incidence ratios (SIRs) were calculated for skin cancer risk. Results We enrolled 3203 participants in each cohort. No significant differences in skin cancers were noted between the two cohorts for the cumulative incidences (log-rank test, P = 0.28) and for the hazard ratio (HRs) [adjusted HR 0.50, 95% confidence interval (CI) 0.15–1.63, P = 0.247] in the competing risk regression model. There were also no significant differences between those receiving higher-dose MTX and UVB alone in the cumulative incidences of skin cancers (P = 0.23) and the HR (adjusted HR = 0.29, 95% CI 0.04–2.21, P = 0.23) in the multivariate analysis. There was no significant difference in the SIR between the two cohorts compared with the general population. Conclusions In the Taiwanese population, MTX does not increase skin cancer risk in patients with moderate-to-severe psoriasis receiving NB-UVB. [ABSTRACT FROM AUTHOR]

NME3 is a member of the nucleoside diphosphate kinase (NDPK) family localized on the mitochondrial outer membrane (MOM). Here, we report a role of NME3 in hypoxia-induced mitophagy dependent on its active site phosphohistidine but not the NDPK function. Mice carrying a knock-in mutation in the Nme3 gene disrupting NME3 active site histidine phosphorylation are vulnerable to ischemia/reperfusion-induced infarction and develop abnormalities in cerebellar function. Our mechanistic analysis reveals that hypoxia-induced phosphatidic acid (PA) on mitochondria is essential for mitophagy and the interaction of DRP1 with NME3. The PA binding function of MOM-localized NME3 is required for hypoxia-induced mitophagy. Further investigation demonstrates that the interaction with active NME3 prevents DRP1 susceptibility to MUL1-mediated ubiquitination, thereby allowing a sufficient amount of active DRP1 to mediate mitophagy. Furthermore, MUL1 overexpression suppresses hypoxia-induced mitophagy, which is reversed by co-expression of ubiquitin-resistant DRP1 mutant or histidine phosphorylatable NME3. Thus, the site-specific interaction with active NME3 provides DRP1 a microenvironment for stabilization to proceed the segregation process in mitophagy. NME3 is a member of NDPK family. Here, Chen et. al., discover that histidine phosphorylatable NME3 is required for hypoxia-induced mitophagy via PA-dependent interaction with Drp1, which is protected from MUL1-mediated ubiquitination for mitophagy. [ABSTRACT FROM AUTHOR]

Disparities in data underlying clinical genomic interpretation is an acknowledged problem, but there is a paucity of data demonstrating it. The All of Us Research Program is collecting data including whole-genome sequences, health records, and surveys for at least a million participants with diverse ancestry and access to healthcare, representing one of the largest biomedical research repositories of its kind. Here, we examine pathogenic and likely pathogenic variants that were identified in the All of Us cohort. The European ancestry subgroup showed the highest overall rate of pathogenic variation, with 2.26% of participants having a pathogenic variant. Other ancestry groups had lower rates of pathogenic variation, including 1.62% for the African ancestry group and 1.32% in the Latino/Admixed American ancestry group. Pathogenic variants were most frequently observed in genes related to Breast/Ovarian Cancer or Hypercholesterolemia. Variant frequencies in many genes were consistent with the data from the public gnomAD database, with some notable exceptions resolved using gnomAD subsets. Differences in pathogenic variant frequency observed between ancestral groups generally indicate biases of ascertainment of knowledge about those variants, but some deviations may be indicative of differences in disease prevalence. This work will allow targeted precision medicine efforts at revealed disparities. A comparison of the frequency of pathogenic mutations in 73 genes in the All of Us cohort highlights the differences in pathogenic variation attributed to ancestry. [ABSTRACT FROM AUTHOR]

The prevalence of drug‐resistant bacterial pathogens foreshadows a healthcare crisis. Calcium‐dependent antibiotics (CDAs) are promising candidates to combat infectious diseases as many of them show modes of action (MOA) orthogonal to widespread resistance mechanisms. The calcium dependence is nonetheless one of the hurdles toward realizing their full potential. Using laspartomycin C (LspC) as a model, we explored the possibility of reducing, or even eliminating, its calcium dependence. We report herein a synthetic LspC analogue (B1) whose activity no longer depends on calcium and is instead induced by phenylboronic acid (PBA). In LspC, Asp1 and Asp7 coordinate to calcium to anchor it in the active conformation; these residues are replaced by serine in B1 and condense with PBA to form a boronic ester with the same anchoring effect. Using thin‐layer chromatography, MS, NMR, and complementation assays, we demonstrate that B1 inhibits bacterial growth via the same MOA as LspC, i.e. sequestering the cell wall biosynthetic intermediate undecaprenyl phosphate. B1 is as potent and effective as LspC against several Gram‐positive bacteria, including methicillin‐resistant Staphylococcus aureus and vancomycin‐resistant Enterococcus. Our success in converting a CDA to a boron‐dependent antibiotic opens a new avenue in the design and functional control of drug molecules. [ABSTRACT FROM AUTHOR]

The prevalence of drug‐resistant bacterial pathogens foreshadows a healthcare crisis. Calcium‐dependent antibiotics (CDAs) are promising candidates to combat infectious diseases as many of them show modes of action (MOA) orthogonal to widespread resistance mechanisms. The calcium dependence is nonetheless one of the hurdles toward realizing their full potential. Using laspartomycin C (LspC) as a model, we explored the possibility of reducing, or even eliminating, its calcium dependence. We report herein a synthetic LspC analogue (B1) whose activity no longer depends on calcium and is instead induced by phenylboronic acid (PBA). In LspC, Asp1 and Asp7 coordinate to calcium to anchor it in the active conformation; these residues are replaced by serine in B1 and condense with PBA to form a boronic ester with the same anchoring effect. Using thin‐layer chromatography, MS, NMR, and complementation assays, we demonstrate that B1 inhibits bacterial growth via the same MOA as LspC, i.e. sequestering the cell wall biosynthetic intermediate undecaprenyl phosphate. B1 is as potent and effective as LspC against several Gram‐positive bacteria, including methicillin‐resistant Staphylococcus aureus and vancomycin‐resistant Enterococcus. Our success in converting a CDA to a boron‐dependent antibiotic opens a new avenue in the design and functional control of drug molecules. [ABSTRACT FROM AUTHOR]

Psoriasis can affect individuals of all age groups. While the epidemiology of psoriasis in adults has been extensively studied, there is limited research specifically investigating pediatric cases. This study aimed to investigate the prevalence and incidence of skin psoriasis (PsO) and psoriatic arthritis (PsA) among pediatric patients in Taiwan. A nationwide cohort of 17 535 patients with psoriatic diseases under the age of 18 was enrolled from the National Health Insurance Research Database for the period 2000–2013, including 16 129 PsO patients and 2022 PsA patients. The age‐ and sex‐standardized prevalence and incidence of pediatric PsO and PsA were calculated. The 2007 yearly reports of age‐ and sex‐specific distribution of the general population was adopted as a standard. The results showed that between 2000 and 2013, the prevalence for pediatric PsO increased from 0.03% to 0.07%, and from 0.003% to 0.014% for pediatric PsA. During the same period, the incidence slightly decreased from 19.81 to 17.55 per 100 000 for pediatric PsO but increased from 1.02 to 5.06 per 100 000 for pediatric PsA. Adolescents (12 to <18 years) had higher prevalence and incidence rates of PsO and PsA than children (aged ≤ 12 years), with no sex difference observed in either age group. PsA preceding PsO was more common among children than adolescents (27.07% vs. 13.46%). This study provides important insights into the prevalence and incidence of psoriatic diseases in the pediatric population. Further research is needed to identify risk factors for pediatric psoriasis and to investigate its long‐term health outcomes. [ABSTRACT FROM AUTHOR]

Objective: Prior studies comparing minimally invasive surgery with open surgery among patients with endometrial cancer have reported similar survival outcomes and improved perioperative outcomes with minimally invasive surgery (MIS). However, patients with Type II endometrial cancer were underrepresented in these studies. We sought to compare the overall survival and surgical outcomes between open surgery and MIS in a large cohort of women with Type II endometrial cancer. Methods: Using data from the National Cancer Database, we identified a cohort of women who underwent hysterectomy for type II endometrial cancer (serous, clear cell, and carcinosarcoma) between January 2010 and December 2014. The primary outcome was a comparison of the overall survival for MIS with that for the open approach. The secondary outcomes included a comparison of the length of hospital stay, readmission within 30 days of discharge, and 30- and 90-day mortality. Outcomes were compared between the cohorts using the Mann–Whitney U test, Pearson's chi-square test, or Fisher's exact test. Multivariable logistic regression with inverse propensity weighting was used to determine clinical characteristics that were statistically significant predictors of outcomes. p values < 0.05 were considered significant. Results: We identified 12,905 patients with Type II, Stage I–III endometrial cancer that underwent a hysterectomy. In total, 7123 of these women (55.2%) underwent MIS. The rate of MIS increased from 39% to 64% over four years. Women who underwent MIS were more often White, privately insured, older, and had a higher income. The laparotomy group had a higher rate of carcinosarcoma histology (30.9% vs. 23.6%, p < 0.001), stage III disease (38.4% vs. 27.4%, p < 0.001), and larger primary tumors (59 vs. 45 mm, p < 0.001). Lymph node dissection was more commonly performed in the MIS group (89.6% vs. 85.4%, p < 0.001). With regard to adjuvant therapy, subjection to postoperative radiation was more common in the MIS group (37% vs. 40.1%, p < 0.001), while chemotherapy was more common in the laparotomy group (37.6% vs. 33.9%, p < 0.001). The time interval between surgery and the initiation of chemotherapy was shorter in the MIS group (39 vs. 42 days, p < 0.001). According to the results of propensity-score-weighted analysis, MIS was associated with superior overall survival (101.7 vs. 86.7 months, p = 0.0003 determined using the long-rank test), which corresponded to a 10% decreased risk of all-cause mortality (HR 0.9; CI 0.857–0.954, p = 0.0002). The survival benefit was uniform across all three histology types and stages. MIS was associated with superior perioperative outcomes, including shorter length of stay (1 vs. 4 days, p < 0.001), lower 30-day readmission rates (2.5% vs. 5%), and lower 30- and 90-day postoperative mortality (0.5% vs. 1.3% and 1.5% vs. 3.6%, respectively; p < 0.001 for both). The increased adoption of MIS from 2010 to 2014 corresponds to a decrease in 90-day postoperative mortality (2.8% to 2.2%, r = −0.89; p = 0.04) and overall mortality (51% to 38%, r = −0.95; p = 0.006). Conclusions: In a large cohort of patients from the National Cancer Database, MIS was associated with improved overall survival and superior perioperative outcomes compared to open surgery among women with Type II endometrial cancer. A decrease in postoperative mortality and a shorter interval between surgery and the initiation of chemotherapy may contribute to the survival benefit of MIS. A racial and economic disparity in the surgical management of Type II endometrial cancer was identified, and further investigation is warranted to narrow this gap and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC), a common primary tumor of liver is a leading cause of cancer‐associated deaths. Improving cellular apoptosis and enhancing autophagic clearance is been considered to improve treatment outcomes of HCC. Polyphenols from Pinus morrisonicola (Hayata) have shown various physiological and therapeutic benefits and the flavonoid chrysin is been known for their anticancer effects. However, the main bioactive principle and the mechanism underlying the antitumor activity of pine needle extract are not clear yet. In this study, the effects of ethanol extract from pine needle on HCC cells were determined. The results show that when compared with administration of chrysin alone, a fraction containing pinocembrin, chrysin, and tiliroside significantly reduced autophagy and increased apoptosis. The results also correlated with decrease in cell cycle regulators and the autophagic proteins like LC3‐II. Collectively, the results imply the fraction containing pinocembrin, chrysin, and tiliroside as an ideal complementary medicine for an effective antitumor activity. [ABSTRACT FROM AUTHOR]

We aimed to develop an accurate and efficient skin cancer classification system using deep-learning technology with a relatively small dataset of clinical images. We proposed a novel skin cancer classification method, SkinFLNet, which utilizes model fusion and lifelong learning technologies. The SkinFLNet's deep convolutional neural networks were trained using a dataset of 1215 clinical images of skin tumors diagnosed at Taichung and Taipei Veterans General Hospital between 2015 and 2020. The dataset comprised five categories: benign nevus, seborrheic keratosis, basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. The SkinFLNet's performance was evaluated using 463 clinical images between January and December 2021. SkinFLNet achieved an overall classification accuracy of 85%, precision of 85%, recall of 82%, F-score of 82%, sensitivity of 82%, and specificity of 93%, outperforming other deep convolutional neural network models. We also compared SkinFLNet's performance with that of three board-certified dermatologists, and the average overall performance of SkinFLNet was comparable to, or even better than, the dermatologists. Our study presents an efficient skin cancer classification system utilizing model fusion and lifelong learning technologies that can be trained on a relatively small dataset. This system can potentially improve skin cancer screening accuracy in clinical practice. [ABSTRACT FROM AUTHOR]

We aimed to develop an accurate and efficient skin cancer classification system using deep-learning technology with a relatively small dataset of clinical images. We proposed a novel skin cancer classification method, SkinFLNet, which utilizes model fusion and lifelong learning technologies. The SkinFLNet's deep convolutional neural networks were trained using a dataset of 1215 clinical images of skin tumors diagnosed at Taichung and Taipei Veterans General Hospital between 2015 and 2020. The dataset comprised five categories: benign nevus, seborrheic keratosis, basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. The SkinFLNet's performance was evaluated using 463 clinical images between January and December 2021. SkinFLNet achieved an overall classification accuracy of 85%, precision of 85%, recall of 82%, F-score of 82%, sensitivity of 82%, and specificity of 93%, outperforming other deep convolutional neural network models. We also compared SkinFLNet's performance with that of three board-certified dermatologists, and the average overall performance of SkinFLNet was comparable to, or even better than, the dermatologists. Our study presents an efficient skin cancer classification system utilizing model fusion and lifelong learning technologies that can be trained on a relatively small dataset. This system can potentially improve skin cancer screening accuracy in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Research studies have demonstrated that Midkine (MDK) can influence the expression and activity of Renin-angiotensin system (RAS) components. Angiotensin II is involved in tumor growth and angiogenesis in different cancers. We previously observed Angiotensin II receptor blockers (ARBs) improve the survival rates of patients with oral cancers. These findings have prompted us to investigate whether MDK can influence the RAS pathway, mainly through its association with angiotensin II type 1 receptor (AT1R), which contributes to the observed poor prognosis in head and neck squamous cell carcinoma (HNSCC) patients. Methods: MDK and AT1R expressions were examined in 150 HNSCC patients post-operation by immunohistochemical staining between 1 January 2010 and 31 December 2016. We tested the over-expression and silencing of MDK to evaluate the AT1R expression and functional biological assays in HNSCC cell lines HSC-3 and SAS. Results: Positive expression of MDK is correlated with positive AT1R expression. MDK predicted poor NSCC patients' survival. Silencing MDK could suppress AT1R and pAKT expression and reduce the growth, migration, and invasion of HNSCC cells. ARB also inhibits MDK stimulating HNSCC cell proliferation. Overexpression of MDK could upregulate AT1R and pAKT. Conclusions: MDK is an independent prognostic factor of HNSCC post-operation, and AT1R regulates HNSCC cell growth, invasion, and migration. Positive MDK and AT1R expressions are highly correlated. Mechanistically, the interaction between MDK and AT1R is crucial for MDK-mediated cell viability, and inhibiting AT1R can effectively counteract or abolish these effects. Furthermore, MDK exerts a regulatory role in the expression of AT1R, as well as in the growth and motility of HNSCC cells. These findings highlight the involvement of the interaction between MDK, AT1R, and the pAkt signaling pathways in HNSCC cell viability growth. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most prevalent human cancer globally. 5-Fluorouracil (5-FU)-based systemic chemotherapy is the primary strategy for advanced CRC treatment, yet is limited by poor response rate. Deregulated activation of signal transducer and activator of transcription 3 (STAT3) is fundamental to driving CRC malignant transformation and a poor prognostic marker for CRC, underscoring STAT3 as a promising CRC drug target. Dehydroxyhispolon methyl ether (DHME) is an analog of Hispolon, an anticancer polyphenol abundant in the medicinal mushroom Phellinus linteus. Previously, we have established DHME's cytotoxic effect on human CRC cell lines by eliciting apoptosis through the blockade of WNT/β-catenin signaling, a preeminent CRC oncogenic pathway. Herein, we unraveled that compared with 5-FU, DHME is a more potent killer of CRC cells while being much less toxic to normal colon epithelial cells. DHME suppressed both constitutive and interleukin 6 (IL-6)-induced STAT3 activation represented by tyrosine 705 phosphorylation of STAT3 (p-STAT3 (Y705)); notably, DHME-induced CRC apoptosis and clonogenicity limitation were abrogated by ectopic expression of STAT3-C, a dominant-active STAT3 mutant. Additionally, we proved that BCL-2 downregulation caused by DHME-mediated STAT3 blockage is responsible for DHME-induced CRC cell apoptosis. Lastly, DHME inhibited SRC activation, and v-src overexpression restored p-STAT3 (Y705) levels along with lowering the levels of apoptosis in DHME-treated CRC cells. We conclude DHME provokes CRC cell apoptosis by blocking the SRC/STAT3/BCL-2 axis besides thwarting WNT/β-catenin signaling. The notion that DHME targets two fundamental CRC signaling pathways underpins the potential of DHME as a CRC chemotherapy agent. [ABSTRACT FROM AUTHOR]

COVID-19 is a highly transmittable respiratory illness caused by SARS-CoV-2, and acute lung injury (ALI) is the major complication of COVID-19. The challenge in studying SARS-CoV-2 pathogenicity is the limited availability of animal models. Therefore, it is necessary to establish animal models that can reproduce multiple characteristics of ALI to study therapeutic applications. The present study established a mouse model that has features of ALI that are similar to COVID-19 syndrome to investigate the role of ACE2 and the administration of the Chinese herbal prescription NRICM101 in ALI. Mice with genetic modifications, including overexpression of human ACE2 (K18-hACE2 TG) and absence of ACE2 (mACE2 KO), were intratracheally instillated with hydrochloric acid. The acid intratracheal instillation induced severe immune cell infiltration, cytokine storms, and pulmonary disease in mice. Compared with K18-hACE2 TG mice, mACE2 KO mice exhibited dramatically increased levels of multiple inflammatory cytokines (IL-6 and TNF-α) in bronchoalveolar lavage fluid, histological evidence of lung injury, and dysregulation of MAPK and MMP activation. In mACE2 KO mice, NRICM101 could ameliorate the disease progression of acid-induced ALI. In conclusion, the established mouse model provided an effective platform for researchers to investigate pathological mechanisms and develop therapeutic strategies for ALI, including COVID-19-related ALI. [ABSTRACT FROM AUTHOR]

Thrips-transmitted tomato spotted wilt orthotospovirus (TSWV) causes spotted wilt disease in peanut (Arachis hypogaea L.) and limits yield. Breeding programs have been developing TSWV-resistant cultivars, but availability of sources of resistance against TSWV in cultivated germplasm is extremely limited. Diploid wild Arachis species can serve as important sources of resistance, and despite ploidy barriers (cultivated peanut is tetraploid), their usage in breeding programs is now possible because of the knowledge and development of induced interspecific allotetraploid hybrids. This study screened 10 wild diploid Arachis and six induced allotetraploid genotypes via thrips-mediated TSWV transmission assays and thrips' feeding assays in the greenhouse. Three parameters were evaluated: percent TSWV infection, virus accumulation, and temporal severity of thrips feeding injury. Results indicated that the diploid A. stenosperma accession V10309 and its derivative-induced allotetraploid ValSten1 had the lowest TSWV infection incidences among the evaluated genotypes. Allotetraploid BatDur1 had the lowest thrips-inflicted damage at each week post thrips release, while diploid A. batizocoi accession K9484 and A. duranensis accession V14167 had reduced feeding damage one week post thrips release, and diploids A. valida accession GK30011 and A. batizocoi had reduced feeding damage three weeks post thrips releasethan the others. Overall, plausible TSWV resistance in diploid species and their allotetraploid hybrids was characterized by reduced percent TSWV infection, virus accumulation, and feeding severity. Furthermore, a few diploids and tetraploid hybrids displayed antibiosis against thrips. These results document evidence for resistance against TSWV and thrips in wild diploid Arachis species and peanut-compatible-induced allotetraploids. [ABSTRACT FROM AUTHOR]

Background: Acitretin has been linked to the development of psychiatric disturbance. Objectives: The aim of this study was to assess the psychiatric hazards in patients with psoriasis prescribed acitretin compared with those prescribed disease-modifying antirheumatic drugs (DMARDs). Methods: This is a nationwide matched cohort study. From Taiwan's National Health Insurance Research Database, adult patients with psoriasis between 1997 and 2013 were screened. Patients prescribed acitretin for at least 30 days per year on average (acitretin cohort) were matched 1:2 with those prescribed DMARDs for at least 30 days per year on average (reference cohort), by means of age, gender, and psoriasis duration. Patients prescribed medication of the corresponding cohort for more than 7 days during the observation period were excluded. Cumulative incidences of psychiatric disorders in both cohorts were plotted with the Kaplan-Meier method. The modified Cox regression models were constructed to estimate hazard ratios (HRs). Results: In total, 1,152 and 2,304 patients in the acitretin and the reference cohorts, respectively, were included. The 4-year cumulative incidence of overall psychiatric disorders (19.62% vs. 12.06%; p < 0.001), mood disorders (12.81% vs. 7.67%; p < 0.001), and psychosis (7.21% vs. 4.63%; p < 0.001) in the acitretin cohort was significantly higher than that in the reference cohort. Acitretin was independently associated with psychiatric disorders (HR 1.51, 95% confidence interval [CI] 1.23–1.85). The risk is more accentuated in the subgroups of comorbid chronic liver disease (HR 2.60, 95% CI: 1.56–4.33) or psoriatic arthritis (HR 3.23, 95% CI: 1.75–5.97). Other independent risk factors included insomnia, acute coronary syndrome, females, and age. Conclusions: Compared with DMARDs, acitretin was associated with higher hazards of psychiatric disorders among psoriasis patients. [ABSTRACT FROM AUTHOR]

Background: Mealtime difficulties related to cognitive functioning negatively impact a patient's life during the various stages of dementia, and they typically cause a burden and stress on family caregivers. Most people with dementia live at home alone or are cared for by informal caregivers, typically their spouses or other family members. However, no suitable screening tools for home-dwelling patients with dementia have been developed, nor have measurements focused on executive and self-eating functions. This study aimed to develop and evaluate the psychometric properties of the Dietary Function Assessment Scale (DFAS) for community-dwelling persons with dementia. Methods: A mixed-method design was used to develop the instrument. Methods included a comprehensive literature review to identify the item pool and an expert panel to assess the initial item pool. We performed convenience sampling of 190 home-dwelling people with dementia for psychometrical evaluation. The psychometric properties tests included item and factor analyses, criterion-related validity testing, internal consistency reliability testing, and defining the optimal cut-off values. The study was conducted from 2018 to 2019. Results: Items were generated based on an extensive literature review and pre-existing scales related to mealtime and executive functions in persons with dementia. The S-CVI/Ave of the DFAS was 0.89. A Principal Component factor analysis demonstrated seven items, with a two-factor structure accounting for 56.94% of the total variance. The two extracted factors were Self-eating ability and Dietary executive function. The confirmatory factor analysis indicated a good model fit. The criterion-related validity was adequate (r = -0.528, p < 0.01). The reliability of Cronbach's alpha internal consistency was 0.74, and McDonald's Omega coefficient was 0.80; the optimal cut-off value of 13 points with an AUC of 0.74 was established to determine poor dietary functioning in persons with dementia. Conclusion: The DFAS was simple, user-friendly, and a valid and reliable instrument to assess dietary functioning in community-dwelling persons with dementia. This short scale can be helpful for caretakers, who can use it to identify the dietary needs of home-dwelling persons with dementia and improve their care and eating experience. [ABSTRACT FROM AUTHOR]

To assess the degree to which removal of FDA' Pregnancy Categories (PC) of medications (A, B, C, and D) from labeling, affects the likelihood that providers will prescribe those medications. Over a one-year period a convenience sample of providers was recruited into a randomized, survey-based, study. Two versions of the survey were randomly distributed; version 1 presented clinical vignettes, drug information, and PC, while version 2, presented the identical information without the PC. Respondents were asked to estimate their likelihood of prescribing the drug. A mixed linear model was constructed, with likelihood of prescription as the dependent variable, treated as interval-scaled. Out of 169 surveys given out, 162 (96%) were returned. Simple effects analysis showed that the presence of PC letter significantly affected the decision to prescribe category B (p<0.001) and C drugs (p=0.008) but not the A or D. Participants were significantly less likely to prescribe class B and C drugs when the letters were not available for review. These findings remained significant even when controlling for covariates (p=0.001). When a PC letter is absent on labeling, physicians were less likely to use category B and C drugs, the most common medications prescribed in pregnancy. [ABSTRACT FROM AUTHOR]

Objective: Whether oral lichen planus (OLP) was potentially malignant remains controversial. Here, we examined associations of ZNF582 methylation (ZNF582m) with OLP lesions, dysplastic features and squamous cell carcinoma (OSCC). Materials and Methods: This is a case–control study. ZNF582m was evaluated in both lesion and adjacent normal sites of 42 dysplasia, 90 OSCC and 43 OLP patients, whereas ZNF582m was evaluated only in one mucosal site of 45 normal controls. High‐risk habits affecting ZNF582m such as betel nut chewing and cigarette smoking were also compared in those groups. Results: OLP lesions showed significantly lower ZNF582m than those of dysplasia and OSCC. At adjacent normal mucosa, ZNF582m increased from patients of OLP, dysplasia, to OSCC. In addition, ZNF582m at adjacent normal sites in OLP patients was comparable to normal mucosa in control group. Dysplasia/OSCC patients with high‐risk habits exhibited significantly higher ZNF582m than those without high‐risk habits. However, ZNF582m in OLP patients was not affected by those high‐risk habits. Conclusions: OLP is unlikely to be potentially malignant based on ZNF582m levels. ZNF582m may also be a potential biomarker for distinguishing OLP from true dysplastic features and OSCC, and for monitoring the malignant transformation of OLP, potentially malignant disorders with dysplastic features and OSCC. [ABSTRACT FROM AUTHOR]

Hexabromocyclododecanes (HBCDs) are endocrine-disrupting and persistent organic compounds commonly used in consumer products such as styrofoam, fire-resistant curtains, construction, aquaculture products, and food containers. Humans can expose to HBCD via dermal, ingestion, and inhalation routes; however, the inhalation exposure to HBCDs is not well characterized, especially for the size-segregated particles, which could quickly deposit into the respiratory system. In this study, we systematically characterized the dermal and inhalation exposures and performed an aggregate risk assessment of HBCDs in Taiwan. Sampling sites were selected considering the traffic or industrial contribution for air (n = 2, Sanchung, and Taichung) and soil sampling (n = 19, near the industrial zones). The quantitative analysis of HBCDs in extracted samples was achieved using LC–MS/MS. Our results showed that the concentrations of total HBCDs ranged from 0.1 to 6.6 pg m−3 in the particulate matter samples and 0.63 to 187 μg kg−1 in soil samples, where γ-HBCD was the dominant species, followed by α-HBCD and β-HBCD. The total HBCDs in the finest particles (i.e., particle size below 0.49 μm) ranged from N.D. to 1.5 pg m−3. However, no consistent trend was observed for the isomer distribution of HBCDs among air samples. Furthermore, the margin of exposure was the lowest through the ingestion pathway (5152 to 22555) and the highest through the inhalation pathway (6.71 × 105 to 2.09 × 107), showing that HBCD-induced health risk can predominantly attribute to ingestion exposure. Nevertheless, the traffic and industrial contribution of inhalable HBCD deserves further studies. [ABSTRACT FROM AUTHOR]

Background: Bowel gangrene represents a major fatal event in acute mesenteric ischemia. Intestinal resection is inevitable in patients with peritonitis and bowel gangrene. This retrospective study aimed to elucidate the benefit of postoperative parenteral anticoagulation in patients with intestinal resection. Methods: Patients with acute mesenteric ischemia and bowel gangrene were recruited retrospectively between January 2007 and December 2019. All patients underwent bowel resection. They were categorized into two groups: patients without immediate parenteral anticoagulant therapy (Group A) and those with immediate parenteral anticoagulant therapy (Group B). Thirty-day mortality and survival were analyzed. Results: A total of 85 patients were included, with 29 patients in Group A and 56 patients in Group B. Patients in Group B had lower 30-day mortality (16.1%) and a higher 2-year survival rate (45.4%) than patients in Group A (30-day mortality: 51.7%, p = 0.001; 2-year survival rate: 19.0%, p = 0.001). In the 30-day mortality multivariate analysis, patients in Group B had a better outcome (odds ratio = 0.080, 95% confidence interval between 0.011 and 0.605, p = 0.014). Patients in Group B also had a better outcome in the survival multivariate analysis (hazard ratio: 0.435, 95% confidence interval between 0.213 and 0.887, p = 0.022). Conclusions: Immediate postoperative parenteral anticoagulant therapy improves prognosis in patients with acute mesenteric ischemia treated by intestinal resection. Trial registration This research was retrospectively approved by the Institutional Review Board (IRB) I&II of Taichung Veterans General Hospital (TCVGH-IRB No.CE21256B) on July 28th, 2021. The informed consent waiver was also approved by IRB I&II of Taichung Veterans General Hospital. The Declaration of Helsinki and ICH-GCP guidelines were followed during this study. [ABSTRACT FROM AUTHOR]

Simple Summary: In 2017, two chimeric antigen receptor-T (CAR-T) therapies were approved by the FDA for advanced/resistant lymphoma and acute lymphoblastic leukemia. However, despite the breakthrough efficacy results, the safety of CAR-T treatment is still a concern for treating physicians and their patients. Moreover, the high rate of relapse in up to 60% of patients previously treated with CAR-T represents a major challenge. There is currently extensive research activity aimed at addressing these shortfalls; strategies include changing the administration plans of CAR-T, combining it with chemotherapy, and even developing new types of CAR-T therapies. This article will focus on new CAR-T strategies that are under investigation and the results of their studies. The year 2017 was marked by the Food and Drug Administration (FDA) approval of the first two chimeric antigen receptor-T (CAR-T) therapies. The approved indications were for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and for the treatment of patients up to 25 years of age with acute lymphoblastic leukemia (ALL) that is refractory or in a second or later relapse. Since then, extensive research activities have been ongoing globally on different hematologic and solid tumors to assess the safety and efficacy of CAR-T therapy for these diseases. Limitations to CAR-T therapy became apparent from, e.g., the relapse in up to 60% of patients and certain side effects such as cytokine release syndrome (CRS). This led to extensive clinical activities aimed at overcoming these obstacles, so that the use of CAR-T therapy can be expanded. Attempts to improve on efficacy and safety include changing the CAR-T administration schedule, combining it with chemotherapy, and the development of next-generation CAR-T therapies, e.g., through the use of CAR-natural killer (CAR-NK) and CAR macrophages (CAR-Ms). This review will focus on new CAR-T treatment strategies in hematologic malignancies, clinical trials aimed at improving efficacy and addressing side effects, the challenges that CAR-T therapy faces in solid tumors, and the ongoing research aimed at overcoming these challenges. [ABSTRACT FROM AUTHOR]

The present chemical investigation on the organic extract of the soft coral Sarcophyton cinereum has contributed to the isolation of four new cembranoids: 16β- and 16α-hydroperoxyisosarcophytoxides (1 and 2), 16β- and 16α-methoxyisosarcophytoxides (3 and 4), and a known cembranoid, lobocrasol (5). The structures of all isolates were elucidated by detailed spectroscopic analysis. Their structures were characterized by a 2,5-dihydrofuran moiety, of which the relative configuration was determined by DU8-based calculation for long-range coupling constants (4JH,H). The cytotoxicity and immunosuppressive activities of all isolates were evaluated in this study. [ABSTRACT FROM AUTHOR]

We performed molecular dynamics simulations to characterize the role of enthalpic interaction in impacting the static and dynamic properties of solvent-free polymer brushes. The intrinsic enthalpic interaction in the simulation was introduced using different attraction strengths between distinct species. Two model systems were considered: one consisting of binary brushes of two different polymer types and the other containing a mixture of homopolymer brushes and free molecules. In the first system, we observed that, when two originally incompatible polymers were grafted to opposing surfaces, the miscibility between them was significantly enhanced. A less favorable intrinsic enthalpic interaction in the brushes resulted in a more stretched chain configuration, a lower degree of inter-brush penetration, and faster segmental relaxation. In the second system, we characterized the solvent capacity of the homopolymer brushes from variations in the energy components of the system as a function of the number of free molecules. We determined that molecular absorption was driven by the release of the entropic frustration for the grafted chains in conjunction with the chemical affinity between the solutes and polymers. The solute distribution function within the inter-wall space showed that solute–polymer mixing in the middle of the gap occurred preferentially when the enthalpic interaction was more favorable. When this was not the case, absorption was predominantly localized near the grafting surface. From the mean square displacement of the solute, we found that the brush profiles restrained the molecular diffusion perpendicular to the grafting wall; the weaker the attraction from the brush, the higher the solute mobility. [ABSTRACT FROM AUTHOR]

Six new polyoxygenated terpenoids, podovirosanes A–F (1–6), and two known polyketides (7 and 8) were isolated from the roots of F. virosa. Their structures, along with absolute configurations, were deduced using spectroscopic analysis as well as computational calculations, including TDDFT calculation of ECD spectra and GIAO NMR calculations combined with DP4+ probability analysis. Compounds 2, 3, 5, and 8 were found to reduce the phosphorylation levels of NF-κB p65 in SARS-CoV-2 pseudovirus-stimulated PMA-differentiated THP-1 cells. [ABSTRACT FROM AUTHOR]

Hematopoietic stem and progenitor cells (HSPCs) mobilization is the movement of HSPCs from the bone marrow to the peripheral blood or tissue induced by stress. HSPC mobilization is a well-known response to protect the host during infection through urgent differentiation of HSPCs to immune cells. Dengue virus (DENV) infection is known to cause stress in infected humans and the mobilizing capacity of HSPCs during DENV infection in affected patients has not been fully investigated. Here, we investigated whether DENV infection can induce HSPC mobilization and if the mobilized HSPCs are permissive to DENV infection. White blood cells (WBCs) were collected from dengue patients (DENV+) and healthy donors and analyzed by flow cytometry and plaque assay. Elevated HSPCs levels were found in the WBCs of the DENV+ group when compared to the healthy group. Mobilization of HSPCs and homing markers (skin and gut) expression decreased as the patients proceeded from dengue without symptoms (DWoWS) to severe dengue (SD). Mobilizing HSPCs were not only permissive to DENV infection, but infectious DENV could be recovered after coculture. Our results highlight the need for further investigation into HSPC mobilization or alterations of hematopoiesis during viral infections such as DENV in order to develop appropriate countermeasures. [ABSTRACT FROM AUTHOR]

Dengue caused by dengue virus (DENV) is a mosquito-borne disease. Dengue exhibits a wide range of symptoms, ranging from asymptomatic to flu-like illness, and a few symptomatic cases may develop into severe dengue, leading to death. However, there are no effective and safe therapeutics for DENV infections. We have previously reported that cytokine expression, especially inflammatory cytokines, was altered in patients with different severities of dengue. Antrodia cinnamomea (A. cinnamomea) is a precious and endemic medical mushroom in Taiwan. It contains unique chemical components and exhibits biological activities, including suppressing effects on inflammation and viral infection-related diseases. According to previous studies, megakaryocytes can support DENV infection, and the number of megakaryocytes is positively correlated with the viral load in the serum of acute dengue patients. In the study, we investigated the anti-DENV effects of two ethanolic extracts (ACEs 1–2) and three isolated compounds (ACEs 3–5) from A. cinnamomea on DENV infection in Meg-01 cells. Our results not only demonstrated that ACE-3 and ACE-4 significantly suppressed DENV infection, but also reduced interleukin (IL)-6 and IL-8 levels. Moreover, the level of the antiviral cytokine interferon (IFN)-α was also increased by ACE-3 and ACE-4 in Meg-01 cells after DENV infection. Here, we provide new insights into the potential use of A. cinnamomea extracts as therapeutic agents against DENV infection. However, the detailed mechanisms underlying these processes require further investigation. [ABSTRACT FROM AUTHOR]

Back-end-of-line compatible 400°C thermally robust perpendicular spin-orbit torque (p-SOT) cells with reduced MgO short fails are demonstrated by the etch-stop-on-MgO process. The stop-on-MgO cell features the SOT channel continuity and no metal redeposition at MgO sidewall after ion beam etching. To the best of our knowledge, the endurance as high as 1010 cycles using the field-free spin-transfer torque (STT) assisted SOT writing is achieved for the first time. The SOT switching current density can be reduced by increasing the STT current density to save write energy. The stop-on-MgO cell does not degrade the cell switching speed, since the switching always starts from the inner free layer and the domain propagation at the extended free layer does not affect junction resistance, as shown by micromagnetic simulation. The simulation also reveals that the thermal stability factor of stop-on-MgO cells is enhanced by the extended free layer, which suffers less from the interference of pinned layer edge stray field. [ABSTRACT FROM AUTHOR]

This study evaluated dose differences in normal organs at risk, such as the lungs, heart, left anterior descending artery (LAD), right coronary artery, left ventricle, and right breast under personalized breast holder (PERSBRA), when using intensity-modulated radiation therapy (IMRT). This study evaluated the radiation protection offered by PERSBRA in left breast cancer radiation therapy. Here, we retrospectively collected data from 24 patients with left breast cancer who underwent breast-conserving surgery as well as IMRT radiotherapy. We compared the dose differences in target coverage and organs at risk with and without PERSBRA. For target coverage, tumor prescribed dose 95% coverage, conformity index, and homogeneity index were evaluated. For organs at risk, we compared the mean heart dose, mean left ventricle dose, LAD maximum and mean dose, mean left lung receiving 20 Gy, 10 Gy, and 5 Gy of left lung volume, maximum and mean coronary artery of the right, maximum of right breast, and mean dose. Good target coverage was achieved with and without PERSBRA. When PERSBRA was used with IMRT, the mean dose of the heart decreased by 42%, the maximum dose of LAD decreased by 26.4%, and the mean dose of LAD decreased by 47.0%. The mean dose of the left ventricle decreased by 54.1%, the volume (V20) of the left lung that received 20 Gy decreased by 22.8%, the volume (V10) of the left lung that received 10 Gy decreased by 19.8%, the volume (V5) of the left lung that received 5 Gy decreased by 15.7%, and the mean dose of the left lung decreased by 23.3%. Using PERSBRA with IMRT greatly decreases the dose to organs at risk (left lung, heart, left ventricle, and LAD). This study found that PERSBRA with IMRT can achieve results similar to deep inspiration breath-hold radiotherapy (DIBH) in terms of reducing the heart radiation dose and the risk of developing heart disease in patients with left breast cancer who cannot undergo DIBH. [ABSTRACT FROM AUTHOR]

Objectives: To utilize the UK Biobank to identify genetic variants associated with the ICD10 (International Classification of Diseases10)-based diagnosis of cerebrovascular disease (CeVD). Background: Cerebrovascular disease occurs because of a complex interplay between vascular, environmental, and genetic factors. It is the second leading cause of disability worldwide. Understanding who may be genetically predisposed to cerebrovascular disease can help guide preventative efforts. Moreover, there is considerable interest in the use of real-world data, such as EHR (electronic health records) to better understand disease mechanisms and to discover new treatment strategies, but whether ICD10-based diagnosis can be used to study CeVD genetics is unknown. Methods: Using the UK Biobank, we conducted a genome-wide association study (GWAS) where we analyzed the genomes of 11,155 cases and 122,705 controls who were sex, age and ancestry-matched in a 1:11 case: control design. Genetic variants were identified by Plink's firth logistic regression and assessed for association with the ICD10 codes corresponding to CeVD. Results: We identified two groups of SNPs closely linked to PITX2 and LRRTM4 that were significantly associated with CeVD in this study (p < 5 x 10−8) and had a minor allele frequency of > 0.5%. Discussion: Disease assignment based on ICD10 codes may underestimate prevalence; however, for CeVD, this does not appear to be the case. Compared to the age- and sex-matched control population, individuals with CeVD were more frequently diagnosed with comorbid conditions, such as hypertension, hyperlipidemia & atrial fibrillation or flutter, confirming their contribution to CeVD. The UK Biobank based ICD10 study identified 2 groups of variants that were associated with CeVD. The association between PITX2 and CeVD is likely explained by the increased rates of atrial fibrillation and flutter. While the mechanism explaining the relationship between LRRTM4 and CeVD is unclear, this has been documented in previous studies. [ABSTRACT FROM AUTHOR]

The aggressive nature and poor prognosis of lung cancer led us to explore the mechanisms driving disease progression. Utilizing our invasive cell‐based model, we identified methylthioadenosine phosphorylase (MTAP) and confirmed its suppressive effects on tumorigenesis and metastasis. Patients with low MTAP expression display worse overall and progression‐free survival. Mechanistically, accumulation of methylthioadenosine substrate in MTAP‐deficient cells reduce the level of protein arginine methyltransferase 5 (PRMT5)‐mediated symmetric dimethylarginine (sDMA) modification on proteins. We identify vimentin as a dimethyl‐protein whose dimethylation levels drop in response to MTAP deficiency. The sDMA modification on vimentin reduces its protein abundance but trivially affects its filamentous structure. In MTAP‐deficient cells, lower sDMA modification prevents ubiquitination‐mediated vimentin degradation, thereby stabilizing vimentin and contributing to cell invasion. MTAP and PRMT5 negatively correlate with vimentin in lung cancer samples. Taken together, we propose a mechanism for metastasis involving vimentin post‐translational regulation. Synopsis: Repression of MTAP‐dependent symmetric dimethylation mediated by PRMT5 increases vimentin protein stability and leads to invasion and metastasis in MTAP‐deficient lung cancer. MTAP loss promotes lung cancer metastasis.MTA accumulation in MTAP‐deficient cancer cells inhibits PRMT5‐mediated symmetric dimethylation on arginine residues of vimentin.Vimentin is destabilized by PRMT5‐mediated symmetric dimethylation.Reduced dimethylation and stabilization of vimentin in MTAP‐deficient cancer cells contributes to invasion and metastasis. [ABSTRACT FROM AUTHOR]

Introduction: The human JC polyomavirus (JCPyV) has been detected in colorectal cancer (CRC) tissues and is suggested to contribute to CRC tumorigenesis. The rearrangement of the JCPyV regulatory region is supposedly associated with CRC development. The progression of CRC involves the stepwise accumulation of mutations. The large tumor antigen (LT) of JCPyV can trigger uncontrolled cell cycle progression by targeting oncogenes, and tumor suppressor genes, and causing chromosome instability. Few studies have focused on the presence of JCPyV DNA in the higher grade of CRC tissues. Methods: We collected 95 tissue blocks from samples of stages I, II, III, and IV CRC. Nested PCR targeting the regulatory region of the viral genome was performed to determine the presence of JCPyV DNA in the various stages of colorectal cancer tissues. Results: The nested PCR results showed that the positive rate of JCPyV DNA increased with the progression of CRC stages. The archetypal-like, non-rearrangement genotype of JCPyV with subtle mutations was the major genotype found in CRC samples. Conclusions: This finding in our study suggests that there may be an association between JCPyV and CRC progression. [ABSTRACT FROM AUTHOR]