Search

Pao-Wen Yen,1 Hsing-Yu Lin,2 Chien-Chih Wu,2 Tai-Chung Huang,3 Shang-Ju Wu,3 Szu-Yu Pan,1,4 Kuan-Yu Hung1,5 1Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan; 2Department of Pharmacy, National Taiwan University Hospital, Taipei City, Taiwan; 3Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan; 4Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei City, Taiwan; 5Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, TaiwanCorrespondence: Chien-Chih Wu, Department of Pharmacy, National Taiwan University Hospital, Taipei City, Taiwan, Tel +886-2-23123456, Email r93451011@gmail.com Kuan-Yu Hung, Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan, Tel +886-2-23123456, Email kyhung@ntu.edu.twBackground: Acute kidney injury (AKI) is a serious complication following high-dose methotrexate (HD-MTX) treatment, despite established preventive measures. This study presents a case report and a retrospective review of patients treated with HD-MTX, aiming to identify risk factors for AKI and propose a modified treatment protocol.Methods: We report a case of a 43-year-old man with diffuse large B-cell lymphoma who developed severe AKI after HD-MTX therapy. Additionally, a retrospective review of 70 patients receiving HD-MTX at our institution was conducted to identify predictors of AKI. Serum methotrexate levels were analyzed to determine their significance in predicting AKI.Results: The index patient developed methotrexate intoxication and severe AKI despite receiving standard prophylactic measures, requiring temporary hemodialysis. The retrospective review identified serum methotrexate levels as a significant predictor of AKI (OR 11.84, 95% CI: 2.62– 53.53, p = 0.001). Higher initial serum methotrexate levels correlated with the development of AKI.Conclusion: Timely measurement of serum methotrexate levels is crucial in managing and preventing AKI in patients undergoing HD-MTX therapy. Based on our findings, we propose a modified HD-MTX treatment protocol to reduce the incidence of AKI. This includes earlier serum methotrexate level monitoring and adjustments in urine alkalization and leucovorin dosing strategies.Keywords: methotrexate, acute kidney injury

Xian Pan,1,2,* Shao-Jie Wu,1,2,* Yi Tang,1,2,* Yan-Feng Zhou,1,2 Jie-Wei Luo,1,3 Zhu-Ting Fang1,2 1Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, People’s Republic of China; 2Department of Interventional Radiology, Fujian Provincial Hospital, Fuzhou, People’s Republic of China; 3Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Fuzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie-Wei Luo; Zhu-Ting Fang, Tel +86 59188217540, Email docluo0421@aliyun.com; 470389481@qq.comPurpose: In China, many patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage. Several studies have shown that triple therapy [transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs)] is beneficial for patient survival. In this study, we aimed to evaluate the efficacy of triple therapy (TACE + TKIs + ICIs) for unresectable HCC (uHCC) and the conversion rate of surgical resection (SR). The primary endpoints were objective response rate (ORR) and disease control rate (DCR) based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST v1.1 and adverse events (AEs), while the secondary endpoint was the conversion rate of patients with uHCC treated with triple therapy followed by SR.Patients and Methods: Forty-nine patients with uHCC who received triple therapy at Fujian Provincial Hospital between January 2020 and June 2022 were retrospectively included. The treatment efficacy, SR conversion rate, and associated AEs were recorded.Results: Among the 49 patients enrolled, the ORRs assessed by mRECIST and RECIST v1.1 were 57.1% (24/42) and 14.3% (6/42), respectively, and the DCRs were 92.9% (39/42) and 88.1% (37/42), respectively. Seventeen (34.7%) patients met the criteria for resectable HCC and underwent resection. The median interval between the start of triple therapy and resection was 113.5 days (range 94.75 to 182 d), and the median number of TACE was 2 (range 1 to 2.5). The patients did not achieve median overall survival or median progression-free survival. Treatment-related AEs occurred in 48 (98%) patients, and 18 (36.7%) patients had grade ≥ 3 AEs.Conclusion: Triple combination therapy resulted in a relatively high ORR and conversion resection rate following uHCC treatment.Keywords: TACE, immune checkpoint inhibitors, tyrosine kinase inhibitor, surgical resection

Shao-Jie Wu,1,2,* Dan-Dan Ruan,1,* Qiu-Yan Wu,1,* Yi Tang,1,2 Jian-Hui Zhang,1 Sen-Lin Cai,1,2 Yan-Feng Zhou,1,2 Jie-Wei Luo,1,3 Zhu-Ting Fang1,2 1Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, People’s Republic of China; 2Department of Interventional Radiology, Fujian Provincial Hospital, Fuzhou, People’s Republic of China; 3Department of Traditional Chinese Medicine, Fujian provincial hospital, Fuzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie-Wei Luo; Zhu-Ting Fang, Email docluo0421@aliyun.com; 470389481@qq.comBackground: Drug-eluting bead transarterial chemoembolization (DEB-TACE) has good efficacy in the treatment of unresectable hepatocellular carcinoma (uHCC), with a relatively high objective response rate (ORR) compared to conventional transarterial chemoembolization (cTACE). This study aimed to evaluate the safety and medium-term clinical efficacy of DEB-TACE combined with lenvatinib (LEN) plus PD-1 inhibitors as a triple therapy for the treatment of uHCC.Methods: Data of patients with uHCC who received triple therapy of DEB-TACE combined with LEN plus PD-1 inhibitors from January 2019 to June 2021 were analyzed retrospectively. The study endpoints were ORR, progression-free survival (PFS), and treatment-related adverse events based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST).Results: Thirty-five patients were included in this study, with a median follow-up period of 15 months. The median cycle of DEB-TACE was 1, while that of all forms of TACE procedures per patient was 2. The median administration time of LEN was 7 months, and the median number of PD-1 inhibitor treatment was 4 cycles. The ORR based on mRECIST was 82.9%, disease control rate was 91.4%, and the median time to response was 7 weeks. Among these, the ORR of Barcelona Clinic Liver Cancer (BCLC) stage A reached 100%, while that of BCLC stages B and C reached 84.6% and 78.9%, respectively. The median PFS was 9 months; the mOS was not reached. Fourteen patients (40%) successfully underwent downstaging conversion and surgical resection, 32 patients (91.4%) experienced treatment-related adverse events, and no grade 5-related adverse reactions occurred.Conclusion: DEB-TACE combined with LEN and PD-1 inhibitors has a high ORR and surgical conversion rate in the treatment of uHCC tumors, and the toxicity and side effects were tolerable.Keywords: unresectable hepatocellular carcinoma, transarterial chemoembolization, drug-eluting bead, lenvatinib, PD-1 inhibitor, combined therapy

Hui Ye,1,2 Jiansong Tong,2 Jianzhang Wu,3 Xia Xu,4 Shenjie Wu,5 Botao Tan,6 Mengjing Shi,5 Jianguang Wang,1 Weibo Zhao,5 Heng Jiang,5 Sha Jin5 1School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Department of Cellular and Molecular Biology, Scripps Research Institute, La Jolla, CA, USA; 3Pharmaceutical College, Wenzhou Medical University, Wenzhou, 4School of Medicine, Zhejiang University, Hangzhou, 5School of the 1st Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, 6School of Medicine, Lishui University, Lishui, People’s Republic of China Abstract: Magnetoliposomes are phospholipid vesicles encapsulating magnetic nanoparticles that can be used to encapsulate therapeutic drugs for delivery into specific organs. Herein, we developed magnetoliposomes containing recombinant human IFNα2b, designated as MIL, and evaluated this combination’s biological safety and therapeutic effect on both cellular and animal hepatocellular carcinoma models. Our data showed that MIL neither hemolyzed erythrocytes nor affected platelet-aggregation rates in blood. Nitroblue tetrazolium-reducing testing showed that MIL did not change the absolute numbers or phagocytic activities of leukocytes. Acute-toxicity testing also showed that MIL had no devastating effect on mice behaviors. All the results indicated that the nanoparticles could be a safe biomaterial. Pharmacokinetic analysis and tissue-distribution studies showed that MIL maintained stable and sustained drug concentrations in target organs under a magnetic field, helped to increase bioavailability, and reduced administration time. MIL also dramatically inhibited the growth of hepatoma cells. Targeting of MIL in the livers of nude mice bearing human hepatocellular carcinoma showed that MIL significantly reduced the tumor size to 38% of that of the control group. Further studies proved that growth inhibition of cells or tumors was due to apoptosis-signaling pathway activation by human IFNα2b. Keywords: recombinant human interferon-α2b, magnetoliposome, hepatocellular carcinoma

Objectives: To investigate whether (18)F- FDG uptake can be applied in dosimetry to facilitate the rapid and accurate evaluation of individual radiation doses after a nuclear accident.Methods: Forty-eight Tibetan minipigs were randomised into a control group (n = 3) and treatment groups (n = 45). (18)F-FDG combined positron-emission tomography and computed tomography (PET/CT) were carried out before total body irradiation (TBI) and at 6, 24 and 72 h after receiving TBI doses ranging from 1 to 11 Gy. Spleen tissues and blood samples were also collected for histological examination, apoptosis and blood analysis.Results: Mean standardised uptake values (SUVs) of the spleen showed significant differences between the experimental and the control groups. Spleen SUV at 6 h post-irradiation showed significant correlation with radiation dose; Spearman's correlation coefficient was 0.97 (P < 0.01). Histological observations showed that damage to the splenic lymphocyte became more severe with an increase in the radiation dose. Moreover, apoptosis was one of the major routes of splenic lymphocyte death, which was also confirmed by flow cytometry analysis.Conclusions: In the Tibetan minipig model, radiation doses have a close relationship with the (18)F-FDG uptake of the spleen. This finding suggests that (18)F-FDG PET/CT may be useful for the rapid detection of individual radiation doses. [ABSTRACT FROM AUTHOR]

This study investigated the mechanisms underlying tubular apoptosis in diabetes by identifying proapoptotic genes that are differentially upregulated by reactive oxygen species in renal proximal tubular cells (RPTCs) in models of diabetes. Total RNAs isolated from renal proximal tubules (RPTs) of 20-week-old heterozygous db/m+, db/db, and db/db catalase (CAT)-transgenic (Tg) mice were used for DNA chip microarray analysis. Real-time quantitative PCR assays, immunohistochemistry, and mice rendered diabetic with streptozotocin were used to validate the proapoptotic gene expression in RPTs. Cultured rat RPTCs were used to confirm the apoptotic activity and regulation of proapoptotic gene expression. Additionally, studies in kidney tissues from patients with and without diabetes were used to confirm enhanced proapoptotic gene expression in RPTs. Bcl-2-modifying factor (Bmf) was differentially upregulated (P<0.01) in RPTs of db/db mice compared with db/m+ and db/db CAT-Tg mice and in RPTs of streptozotocin-induced diabetic mice in which insulin reversed this finding. In vitro, Bmf cDNA overexpression in rat RPTCs coimmunoprecipated with Bcl-2, enhanced caspase-3 activity, and promoted apoptosis. High glucose (25 mmol/L) induced Bmf mRNA expression in RPTCs, whereas rotenone, catalase, diphenylene iodinium, and apocynin decreased it. Knockdown of Bmf with small interfering RNA reduced high glucose-induced apoptosis in RPTCs. More important, enhanced Bmf expression was detected in RPTs of kidneys from patients with diabetes. These data demonstrate differential upregulation of Bmf in diabetic RPTs and suggest a potential role for Bmf in regulating RPTC apoptosis and tubular atrophy in diabetes. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to systematically evaluate the available evidence on risk factors for professional instrumentalists' developing musculoskeletal (MSK) disorders. Methods: Relevant studies were identified by a search of MEDLINE, CINAHL, EMBASE, a manual search of Medical Problems of Performing Artists, and a search of the Performing Arts Medicine Association's online bibliography. Two independent reviewers assessed the methodologic quality of the selected publications using a standardized checklist. The studies' sample characteristics, findings, and quality scores were presented in an evidence table. Results: Two case-control studies and 6 cross-sectional survey designs were included in this review. The median method-score was 61%. Potential risk factors associated with developing MSK complaints included gender, years of playing experience, type of instrument played, playing-related physical (long hours, over-practicing) and psychological stressors (self-pressure/academic), lack of preventive wellness behaviours (taking breaks), and previous trauma. The high degree of methodological (including sample profile) heterogeneity among the studies impeded statistical pooling of relative effect sizes such as odds ratios. Conclusion: The etiology of MSK conditions in instrumental musicians is multifactorial; however, because the majority of research designs were of a cross-sectional survey nature, a temporal relationship between risk factors and the onset of MSK complaints could not be established. Additional case-control studies should be conducted to reveal the most relevant confounding factors, such as exposure to physical stressors during leisure time, the psychosocial environment, and musical work load. Longer-term studies should then focus on more accurately quantifying the degree of risk associated with these risk factors. [ABSTRACT FROM AUTHOR]

Opioid receptors within the CNS regulate pain sensation and mood and are key targets for drugs of abuse. Within the adult rodent hippocampus (HPC), μ-opioid receptor agonists suppress inhibitory parvalbumin-expressing interneurons (PV-INs), thus disinhibiting the circuit. However, it is uncertain if this disinhibitory motif is conserved in other cortical regions, species, or across development. We observed that PV-IN mediated inhibition is robustly suppressed by opioids in hippocampus proper but not neocortex in mice and nonhuman primates, with spontaneous inhibitory tone in resected human tissue also following a consistent dichotomy. This hippocampal disinhibitory motif was established in early development when PV-INs and opioids were found to regulate primordial network rhythmogenesis. Acute opioid-mediated modulation was partially occluded with morphine pretreatment, with implications for the effects of opioids on hippocampal network activity important for learning and memory. Together, these findings demonstrate that PV-INs exhibit a divergence in opioid sensitivity across brain regions that is remarkably conserved across evolution and highlights the underappreciated role of opioids acting through immature PV-INs in shaping hippocampal development.

Background: The effects of physical activity on the development of different types of cancers have not been comprehensively studied. This nationwide, population-based cohort study investigated the effects of leisure-time physical activity (LTPA) on the development of different types of cancer in Taiwanese adults. A total of 67,890 adult participants (≥ 18 y old) from five rounds (2001, 2005, 2009, 2013, and 2017) of the Taiwan National Health Interview Survey were included. LTPA was measured as the metabolic equivalent of task (MET) expenditure per week and was classified as inactive (< 1 MET-h), low (1-7.49 MET-h), or high (≥ 7.5 MET-h). The LTPA and other covariates were collected through in-person interviews at baseline. New-onset cancer was ascertained from histopathological reports. The Fine-Gray sub-distribution method, with death as a competing risk, was used to determine the impact of LTPA on incident cancer risk., Results: During the 844,337 person-years of follow-up, 4,435 individuals developed cancer. Compared to inactive adults, individuals engaging in high levels of LTPA (≥ 7.5 MET-h/week) were significantly associated with a reduced risk of developing cancer (adjusted hazard ratio [aHR] = 0.93; 95% confidence interval [CI] = 0.87-0.99). However, those with low levels of LTPA (1-7.49 MET-h/week) did not exhibit a significant association with a reduced risk of developing cancer (aHR = 1.00; 95% CI = 0.92-1.10). When considering specific types of cancers, participants with high levels of LTPA (≥ 7.5 MET-h/week) had a significantly lower risk of developing bladder cancer (aHR = 0.68; 95% CI = 0.47-0.99), cervical cancer (aHR = 0.48; 95% CI = 0.24-0.95), and thyroid cancer (aHR = 0.64; 95% CI = 0.44-0.93)., Conclusions: Our findings suggest that high LTPA (≥ 7.5 MET-h/week) is significantly associated with a low risk of incident bladder, cervical, and thyroid cancers., (© 2024. The Author(s).)

Cervical cancer, CC, is one of the malignant cancers in women worldwide. Many studies about the genesis and progression of CC have been done at genomic, transcriptional, translational, and epigenetic levels. However, much less is done at post-translational modification (PTM) level. We first used pan-PTM antibodies to compare the pan PTM levels between clinical normal cervical tissues and CC tissues; we then sent the selected samples for label-free identification of acetylation sites. Next, we employed WT or K119A mutant PARP1-EGFP-STREPII plasmid transfection in Hela cells and examined various indexes including colony formation, wound healing, ROS generation, early apoptosis, and immunofluorescence and quantification of proliferation markers (Ki67, PCNA, and p-P53). Last, we examined the levels of multiple important kinases regulating cervical cancer progression. We found that pan-acetylation was the most downregulated in clinical CC samples, whereas the acetylation of PARP1, Poly(ADP-ribose) polymerase-1, was upregulated at K119. Next, we showed that PARP1-WT overexpression significantly suppressed the proliferation and progression in CC cell line Hela, while K119A overexpression didn't show any impact. Finally, PARP1-WT overexpression significantly decreased p-ERK1/2 while didn't affect the phosphorylation levels of other important kinases such as AKT, MTOR, and RPS6. This study discovered a new type of PTM of PARP1 in CC, and showed that PARP1 acetylation at K119 is essential in regulating the proliferation and progression of CC through ERK1/2. Further studies are required to investigate how PARP1 acetylation impact its function., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Denaturation and/or aggregation of proteins under adverse environmental conditions can greatly impair their bioactivity and functional properties. Based on this, this study aims to improve the functional properties of lactoferrin by complexing with berberine and investigate the mechanism using multispectral techniques, molecular docking and dynamics simulations. The results showed that berberine bound to lactoferrin through hydrogen bonding and van der Waals forces and altered its conformation, surface hydrophobicity, amino acid microenvironment, and secondary structure. Molecular docking and dynamics simulations further revealed that berberine inhibited the drastic changes in the lactoferrin structure, contributing to the complex stability. Consequently, the denaturation temperature and degradation temperature (224 °C to 230 °C) and the tolerance to extreme pH, high temperature, and ions of the lactoferrin-berberine complex were improved. This study systematically revealed the mechanism of berberine to improve the functional properties of lactoferrin, contributing to the development and application of novel functional ingredients., Competing Interests: Declaration of competing interest The authors have no conflicts of interest or personal relationships that might influenced the work related to this study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

When operating in space, on-board Silicon Geiger-Mode Avalanche Photodiodes (GM-APDs) are exposed to radiation damage that result in an increase in dark count rates. Thermal annealing has been found to mitigate the damage, although prior studies have largely focused on annealing following a single session of proton irradiation. This work reports that thermal annealing can be performed simply with the built-in thermo-electric coolers of the GM-APDs. Annealing was also done in 10 min intervals for a clearer view of the recovery curve. Mitigation of damage from repeated γ radiation was observed from the: (1) halving of the increase in dark count rates on average and (2) outperformance of room temperature annealing ( 25 ∘ C) by 33 % . Additionally, we show that heavy doses of γ radiation (21 krad) have a probability of causing Random Telegraph Signals in GM-APDs that can be suppressed by lowering the operating temperature., (© 2024. The Author(s).)

Mutations in the well-known Myostatin ( MSTN ) produce a 'double-muscle' phenotype, which makes it commercially invaluable for improving livestock meat production and providing high-quality protein for humans. However, mutations at different loci of the MSTN often produce a variety of different phenotypes. In the current study, we increased the delivery ratio of Cas9 mRNA to sgRNA from the traditional 1:2 to 1:10, which improves the efficiency of the homozygous mutation of biallelic gene. Here, a MSTN Del73C mutation with FGF5 knockout sheep, in which the MSTN and FGF5 dual-gene biallelic homozygous mutations were produced via the deletion of 3-base pairs of AGC in the third exon of MSTN , resulting in cysteine-depleted at amino acid position 73, and the FGF5 double allele mutation led to inactivation of FGF5 gene. The MSTN Del73C mutation with FGF5 knockout sheep highlights a dominant 'double-muscle' phenotype, which can be stably inherited. Both F0 and F1 generation mutants highlight the excellent trait of high-yield meat with a smaller cross-sectional area and higher number of muscle fibers per unit area. Mechanistically, the MSTN Del73C mutation with FGF5 knockout mediated the activation of FOSL1 via the MEK-ERK-FOSL1 axis. The activated FOSL1 promotes skeletal muscle satellite cell proliferation and inhibits myogenic differentiation by inhibiting the expression of MyoD1, and resulting in smaller myotubes. In addition, activated ERK1/2 may inhibit the secondary fusion of myotubes by Ca 2+ -dependent CaMKII activation pathway, leading to myoblasts fusion to form smaller myotubes., Competing Interests: MC, YZ, KY, XX, XZ, JZ, SW, ZL, YY, XG, SQ, GY, SW, HL, AW, GL, SD, HH, FL, DL, ZL No competing interests declared, (© 2023, Chen, Zhao, Yu et al.)

Introduction: Some patients with an infective native aortic aneurysm (INAA) develop an aortic vascular graft or endograft infection (VGEI) even after successful open surgical repair or endovascular intervention. The aim of the systematic review and meta-analysis performed herein was to compare the clinical outcomes of different surgical and antibiotic treatment strategies., Methods: We systematically searched PubMed, MEDLINE, EMBASE and Web of Science. The keywords used for the search were "mycotic aortic aneurysm", "infected aortic aneurysm", "infective native aortic aneurysm", "antibiotics", "surgery", and "endovascular". The search was limited to articles written in English and to studies involving humans. Articles published before 2000 were excluded. Case reports and review articles were excluded., Results: Of the 524 studies retrieved from our search of the databases, 47 articles were included in this study. Among the 47 articles (1546 patients, 72.8% of whom were male) retrieved, five articles were excluded from the subgroup analysis because the data concerning open surgical repair and endovascular intervention could not be separated. The remaining 42 articles included a total of 1179 patients who underwent open surgical repair (622 patients) or endovascular intervention (557 patients) for INAA. There was a statistically significant difference (p = 0.001) in the pooled in-hospital mortality rate between the open surgical repair group (13.2%, 82/622) and the endovascular intervention group (7.2%, 40/557). However, there was a statistically significant difference (p < 0.001) in the aortic VGEI rate between the open surgical repair group (5.4%). 29/540) and endovascular intervention (13.3%, 69/517) group. For patients who underwent open surgical repair, a lower rate of aortic vascular graft infection was associated with long-term antibiotic use (p = 0.005). For patients who underwent endovascular intervention, there was a trend of association (p = 0.071) between the lower rate of aortic endograft infection and lifelong antibiotic use., Conclusion: Infective native aortic aneurysms are life-threatening. The pooled in-hospital mortality rate of the open surgical repair group was significantly higher than that of the endovascular intervention group, whereas the rate of the aortic VGEI in the open surgical repair group was significantly lower than that in the endovascular intervention group. Regardless of whether open surgical repair or endovascular intervention is performed, better long-term outcomes can be achieved with aggressive antibiotic treatment, which is especially important for patients who undergo endovascular intervention., (© 2024. The Author(s).)

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune-mediated primary inflammatory myelinopathy of the central nervous system that primarily affects the optic nerve and spinal cord. The aquaporin 4 antibody (AQP4-Ab) is a specific autoantibody marker for NMOSD. Most patients with NMOSD are seropositive for AQP4-Ab, thus aiding physicians in identifying ways to treat NMOSD. AQP4-Ab has been tested in many clinical and laboratory studies, demonstrating effectiveness in diagnosing NMOSD. Recently, novel assays have been developed for the rapid and accurate detection of AQP4-Ab, providing further guidance for the diagnosis and treatment of NMOSD. This article summarizes the importance of rapid and accurate diagnosis for treating NMOSD based on a review of the latest relevant literature. We discussed current challenges and methods for improvement to offer new ideas for exploring rapid and accurate AQP4-Ab detection methods, aiming for early diagnosis of NMOSD., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To analyse the correlation between temporomandibular joint (TMJ) disc perforation and degenerative joint changes (DJC) on cone-beam computed tomography (CBCT) and related factors., Study Design: A total of 238 female patients with anterior disc displacement without reduction (ADDwoR), accounting for 348 affected joints, requiring TMJ disc open anchorage surgery were included in the study conducted from June 2021 to August 2022. Following TMJ disc open anchorage surgery, patients were divided into two groups: disc perforation (DP) and disc non-perforation (DNP). CBCT was utilised to assess different grades of condyle and articular eminence degenerative changes, and comparisons were made between the two groups regarding DJC and clinically relevant factors., Results: In comparison with the DNP group, the DP group exhibited statistically significant differences in mid- and late-stage condyle bone degenerative changes and bone alterations of the articular eminence (odds ratio [OR] = 7.822; 95% CI [4.438-13.785]; p < 0.001 and OR = 5.575; 95% CI [3.128-9.936]; p < 0.001). Additionally, persistent joint sounds (OR = 1.932; 95% CI [1.011-3.691]; p = 0.046) and longer disease duration (OR = 4.901; 95% CI [2.395-10.028]; p < 0.001) demonstrated statistically significant differences. However, no significant differences were observed between the two groups in terms of age, joint pain and limited mouth opening., Conclusions: Bone degeneration changes in TMJ CBCT images are a high possible risk factor for DP. With an escalation in the degree of condyle degeneration, the risk of DP may increased correspondingly. Persistent joint sounds and extended duration of the disease were also confirmed to be noteworthy clinical risks of DP., (© 2024 John Wiley & Sons Ltd.)

Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of several pain-related substrates in spinal cord dorsal horn and are critically involved in the modification of pain transmission. The current study demonstrated that protein tyrosine phosphatase 1B (PTP1B), a unique endoplasmic reticulum-resident member of PTP family, displayed an activity-dependent increase in its protein expression and synaptic localization in spinal dorsal horn of adult male rats. PTP1B interacted with the Src Homology 3 (SH3) domain of Synapse-Associated Protein 102 (SAP102), one of the postsynaptic scaffolding proteins that anchored PTP1B at postsynaptic sites. The SAP102-tethered PTP1B augmented the synaptic transmission mediated specifically by GluN2B subunit-containing N-methyl-D-aspartate subtype glutamate receptors. Interference with PTP1B activity or disruption of its interaction with SAP102 attenuated GluN2B-mediated nociceptive transmission and ameliorated pain sensitization induced by intraplantar injection of Complete Freund's Adjuvant. These data suggested that the activity-dependent synaptic redistribution of PTP1B served as an important mechanism regulating GluN2B receptor activity and that manipulation of PTP1B synaptic targeting might represent an effective approach for the treatment of chronic inflammatory pain., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Papillary renal neoplasm with reverse polarity is a recently recognized low-grade neoplasm with a favorable prognosis. To date, its cytologic features have not been well documented., Methods: Two patients with papillary renal neoplasm with reverse polarity sampled by fine needle aspiration and core needle biopsy are described, one of whom is under active surveillance without clinical progression and the other is alive and well 16 years after partial nephrectomy., Results: The cytologic features included a mix of papillae and dispersed cells with abundant oncocytic cytoplasm and round, bland nuclei apically displaced away from the papillary core. Immunohistochemistry showed positive staining for GATA3 in both cases. Molecular studies on one of the cases showed a KRAS p.G12V mutation., Conclusions: The cytologic features of this distinctive, indolent neoplasm are important to recognize because patients with papillary renal neoplasm with reverse polarity may be excellent candidates for partial nephrectomy or even active surveillance., (© 2024 American Cancer Society.)

Background: Glenohumeral instability is a common pathology, particularly in young, active patients., Methods: A narrative review was performed to describe the history of surgical treatments for anterior shoulder instability., Results: Open surgical techniques were first described by Bankart in 1923. Techniques include both anatomic soft tissue repairs and nonanatomic procedures to provide constraint to motion and dislocation. Osseous techniques to address glenoid bone loss include both autograft techniques, such as the Latarjet procedure, and the use of various allografts. Technologic advances, particularly arthroscopy, have continued to drive the evolution of treatments. The concept of the glenoid track has furthered our understanding of this pathology to guide appropriate treatment to reduce recurrence., Conclusions: Surgical treatment for anterior shoulder instability continues to evolve in an effort to restore function and prevent additional injury., (Copyright © 2024 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Protein synthesis in response to neuronal activity, known as activity-dependent translation, is critical for synaptic plasticity and memory formation. However, the signaling cascades that couple neuronal activity to the translational events remain elusive. In this study, we identified the role of calmodulin (CaM), a conserved Ca 2+ -binding protein, in ribosomal RNA (rRNA) biogenesis in neurons. We found the CaM-regulated rRNA synthesis is Ca 2+ -dependent and necessary for nascent protein synthesis and axon growth in hippocampal neurons. Mechanistically, CaM interacts with nucleolar DEAD (Asp-Glu-Ala-Asp) box RNA helicase (DDX21) in a Ca 2+ -dependent manner to regulate nascent rRNA transcription within nucleoli. We further found CaM alters the conformation of DDX21 to liberate the DDX21-sequestered RPA194, the catalytic subunit of RNA polymerase I, to facilitate transcription of ribosomal DNA. Using high-throughput screening, we identified the small molecules batefenterol and indacaterol that attenuate the CaM-DDX21 interaction and suppress nascent rRNA synthesis and axon growth in hippocampal neurons. These results unveiled the previously unrecognized role of CaM as a messenger to link the activity-induced Ca 2+ influx to the nucleolar events essential for protein synthesis. We thus identified the ability of CaM to transmit information to the nucleoli of neurons in response to stimulation., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Can local democratic decision-making in authoritarian environments increase or pacify civic engagement and government accountability? Here we conducted an intervention reaching over 20 million people in China. Communities were randomly assigned such that citizens in treatment communities were invited to deliberate and make collective decisions on how local community budgets were allocated through both in-person and online communication channels (participatory budgeting). We find that participatory decision-making in community budgeting increased a wide range of civic-engagement behaviours outside of the budgeting domain 6 months after the start of the intervention. Residents in treatment communities reported more need for improvement from the central government, providing a potential foundation for seeking accountability from the authoritarian regime. These changes were accompanied by a more positive societal outlook and increased satisfaction in the country's policies., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Reactive microglia and recruited peripheral macrophages contribute to the pathogenesis of Alzheimer's dementia (AD). Monocytes, macrophages and microglia all express the marker colony-stimulating factor 1 receptor (CSF1R). 4-Cyano-N-(4-(4-methylpiperazin-1-yl)-2-(4-methylpiperidin-1-yl)phenyl)-1H-pyrrole-2-carboxamide (1) is a high-affinity antagonist for CSF1R. We report the radiosynthesis of both [ 3 H]1 and [ 11 C]1. The PET imaging properties of [ 11 C]1 in mice and baboon were investigated. [ 3 H]1 was studied in B max measurement in post-mortem autoradiography in the frontal cortex, inferior parietal cortex and hippocampus from donors diagnosed with AD and age-matched controls. In vitro binding affinity of 1 was measured commercially. Nor-methyl-1 precursor was radiolabeled with [ 11 C]iodomethane or [ 3 H]iodomethane to produce [ 11 C]1 and [ 3 H]1, respectively. Ex vivo brain biodistribution of [ 11 C]1 was compared in normal mice versus lipopolysaccharide-administered (LPS) murine model of neuroinflammation. Dynamic PET imaging was performed in a healthy male Papio anubis baboon. Post-mortem autoradiography with [ 3 H]1 was performed in frozen sections using a standard saturation binding technique., Results: Compound 1 exhibits a high in vitro CSF1R binding affinity (0.59 nM). [ 11 C]1 was synthesized with high yield. [ 3 H]1 was synthesized similarly (commercially). Biodistribution of [ 11 C]1 in healthy mice demonstrated moderate brain uptake. In LPS-treated mice the brain uptake of [ 11 C]1 was ~ 50% specific for CSF1R. PET/CT [ 11 C]1 study in baboon revealed low brain uptake (0.36 SUV) of [ 11 C]1. Autoradiography with [ 3 H]1 gave significantly elevated B max values in AD frontal cortex versus control (47.78 ± 26.80 fmol/mg vs. 12.80 ± 5.30 fmol/mg, respectively, P = 0.023) and elevated, but not significantly different binding in AD hippocampus grey matter and inferior parietal cortex (IPC) white matter., Conclusions: Compound 1 exhibits a high in vitro CSF1R binding affinity. [ 11 C]1 specifically labels CSF1R in the mouse neuroinflammation, but lacks the ability to efficiently cross the blood-brain barrier in baboon PET. [ 3 H]1 specifically labels CSF1R in post-mortem human brain. The binding of [ 3 H]1 is significantly higher in the post-mortem frontal cortex of AD versus control subjects., (© 2024. The Author(s).)

The European Commission (EC) has tasked the European Medicines Agency (EMA) to provide a recommendation towards the acceptability of titanium dioxide (TiO 2 ) in pharmaceutical products by early 2024 to inform on final decision in early 2025[1]. Unlike the already implemented ban of TiO 2 in foods, removing this excipient from pharmaceutical products will likely have significant impact on the pharmaceutical industry, regulatory agencies, and patients. This commentary explores the challenges facing the pharmaceutical industry tasked with supporting the development and registration of TiO 2 free (TF) drug products. Specifically, justification of formulation changes and potential impact to in vitro and in vivo performance, as well as differences in global regulatory comparative dissolution requirements to justify changing to TF drug product are discussed. Particularly, the uncertainties around how a formulation change such as removal of TiO 2 from immediate release solid oral dosage forms will be viewed in Europe compared to other regions is discussed. To respond to these challenges and avoid disruption to the medicines supply chain in case in vitro data such as dissolution is either too challenging or insufficient to justify changing to TF product, pharmaceutical companies may have to decide if the level of risk is worth the effort needed to reformulate, develop, and register a new TF product., Competing Interests: Declaration of 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., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Within the past decade, single domain antibodies (sdAbs) have been recognized as unique affinity binding reagents that can be tailored for performance in a variety of immunoassay formats. Luminex MagPlex color-coded magnetic microspheres provide a high-throughput platform that enables multiplexed immunoassays. We developed a MagPlex bead-based assay for the detection of SARS-CoV-2, using sdAbs against SARS-CoV-2 nucleocapsid (N) protein in which we engineered the sdAb capture reagents to orient them on the beads. The oriented sdAbs provided an increase in sensitivity over randomly oriented sdAbs for samples of N diluted in buffer, which also translated into better detection of SARS-CoV-2 in clinical samples. We assessed the specificity of the assay by examining seasonal coronavirus clinical samples. In summary, we provide a proof-of-concept that a bead-based assay using sdAbs to detect SARS-CoV-2 is feasible and future research combining it with other sdAb-coated beads that can detect other viruses may provide a useful diagnostic tool., Competing Interests: EG is an inventor on a United States Patent Single Domain Antibodies to SARS-CoV-2 Nucleocapsid Protein. US Patent No. 11,739,137 B2 issued on 8/29/2023. Author AG was employed by Leidos Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Goldman, Sugiharto, Shriver-Lake, Garcia, Wu, Jenkins and Chen.)

The mammalian cerebral cortex comprises a complex neuronal network that maintains a delicate balance between excitatory neurons and inhibitory interneurons. Previous studies, including our own research, have shown that specific interneuron subtypes are closely associated with particular pyramidal neuron types, forming stereotyped local inhibitory microcircuits. However, the developmental processes that establish these precise networks are not well understood. Here we show that pyramidal neuron types are instrumental in driving the terminal differentiation and maintaining the survival of specific associated interneuron subtypes. In a wild-type cortex, the relative abundance of different interneuron subtypes aligns precisely with the pyramidal neuron types to which they synaptically target. In Fezf2 mutant cortex, characterized by the absence of layer 5 pyramidal tract neurons and an expansion of layer 6 intratelencephalic neurons, we observed a corresponding decrease in associated layer 5b interneurons and an increase in layer 6 subtypes. Interestingly, these shifts in composition are achieved through mechanisms specific to different interneuron types. While SST interneurons adjust their abundance to the change in pyramidal neuron prevalence through the regulation of programmed cell death, parvalbumin interneurons alter their identity. These findings illustrate two key strategies by which the dynamic interplay between pyramidal neurons and interneurons allows local microcircuits to be sculpted precisely. These insights underscore the precise roles of extrinsic signals from pyramidal cells in the establishment of interneuron diversity and their subsequent integration into local cortical microcircuits., Competing Interests: Competing interests Gord Fishell is a founder of Regel Therapeutics, which has no competing interests with the present manuscript. Additional Declarations: There is NO Competing Interest.

Flow cytometry can be applied in the detection of fluorescence in situ hybridisation (FISH) signals to efficiently analyse chromosomal aberrations. However, such interphase chromosome (IC) Flow-FISH protocols are currently limited to detecting a single colour. Furthermore, combining IC Flow-FISH with conventional multicolour flow cytometry is difficult because the DNA-denaturation step in FISH assay also disrupts cellular integrity and protein structures, precluding subsequent antigen-antibody binding and hindering concurrent labeling of surface antigens and FISH signals. We developed a working protocol for concurrent multicolour flow cytometry detection of nuclear IC FISH signals and cell surface markers. The protocol was validated by assaying sex chromosome content of blood cells, which was indicative of chimerism status in patients who had received sex-mismatched allogeneic haematopoietic stem cell transplants (allo-HSCT). The method was also adapted to detect trisomy 12 in chronic lymphocytic leukaemia (CLL) subjects. We first demonstrated the feasibility of this protocol in detecting multiple colours and concurrent nuclear and surface signals with high agreement. In clinical validation experiments, chimerism status was identified in clinical samples (n=56) using the optimised IC Flow-FISH method; the results tightly corresponded to those of conventional slide-based FISH (R 2 =0.9649 for XX cells and 0.9786 for XY cells). In samples from patients who received sex-mismatched allo-HSCT, individual chimeric statuses in different lineages could be clearly distinguished with high flexibility in gating strategies. Furthermore, in CLL samples with trisomy 12, this method could demonstrate that enriched trisomy 12 FISH signal was present in B cells rather than in T cells. Finally, by performing combined labelling of chromosome 12, X chromosome, and surface markers, we could detect rare residual recipient CLL cells with trisomy 12 after allo-HSCT. This adaptable protocol for multicolour and lineage-specific IC Flow-FISH advances the technique to allow for its potential application in various clinical contexts where conventional FISH assays are currently being utilised., (Copyright © 2024 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Background: Galectins (GALs) are a family of mammalian sugar-binding proteins specific for β-galactosides. Our previous studies have shown that the larval development of the diamondback moth (Plutella xylostella) is significantly disturbed when fed with recombinant mammalian galectin 1 (GAL1) derived from Escherichia coli. To further explore its applicability, two GAL1-overexpressed Arabidopsis [GAL1-Arabidopsis (whole plant) and GAL1-Arabidopsis-vas (vascular bundle-specific)] lines were established for insecticidal activity and mechanism studies., Results: The expression level of GAL1 in transgenic Arabidopsis is 1-0.5% (GAL1-Arabidopsis) and 0.08-0.01% (GAL1-Arabidopsis-vas) of total leaf soluble protein. Survival, body weight, and food consumption significantly decreased in a time-dependent manner in P. xylostella larvae (with chewing mouthparts) fed on GAL1-Arabidopsis. The mortality of Kolla paulula (with piercing-sucking mouthparts and xylem feeder) fed on GAL1-Arabidopsis-vas was also significantly higher than that fed on wild-type Arabidopsis (WT-Arabidopsis), but was lower than that fed on GAL1-Arabidopsis. The histochemical structure and results of immunostaining suggested that the binding of GAL1 to the midgut epithelium of P. xylostella fed on GAL1-Arabidopsis was dose- and time-dependent. Ultrastructural studies further showed the disruption of microvilli, abnormalities in epithelial cells, and fragments of the peritrophic membrane (PM) in P. xylostella larvae fed on GAL1-Arabidopsis., Conclusion: The insecticidal mechanism of GAL1 involves interference with PM integrity and suggests that GAL1 is a potential candidate for bioinsecticide development. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Metabolic dysfunction-associated fatty liver disease is a metabolic disease caused by abnormal lipid accumulation in the liver. Excessive lipid accumulation results in liver inflammation and fibrosis. Previous studies have demonstrated that the chalcone licochalcone D, which is isolated from Glycyrrhiza inflata Batal, has anti-tumor and anti-inflammatory effects. The present study explored whether licochalcone D can regulate lipid accumulation in fatty liver cells. FL83B hepatocytes were incubated with oleic acid to establish a fatty liver cell model, and then treated with licochalcone D to evaluate the molecular mechanisms underlying the regulation of lipid metabolism. In addition, male C57BL/6 mice were fed a methionine/choline-deficient diet to induce an animal model of metabolic dysfunction-associated steatohepatitis (MASH) and given 5 mg/kg licochalcone D by intraperitoneal injection. In cell experiments, licochalcone D significantly reduced lipid accumulation in fatty liver cells and reduced sterol regulatory element-binding protein 1c expression, blocking fatty acid synthase production. Licochalcone D increased adipose triglyceride lipase and carnitine palmitoyltransferase 1 expression, enhancing lipolysis and fatty acid β-oxidation, respectively. Licochalcone D also significantly increased SIRT-1 and AMPK phosphorylation, reducing acetyl-CoA carboxylase phosphorylation and inhibiting fatty acid synthesis. Licochalcone D also increased the fusion of autophagosomes and lysosomes to promote autophagy, reducing oil droplet accumulation in fatty liver cells. In the animal experiments, licochalcone D effectively reduced the number of lipid vacuoles and degree of fibrosis in liver tissue and inhibited liver inflammation. Thus, licochalcone D can improve MASH by reducing lipid accumulation, inhibiting inflammation, and increasing autophagy., Competing Interests: Declaration of competing interest The authors declared no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Prior studies have investigated cardiac anatomy and clinical parameters as predictors for pulmonary vein and non-pulmonary vein triggers., Objective: We aimed to assess the link between the descending aorta to left inferior pulmonary vein (Dao-LIPV) distance and the occurrence of triggers and drivers in atrial fibrillation (AF) ablation procedures., Methods: Drug-refractory AF patients who underwent first-time index catheter ablation from January 2010 to December 2019 were retrospectively assembled. The Dao-LIPV distance was measured from preablation pulmonary vein computed tomography. Patients were assigned to groups on the basis of the presence of LIPV triggers or drivers. Multivariate logistic regression was used to identify risk factors., Results: A total of 886 consecutive patients with drug-refractory AF were studied, and 63 (7.1%) patients were identified to have LIPV triggers or drivers. The Dao-LIPV distance had a better predictive performance (area under the curve, 0.70) compared with persistent AF (area under the curve, 0.57). Multivariate logistic regression analysis showed that Dao-LIPV distance ≤2.5 mm (odds ratio, 3.96; 95% CI, 2.15-7.29; P < .001) and persistent AF (odds ratio, 1.73; 95% CI, 1.02-2.94]; P = .044) were independent predictors for the presence of LIPV triggers or drivers. A risk score model was established to predict the probability of LIPV triggers or drivers with persistent AF (10.2%), Dao-LIPV distance ≤2.5 mm (11.4%), and both (15.0%)., Conclusion: The proximity of the Dao-LIPV was correlated to the presence of LIPV triggers or drivers. We developed a risk score model indicating that persistent AF and Dao-LIPV distances ≤2.5 mm significantly increase the risk of LIPV triggers or drivers, aiding electrophysiologists in preparing for and performing catheter ablation more effectively., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)