Impact of comorbidities on relapsing rates of Neuromyelitis Optica Spectrum Disorders: Insights from a longitudinal study in Taiwan.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory demyelinating disease characterized by relapsing clinical episodes and the presence of autoantibodies. The impact of comorbidities on relapsing rate of NMOSD patients in Taiwan remains unclear. METHODS: We conducted a longitudinal retrospective study using the largest hospital system in Taiwan from 2006 to 2021. Demographic characteristics, annualized relapse rates (ARR), and comorbidities were examined. RESULTS: We identified 485 NMOSD patients from 2006 to 2021. Of these, 466 had the adult form and 19 (3.9 %) had the pediatric form of NMOSD. The median ARR was 0.51 (interquartile range (IQR): 0.26-1.11) for adults and 0.39 (IQR: 0.21-0.77) for pediatric patients. Comorbidities included malignancy (6.7 %) and autoimmune diseases (21.7 %). The recommended age for malignancy surveillance in NMOSD patients was 43.3 years. Neither malignancy nor autoimmune disease increased the ARR within 3 years post diagnosis in NMOSD patients with comorbidities compared with those without comorbidities. CONCLUSIONS: Our study revealed the ARR within the initial three years after diagnosis was significantly higher, emphasizing the importance of early treatment. We also observed an association between malignancy and NMOSD, and a significantly higher risk of malignancy in adult patients with NMOSD than in the general population (the relative risk was 5.99) that requiring further investigations into the underlying mechanisms. These findings contribute to a better understanding of NMOSD and its comorbidities in Taiwan.

Fused in sarcoma (FUS) inhibits milk production efficiency in mammals.

Efficient milk production in mammals confers evolutionary advantages by facilitating the transmission of energy from mother to offspring. However, the regulatory mechanism responsible for the gradual establishment of milk production efficiency in mammals, from marsupials to eutherians, remains elusive. Here, we find that mammary gland of the marsupial sugar glider contained milk components during adolescence, and that mammary gland development is less dynamically cyclic compared to that in placental mammals. Furthermore, fused in sarcoma (FUS) is found to be partially responsible for this establishment of low efficiency. In mouse model, FUS inhibit mammary epithelial cell differentiation through the cyclin-dependent kinase inhibitor p57Kip2, leading to lactation failure and pup starvation. Clinically, FUS levels are negatively correlated with milk production in lactating women. Overall, our results shed light on FUS as a negative regulator of milk production, providing a potential mechanism for the establishment of milk production from marsupial to eutherian mammals.

The detection methods currently available for protein aggregation in neurological diseases.

Protein aggregation is a pathological feature in various neurodegenerative diseases and is thought to play a crucial role in the onset and progression of neurological disorders. This pathological phenomenon has attracted increasing attention from researchers, but the underlying mechanism has not been fully elucidated yet. Researchers are increasingly interested in identifying chemicals or methods that can effectively detect protein aggregation or maintain protein stability to prevent aggregation formation. To date, several methods are available for detecting protein aggregates, including fluorescence correlation spectroscopy, electron microscopy, and molecular detection methods. Unfortunately, there is still a lack of methods to observe protein aggregation in situ under a microscope. This article reviews the two main aspects of protein aggregation: the mechanisms and detection methods of protein aggregation. The aim is to provide clues for the development of new methods to study this pathological phenomenon.

How renal toxins respond to renal function deterioration and oral toxic adsorbent in pH-controlled releasing capsule.

The number of patients with chronic kidney disease (CKD) is increasing. Oral toxin adsorbents may provide some value. Several uremic toxins, including indoxyl sulfate (IS), p-cresol (PCS), acrolein, per- and poly-fluoroalkyl substances (PFAS), and inflammation markers (interleukin 6 [IL-6] and tumor necrosis factor [TNF]-alpha) have been shown to be related to CKD progression. A total of 81 patients taking oral activated charcoal toxin adsorbents (AC-134), which were embedded in capsules that dissolved in the terminal ileum, three times a day for 1 month, were recruited. The renal function, hemoglobulin (Hb), inflammation markers, three PFAS (PFOA, PFOS, and PFNA), and acrolein were quantified. Compared with the baseline, an improved glomerular filtration rate (GFR) and significantly lower acrolein were noted. Furthermore, the CKD stage 4 and 5 group had significantly higher concentrations of IS, PCS, IL-6, and TNF but lower levels of Hb and PFAS compared with the CKD Stage 3 group at baseline and after the intervention. Hb was increased only in the CKD Stage 3 group after the trial (p = .032). Acrolein did not differ between the different CKD stage groups. Patients with improved GFR (responders) (about 77%) and nonresponders had similar baseline GFR. Responders had higher acrolein and PFOA levels throughout the study and a more significant reduction in acrolein, indicating a better digestion function. Responders had higher acrolein and PFOA levels throughout the study and a more significant reduction in acrolein, while PFOA increased in responders. Both the higher PFOA and lower acrolein may be related to improved eGFR (and possibly to improvements in proteinuria, which we did not measure. Proteinuria is associated with PFAS loss in the urine), AC-134 showed the potential to improve the GFR and decrease acrolein, which might better indicate renal function change. Future studies are needed with longer follow-ups.

Research progress on insect visual electrophysiological techniques.

Insect visual electrophysiological techniques are important to study the electrical characteristics of photoreceptor cells and visual neurons in insects, including electroretinography (ERG) and microelectrode intracellular recording (MIR). ERG records the changes of voltage or electric current in the retina of insects in response to different light stimuli, which occurs outside the cell. MIR records the changes in individual photoreceptor cells or visual neurons of an insect exposed to different lights, which occurs inside the cell. Insect visual electrophysiological techniques can explore the mechanism of electrophysiological response of insects' vision to light and reveal their sensitive light spectra and photoreceptor types. This review introduced the basic structure and the principle of ERG and MIR, and summarized their applications in insect researches in the past 20 years, which would provide references for elucidating the mechanism of light perception in insects and the use of insect phototropism to control pests.

The phosphorylation of carboxyl-terminal eIF2α by SPA kinases contributes to enhanced translation efficiency during photomorphogenesis.

Light triggers an enhancement of global translation during photomorphogenesis in Arabidopsis, but little is known about the underlying mechanisms. The phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2α) at a conserved serine residue in the N-terminus has been shown as an important mechanism for the regulation of protein synthesis in mammalian and yeast cells. However, whether the phosphorylation of this residue in plant eIF2α plays a role in regulation of translation remains elusive. Here, we show that the quadruple mutant of SUPPRESSOR OF PHYA-105 family members (SPA1-SPA4) display repressed translation efficiency after light illumination. Moreover, SPA1 directly phosphorylates the eIF2α C-terminus under light conditions. The C-term-phosphorylated eIF2α promotes translation efficiency and photomorphogenesis, whereas the C-term-unphosphorylated eIF2α results in a decreased translation efficiency. We also demonstrate that the phosphorylated eIF2α enhances ternary complex assembly by promoting its affinity to eIF2ß and eIF2γ. This study reveals a unique mechanism by which light promotes translation via SPA1-mediated phosphorylation of the C-terminus of eIF2α in plants.

US-based Sequential Algorithm Integrating an AI Model for Advanced Liver Fibrosis Screening.

Background Noninvasive tests can be used to screen patients with chronic liver disease for advanced liver fibrosis; however, the use of single tests may not be adequate. Purpose To construct sequential clinical algorithms that include a US deep learning (DL) model and compare their ability to predict advanced liver fibrosis with that of other noninvasive tests. Materials and Methods This retrospective study included adult patients with a history of chronic liver disease or unexplained abnormal liver function test results who underwent B-mode US of the liver between January 2014 and September 2022 at three health care facilities. A US-based DL network (FIB-Net) was trained on US images to predict whether the shear-wave elastography (SWE) value was 8.7 kPa or higher, indicative of advanced fibrosis. In the internal and external test sets, a two-step algorithm (Two-step#1) using the Fibrosis-4 Index (FIB-4) followed by FIB-Net and a three-step algorithm (Three-step#1) using FIB-4 followed by FIB-Net and SWE were used to simulate screening scenarios where liver stiffness measurements were not or were available, respectively. Measures of diagnostic accuracy were calculated using liver biopsy as the reference standard and compared between FIB-4, SWE, FIB-Net, and European Association for the Study of the Liver guidelines (ie, FIB-4 followed by SWE), along with sequential algorithms. Results The training, validation, and test data sets included 3067 (median age, 42 years [IQR, 33-53 years]; 2083 male), 1599 (median age, 41 years [IQR, 33-51 years]; 1124 male), and 1228 (median age, 44 years [IQR, 33-55 years]; 741 male) patients, respectively. FIB-Net obtained a noninferior specificity with a margin of 5% (P < .001) compared with SWE (80% vs 82%). The Two-step#1 algorithm showed higher specificity and positive predictive value (PPV) than FIB-4 (specificity, 79% vs 57%; PPV, 44% vs 32%) while reducing unnecessary referrals by 42%. The Three-step#1 algorithm had higher specificity and PPV compared with European Association for the Study of the Liver guidelines (specificity, 94% vs 88%; PPV, 73% vs 64%) while reducing unnecessary referrals by 35%. Conclusion A sequential algorithm combining FIB-4 and a US DL model showed higher diagnostic accuracy and improved referral management for all-cause advanced liver fibrosis compared with FIB-4 or the DL model alone. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Ghosh in this issue.

Clinical Research into Central Nervous System Inflammatory Demyelinating Diseases Related to COVID-19 Vaccines.

Various vaccines have been developed in response to the SARS-CoV-2 pandemic, and the safety of vaccines has become an important issue. COVID-19 vaccine-related central nervous system inflammatory demyelinating diseases (CNS IDDs) have been reported recently. We present one case of AstraZeneca vaccine-related myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease and a literature review of another 78 patients published from January 2020 to October 2022. Patients were divided into three vaccine types (viral vector, mRNA, and inactivated vaccines) for further analyses. Among 79 patients with COVID-19 vaccine-related CNS IDDs, 49 (62%) cases received viral vector vaccines, 20 (25.3%) received mRNA vaccines, and 10 (12.7%) received inactivated vaccines. Twenty-seven cases (34.2%) were confirmed with autoantibodies, including fifteen patients (19%) with anti-MOG, eleven (13.9%) with anti-aquaporin 4 (AQP4), and one (1.3%) with both antibodies. Significantly, more males developed CNS IDDs post viral vector vaccines compared to mRNA and inactivated vaccines. Patients receiving mRNA vaccines were older than those receiving other types. Furthermore, mRNA and inactivated vaccines correlated more with anti-AQP4 antibodies, while viral vector vaccines showed higher MOG positivity. This research suggests potential associations between COVID-19 vaccine-related CNS IDDs and gender, age, and autoantibodies, contingent on vaccine types. Protein sequence analysis implies similarities between the S protein and AQP4/MOG. Further studies may elucidate the mechanisms of CNS IDDs, aiding vaccine selection for specific types.

Combined Plasma DHA-Containing Phosphatidylcholine PCaa C38:6 and Tetradecanoyl-Carnitine as an Early Biomarker for Assessing the Mortality Risk among Sarcopenic Patients.

The coming of the hyper-aged society in Taiwan prompts us to investigate the relationship between the metabolic status of sarcopenic patients and their most adverse outcome-death. We studied the association between any plasma metabolites and the risk for mortality among older Taiwanese sarcopenic patients. We applied a targeted metabolomic approach to study the plasma metabolites of adults aged ≥65 years, and identified the metabolic signature predictive of the mortality of sarcopenic patients who died within a 5.5-year follow-up period. Thirty-five sarcopenic patients who died within the follow-up period (Dead cohort) had shown a specific plasma metabolic signature, as compared with 54 patients who were alive (Alive cohort). Only 10 of 116 non-sarcopenic individuals died during the same period. After multivariable adjustment, we found that sex, hypertension, tetradecanoyl-carnitine (C14-carnitine), and docosahexaenoic acid (DHA)-containing phosphatidylcholine diacyl (PCaa) C38:6 and C40:6 were important risk factors for the mortality of sarcopenic patients. Low PCaa C38:6 levels and high C14-carnitine levels correlated with an increased mortality risk; this was even the same for those patients with hypertension (HTN). Our findings suggest that plasma PCaa C38:6 and acylcarnitine C14-carnitine, when combined, can be a better early biomarker for evaluating the mortality risk of sarcopenia patients.

The regulation of MFG-E8 on the mitophagy in diabetic sarcopenia via the HSPA1L-Parkin pathway and the effect of D-pinitol.

BACKGROUND: Diabetic sarcopenia is a disease-related skeletal muscle disorder that causes progressive symptoms. The complete understanding of its pathogenesis is yet to be unravelled, which makes it difficult to develop effective therapeutic strategies. This study investigates how MFG-E8 affects mitophagy and the protective role of D-pinitol (DP) in diabetic sarcopenia. METHODS: In vivo, streptozotocin-induced diabetic SAM-R1 (STZ-R1) and SAM-P8 (STZ-P8) mice (16-week-old) were used, and STZ-P8 mice were administrated of DP (150 mg/kg per day) for 6 weeks. Gastrocnemius muscles were harvested for histological analysis including transmission electron microscopy. Proteins were evaluated via immunohistochemistry (IHC), immunofluorescence (IF), and western blotting (WB) assay. In vitro, advanced glycation end products (AGEs) induced diabetic and D-galactose (DG) induced senescent C2C12 models were established and received DP, MFG-E8 plasmid (Mover)/siRNA (MsiRNA), or 3-MA/Torin-1 intervention. Proteins were evaluated by IF and WB assay. Immunoprecipitation (IP) and co-immunoprecipitation (CO-IP) were used for hunting the interacted proteins of MFG-E8. RESULTS: In vivo, sarcopenia, mitophagy deficiency, and up-regulated MFG-E8 were confirmed in the STZ-P8 group. DP exerted protective effects on sarcopenia and mitophagy (DP + STZ-P8 vs. STZ-P8; all P < 0.01), such as increased lean mass (8.47 ± 0.81 g vs. 7.08 ± 1.64 g), grip strength (208.62 ± 39.45 g vs. 160.87 ± 26.95 g), rotarod tests (109.7 ± 11.81 s vs. 59.3 ± 20.97 s), muscle cross-sectional area (CSA) (1912.17 ± 535.61 µm2 vs. 1557.19 ± 588.38 µm2), autophagosomes (0.07 ± 0.02 per µm2 vs. 0.02 ± 0.01 per µm2), and cytolysosome (0.07 ± 0.03 per µm2 vs. 0.03 ± 0.01 per µm2). DP down-regulated MFG-E8 in both serum (DP + STZ-P8: 253.19 ± 34.75 pg/mL vs. STZ-P8: 404.69 ± 78.97 pg/mL; P < 0.001) and gastrocnemius muscle (WB assay. DP + STZ-P8: 0.39 ± 0.04 vs. STZ-P8: 0.55 ± 0.08; P < 0.01). DP also up-regulated PINK1, Parkin and LC3B-II/I ratio, and down-regulated P62 in gastrocnemius muscles (all P < 0.01). In vitro, mitophagy deficiency and MFG-E8 up-regulation were confirmed in diabetic and senescent models (all P < 0.05). DP and MsiRNA down-regulated MFG-E8 and P62, and up-regulated PINK1, Parkin and LC3B-II/I ratio to promote mitophagy as Torin-1 does (all P < 0.05). HSPA1L was confirmed as an interacted protein of MFG-E8 in IP and CO-IP assay. Mover down-regulated the expression of Parkin via the HSPA1L-Parkin pathway, leading to mitophagy inhibition. MsiRNA up-regulated the expression of PINK1 via SGK1, FOXO1, and STAT3 phosphorylation pathways, leading to mitophagy stimulation. CONCLUSIONS: MFG-E8 is a crucial target protein of DP and plays a distinct role in mitophagy regulation. DP down-regulates the expression of MFG-E8, reduces mitophagy deficiency, and alleviates the symptoms of diabetic sarcopenia, which could be considered a novel therapeutic strategy for diabetic sarcopenia.

Association Between Leg Muscle Thickness and Walking Test with the Haemophilia-Specific Functional Parameters.

OBJECTIVE: To evaluate the muscle thickness and walking test in people with haemophilia A (PWH) and their correlation to joint health and functional impairments. DESIGN: Cross-sectional study. RESULTS: 29 severe/moderate PWH were enrolled. Muscle thickness of quadriceps and medial gastrocnemius were measured using ultrasound. Joint health and functional capacity were assessed using Haemophilia Joint Health Score (HJHS), Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US), 6-Minute Walking test (6MWT), Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL), and Haemophilia Activities List (HAL). Quadriceps muscle thickness significantly correlated with HJHS knee, HEAD-US knee, and HAL. Calf muscle thickness significantly correlated with the HJHS ankle. After adjusted age and BMI, calf muscle thickness was inversely associated with the HJHS ankle. 6MWT was found to significantly correlate with HJHS total, HEAD-US total, Haem-A-QoL, and HAL. CONCLUSION: Muscle thickness and the distance of 6MWT were linked to assessment of joint health, quality of life and activity participation in PWH. Ultrasound measurement of muscle thickness and walking test appear to be useful tools for the assessment of joint health and functional status in PWH.

CXCL13/CXCR5 promote chronic postsurgical pain and astrocyte activation in rats by targeting NLRP3.

Chronic postsurgical pain (CPSP) with high incidence negatively impacts the quality of life. X-C motif chemokine 13 (CXCL13) has been associated with postsurgery inflammation and exacerbates neuropathic pain in patients with CPSP. This study was aimed to illustrate the relationship between CXCL13 and nod-like receptor protein-3 (NLRP3), which is also involved in CPSP. A CPSP model was constructed by skin/muscle incision and retraction (SMIR) in right medial thigh, and the rats were divided into three groups: Sham, SMIR, and SMIR + anti-CXCL13 (intrathecally injected with anti-CXCL13 antibody). Then, the paw withdrawal threshold (PWT) score of rats was recorded. Primary rat astrocytes were isolated and treated with recombinant protein CXCL13 with or without NLRP3 inhibitor INF39. The expressions of CXCL13, CXCR5, IL-1ß, IL-18, GFAP, NLRP3, and Caspase-1 p20 were detected by real-time quantitative reverse transcription PCR, western blot, ELISA, immunocytochemistry, and immunofluorescence analyses. The anti-CXCL13 antibody alleviated SMIR-induced decreased PWT and increased expression of GFAP, CXCL13, CXCR5, NLRP3, and Caspase-1 p20 in spinal cord tissues. The production of IL-1ß, IL-18, and expression of CXCL13, CXCR5, GFAP, NLRP3, and Caspase-1 p20 were increased in recombinant protein CXCL13-treated primary rat astrocytes in a dose-dependent manner. Treatment with NLRP3 inhibitor INF39 inhibited the function of recombinant protein CXCL13 in primary rat astrocytes. The CXCL13/CXCR5 signaling could promote neuropathic pain, astrocytes activation, and NLRP3 inflammasome activation in CPSP model rats by targeting NLRP3. NLRP3 may be a potential target for the management of CPSP.

Integrating Network Pharmacology and Experimental Validation to Reveal the Mechanism of Vine Grape Tea Polyphenols on Hyperuricemia-Induced Renal Injury in Mice.

Hyperuricemia (HUA) is a metabolic disease and contributes to renal injury (RI). Vine grape tea polyphenols (VGTP) have been widely used to treat HUA and RI. However, the potential mechanism of VGTP activity remains unclear. To explore the underlying mechanism of VGTP treatment for HUA-induced RI based on network pharmacology that is confirmed by an in vivo study. All ingredients of VGTP were retrieved using a Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and Comparative Toxicogenomics Database systems. The related targets of HUA and RI were obtained from GeneCards and National Center for Biotechnology Information (NCBI) databases. Some ingredients and targets were selected for molecular docking verification. One hour after administering potassium oxonate (300 mg/kg), VGTP (50, 100, and 200 mg/kg/d) was orally administered to HUA mice for 4 weeks. Histopathology and western blotting were performed in renal tissue. Our results showed that VGTP significantly reduced blood urea nitrogen, creatinine, uric acid, and significantly improved the RI and fibrosis of HUA mice. There were 54 active ingredients and 62 targets of HUA-induced RI. Further studies showed that VGTP decreased the expression of Bax, cleaved caspase 3, transforming growth factor-ß (TGF-ß1), CHOP, p-STAT3, and P53, and increased Bcl-2 expression in renal tissue. The related signaling pathways have apoptosis, TGF-ß1, P53 and STAT, and endoplasmic reticulum stress (ERS). In this study, VGTP exerted antihyperuricemic and anti fibrosis effects by regulating the apoptosis and ERS signaling pathways. VGTP is expected to become a drug for combating HUA and RI.

COP1-ERF1-SCE1 regulatory module fine-tunes stress response under light-dark cycle in Arabidopsis.

ETHYLENE RESPONSE FACTOR 1 (ERF1) plays an important role in integrating hormone crosstalk and stress responses. Previous studies have shown that ERF1 is unstable in the dark and its degradation is mediated by UBIQUITIN-CONJUGATING ENZYME 18. However, whether there are other enzymes regulating ERF1's stability remains unclear. Here, we use various in vitro and in vivo biochemical, genetic and stress-tolerance tests to demonstrate that both CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) and SUMO-CONJUGATING ENZYME 1 (SCE1) regulate the stability of ERF1. We also performed transcriptomic analyses to understand their common regulatory pathways. We show that COP1 mediates ERF1 ubiquitination in the dark while SCE1 mediates ERF1 sumoylation in the light. ERF1 stability is positively regulated by SCE1 and negatively regulated by COP1. Upon abiotic stress, SCE1 plays a positive role in stress defence by regulating the expression of ERF1's downstream stress-responsive genes, whereas COP1 plays a negative role in stress response. Moreover, ERF1 also promotes photomorphogenesis and the expression of light-responsive genes. Our study reveals the molecular mechanism of how COP1 and SCE1 counteract to regulate ERF1's stability and light-stress signalling crosstalk.

D-pinitol alleviates diabetic cardiomyopathy by inhibiting the optineurin-mediated endoplasmic reticulum stress and glycophagy signaling pathway.

Diabetic cardiomyopathy (DCM) is an important complication resulting in heart failure and death of diabetic patients. However, there is no effective drug for treatments. This study investigated the effect of D-pinitol (DP) on cardiac injury using diabetic mice and glycosylation injury of cardiomyocytes and its molecular mechanisms. We established the streptozotocin-induced SAMR1 and SAMP8 mice and DP (150 mg/kg/day) intragastrically and advanced glycation end-products (AGEs)-induced H9C2 cells. H9C2 cells were transfected with optineurin (OPTN) siRNA and overexpression plasmids. The metabolic disorder indices, cardiac dysfunction, histopathology, immunofluorescence, western blot, and immunoprecipitation were investigated. Our results showed that DP reduced the blood glucose and AGEs, and increased the expression of heart OPTN in diabetic mice and H9C2 cells, thereby inhibiting the endoplasmic reticulum stress (GRP78, CHOP) and glycophagy (STBD1, GABARAPL1), and alleviating the myocardial apoptosis and fibrosis of DCM. The expression of filamin A as an interaction protein of OPTN downregulated by AGEs decreased OPTN abundance. Moreover, OPTN siRNA increased the expression of GRP78, CHOP, STBD1, and GABARAPL1 and inhibited the expression of GAA via GSK3ß phosphorylation and FoxO1. DP may be helpful to treat the onset of DCM. Targeting OPTN with DP could be translated into clinical application in the fighting against DCM.

Rapid and Direct Detection of Trimethylamine N-oxide Using an Off-Chip Capacitance Biosensor with Readout SoC for Early-Stage Thrombosis and Cardiovascular Disease.

A demonstration of an off-chip capacitance array sensor with a limit of detection of 1 µM trimethylamine N-oxide (TMAO) to diagnose a chronic metabolism disease in urine is presented. The improved Cole-Cole model is employed to determine the parameters of R_catalyzed, C_catalyzed, and Rp_catalyzed, enabling the prediction of the catalytic resistance of enzyme, reduction effects of the analyte, and characterize the small signal alternating current properties of ionic strength caused by catalysis. Based on the standard solutions, we investigate the effects of pixel geometry parameters, driving electrode width, and sensing electrode width on the electrical field change of the off-chip capacitance sensor; the proposed off-chip sensor with readout system-on-chip exhibits a high sensitivity of 21 analog-to-digital converter counts/µM TMAO (or 2.5 mV/µM TMAO), response time of 1 s, repetition of 98.9%, and drift over time of 0.5 mV. The proposed off-chip sensor effectively discriminates TMAO in a phosphate-buffered saline solution based on minute changes in capacitance induced by the TorA enzyme, resulting in a discernible 2.15% distinction. These measurements have been successfully corroborated using the conventional cyclic voltammetry method, demonstrating a mere 0.024% variance. The off-chip sensor is crafted with a specific focus on detecting TMAO, achieved by excluding any reduction reactions between the TMAO-specific enzyme TorA and the compounds creatine and creatinine present in urine. This deliberate omission ensures that the sensor's attention remains solely on TMAO, thereby enhancing its precision in achieving accurate and reliable TMAO detection.

CX­5461 potentiates imatinib­induced apoptosis in K562 cells by stimulating KIF1B expression.

The selective RNA polymerase I inhibitor CX-5461 has been shown to be effective in treating some types of leukemic disorders. Emerging evidence suggests that combined treatments with CX-5461 and other chemotherapeutic agents may achieve enhanced effectiveness as compared with monotherapies. Currently, pharmacodynamic properties of the combination of CX-5461 with tyrosine kinase inhibitors remain to be explored. The present study tested whether CX-5461 could potentiate the effect of imatinib in the human chronic myeloid leukemia cell line K562, which is p53-deficient. It was demonstrated that CX-5461 at 100 nM, which was non-cytotoxic in K562 cells, potentiated the pro-apoptotic effect of imatinib. Mechanistically, the present study identified that the upregulated expression of kinesin family member 1B (KIF1B) gene might be involved in mediating the pro-apoptotic effect of imatinib/CX-5461 combination. Under the present experimental settings, however, neither CX-5461 nor imatinib alone exhibited a significant effect on KIF1B expression. Moreover, using other leukemic cell lines, it was demonstrated that regulation of KIF1B expression by imatinib/CX-5461 was not a ubiquitous phenomenon in leukemic cells and should be studied in a cell type-specific manner. In conclusion, the results suggested that the synergistic interaction between CX-5461 and imatinib may be of potential clinical value for the treatment of tyrosine kinase inhibitor-resistant chronic myeloid leukemia.

Evaluation of Malignancy Risk of Ampullary Tumors Detected by Endoscopy Using 2-[18F]FDG PET/CT.

OBJECTIVE: We aimed to investigate whether 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (2-[18F]FDG PET/CT) can aid in evaluating the risk of malignancy in ampullary tumors detected by endoscopy. MATERIALS AND METHODS: This single-center retrospective cohort study analyzed 155 patients (79 male, 76 female; mean age, 65.7 ± 12.7 years) receiving 2-[18F]FDG PET/CT for endoscopy-detected ampullary tumors 5-87 days (median, 7 days) after the diagnostic endoscopy between June 2007 and December 2020. The final diagnosis was made based on histopathological findings. The PET imaging parameters were compared with clinical data and endoscopic features. A model to predict the risk of malignancy, based on PET, endoscopy, and clinical findings, was generated and validated using multivariable logistic regression analysis and an additional bootstrapping method. The final model was compared with standard endoscopy for the diagnosis of ampullary cancer using the DeLong test. RESULTS: The mean tumor size was 17.1 ± 7.7 mm. Sixty-four (41.3%) tumors were benign, and 91 (58.7%) were malignant. Univariable analysis found that ampullary neoplasms with a blood-pool corrected peak standardized uptake value in early-phase scan (SUVe) ≥ 1.7 were more likely to be malignant (odds ratio [OR], 16.06; 95% confidence interval [CI], 7.13-36.18; P < 0.001). Multivariable analysis identified the presence of jaundice (adjusted OR [aOR], 4.89; 95% CI, 1.80-13.33; P = 0.002), malignant traits in endoscopy (aOR, 6.80; 95% CI, 2.41-19.20; P < 0.001), SUVe ≥ 1.7 in PET (aOR, 5.43; 95% CI, 2.00-14.72; P < 0.001), and PET-detected nodal disease (aOR, 5.03; 95% CI, 1.16-21.86; P = 0.041) as independent predictors of malignancy. The model combining these four factors predicted ampullary cancers better than endoscopic diagnosis alone (area under the curve [AUC] and 95% CI: 0.925 [0.874-0.956] vs. 0.815 [0.732-0.873], P < 0.001). The model demonstrated an AUC of 0.921 (95% CI, 0.816-0.967) in candidates for endoscopic papillectomy. CONCLUSION: Adding 2-[18F]FDG PET/CT to endoscopy can improve the diagnosis of ampullary cancer and may help refine therapeutic decision-making, particularly when contemplating endoscopic papillectomy.

Use of Technetium-99m-Pyrophosphate Single-Photon Emission Computed Tomography/Computed Tomography in Monitoring Therapeutic Changes of Eplontersen in Patients With Hereditary Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Hereditary transthyretin amyloid cardiomyopathy (hATTR-CM) is a progressive and fatal disease. Recent evidence indicates that bone scintigraphy may serve as a tool to monitor the effectiveness of hATTR-CM treatment. The objective of this study was to examine how eplontersen therapy influences the semiquantitative uptake of technetium-99m-pyrophosphate in individuals diagnosed with hATTR-CM. METHODS AND RESULTS: We retrospectively analyzed a prospective cohort from the NEURO-TTRansform trial, including patients with hATTR-CM receiving eplontersen (45 mg/4 weeks). A control group comprised patients with hATTR-CM who had not received eplontersen, inotersen, tafamidis, or patisiran. Technetium-99m-pyrophosphate single-photon emission computed tomography/computed tomography was conducted at baseline and during follow-up. Thirteen patients with hATTR-CM were enrolled, with 6 receiving eplontersen and 7 serving as the control group. The median follow-up time was 544 days. The eplontersen group exhibited a significant decrease in volumetric heart and lung ratio (3.774 to 2.979, P=0.028), whereas the control group showed no significant change (4.079 to 3.915, P=0.237). Patients receiving eplontersen demonstrated a significantly greater reduction in volumetric heart and lung ratio compared with the control group (-20.7% versus -3.4%, P=0.007). CONCLUSIONS: The volumetric heart and lung ratio used to quantify technetium-99m-pyrophosphate uptake showed a significant reduction subsequent to eplontersen treatment in individuals diagnosed with hATTR-CM. These findings suggest the potential efficacy of eplontersen in treating hATTR-CM and highlight the value of technetium-99m-pyrophosphate single-photon emission computed tomography/computed tomography as a tool for monitoring therapeutic effectiveness.