Deep learning-based k-space-to-image reconstruction and super resolution for diffusion-weighted imaging in whole-spine MRI.

PURPOSE: To assess the feasibility of deep learning (DL)-based k-space-to-image reconstruction and super resolution for whole-spine diffusion-weighted imaging (DWI). METHOD: This retrospective study included 97 consecutive patients with hematologic and/or oncologic diseases who underwent DL-processed whole-spine MRI from July 2022 to March 2023. For each patient, conventional (CONV) axial single-shot echo-planar DWI (b = 50, 800 s/mm2) was performed, followed by DL reconstruction and super resolution processing. The presence of malignant lesions and qualitative (overall image quality and diagnostic confidence) and quantitative (nonuniformity [NU], lesion contrast, signal-to-noise ratio [SNR], contrast-to-noise ratio [CNR], and ADC values) parameters were assessed for DL and CONV DWI. RESULTS: Ultimately, 67 patients (mean age, 63.0 years; 35 females) were analyzed. The proportions of vertebrae with malignant lesions for both protocols were not significantly different (P: [0.55-0.99]). The overall image quality and diagnostic confidence scores were higher for DL DWI (all P ≤ 0.002) than CONV DWI. The NU, lesion contrast, SNR, and CNR of each vertebral segment (P ≤ 0.04) but not the NU of the sacral segment (P = 0.51) showed significant differences between protocols. For DL DWI, the NU was lower, and lesion contrast, SNR, and CNR were higher than those of CONV DWI (median values of all segments; 19.8 vs. 22.2, 5.4 vs. 4.3, 7.3 vs. 5.5, and 0.8 vs. 0.7). Mean ADC values of the lesions did not significantly differ between the protocols (P: [0.16-0.89]). CONCLUSIONS: DL reconstruction can improve the image quality of whole-spine diffusion imaging.

Value of Edema-like Marrow Signal Intensity in Diagnosis of Joint Pain: Radiologists' Perspective.

Musculoskeletal pain is a significant contributor to disability. The mechanism and target of the treatment should be optimized by imaging, but currently no accepted gold standard exists to image pain. In addition to end-organ pathology, other mediators also contribute to nociception, such as angiogenesis, axonal extension, immunologic modulation, and central sensitization. Recent research indicates that local inflammation is a significant contributor to pain in the extremities; therefore, we focus here on edema-like marrow signal intensity (ELMSI). We examine both the relevance of ELMSI for pain and novel imaging techniques.

Development of a Semiquantitative Whole-Body MRI Scoring System for Multiple Myeloma.

Background In patients with multiple myeloma (MM), the serum marker ß2-microglobulin does not always accurately reflect tumor load. In contrast, whole-body (WB) MRI has shown high sensitivity for detecting bone lesions. Purpose To develop and validate a semiquantitative WB MRI scoring system for newly diagnosed MM and to compare it with the International Staging System (ISS) and Revised ISS (R-ISS). Materials and Methods This study included two retrospective groups (group 1, July 2015 to September 2021; group 2, February 2020 to September 2021) and one prospective group (group 3, October 2021 to February 2022) of patients with newly diagnosed MM. A new scoring system for MM was developed using spine MRI scans in group 1 and WB MRI scans in group 2 that integrated three features: (a) background marrow pattern, (b) number of focal bone lesions, and (c) presence of extramedullary or paramedullary lesions. The summed total score ranged from zero to nine. The interobserver agreement for each feature was assessed using Fleiss or Cohen weighted κ. WB MRI total scores in group 3 were compared across ISS and R-ISS stages using two-way analysis of variance. Results Groups 1, 2, and 3 included 103 patients (mean age, 62.1 years ± 9.1 [SD]; 60 men), 36 patients (mean age 65.4 years ± 11.3 [SD]; 19 women), and 39 participants (mean age, 62.0 years ± 11.7 [SD]; 20 men), respectively. The interobserver agreements for the three features composing the scoring system were substantial (κ range, 0.69-0.80). WB MRI total score increased with increasing ISS stage (mean score for ISS 1, 2, and 3 was 2.2, 4.2, and 5.8, respectively; P = .009) and R-ISS stage (mean score for R-ISS 1, 2, and 3 was 2.1, 3.8, and 5.9, respectively; P = .005). Conclusion The developed WB MRI scoring system for MM demonstrated substantial observer agreement and corresponded well with ISS and R-ISS stages. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Dragan and Messiou in this issue.

Proteomic insight into human directed selection of the domesticated chicken Gallus gallus.

Chicken domestication began at least 3,500 years ago for purposes of divination, cockfighting, and food. Prior to industrial scale chicken production, domestication selected larger birds with increased egg production. In the mid-20th century companies began intensive selection with the broiler (meat) industry focusing on improved feed conversion, rapid growth, and breast muscle yield. Here we present proteomic analysis comparing the modern broiler line, Ross 708, with the UIUC legacy line which is not selected for growth traits. Breast muscle proteome analysis identifies cellular processes that have responded to human directed artificial selection. Mass spectrometry was used to identify protein level differences in the breast muscle of 6-day old chicks from Modern and Legacy lines. Our results indicate elevated levels of stress proteins, ribosomal proteins and proteins that participate in the innate immune pathway in the Modern chickens. Furthermore, the comparative analyses indicated expression differences for proteins involved in multiple biochemical pathways. In particular, the Modern line had elevated levels of proteins affecting the pentose phosphate pathway, TCA cycle and fatty acid oxidation while proteins involved in the first phase of glycolysis were reduced compared to the Legacy line. These analyses provide hypotheses linking the morphometric changes driven by human directed selection to biochemical pathways. These results also have implications for the poultry industry, specifically Wooden Breast disease which is linked to rapid breast muscle growth.

Microfluidic-Integrated Multimodal Wearable Hybrid Patch for Wireless and Continuous Physiological Monitoring.

Despite extensive advances in wearable monitoring systems, most designs focus on the detection of physical parameters or metabolites and do not consider the integration of microfluidic channels, miniaturization, and multimodality. In this study, a combination of multimodal (biochemical and electrophysiological) biosensing and microfluidic channel-integrated patch-based wireless systems is designed and fabricated using flexible materials for improved wearability, ease of operation, and real-time and continuous monitoring. The reduced graphene oxide-based microfluidic channel-integrated glucose biosensor exhibits a good sensitivity of 19.97 (44.56 without fluidic channels) µA mM-1 cm-2 within physiological levels (10 µM-0.4 mM) with good long-term and bending stability. All the sensors in the patch are initially validated using sauna gown sweat-based on-body and real-time tests with five separate individuals who perspired three times each. Multimodal glucose and electrocardiogram (ECG) sensing, along with their real-time adjustment based on sweat pH and temperature fluctuations, optimize sensing accuracy. Laser-burned hierarchical MXene-polyvinylidene fluoride-based conductive carbon nanofiber-based dry ECG electrodes exhibit low skin contact impedance (40.5 kΩ cm2) and high-quality electrophysiological signals (signal-to-noise ratios = 23.4-32.8 dB). The developed system is utilized to accurately and wirelessly monitor the sweat glucose and ECG of a human subject engaged in physical exercise in real time.

[Clinical Application and Limitations of Myeloma Response Assessment and Diagnosis System (MY-RADS)]. / ê³¨ìˆ˜ì¢ ë°˜ì‘í‰ê°€ì™€ 진단체계의 ìž„ìƒì ìš© 및 ì œí•œì .

Multiple myeloma, which is a proliferative disease of plasma cells that originate from a single clone, is the second most common hematologic malignancy following non-Hodgkin lymphoma. In the past, its diagnosis was made based on clinical findings (so-called "CRAB") and a skeletal survey using radiographs. However, since the implementation of the International Myeloma Working Group's revised guideline regarding the radiologic diagnosis of multiple myeloma, whole-body (WB) MRI has emerged to play a central role in the early diagnosis of multiple myeloma. Diffusion-weighted imaging and fat quantification using Dixon methods enable treatment response assessment by MRI. In keeping with the trend, a multi-institutional and multidisciplinary consensus for standardized image acquisition and reporting known as the Myeloma Response Assessment and Diagnostic System (MY-RADS) has recently been proposed. This review aims to describe the clinical application of WB-MRI based on MY-RADS in multiple myeloma, discuss its limitations, and suggest future directions for improvement.

Solid Pseudopapillary Neoplasm of the Pancreas with Lymph Node Metastasis in a Young Male Patient.

Solid pseudopapillary pancreatic neoplasms are rare. The male-to-female ratio is 1:9, and metastasis occurs only in a few cases. A 39-year-old male with a solid pseudopapillary neoplasm (SPN) with lymph node metastasis underwent ultrasonography, CT, and MRI, which revealed a mass (8 cm) in the pancreatic head. Fluorodeoxyglucose (FDG)-PET showed a hypermetabolic lymph node in the root area of the superior mesenteric artery (SMA). The patient underwent pylorus-preserving pancreaticoduodenectomy, which confirmed a peripancreatic lymph node metastasis. The lymph node of the SMA root area remained because of the encasing of the superior mesenteric artery. After 14 months of follow-up (with no adjuvant therapy initiated), the residual metastatic lymph nodes showed no change and no recurrence. In conclusion, surgery of the primary tumor for patients with SPN is recommended, even in cases with metastatic lymph nodes remaining.

Ambulatory blood pressure response to S-amlodipine in Korean adult patients with uncontrolled essential hypertension: A prospective, observational study.

Although amlodipine is recommended as the first-line therapy for the treatment of hypertension, its use is limited by its potential side effects. S-amlodipine is expected to be able to minimize side effects of amlodipine with a similar antihypertensive effect by removing the malicious R-chiral form. However, sustainable blood pressure control with S-amlodipine has not been well established yet. The purpose of the current study was to evaluate ambulatory blood pressure (ABP) profiles before and after a 12-week treatment of S-amlodipine. Patients received once-daily S-amlodipine 2.5 or 5 mg. ABP during 24 hr and office blood pressure were measured at baseline and after the 12-week treatment. Primary endpoints were changes of systolic and diastolic 24 hr ABP. After 12-week S-amlodipine treatment, mean systolic ABP (-15.1 ± 16.2 mmHg, p < .001) and diastolic ABP (-8.9 ± 9.8 mmHg, p < .001) were decreased significantly. Both daytime and night-time mean systolic BP and diastolic BP were also significantly decreased after the 12-week treatment. Global trough-to-peak ratio and smoothness index after 12-week S-amlodipine treatment were .75 and .79 for SBP and .65 and .61 for DBP, respectively. Age ≥65 years (hazard ratio [HR]: 3.13; 95% confidence interval [CI]: 1.67-14.3) and nonalcohol drinking (HR: 3.09; 95% CI: 1.34-7.17) were independent clinical factors for target ABP achievement. Adverse drug reactions (ADR) were developed in 16 (6.4%) patients, including two (.8%) cases of peripheral edema. In conclusion, this study demonstrated the efficacy and safety of S-amlodipine in patients with uncontrolled essential hypertension.

Unenhanced computed tomography for non-invasive diagnosis of hepatic steatosis with low tube potential protocol.

BACKGROUND: Lowering kVp affects the image contrast and computed tomography (CT) attenuation values of low kVp CT is different from those of conventional 120-kVp scans. The purpose of this study is to determine the diagnostic performance and to establish the reference range of low-kVp unenhanced CT for the assessment of hepatic steatosis in liver transplantation donors using magnetic resonance (MR) spectroscopy as a reference standard. METHODS: This retrospective study included 165 potential donors (male:female =114:51, 36.5±12.0 years old) who underwent 100-kVp single-slice unenhanced CT scan and MR spectroscopy. The difference between hepatic and splenic attenuation (CTL-S) and liver-to-spleen attenuation ratio (CTL/S) were calculated. Reference standard was the fat signal fraction measured by MR spectroscopy. Limits of agreement between CT measurements and the reference standard were calculated. Areas under receiver operating characteristic curves (AUROCs) of CTL-S and CTL/S were compared for the diagnosis of moderate to severe steatosis. Cut-off values of CTL-S and CTL/S that provided a balance between sensitivity and specificity and the highest specificity using the lower limit of the reference range were calculated. RESULTS: Eighty-seven subjects had a non-steatotic liver. Sixty-one subjects had mild steatosis and 17 subjects had moderate to severe steatosis based on MR spectroscopy. CTL-S and CTL/S values were negatively correlated with the fat signal fraction (P<0.001) and limits of agreement were -8.4% to 8.4% for CTL-S and -9.6% to 9.6% for CTL/S. AUROCs of CTL-S and CTL/S for diagnosing moderate to severe steatosis were 0.956 and 0.957, respectively. Cut-off values of CTL-S and CTL/S for diagnosis of moderate to severe steatosis by the Youden index were -0.5 HU for CTL-S and 0.99 for CTL/S. Reference ranges of non-steatotic liver were -6.90 to 31.40 HU for CTL-S and 0.89 to 1.77 for CTL/S. Using -6.9 HU for CTL-S and 0.89 for CTL/S as cut-off values, the sensitivity and specificity for diagnosing moderate to severe steatosis were 70.59% and 90.54% (CTL-S) and 76.47% and 90.54% (CTL/S), respectively. CONCLUSIONS: Measurements from a low-kVp unenhanced CT scan were negatively correlated with the degree of hepatic steatosis. Low-kVp unenhanced CT is a robust technique with reduced radiation exposure for diagnosing moderate to severe hepatic steatosis.

The impact of face shields on the quality of gastrointestinal endoscopy during the COVID-19 pandemic.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has become a global pandemic, with healthcare workers at a high risk of exposure. During this pandemic, endoscopists must wear personal protective equipment (PPE), including face shields, to prevent COVID-19 transmission; however, few studies have reported the impact of face shields on the quality of gastrointestinal (GI) endoscopy. We aimed to determine whether the use of PPE, including face shields, affected the quality of GI endoscopy during the COVID-19 pandemic. METHODS: The medical records of patients who had undergone screening or surveillance colonoscopy and gastric endoscopic submucosal dissection (ESD) at Dong-A University Hospital between June 2020 and March 2021 were retrospectively reviewed. Endoscopists wore isolation gowns, disposable gloves, and KF94 masks from June 2020 to October 2020. From November 2020, endoscopists also wore face shields. We compared GI endoscopy quality indicators between the first five months (no face shields) and the second five months (with face shields). In the non-face shield and face shield groups, we calculated the overall adenoma detection rates (ADRs), polyp detection rate (PDR), sessile serrated lesion detection rate (SSLDR), advanced neoplasia detection rate (ANDR), complete resection rate (CRR), number of polyps and/or adenomas per colonoscopy, and gastric ESD procedure time. RESULTS: In total, 1359 study patients had undergone screening or surveillance colonoscopy (face shield group, n = 679; non-face shield group, n = 680). No statistically significant between-group differences were observed (PDR, 49.04 vs. 52.50%, p = 0.202; ADR, 38.59 vs. 38.97%, p = 0.884; SSPDR, 1.91 vs. 1.32%, p = 0.388; ANDR, 3.98 vs. 3.97%, p = 0.991, respectively). No difference was found in colonoscopy quality indicators between patients examined by experienced and trainee endoscopists with and without face shields. Of 144 study patients who had undergone gastric ESD for gastric neoplasms, there were 72 patients in each group. No statistically significant differences were found in the CRR (94.44 vs 93.05%, p = 1.000) and procedure times (19.22 ± 9.33 vs. 19.03 ± 11.49, p = 0.911). CONCLUSIONS: Wearing face shields during the COVID-19 pandemic did not affect the quality indicators for GI endoscopy.

[Inflammatory Myofibroblastic Tumor Misdiagnosed as Intrahepatic Cholangiocarcinoma].

An inflammatory myofibroblastic tumor (IMT) is a rare tumor that is currently classified as an intermediate cancer according to the World Health Organization classification system. The pathophysiology of its occurrence is still unknown. Imaging tests, such as CT or MRI, can be helpful in diagnosis, but the final diagnosis is confirmed by a pathological examination through a biopsy and immunohistochemistry stain. The patient, in this case, presented an asymptomatic intrahepatic mass discovered incidentally on an imaging examination. Initially, intrahepatic cholangiocarcinoma was suspected, but she was finally diagnosed with IMT through a histological examination after a liver resection.

Endoscopic Removal Through a Gastrostomy of Swallowed Acupuncture Needles.

Acupuncture is a representative treatment field in oriental medicine that is used widely in various medical conditions. Although acupuncture is considered a safe procedure, it can cause complications. This paper reports the case of a 44-year-old quadriplegic woman who received a percutaneous gastrostomy (PEG) tube and was referred for the endoscopic removal of swallowed acupuncture needles. The needles were removed successfully by endoscopy through the PEG tube using the rendezvous technique without significant complications.

High sensitivity bolometers based on metal nanoantenna dimers with a nanogap filled with vanadium dioxide.

One critical factor for bolometer sensitivity is efficient electromagnetic heating of thermistor materials, which plasmonic nanogap structures can provide through the electric field enhancement. In this report, using finite element method simulation, electromagnetic heating of nanorod dimer antennas with a nanogap filled with vanadium dioxide (VO2) was studied for long-wavelength infrared detection. Because VO2 is a thermistor material, the electrical resistance between the two dimer ends depends on the dimer's temperature. The simulation results show that, due to the high heating ability of the nanogap, the temperature rise is several times higher than expected from the areal coverage. This excellent performance is observed over various nanorod lengths and gap widths, ensuring wavelength tunability and ultrafast operating speed, thereby making the dimer structures a promising candidate for high sensitivity bolometers.

Pharmacokinetic interaction between dronedarone and ticagrelor following oral administration in rats.

Dronedarone and ticagrelor have high co-administration potential in patients with both acute coronary syndrome and atrial fibrillation. The objective of the present in vivo study was to investigate the potential interaction between dronedarone (5 and 10 mg/kg) and ticagrelor (5 and 10 mg/kg) when administered orally to rats. Forty Sprague-Dawley rats were randomly distributed into eight groups; consisting of a dronedarone only group, a ticagrelor only group, a dronedarone with ticagrelor-pretreatment group, and a ticagrelor with dronedarone-pretreatment group. Pharmacokinetic exposure (AUCinf = 1472 ng·h/mL) associated with administration of 10 mg/kg of dronedarone increased significantly, with delayed T max in the group that received ticagrelor-pretreatment when compared to the dronedarone only group (AUCinf = 723 ng·h/mL). In addition, pharmacokinetic exposure (AUCinf = 2391 ng·h/mL) associated with administration of 10 mg/kg of ticagrelor increased significantly, with increased K el (0.31 h-1) and decreased V z/F (14.6 L/kg) in the dronedarone-pretreatment group when compared to the ticagrelor only group (AUCinf = 1616 ng·h/mL; K el = 0.21 h-1; V z/F = 31.3 L/kg). Results of our study suggest that further investigation of a potential interaction between dronedarone and ticagrelor in humans is justified and that caution may need to be exercised when dronedarone and ticagrelor pharmacotherapies concomitantly.

In Vitro Interaction of AB-FUBINACA with Human Cytochrome P450, UDP-Glucuronosyltransferase Enzymes and Drug Transporters.

AB-FUBINACA, a synthetic indazole carboxamide cannabinoid, has been used worldwide as a new psychoactive substance. Because drug abusers take various drugs concomitantly, it is necessary to explore potential AB-FUBINACA-induced drug-drug interactions caused by modulation of drug-metabolizing enzymes and transporters. In this study, the inhibitory effects of AB-FUBINACA on eight major human cytochrome P450s (CYPs) and six uridine 5'-diphospho-glucuronosyltransferases (UGTs) of human liver microsomes, and on eight clinically important transport activities including organic cation transporters (OCT)1 and OCT2, organic anion transporters (OAT)1 and OAT3, organic anion transporting polypeptide transporters (OATP)1B1 and OATP1B3, P-glycoprotein, and breast cancer resistance protein (BCRP) in transporter-overexpressing cells were investigated. AB-FUBINACA inhibited CYP2B6-mediated bupropion hydroxylation via mixed inhibition with Ki value of 15.0 µM and competitively inhibited CYP2C8-catalyzed amodiaquine N-de-ethylation, CYP2C9-catalyzed diclofenac 4'-hydroxylation, CYP2C19-catalyzed [S]-mephenytoin 4'-hydroxylation, and CYP2D6-catalyzed bufuralol 1'-hydroxylation with Ki values of 19.9, 13.1, 6.3, and 20.8 µM, respectively. AB-FUBINACA inhibited OCT2-mediated MPP+ uptake via mixed inhibition (Ki, 54.2 µM) and competitively inhibited OATP1B1-mediated estrone-3-sulfate uptake (Ki, 94.4 µM). However, AB-FUBINACA did not significantly inhibit CYP1A2, CYP2A6, CYP3A4, UGT1A1, UGT1A3, UGT1A4, UGT1A6, or UGT2B7 enzyme activities at concentrations up to 100 µM. AB-FUBINACA did not significantly inhibit the transport activities of OCT1, OAT1/3, OATP1B3, P-glycoprotein, or BCRP at concentrations up to 250 µM. As the pharmacokinetics of AB-FUBINACA in humans and animals remain unknown, it is necessary to clinically evaluate potential in vivo pharmacokinetic drug-drug interactions induced by AB-FUBINACA-mediated inhibition of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, OCT2, and OATP1B1 activities.

In Vitro Metabolism of DWP16001, a Novel Sodium-Glucose Cotransporter 2 Inhibitor, in Human and Animal Hepatocytes.

DWP16001 is currently in a phase 2 clinical trial as a novel anti-diabetes drug for the treatment of type 2 diabetes by selective inhibition of sodium-glucose cotransporter 2. This in vitro study was performed to compare the metabolism of DWP16001 in human, dog, monkey, mouse, and rat hepatocytes, and the drug-metabolizing enzymes responsible for the metabolism of DWP16001 were characterized using recombinant human cytochrome 450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes expressed from cDNAs. The hepatic extraction ratio of DWP16001 in five species ranged from 0.15 to 0.56, suggesting that DWP16001 may be subject to species-dependent and weak-to-moderate hepatic metabolism. Five phase I metabolites (M1-M5) produced by oxidation as well as three DWP16001 glucuronides (U1-U3) and two hydroxy-DWP16001 (M1) glucuronides (U4, U5), were identified from hepatocytes incubated with DWP16001 by liquid chromatography-high resolution mass spectrometry. In human hepatocytes, M1, M2, M3, U1, and U2 were identified. Formation of M1 and M2 from DWP16001 was catalyzed by CYP3A4 and CYP2C19. M3 was produced by hydroxylation of M1, while M4 was produced by hydroxylation of M2; both hydroxylation reactions were catalyzed by CYP3A4. The formation of U1 was catalyzed by UGT2B7, but UGT1A4, UGT1A9, and UGT2B7 contributed to the formation of U2. In conclusion, DWP16001 is a substrate for CYP3A4, CYP2C19, UGT1A4, UGT1A9, and UGT2B7 enzymes. Overall, DWP16001 is weakly metabolized in human hepatocytes, but there is a potential for the pharmacokinetic modulation and drug-drug interactions, involved in the responsible metabolizing enzymes of DWP16001 in humans.

Drivers shaping episodic and gradual changes in phytoplankton community succession: Taxonomic versus functional groups.

Describing temporal changes in phytoplankton communities is complicated owing to (i) multivariate environmental drivers, (ii) inter-specific relationships, and (iii) various species. With long-term research data from the lower Nakdong River from 1993 to 2016, we examined the temporal changes at two scales-episodic (from weekly to monthly) and long-term (yearly)-and screened the potential environmental drivers. Phytoplankton community component patterns were modeled with the drivers as covariates, using multivariate autoregressive state-space (MARSS) models, to assess their response to environmental drivers and biotic interactions. We assumed that compared to taxonomic classification, functional classification would obtain a better identification of community response to temporal variability. Over 24 years, the succession patterns of the dominant taxonomic and functional groups decreased in diversity, with the greatest decreases in biomass of Bacillariophyceae and group D (mainly the diatom Stephanodiscus hantzschii), and coincided with the introduction of group H1 (dinitrogen-fixing nostocaleans). The potential drivers for these changes were precipitation, water level, and total nitrogen (TN) for taxonomic groups and TN, total phosphorus, and euphotic zone depth for functional groups. The results of the MARSS model and temporal trends for each driver indicated that the increases in the water level and light availability were mostly related with the taxonomic and functional groups, respectively. The model for functional groups proposed a total of 24 significant inter-group relationships, where five relationships supported the succession patterns of dominant groups in the Nakdong River. Combined with the effects of increased light availability, a positive relationship between groups H1 and M (mainly Cyanobacteria and Microcystis aeruginosa) appears to induce cyanobacterial bloom development over a long period. These results can be fundamental information for river system management concerning the resulting cascading effects of changes in environmental drivers and inter-group relationships on the phytoplankton community composition.

Liquid Chromatography-Tandem Mass Spectrometry for the Simultaneous Determination of Doxorubicin and its Metabolites Doxorubicinol, Doxorubicinone, Doxorubicinolone, and 7-Deoxydoxorubicinone in Mouse Plasma.

Doxorubicin, an anthracycline antitumor antibiotic, acts as a cancer treatment by interfering with the function of DNA. Herein, liquid chromatography-tandem mass spectrometry was for the first time developed and validated for the simultaneous determination of doxorubicin and its major metabolites doxorubicinol, doxorubicinone, doxorubicinolone, and 7-deoxydoxorubicinone in mouse plasma. The liquid-liquid extraction of a 10 µL mouse plasma sample with chloroform:methanol (4:1, v/v) and use of the selected reaction monitoring mode led to less matrix effect and better sensitivity. The lower limits of quantification levels were 0.5 ng/mL for doxorubicin, 0.1 ng/mL for doxorubicinol, and 0.01 ng/mL for doxorubicinone, doxorubicinolone, and 7-deoxydoxorubicinone. The standard curves were linear over the range of 0.5-200 ng/mL for doxorubicin; 0.1-200 ng/mL for doxorubicinol; and 0.01-50 ng/mL for doxorubicinone, doxorubicinolone, and 7-deoxydoxorubicinone in mouse plasma. The intra and inter-day relative standard deviation and relative errors for doxorubicin and its four metabolites at four quality control concentrations were 0.9-13.6% and -13.0% to 14.9%, respectively. This method was successfully applied to the pharmacokinetic study of doxorubicin and its metabolites after intravenous administration of doxorubicin at a dose of 1.3 mg/kg to female BALB/c nude mice.

Mertansine Inhibits mRNA Expression and Enzyme Activities of Cytochrome P450s and Uridine 5'-Diphospho-Glucuronosyltransferases in Human Hepatocytes and Liver Microsomes.

Mertansine, a tubulin inhibitor, is used as the cytotoxic component of antibody-drug conjugates (ADCs) for cancer therapy. The effects of mertansine on uridine 5'-diphospho-glucuronosyltransferase (UGT) activities in human liver microsomes and its effects on the mRNA expression of cytochrome P450s (CYPs) and UGTs in human hepatocytes were evaluated to assess the potential for drug-drug interactions (DDIs). Mertansine potently inhibited UGT1A1-catalyzed SN-38 glucuronidation, UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-ß-glucuronidation, and UGT1A4-catalyzed trifluoperazine N-ß-d-glucuronidation, with Ki values of 13.5 µM, 4.3 µM, and 21.2 µM, respectively, but no inhibition of UGT1A6, UGT1A9, and UGT2B7 enzyme activities was observed in human liver microsomes. A 48 h treatment of mertansine (1.25-2500 nM) in human hepatocytes resulted in the dose-dependent suppression of mRNA levels of CYP1A2, CYP2B6, CYP3A4, CYP2C8, CYP2C9, CYP2C19, UGT1A1, and UGT1A9, with IC50 values of 93.7 109.1, 36.8 18.3, 160.6 167.4, 32.1 14.9, 578.4 452.0, 539.5 233.4, 856.7 781.9, and 54.1 29.1 nM, respectively, and decreased the activities of CYP1A2-mediated phenacetin O-deethylase, CYP2B6-mediated bupropion hydroxylase, and CYP3A4-mediated midazolam 1-hydroxylase. These in vitro DDI potentials of mertansine with CYP1A2, CYP2B6, CYP2C8/9/19, CYP3A4, UGT1A1, and UGT1A9 substrates suggest that it is necessary to carefully characterize the DDI potentials of ADC candidates with mertansine as a payload in the clinic.