Journals
2025 EN
Cohen Michael · Orgel Etan · NevarezMejia Jessica
+4 more
ABSTRACT Introduction Obesity contributes to poorer clinical outcomes in patients with acute lymphoblastic leukemia. We have shown that adipocytes cause anthracycline resistance by absorbing and metabolizing them into less‐active alcohol metabolites. Methods We hypothesized that mitoxantrone, which has a similar cytotoxic mechanism to anthracyclines but is metabolized through different pathways, might overcome this adipocyte‐mediated chemoresistance. We treated human BV173 acute lymphoblastic leukemia cells with daunorubicin and mitoxantrone that had been incubated with or without 3T3‐L1 adipocytes. Results Contrary to our hypothesis, adipocytes induced similar chemoresistance to both drugs. Conclusion Mitoxantrone is unlikely to be an attractive alternative to overcome adipocyte‐mediated anthracycline resistance in patients with obesity. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission.
Journals
2025 EN
Magdalenic Katarina · Morillon Donatien · De Jonghe Steven
+6 more
ABSTRACT Cancer chemotherapy is continuously challenged by serious complications like pronounced side effects and multidrug resistance (MDR). Natural products, such as curcumin, offer promising alternatives due to their diverse biological applications and low toxicity. However, curcumin's clinical utility is limited by poor bioavailability, rapid metabolism, and non‐specific (PAINS) activity. Building on previous findings, this study explored the structural modification of curcumin‐inspired benzothiazepane derivatives in an attempt to enhance their therapeutic potential through modifications of the two peripheral (hetero)aromatic rings and the benzothiazepane scaffold. In this way, eight new 2‐(hetero)aryl‐4‐(4‐(hetero)aryl‐2‐oxobut‐3‐en‐1‐ylidene)benzothiazepanes and two 4‐thiobutan‐2‐one “double Michael addition” derivatives were synthesized and tested for cytotoxicity against a panel of eight cancer cell lines. The screening results indicated that bis‐(4‐hydroxyphenyl) analogs bearing a chlorinated benzothiazepane ring exhibited the highest potency and broad‐spectrum activity at the low micromolar range. Bis‐substitutions with 3‐pyridinyl and 2‐furyl groups showed less potent but more specific activity profiles, potentially reducing PAINS effects. 2‐Aminothiophenol‐derived double Michael addition products demonstrated increased broad‐spectrum activity, highlighting the importance of the free aniline amino group for targeted effects. This study underscores the potential of benzothiazepane derivatives as viable cancer cell cytotoxic agents and provides useful insights for future optimization and evaluation.
Journals
2025 EN
Bhatla Anjali · Menez Steven · Feldman Leonard
Visual Abstract
Journals
2025 EN
Kamijo Kyosuke · Wada Yoshimitsu · Ishida Kentaro
+3 more
Abstract This study investigates the factors contributing to the decline in obstetrics and gynecology (OB/GYN) malpractice claims in Japan and highlights professional attitudes, institutional support systems, clinical practices, and policies that can further reduce such claims, while comparing these findings with malpractice data from the United States. We analyzed OB/GYN closed malpractice claims from the Supreme Court of Japan, along with data on maternal and neonatal mortality rates from the Ministry of Health, Labour and Welfare. We used Jonckheere‐Terpstra tests to evaluate trends, considering p ‐values < 0.05 as statistically significant. In Japan, the proportion of medical malpractice claims in OB/GYN dropped significantly from 15.1% in 2004 to 5.2% in 2022 ( p < 0.001). The number of claims per 100 OB/GYN physicians also significantly decreased from 0.9 in 2007 to 0.4 in 2016 ( p < 0.001). Despite an increase in the cesarean delivery rate, both maternal and neonatal mortality rates have significantly decreased ( p < 0.001 and p < 0.05, respectively). Japan's OB/GYN field saw a dramatic reduction in claims due to heightened awareness after a wrongful criminally charge, the establishment of financial compensation for cerebral palsy, standardized clinical guidelines, and adverse event investigation system.
Journals
2025 EN
King Melissa A. · Heger Katherine C. · Drikic Marija
+7 more
ABSTRACT The dilated cardiomyopathy with ataxia (DCMA) syndrome is a rare mitochondrial disorder caused by mutations in the poorly understood DNAJC19 gene. Cardiac involvement in DCMA ranges from mild conduction abnormalities to early severe myocardial dysfunction. Although evidence suggests that DCMA is linked to abnormalities in mitochondrial function, the molecular underpinnings of this condition are unclear, and there is no way to predict which patients will develop life‐threatening disease. To address this, we developed a metabolic flux assay for assessing the metabolic function of mitochondria in fibroblasts derived from DCMA patients. Using this approach, we discovered that DCMA fibroblasts have elevated glutamine uptake, increased glutamate and ammonium secretion, and elevated lactate production. Moreover, we observed that these cellular perturbations were closely correlated with cardiac dysfunction in a blinded cohort of patient cell lines. These findings suggest that glutamine catabolism is abnormal in DCMA and may serve as a predictor of clinical progression.
Journals
2025 EN
Yuskiv Nataliya · Saad Ammar · Potter Beth K.
+26 more
ABSTRACT Achieving and maintaining metabolic control is critical for children with phenylalanine hydroxylase (PAH) deficiency. This retrospective longitudinal cohort study investigated metabolic control and monitoring frequency of children with PAH deficiency (≤ 12 years) treated at one of 12 pediatric metabolic centres across Canada. We abstracted data from medical charts and analyzed outcomes by age and diagnostic classification, using mixed effects regression. Of 215 children included in the study, 43% had a chart diagnosis of classic phenylketonuria (PKU); the remainder had a diagnosis of mild PKU or mild hyperphenylalaninemia (grouped as “less severe PAH deficiency”). During the first month of life, blood phenylalanine levels of children with classic PKU reached the target therapeutic range of 120–360 μmol/L at a median age of 15 days, but 74.3% and 32.9% had ≥ 1 and ≥ 3 values below 120 μmol/L, respectively. From age > 1 month to 12 years, mean blood phenylalanine values were 260.6 and 236.7 μmol/L for children with classic PKU and less severe PAH deficiency, respectively, with a trend of increased blood phenylalanine levels with increasing age ( p < 0.001). Fewer children with classic PKU (37.2%) versus less severe PAH deficiency (77.9%) had > 60% of values in the therapeutic range, indicating less optimal metabolic control. Frequency of blood phenylalanine testing and communication with metabolic centres decreased with age. Our findings suggest a need to better understand the reasons for blood phenylalanine variability across child age and disease severity in order to inform supports for children with PAH deficiency and their caregivers to maintain metabolic control.
Journals
2025 EN
Zottoli Steven J. · Kaczmarek Leonard K. · Faber Donald S.
ABSTRACT Mauthner cells are found in most fish and amphibians. The prominence of their large fiber is commonly used as one criterion to identify the presence of these cells in fish and the largest of these fibers have been reported in lungfish. While some authors believe that Mauthner fibers in lungfish contain a single axon, others report that many processes join the Mauthner axon (M‐axon) inside a common myelin sheath to form a “multi‐axial fiber.” To distinguish between these two possibilities, we have used light and transmission electron microscopy to determine whether multi‐axial fibers exist in African, Protopterus annectens , Australian, Neoceratodus forsteri , and South American, Lepidosiren paradoxa , lungfish. Ultrastructural analysis provides evidence of a multi‐axial fiber that contains a M‐axon, non‐M‐axons and glial processes within a common myelin sheath. The glial processes form myelin and paranodal‐like structures. Stacked desmosome‐like structures have been identified that may be part of Schmidt‐Lanterman incisures. We discuss how the electrical activity of a select group of axons may affect that of other axons within a common myelin sheath.
Journals
2025 EN
Tyler Christopher · Koganti Lahari · Liu Jun
+5 more
ABSTRACT Supramedullary neurons (SMNs) were described almost 150 years ago as large, unipolar cells whose somata are located on the dorsal aspect of the medulla oblongata and spinal cord in adults of teleost fishes. SMNs are either aligned in a single, median longitudinal row, generally extending over the rostral third of the spinal cord, or clustered over the medulla oblongata and rostral spinal cord. We add to the list of species that have SMNs and provide the first description of a novel distribution of SMNs along most of the spinal cord in the oyster toadfish ( Opsanus tau ) and sea raven ( Hemitripterus americanus ). The number of SMNs ranges from 27 in the Atlantic butterfish ( Peprilus triacanthus ) to 3712 in the oyster toadfish ( Opsanus tau ), and soma diameter ranges from an average of 23 µm in the Atlantic butterfish to 232 µm in the Southern pufferfish ( Sphoeroides nephelus ). SMNs could not be identified in 11 species, including seven freshwater fishes. We discuss factors that may affect the presence/absence of SMNs including age, length of time in captivity, and habitat salinity. Proposed functions of SMNs include neurosecretion and mucous secretion, and we suggest approaches that may aid in the discovery of the role of these fascinating neurons.
Journals
2025 EN
Zabihollahy Fatemeh · Miao Qi · Naim Sohaib
+8 more
Background Understanding the characteristics of multiparametric MRI (mpMRI) in patients from different racial/ethnic backgrounds is important for reducing the observed gaps in clinical outcomes. Purpose To investigate the diagnostic performance of mpMRI and quantitative MRI parameters of prostate cancer (PCa) in African American (AA) and matched White (W) men. Study Type Retrospective. Subjects One hundred twenty‐nine patients (43 AA, 86 W) with histologically proven PCa who underwent mpMRI before radical prostatectomy. Field Strength/Sequence 3.0 T, T2‐weighted turbo spin echo imaging, a single‐shot spin‐echo EPI sequence diffusion‐weighted imaging, and a gradient echo sequence dynamic contrast‐enhanced MRI with an ultrafast 3D spoiled gradient‐echo sequence. Assessment The diagnostic performance of mpMRI in AA and W men was assessed using detection rates (DRs) and positive predictive values (PPVs) in zones defined by the PI‐RADS v2.1 prostate sector map. Quantitative MRI parameters, including K trans and v e of clinically significant (cs) PCa (Gleason score ≥ 7) tumors were compared between AA and W sub‐cohorts after matching age, prostate‐specific antigen (PSA), and prostate volume. Statistical Tests Weighted Pearson's chi‐square and Mann–Whitney U tests with a statistically significant level of 0.05 were used to examine differences in DR and PPV and to compare parameters between AA and matched W men, respectively. Results A total number of 264 PCa lesions were identified in the study cohort. The PPVs in the peripheral zone (PZ) and posterior prostate of mpMRI for csPCa lesions were significantly higher in AA men than in matched W men (87.8% vs. 68.1% in PZ, and 89.3% vs. 69.6% in posterior prostate). The K trans of index csPCa lesions in AA men was significantly higher than in W men (0.25 ± 0.12 vs. 0.20 ± 0.08 min −1 ; P < 0.01). Data Conclusion This study demonstrated race‐related differences in the diagnostic performances and quantitative MRI measures of csPCa that were not reflected in age, PSA, and prostate volume. Evidence Level 3 Technical Efficacy Stage 2
Journals
2025 EN
Cho Steven K.S. · Darby Jack R.T. · Williams Georgia K.
+8 more
Background Cardiac MRI feature tracking (FT) allows objective assessment of segmental left ventricular (LV) function following a myocardial infarction (MI), but its utilization in sheep, where interventions can be tested, is lacking. Purpose To apply and validate FT in a sheep model of MI and describe post‐MI LV remodeling. Study Type Animal model, longitudinal. Animal Model Eighteen lambs (6 months, male, n = 14; female, n = 4; 25.2 ± 4.5 kg). Field Strength/Sequence Two‐dimensional balanced steady‐state free precession (bSSFP) and 3D inversion recovery fast low angle shot (IR‐FLASH) sequences at 3 T. Assessment Seven lambs underwent test–retest imaging to assess FT interstudy reproducibility. MI was induced in the remaining 11 by coronary ligation with MRI being undertaken before and 15 days post‐MI. Injury size was measured by late gadolinium enhancement (LGE) and LV volumes, LV mass, ejection fraction (LVEF), and wall thickness (LVWT) were measured, with FT measures of global and segmental radial, circumferential, and longitudinal strain. Statistical Tests Sampling variability, inter‐study, intra and interobserver reproducibility were assessed using Pearson's correlation, Bland–Altman analyses, and intra‐class correlation coefficients (ICC). Diagnostic performance of segmental strain to predict LGE was assessed using receiver operating characteristic curve analysis. Significant differences were considered P < 0.05. Results Inter‐study reproducibility of FT was overall good to excellent, with global strain being more reproducible than segmental strain (ICC = 0.89–0.98 vs. 0.77–0.96). MI (4.0 ± 3.7% LV mass) led to LV remodeling, as evident by significantly increased LV volumes and LV mass, and significantly decreased LVWT in injured regions, while LVEF was preserved (54.9 ± 6.9% vs. 55.6 ± 5.7%; P = 0.778). Segmental circumferential strain (CS) correlated most strongly with LGE. Basal and mid‐ CS increased significantly, while apical CS significantly decreased post‐MI. Data Conclusion FT is reproducible and compensation by hyperkinetic remote myocardium may manifest as overall preserved global LV function. Evidence Level N/A Technical Efficacy Stage 2