医学最新文献

T-cell receptor mimic (TCRm) antibodies are an emerging class of tumor-targeting agents used in advanced immunotherapies such as bispecific T-cell engagers and CAR-T cells. Unlike conventional antibodies, TCRms are designed to recognize peptide - human leukocyte antigen (pHLA) complexes that present intracellular tumor-derived peptides on the cell surface. Due to the typically low surface abundance and high sequence similarity of pHLAs, TCRms require high affinity and exceptional specificity to avoid off-target toxicity. Conventional methods for off-target identification such as sequence similarity searches, motif-based screening, and structural modeling focus on the peptide and are limited in detecting cross-reactive peptides with little or no sequence homology to the target. To address this gap, we developed EpiPredict, a TCRm-specific machine learning framework trained on high-throughput kinetic off-target screening data. EpiPredict learns an antibody-specific mapping from peptide sequence to binding strength, enabling prediction of interactions with unmeasured pHLA sequences, including sequence-dissimilar peptides. We applied EpiPredict to two distinct TCRms targeting the cancer-testis antigen MAGE-A4. The model successfully predicted multiple off-targets with minimal sequence similarity to the intended epitope, many of which were experimentally validated via T2 cell binding assays. These findings establish EpiPredict as a valuable tool for lead optimization of TCRms, enabling the identification of antibody-specific off-targets beyond the scope of traditional peptide-centric methods and supporting the preclinical de-risking of TCRm-based therapies.

Context: Several coumarins have been isolated from Ruta graveolens L., but the chirality of many remains uncharacterized or their absolute configurations unresolved.

Objective: This study aimed to comprehensively separate and characterize the chirality of 3'-methyl-3'-butenylcoumarins from R. graveolens extracts, determine their absolute configurations, and evaluate their anticoagulant and anti-inflammatory activities.

Materials and methods: Comprehensive chromatographic separation and chiral HPLC analysis were employed on the R. graveolens extract. The structures of isolated compounds were elucidated using extensive spectroscopic data analysis (HR-ESI-MS, NMR) and by comparing experimental circular dichroism (CD) spectra with calculated electronic circular dichroism (ECD) spectra. The anticoagulant and anti-inflammatory (specifically inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages) activities of the isolated compounds were evaluated.

Results: The study led to the isolation of two pairs of enantiomeric 3'-methyl-3'-butenylcoumarins, present in both equivalent and inequivalent ratios. This included two previously undescribed chiral 3'-methyl-3'-butenylcoumarins with specific absolute configurations [(+)-2'R-2 and (-)-2'S-3] and one undescribed achiral 3'-methyl-3'-butenylcoumarin (1). Among the tested compounds, only the racemic mixture (±)-3 exhibited moderate inhibition of NO production in the anti-inflammatory assay. No significant anticoagulant activity was reported for the compounds.

Conclusions: This study successfully characterized the chirality and determined the absolute configurations of specific 3'-methyl-3'-butenylcoumarins from R. graveolens, including the discovery of three new compounds. While most isolated compounds lacked significant anticoagulant or anti-inflammatory activity in the tested models, racemic (±)-3 showed moderate anti-inflammatory potential by inhibiting NO production. These findings provide new insights for the future development and utilization of coumarins from R. graveolens.

Background: Integrating electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) with naturalistic stimuli has advanced our understanding of the neural mechanisms underlying mental disorders. Naturalistic paradigms use dynamic, multimodal stimuli that capture complex emotional and cognitive processes more effectively than traditional experimental designs. Objective: This review synthesizes research from 2014 to 2024 exploring neural mechanisms of anxiety, depression, and schizophrenia within naturalistic paradigms. Methods: Recent EEG-fMRI studies employing naturalistic tasks were examined to identify common and disorder-specific neural alterations across affective and cognitive networks. Results: In anxiety, hyperactivity in the amygdala, prefrontal cortex, anterior cingulate cortex, and insula, together with changes in the dorsal attention, default mode, and frontoparietal networks, reflects excessive fear responses and impaired regulation. Depression is characterized by disruptions in default mode and frontoparietal connectivity and altered amygdala-prefrontal interactions, indicating maladaptive introspection and cognitive control. Schizophrenia shows abnormalities in motor and language processing, with aberrant activity in frontal, parietal, and temporal regions including the insula and temporoparietal junction. Conclusion: These findings highlight the shared involvement of the amygdala, prefrontal cortex, anterior cingulate cortex, and insula across disorders and demonstrate the potential of naturalistic paradigms for advancing personalized diagnostics and interventions in mental health.

Low molecular weight heparin (LMWH) is widely used for the treatment and prevention of many venous thromboembolic disorders. LMWH acts through its ability to potentiate inhibition of factor Xa. LMWH undergoes primary renal excretion and therefore its elimination can be severely impacted by kidney disease. We report on the case of an infant with stage 5 chronic kidney disease (CKD) who received a prolonged accidental overdose of dalteparin. The infant was symptomatic with a falling haemoglobin, perinephric hematoma, and oozing venipuncture sites. Given the inability to predict drug clearance in this infant and her significant risk of bleeding, she underwent a successful trial of continuous veno-venous hemofiltration (CVVH) for the treatment of LMWH overdose. Whilst on CVVH, a steady downward trend in anti-Xa levels over 24 h was observed.

Background: This retrospective, descriptive study, conducted in a single-center PICU from June 2014 to May 2023, aimed to analyze the efficacy of adjunctive regional citrate anticoagulation for continuous kidney replacement therapy (CKRT) circuits during extracorporeal membrane oxygenation (ECMO).

Methods: Patients were divided into two groups based on their CKRT anticoagulation strategy: those receiving regional citrate anticoagulation in addition to systemic heparin (UFH + RCA group) and those receiving only systemic heparin (UFH group). CKRT circuits were also classified as either UFH + RCA or UFH to analyze outcomes specific to each anticoagulation strategy. CKRT circuit lifespan estimation was calculated by dividing the total CKRT duration by the number of circuits used.

Results: During the study period, 110 pediatric patients were treated with ECMO at our PICU. During ECMO, 64 (58.2%) of these patients required CKRT. Fluid overload and acute kidney injury were the primary indications for CKRT. While not statistically significant, the median estimate CKRT circuit lifespan was longer in the citrate group [84 (38.4-112.0)] than the heparin group [52 (12.0-408.0)]. Circuit changes due to clotting were significantly higher in the heparin group compared to the citrate group (58.1% vs. 31.7%, p = 0.00). Kaplan-Meier analysis revealed a statistically significant difference in the timing of clotting-related circuit changes, favoring UFH + RCA (p = 0.02).

Conclusions: To the best of our knowledge, our study represents the first comparison of UFH + RCA and UFH alone for CKRT in pediatric ECMO patients. Our findings suggest that using UFH + RCA might help the circuit last longer by decreasing changes caused by clotting. Prospective studies on this topic are needed.

Background: Kidney involvement in pediatric sarcoidosis is rare and often underrecognized, leading to diagnostic delays and treatment challenges. We report six patients with renal sarcoidosis to highlight their diverse presentations and outcomes and challenges in management.

Methods: Medical records of patients diagnosed with renal sarcoidosis during 2020-24 were reviewed. Sarcoidosis was diagnosed based on clinical and histological features and exclusion of alternative causes and managed according to unit protocols. Information on clinical features, laboratory and radiologic findings, histopathology, treatment, and follow-up were compiled.

Results: We present six patients with sarcoidosis, presenting with kidney involvement at the age of 1.5-14 years, and followed up for 7-138 months. All patients had acute kidney injury (AKI) of whom two required hemodialysis. Proteinuria was present in all patients, while four patients had microscopic hematuria or leukocyturia. Hypercalcemia with hypercalciuria, distal renal tubular acidosis, and nephrocalcinosis were seen in five, two, and one case, respectively. Granulomatous interstitial nephritis was confirmed histologically in all cases. While initial therapy with corticosteroids led to clinical remission in all cases, five patients had nine relapses, necessitating second-line immunosuppression with mycophenolate mofetil, azathioprine, or methotrexate; one patient received antitumor necrosis factor therapy. Median eGFR at last follow up was 59.7 (range 12.7-132) ml/min/1.73 m²; three progressed to chronic kidney disease (CKD) stages G3-G5.

Conclusions: Kidney involvement in pediatric sarcoidosis manifests in diverse forms, ranging from isolated biochemical abnormalities to severe AKI. While prompt immunosuppression might preserve kidney function, patients require close monitoring for relapses, and progression to CKD.

Introduction: Evidence provides support for the therapeutic benefits of targeting avoidance in prolonged grief. However, it is not clear whether avoidance interferes with mourning through altered resilience to stress, as measured by heart rate variability (HRV).

Methods: Thirty-five adults (30 female; mean age: 39.2 years), who had been bereaved for more than one year, participated in this prospective, observational study. At each of the initial assessments and up to six-month follow-ups, grief symptoms were assessed using the Complicated Grief Questionnaire, and a resting electrocardiogram was recorded to extract the high-frequency component of HRV (HF-HRV). To differentiate avoidance from grief itself, principal component analysis was used.

Results: A nonlinear cross-sectional relationship was observed between avoidance and HF-HRV (coefficient = 0.29, p = .003); the lower the avoidance, the lower the HF-HRV in the low avoidance group. Grief improved only in the low avoidance group longitudinally. The observed relationship between increased HF-HRV and decreased grief was modified by the avoidance group, such that the low-avoidance group drove this association (estimate -0.53, 95% CI -0.86, -0.21, p = .001), while the high-avoidance group did not (estimate 0.44, 95% CI -0.32, 1.20, p = .26).

Conclusion: Despite its palliative gain, avoidance relates to the maintenance of grief longitudinally through attenuated autonomic resilience to stress.

Background: Nephrotic syndrome (NS) is a common pediatric kidney disorder characterized by proteinuria, hypoalbuminemia, and edema. Leukotrienes (LTs), as inflammatory mediators, may contribute to NS pathogenesis and influence treatment response. This study aimed to assess urinary leukotriene E4 (LTE4) levels in children with an initial onset of NS and evaluate their potential as biomarkers for steroid responsiveness.

Methods: In this observational cohort study, 41 children with a first episode of NS and 41 age- and sex-matched healthy controls were enrolled. Patients were classified into steroid-sensitive NS (SSNS; n = 29) and steroid-resistant NS (SRNS; n = 12) groups following initial steroid therapy. Urinary LTE4 levels were measured prior to treatment, using enzyme-linked immunosorbent assay (ELISA).

Results: Urinary LTE4 levels were significantly elevated in children with NS compared to controls (p = 0.001). Although urinary LTE4 to urinary creatinine (U cr) ratios were also higher in patients, the difference did not reach statistical significance (p = 0.09). No significant correlations were observed between urinary LTE4 levels and urinary protein excretion or serum albumin. Furthermore, urinary LTE4 levels did not significantly differ between SSNS and SRNS groups. A receiver operating characteristic (ROC) curve analysis showed poor predictive value of urinary LTE4 for steroid responsiveness, with area-under-the-curve (AUC) values near 0.5.

Conclusions: While urinary LTE4 levels are elevated in children with NS, they failed to reliably differentiate between SSNS and SRNS. These findings suggest a limited role for urinary LTE4 as a predictive biomarker of steroid responsiveness in pediatric NS. However, future large-scale studies incorporating both plasma and urinary leukotriene profiles are warranted to validate its role in disease pathogenesis and treatment response.

Background: Neuropsychiatric systemic lupus erythematosus (NPSLE) and lupus nephritis (LN) are two major, life-threatening complications in childhood-onset SLE (cSLE). Data regarding the epidemiology and prognosis of children with concurrent NPSLE and LN remain scarce. This study aimed to investigate the clinical characteristics, associated factors, and outcomes of NPSLE in Chinese children with LN.

Methods: A retrospective cohort study was conducted at the Paediatric Nephrology Centre of Hong Kong Children's Hospital, including 95 Chinese children with biopsy-proven cLN. Comparisons were made between children with and without NPSLE.

Results: Of 95 Chinese children with cLN, 11 (12%) developed NPSLE, and 31 NPSLE events were reported. Estimated glomerular filtration rate < 30 mL/min/1.73 m² at diagnosis of LN (OR_adj 6.7, 95% CI 1.29-35.1) and higher maximal proteinuria during the observation period (OR_adj 1.07, 95% CI 1-1.13) were predictive of NPSLE upon multivariable analysis. Compared to children with LN who did not develop NPSLE, significantly more children who developed subsequent NPSLE flare following initial kidney involvement had a history of medication non-adherence (100% vs. 25%, p < 0.001), higher degree of proteinuria at the diagnosis of LN (urine protein/creatinine ratio, 5.7 vs. 2.4 mg/mg, p = 0.04) and during the entire observation period (urine protein/creatinine ratio, 13.2 vs. 3.3 mg/mg, p = 0.004). Patients with NPSLE had significantly lower complete remission rates for LN at 6- and 12-month post-induction (27.3% vs. 70.2%, p = 0.014; 45.5% vs. 83.3%, p = 0.01, respectively). Kaplan-Meier analysis showed that patients with NPSLE had worse kidney and patient survivals (log-rank test, p < 0.001, 0.0014, respectively) than those without NPSLE.

Conclusions: Worse kidney and patient survivals are observed in cLN patients with NPSLE. Severe LN manifestation and medication non-adherence are associated with the development of NPSLE.