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Enhanced immune clearance of L-Asparaginase and its genetic predisposition among children with acute Lymphoblastic Leukaemia

2026-09-17T07:30:17Z

Title: Enhanced immune clearance of L-Asparaginase and its genetic predisposition among children with acute Lymphoblastic Leukaemia Authors: Tan Yan Qi Abstract: Pegylated L-asparaginase (peg-ASNase) is the cornerstone of childhood acute lymphoblastic leukaemia (ALL) chemotherapy. Its immunogenicity often prompts the production of antibodies, rendering the post-administration drug activity suboptimal in patients. Potential genetic variants may increase the risk of the drug's immune- mediated sequelae, with their allelic prevalences in the Southeast Asian patient population remaining obscure. The absence of validated commercial assays for quantifying serum peg-ASNase activity levels and anti-ASNase antibody titres further complicates the assessment of the drug effectiveness in patients. This study aimed (a) to develop and validate biochemical assays for measuring peg-ASNase activity levels and anti-ASNase IgG titres in human serum, (b) to determine the correlation between serum peg-ASNase activity and anti-ASNase IgG titres, (c) to investigate the association of seven genetic variants with serum anti-ASNase IgG titres, and (d) to determine the association between serum peg-ASNase activity and childhood ALL induction outcomes, mainly the marrow morphology status and minimal residual disease. A reversed-phase high- performance liquid chromatography assay with automated sample derivatisation was optimised and validated for measuring serum peg-ASNase activity (%CV range: 3.05%- 4.16%; %error range: -3.03% -0.90%; LLOQ: 0.03 IU/mL). An indirect enzyme-linked immunosorbent assay was developed and validated to quantify human serum anti- ASNase IgG titres (%CV range: 6.54%-14.81%; %recovery range: 95.89%-100.77%; cut-off: ≥1.60 μg/mL). For genetic variants genotyping, conventional PCR and Sanger sequencing were performed. Statistical analysis was conducted using SPSS v29.0.1.0. Mean serum trough peg-ASNase activity levels were 0.11 IU/mL and 0.07 IU/mL for the newly diagnosed and relapsed patients, respectively, with 47.5% (29/61) and 20% (1/5) samples achieving 20.1 IU/mL in the respective cohorts after first drug dosing. There was an inverse correlation between serum peg-ASNase activity levels and anti- ASNase IgG titres (p=0.006). Patients with anti-ASNase IgG were found with lower serum peg-ASNase activity than those without antibody (p=0.002). GRIA1 rs4958351 was inversely associated with post-administration anti-ASNase IgG titres, whereas IL16 rs11556218 was associated with baseline antibody levels. Serum peg-ASNase activity levels were not associated with childhood ALL induction outcomes. This is the first local study on generic peg-ASNase, paving the way for future studies and improvements in drug administration for children using the developed laboratory assays.

Preoperative prediction of lateral cervical lymph node metastasis in papillary thyroid carcinoma using conventional ultrasound, sonazoid contrast enhanced ultrasound, fine needle aspiration thyroglobulin and radiomics

2026-09-17T07:13:21Z

Title: Preoperative prediction of lateral cervical lymph node metastasis in papillary thyroid carcinoma using conventional ultrasound, sonazoid contrast enhanced ultrasound, fine needle aspiration thyroglobulin and radiomics Authors: Liu Yan Abstract: Accurate preoperative identification of lateral cervical lymph node metastasis (LLNM) is crucial for surgical decision-making and prognostic assessment in patients with papillary thyroid carcinoma (PTC). Because prophylactic lateral neck dissection is not routinely recommended owing to the risks of surgical complications and cosmetic impairment, reliable preoperative confirmation of LLNM remains an important clinical challenge. This study aimed to comprehensively evaluate the diagnostic performance of conventional ultrasound, Sonazoid contrast-enhanced ultrasound (CEUS), fine- needle aspiration thyroglobulin (FNA-Tg), and ultrasound-based radiomics for the preoperative prediction of LLNM in PTC. The final analytical cohort comprised 178 patients. Of these, 44 had undergone the relevant examinations as part of routine clinical care between 1 February and 13 June 2024 and were retrospectively included only after local ethical approval was obtained on 14 June 2024. A further 134 patients were enrolled from July 2024 to November 2025 under the approved study protocol. Each patient contributed one lateral cervical lymph node showing the most suspicious or pronounced imaging abnormalities for analysis. All selected lymph nodes underwent conventional ultrasound, Sonazoid CEUS assessment during the arterial, venous, and post-vascular phases, and FNA-Tg measurement. Qualitative and quantitative diagnostic approaches were compared using receiver operating characteristic analysis and paired DeLong tests. Multimodal combinations of conventional ultrasound, Sonazoid CEUS, and FNA-Tg were also evaluated. Radiomics features were extracted from grayscale ultrasound, colour Doppler flow imaging, and images from the three CEUS phases. Eleven machine-learning algorithms were assessed using the area under the receiver operating characteristic curve, decision curve analysis, calibration curves, and sample-level prediction scores. Quantitative approaches generally showed higher diagnostic performance than the corresponding qualitative assessments for conventional ultrasound, multiphase Sonazoid CEUS, and FNA-Tg. Sonazoid CEUS achieved an AUC of 0.979 and significantly outperformed conventional ultrasound (p = 0.0057). Among the multimodal strategies, the combination of conventional ultrasound, Sonazoid CEUS, and FNA-Tg yielded the highest observed AUC of 0.993, although it was not statistically superior to the high-performing two-modality combinations. Radiomics performance varied across imaging modalities. The multilayer perceptron model based on post-vascular-phase CEUS achieved the highest observed test-cohort AUC of 0.882 among the radiomics models evaluated. These findings support a risk- adapted diagnostic approach in which conventional ultrasound provides initial anatomical assessment, Sonazoid CEUS adds functional information, FNA-Tg provides biochemical confirmation, and radiomics offers additional quantitative risk stratification. External multicentre validation is required before the radiomics models or integrated pathway can be adopted routinely.

Exploring the link between Vitamin D deficiency and prediabetes in the Ibb Governorate, Yemen: the prevalence and impact of high-dose Vitamin D supplementation

2026-09-17T04:58:54Z

Title: Exploring the link between Vitamin D deficiency and prediabetes in the Ibb Governorate, Yemen: the prevalence and impact of high-dose Vitamin D supplementation Authors: Mohammed Abdo Mohammed Yaseen Al-Hetar Abstract: Prediabetes and vitamin D deficiency are interrelated public health concems, especially in low-resource regions with high metabolic risk. This study aimed to determine the prevalence of prediabetes among adults in Ibb governorate, Yemen, assess vitamin D status in ADA-defined prediabetic individuals, and evaluate the effects of high-dose vitamin D supplementation on glycaemic parameters, insulin resistance, B-cell function, inflammatory markers, lipid profile, and endothelial function. This two-phase study, conducted from July 2024 to May 2025, included a community-based cross-sectional study followed by a randomized controlled trial involving 1,045 adults aged 18-60 years. Prediabetes was defined using American Diabetes Association criteria based on fasting blood glucose (FBG), 2-hour postprandial plasma glucose (2HPP), or glycated hemoglobin (HbA1c). Of 266 adults with ADA-defined prediabetes, 151 who had vitamin D deficiency were randomised to receive weekly oral cholecalciferol 50,000 IU or placebo for 16 weeks. Vitamin D status was categorized as deficient (<20 ng/mL), insufficient (20-30 ng/mL), or sufficient (>30 ng/mL). Primary outcomes were prediabetes prevalence, vitamin D deficiency among prediabetics, and changes in glycaemic parameters and insulin indices (FBG, 2HPP, HbA1c, HOMA-IR, and HOMA-ẞ). Secondary outcomes included hs-CRP, IL-6, lipid profile, and endothelial function measured by flow-mediated dilation (FMD). Prediabetes prevalence was 23.4% (n=245) (FBG), 14.7% (n=154) (2HPP), and 26.4% (n=276) (HbA1c). Among 266 prediabetics, 74.1% (n=197) were vitamin D deficient, 19.2% (n=51) insufficient, and 6.7% (n=18) sufficient. Post-intervention, 25(OH)D level increased significantly in the vitamin D group compared with placebo (31.13 ± 6.42 vs. 10.64 ± 4.87 ng/mL; p<0.001). Vitamin D supplementation significantly reduced FBG (94 ± 8.1 vs. 100 ± 9.3 mg/dL; p<0.001), improved B-cell function (HOMA-ẞ: 94.79 ± 22.6 vs. 72.16 ± 19.4; p=0.028) and endothelial function (FMD: 15.47 ± 3.2% vs. 2.72 ± 1.1%; p<0.001) compared with placebo. No significant differences were observed for HbA1c, 2HPP, HOMA-IR IL-6, hs-CRP, or lipid parameters between groups. In conclusion, prediabetes and vitamin D deficiency are highly prevalent in Ibb governorate. High- dose vitamin D supplementation improves fasting glycemia, B-cell function, and endothelial function, supporting its potential role as an adjunct strategy for early metabolic and vascular risk modification in vitamin D-deficient prediabetics.

Kesan vitamin E dan steroid ke atas enzim penanda dan detoksifikasi pada plasma dan hepar tikus teraruh barah

2026-09-17T04:48:23Z

Title: Kesan vitamin E dan steroid ke atas enzim penanda dan detoksifikasi pada plasma dan hepar tikus teraruh barah Authors: Asmah Rahmat Abstract: Kesan vitamin E (tokotrienol dan tokoferol) dan steroid ke atas enzim penanda gamma-glutamil transpeptidase (GGT) dan glutation S-transferase (GST) serta enzim detoksikasi lain pada tikus yang diaruh barah oleh dietilnitrosamin (DEN) dan 2-asetilaminofluoren (AAF) telah dikaji. DEN/AAF meningkatkan aras glutation (GSH), GGT dan alkalin fosfatase (ALP) plasma dan UDP-glukuronil transferase (UDPGT), GST dan glutation peroksidase (GPx) hepar. Suplementasi vitamin E kepada tikus perlakuan DEN/AAF menurunkan GGT, ALP dan GST kepada aras di antara kawalan dengan DEN/AAF. Tokotrienol atau tokoferol tidak memberi kesan kepada parameter yang diukur. Dos vitamin E yang berbeza (30, 60 dan 150mg tokotrienol/kg diet) menunjukkan kesan perlindungan yang ketara kecuali dos 15mg tokotrienol/kg diet. Kesan tokotrienol sebanding dengan tokoferol. Perlakuan DEN/AAF jangka masa panjang meningkatkan GSH dan kesemua enzim. Suplementasi tokotrienol (30 mg/kg diet) menurunkan aktiviti enzim di antara kawalan dengan perlakuan DEN/AAF. Aktiviti GPx dengan substrat hidrogen peroksid (HO) menurun seperti kawalan, GPx dengan substrat kumen hidroperoksid (CuOOH) tidak berubah dan glutation reduktase (GRX) serupa DEN/AAF. Suntikan Estradiol (E) sahaja atau E, dan DEN/AAF meningkatkan GGT, UDPGT, ALP, GST dengan substrat 1,2-dikloro-4- nitrobenzen (DCNB) dan GPx (H,O,). Penambahan tokotrienol kepada DEN/AAF/E, tidak memberi kesan kerana hanya menurunkan ALP sahaja. Walaupun suntikan progesteron atau DEN/AAF/progesteron meningkatkan UDPGT, ALP, GSH hepar, GST (DCNB) dan GPx(CuOOH) tetapi GSH plasma menurun selepas 8 minggu. Penambahan tokotrienol kepada DEN/AAF/progesteron meningkatkan GGT plasma selepas 8 minggu di antara DEN/AAF dengan kawalan. Suntikan testosteron meningkatkan UDPGT dan GST (DCNB) sementara ALP meningkat di antara DEN/AAF dengan kawalan. GGT plasma meningkat di antara DEN/AAF dengan kawalan pada perlakuan DEN/AAF/testosteron. Penambahan tokotrienol menurunkan GGT plasma dan menurunkan lagi GPx(CuOOH) daripada nilai kawalan. Suntikan Dexamethasone (Dex) meningkatkan kesemua enzim kecuali UDPGT, ALP (8 minggu) dan GST (DCNB). DEN/AAF/Dex meningkatkan kesemua enzim kecuali GST (DCNB) lapan minggu dan GPX. GGT dan GPx tidak dipengaruhi oleh penambahan tokotrienol kepada DEN/AAF/Dex, sedangkan enzim yang lain meningkat. Kesimpulannya tokotrienol dan tokoferol mengurangkan keterukan hepatokarsinogenesis yang diaruh oleh DEN/AAF. Tokotrienol kurang berkesan untuk perlakuan E, berbanding dengan steroid lain.