The KIT gene, known as proto-oncogene c-Kit, encodes a receptor tyrosine kinase and plays a crucial role in cellular processes through activation that initiates signal transduction pathways. The KIT protein includes five extracellular domains, a kinase domain, a transmembrane helix, and a juxta-membrane domain. The study investigated these domains in chronic myeloid leukemia (CML) patients, revealing insights that enhance clinical protocols for tyrosine kinase inhibitors used in targeted therapy for hematological malignancies. However, mutations in the kinase domain present challenges by impairing drug binding. In this exploratory investigation, mainly through PCR and Sanger sequencing techniques, 50 samples (30 patients and 20 controls) were utilized. A total of 27 mutations were identified. While the following mutations (G753C, G538C, A415T, and A404G) were the most frequent, (G814C, G858T, G876T, and G880A) were only found in control cohort. Interestingly, many unique mutations were detected in the Iraqi population, suggesting specific genetic polymorphisms. Furthermore, the data showed that younger patients had better responses to imatinib with fewer dangerous mutations, while middle-aged patients faced significant resistance, which correlated with weight gain and obesity. Elderly individuals displayed a higher mutation burden, necessitating multiple treatment changes. Despite limitations, this exploratory study stressed the importance of considering patients' genetic backgrounds and BMIs to improve therapeutic outcomes for CML patients.

Activity dysregulation of Abl kinase is the primary cause for chronic myeloid leukemia (CML). Despite extensive characterization, the thermodynamic basis of Abl stability and inhibitor recognition remains incompletely understood. To characterize the cooperative folding organization of Abl and the communication between its structural units, we comprehensively characterized three Abl constructs: the isolated catalytic domain (AblCD), the three-domain regulatory construct (AblSH3SH2CD), and its phosphorylated form ([PO4]AblSH3SH2CD), using high-resolution calorimetric techniques. DSC revealed that the catalytic domain behaves as a single cooperative unfolding unit, with the SH3-SH2 module in AblSH3SH2CD exerting a modest stabilizing effect. The catalytic domain decoupled into two transitions in [PO4]AblSH3SH2CD, an observation rationalized by the disruption of the interlobe structural bridge formed by the A-loop in the unphosphorylated forms. Imatinib and dasatinib had opposite effects on this decoupling, providing calorimetric evidence for the distinct intradomain reorganizations induced by each inhibitor type. ITC showed that both inhibitors bind with distinct thermodynamic signatures, with a modest effect of the regulatory domains on inhibitor recognition. Imatinib binding involved net proton uptake, consistent with Asp381 protonation required for the DFG-out transition, while dasatinib showed no proton linkage. Phosphorylation-induced reduction in imatinib affinity was driven by a large loss of favorable enthalpy reflecting the energetic cost of displacing the ordered A-loop, while dasatinib affinity remained largely unaffected. These results provide a thermodynamic rationale for the superior potency of dasatinib against activated Abl in CML cells, revealing mechanistic features of kinase regulation not accessible from structural data alone.

The global healthcare sector significantly contributes to climate change and other environmental impacts. Despite this, environmental sustainability considerations are often missing from evidence-based clinical guidelines. To address this gap, we developed a methodological guidance report focused on integrating environmental sustainability into clinical guidelines.

Background/Objectives: Protein supplementation may elevate advanced glycation end products (AGEs) through higher dietary AGE (dAGE) content and increase amino acid-driven endogenous formation. Protein supplementation from different sources may differentially affect AGE levels, possibly through differences in amino acid composition, digestion and metabolism, but evidence from randomized controlled trials (RCTs) remains limited. This study aimed to examine the effect of protein supplementation from either casein (animal-based) or soy (plant-based) protein isolates on circulating, skin, and dAGE levels in older adults following a healthy dietary pattern (HDP). Methods: In this 16-week RCT, 55 older adults (mean age: 66 years old) in Singapore were assigned either to control (no supplementation), casein protein isolate supplementation, or soy protein isolate supplementation. This study was registered at clinicaltrials.gov as NCT05400005. Results and Discussion: Overall, there were no alterations in dietary, skin and total circulating AGE levels after protein supplementation when adhering to an HDP such as My Healthy Plate (MHP). However, different sources of protein supplementation resulted in differential changes in specific plasma AGE markers. Two-way ANOVA analysis showed that soy protein supplementation led to a significant increase in plasma N(6)-(1-carboxymethyl)-L-lysine (CML) compared to the other groups (week 0: 0.72 ± 0.10, week 16: 0.80 ± 0.10, pint = 0.040), while a paired t-test showed that casein protein supplementation led to a significant within-group increase in plasma pentosidine (week 0: 0.77 ± 0.06, week 16: 0.80 ± 0.05, p-value = 0.045). Other AGEs showed no significant changes. Conclusions: Protein supplementation while adhering to MHP did not significantly influence overall circulating and skin AGEs in older adults in Singapore. A differential response was observed only for plasma CML levels with soy protein supplementation, whereas the within-group increase in plasma pentosidine following casein supplementation should be interpreted with caution and requires further investigation.

Chronic myeloid leukemia (CML) is driven by constitutive BCR-ABL1 activity and remains clinically challenging due to disease persistence and resistance to tyrosine kinase inhibitors (TKIs). SIRT1, a NAD[+]-dependent deacetylase, has been implicated in leukemic cell survival and chemoresistance through negative regulation of p53. In this study, we evaluated the antileukemic effects of the Sechium hybrid H387 extract and its impact on the SIRT1-p53 signaling axis in K562 CML cells. Cell proliferation was assessed using a crystal violet assay, while gene and protein expression were analyzed by RT-qPCR, immunofluorescence, and flow cytometry. Apoptosis was determined by Annexin V/7-AAD staining. The extract significantly inhibited K562 cell proliferation and downregulated SIRT1 expression, reducing its nuclear localization. These effects were associated with increased p53 acetylation at lysine 382 (Ac-K382-p53) and enhanced apoptosis. Notably, a higher percentage of apoptotic cells was observed following extract treatment than with imatinib under the experimental conditions used, although the two agents have distinct mechanisms of action. These findings suggest that the antileukemic activity of Sechium hybrid H387 extract is associated with modulation of the SIRT1-p53 axis and induction of apoptosis in K562 cells.

Background: Evidence regarding long-term outcomes among offspring following maternal or paternal exposure to BCR::ABL1 tyrosine kinase inhibitors (TKIs) is limited. We described pregnancy outcomes and offspring health through adolescence and early adulthood in a single-centre cohort of patients with chronic myeloid leukemia (CML). Methods: This retrospective, descriptive cohort study included patients with chronic-phase CML who experienced a pregnancy, or whose partner experienced a pregnancy, in association with TKI exposure and for whom longitudinal offspring follow-up was available. Long-term offspring outcomes were ascertained from detailed obstetric and pediatric medical records supplemented by parental reports. Fourteen patients (nine women and five men) contributed 21 pregnancy events and 23 live-born offspring, including two twin pregnancies in the paternal-exposure group. Results: In the maternal-exposure group, median gestational age at delivery was 38.0 weeks (range, 35-40), and four of 15 deliveries were preterm. In the paternal-exposure group, median gestational age was 39.0 weeks (range, 38-41), with no preterm deliveries. Median offspring follow-up was 252 months (range, 212-295), extending through adolescence and into early adulthood. One offspring had a primum atrial septal defect that was surgically corrected. No additional clinically documented major abnormalities in growth or developmental progress were identified during available follow-up. Given the small cohort, these observations were interpreted descriptively and were not considered evidence of equivalence with population-level rates. Conclusions: This small retrospective cohort provides unusually long observational follow-up of offspring after selected maternal or paternal TKI exposures. The findings are clinically informative but cannot establish reproductive safety or exclude rare adverse outcomes. Larger multicentre registries using standardized long-term developmental, neurocognitive, and endocrine assessments are needed.

Policosanol (sugarcane wax alcohol), phosphatidylserine, and Ginkgo biloba leaf extract are Ministry of Food and Drug Safety (MFDS), Republic of Korea-listed functional foods for health-promoting effects. Herein, a combination of policosanol, phosphatidylserine, and G. biloba leaf extract (hereafter PPG) was investigated against metabolic stress induced by a high-cholesterol, high-galactose (HCHG) diet in hyperlipidemic and hyperglycemic zebrafish. After 9 weeks of feeding, the zebrafish following the HCHG diet co-supplemented with PPG exhibited a significant 14.1% (p < 0.02) reduction in body weight and higher zebrafish survivability compared to the HCHG-supplemented group. Significantly reduced total cholesterol (TC, 1.2-fold), triglycerides (TG, 1.4-fold), low-density lipoprotein cholesterol (LDL-C, 1.3-fold), and glucose levels (1.2-fold), along with a 1.5-fold (p = 0.003) elevated high-density lipoprotein cholesterol (HDL-C), were observed in the PPG co-supplemented group relative to the HCHG group. In addition, the HCHG-elevated plasma malondialdehyde (MDA), diminished ferric ion reduction activity (FRA), and paraoxonase (PON)-like activity significantly (p < 0.001) reverted by 1.6-fold, 1.4-fold, and 1.6-fold, respectively, by co-supplementation with PPG. Consistently, the plasma from the PPG-supplemented group showed greater ability to prevent carboxymethyllysine (CML)-induced apoptotic death, altered heart rate, and developmental deformities in zebrafish embryos. Moreover, PPG exerted significant protective effects against HCHG-induced hepatomegaly and fatty liver, accompanied by marked inhibition of hepatic interleukin (IL)-6 and reactive oxygen species (ROS) generation. Consistently, PPG supplementation inhibits ROS generation and senescence in the liver, intestine, brain, kidney, testis and ovary and protects the organ damage caused by exposure to HCHG. Similarly, in intestinal tissue, HCHG-induced fibrosis and oxidative stress were mitigated by the co-supplementation of PPG. The findings indicate that PPG is an effective combination for preventing dyslipidemia, oxidative stress, inflammation, and multi-organ damage associated with HCHG-mediated metabolic stress in zebrafish.

The clinical application of heat shock protein 70 (Hsp70) inhibitors is limited due to their toxicity toward normal tissues. Targeting the Hsp70-Bim protein-protein interaction (PPI) represents a tumor-selective therapeutic strategy for CML. To further mitigate off-target effects, we rationally designed and synthesized three redox-responsive prodrugs (JL-15-B, JL-15-DNBS, and JL-15-S) by masking the critical phenolic hydroxyl group of Hsp70-Bim PPI inhibitor JL-15, aiming to restrict active drug release within the redox-abundant tumor microenvironment. Among these candidates, the GSH-responsive prodrug JL-15-DNBS exhibited efficient intracellular activation in TKI-sensitive and TKI-resistant CML cells. Upon activation, JL-15-DNBS restored Hsp70-Bim PPI-disrupting activity, triggered apoptosis, and downregulated oncogenic client proteins including AKT and eIF4E. Notably, JL-15-DNBS displayed a markedly improved tumor-to-normal-cell selectivity index compared with the parent JL-15. Biochemical assays indicated that the dual-activated prodrug JL-15-S failed to achieve the expected dual-triggered activation, showing only weak ROS-responsive properties, which highlights key lessons for subsequent dual-responsive prodrug structural optimization. Collectively, this work validates a tumor-microenvironment-activated prodrug strategy for Hsp70-Bim PPI inhibitors and identifies JL-15-DNBS as a promising lead compound with enhanced selectivity for CML therapy. Future investigations will focus on in vivo antitumor efficacy assessment, ADMET profiling, and further structural refinement to advance its translational potential.

Tyrosine kinase inhibitors (TKIs) improve survival for people with chronic myeloid leukemia (CML) but may cause adverse events (AEs) that impair quality of life (QoL). Adults with CML receiving first- or second-line TKI therapy in the United States (US) completed validated questionnaires to assess AEs (PRO-CTCAE), QoL (PROMIS Global Physical Health [GPH] and Global Mental Health [GMH]), and work productivity and activity impairment (WPAI:SHP). Of 271 participants, 76.4% experienced ≥1 AE (median 3 [range 0-14]), with the most common being fatigue (53.9%), pain (44.3%), and gastrointestinal symptoms (36.9%). Mean (SD) GPH and GMH T-scores were worse than general population averages (50) at 42.6 (7.0) and 44.4 (7.7), respectively. Mean (SD) activity impairment was 37.3% (24.6). Chronic AEs were associated with worse GPH/GMH T-scores and activity impairment (p < 0.05). The findings demonstrate the relationship between TKI-related AEs and QoL for US patients and the need for improved management strategies.

Textile waste management increasingly depends on sorting discarded garments into suitable reuse, resale, and recycling routes. Yet recyclability assessments often focus on fibre composition while overlooking garment-level design features that may complicate sorting, pre-processing, and preparation of recycling-compatible feedstock. Here we develop a garment-level screening framework to identify such disruptor indicators from retailer web data and apply it to 47,522 garment variants from H&M and Uniqlo in the United Kingdom and Australia. We find that these features are embedded in ordinary garment construction, not limited to visible hardware or exceptional decorative features. Overall, 55.1% of variants exhibited at least one core disruptor indicator. Retained-barrier indicators, including linings, multilayers, trims, coatings, and secondary components, were more prevalent than removable-hardware indicators, affecting 44.9% and 27.2% of variants. Among variants with at least one hardware indicator, 93.4% lacked material-specific information. These findings show that fibre composition alone is insufficient for assessing textile waste processability, and that component-level information on hardware, linings, coatings, trims, and secondary materials is needed to support sorting, pre-processing, and recycling-feedstock preparation.