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Fast, accurate damage assessment of numerous buildings for large areas is vital for saving lives, enhancing decision‐making, and expediting recovery, thereby increasing urban resilience. The traditional methods, relying on expert mobilization, are slow and unsafe. Recent advances in machine learning (ML) have improved assessments; however, quantum‐enhanced ML (QML), a rapidly advancing field, offers greater advantages over classical ML (CML) for large‐scale data, enhancing the speed and accuracy of damage assessments. This study explores the viability of leveraging QML to evaluate the safety of reinforced concrete buildings after earthquakes, focusing on classification accuracy only. A QML algorithm is trained using simulation datasets and tested on real‐world damaged datasets, with its performance compared to various CML algorithms. The classification results demonstrate the potential of QML to revolutionize seismic damage assessments, offering a promising direction for future research and practical applications. [ABSTRACT FROM AUTHOR]

Pityriasis rosea is an acute, self‐limited exanthem that typically occurs in adolescence and young adulthood, classically featuring ovoid erythematous and scaly lesions on the trunk and proximal extremities. While its cause is not definitively known, the classic form of pityriasis rosea may result from the reactivation of latent human herpesvirus (HHV) infections (HHV‐6 and HHV‐7). Interestingly, drug eruptions that clinically and/or histopathologically resemble pityriasis rosea have also been reported. These pityriasis rosea‐like drug eruptions tend to occur at an older age and have a shorter duration than the classic type. As there are different management paradigms, the distinction between classic pityriasis rosea and the mimicking drug eruption is important to recognize. Herein, we report a case of a pityriasis rosea‐like drug eruption that occurred in association with imatinib mesylate treatment for chronic myeloid leukemia. We also review the clinicopathologic features of reported cases of pityriasis rosea‐like drug eruption, including those due to imatinib. While the clinical morphology of the cutaneous drug‐related eruption mimics the lesions seen in classic pityriasis rosea, the presence of unique histopathologic findings, including necrotic keratinocytes, interface dermatitis, and eosinophils, may aid in distinction. [ABSTRACT FROM AUTHOR]

Precise and reliable predictive parameters to accurately identify chronic myeloid leukemia (CML) patients who can successfully discontinue their tyrosine kinase inhibitor (TKI) treatment are lacking. One promising parameter is depth of molecular response measured by BCR::ABL1 digital PCR (dPCR). The aim of this study was to validate a previously described prediction cutoff of 0.0023%IS and to assess the value of dPCR for treatment‐free remission (TFR) prediction in relation to other clinical parameters. A droplet‐based dPCR assay assessed BCR::ABL1 %IS prior to TKI discontinuation. The primary endpoint was molecular recurrence (MolR) by 36 months. A total of 186 patients from Canada, Germany, and the Netherlands were included. In patients with a first TKI discontinuation attempt (n = 163), a BCR::ABL1 dPCR < and ≥0.0023%IS had a MolR probability of 33% and 70%, respectively. Patients treated less than 6 years with a BCR::ABL1 dPCR <0.0023%IS had a MolR probability of 31%. After correction for treatment duration, both high dPCR value and the use of imatinib (vs. second‐generation TKI) were significantly associated with a higher risk of MolR (HR of 3.66, 95%CI 2.06–6.51, p <.001; and 2.85, 95%CI 1.25–6.46, p =.013, respectively). BCR::ABL1 dPCR was not associated with TFR outcome after second TKI discontinuation, however, with the limitation of a small number of patients analyzed (n = 23). In conclusion, BCR::ABL1 digital PCR based on the cutoff of 0.0023%IS is a valuable predictive tool to identify CML patients with a high probability of TFR success after first TKI discontinuation, including patients treated for less than 6 years. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Methods Results Conclusion Asciminib, a novel allosteric BCR::ABL1 inhibitor, targets the ABL1 myristoyl pocket to potentially reduce toxicity and enhance efficacy. It is approved for Philadelphia chromosome‐positive chronic‐phase chronic myeloid leukemia (CML‐CP) in patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs) or those with the T315I mutation.This retrospective analysis evaluated patients with CML treated with asciminib under a managed‐access program across eight Israeli centers from July 2019 to August 2022. We assessed treatment responses, toxicities, event‐free survival (EFS), and overall survival (OS) using Kaplan–Meier methods.The study included 30 patients who had received a median of three prior TKIs, with 73% starting asciminib due to intolerance. After a median follow‐up of 7.1 months, 85% of those without prior complete cytogenetic response (CCyR) achieved CCyR, and 60% previously not in major molecular response (MMR) attained MMR. Resistance was rare (10%), with no cardiovascular events reported despite high baseline comorbidity (73%). Median EFS was 47 months; median OS was not reached.Asciminib demonstrates significant efficacy and tolerability in heavily pretreated patients with CML‐CP, with no new cardiovascular events observed. Further long‐term studies are necessary to explore its full cardiovascular impact. [ABSTRACT FROM AUTHOR]

Summary Third‐generation tyrosine kinase inhibitors (TKIs) have much potential for the treatment of BCR::ABL1‐positive leukaemia, particularly that harbouring the ABL1 T315I mutation. Olverembatinib (HQP1351), a novel third‐generation TKI, has favourable efficacy and safety profiles in chronic myeloid leukaemia. Here, we present the clinical findings from 31 BCR::ABL1‐positive acute lymphoblastic leukaemia (ALL) patients who received olverembatinib. Among the 14 patients with overt relapsed/refractory (R/R) disease (including 10 with the T315I mutation), 71.4% achieved an overall response. Of the other 17 patients with minimal residual disease (MRD)‐positive ALL (including 14 with the T315I mutation), 60.0% and 47.1% achieved MRD flow negativity and complete molecular remission, respectively. With a median follow‐up time of 16.3 months, the median event‐free survival and overall survival were 3.9 and 8.3 months respectively, in overt R/R patients, and 11.5 and 18.4 months in MRD‐positive patients. Allogeneic haematopoietic stem cell transplantation further improved outcomes among responders. The safety profile was generally manageable. This study suggests that olverembatinib‐based therapy is another promising option for BCR::ABL1‐positive ALL in addition to ponatinib, especially for patients with MRD‐positive disease and a single T315I mutation. [ABSTRACT FROM AUTHOR]

Background: Ponatinib is a third‐generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with robust activity in Philadelphia chromosome–positive leukemias. Herein, we report the long‐term follow‐up of the phase 2 trial of ponatinib in chronic myeloid leukemia in chronic phase. Methods: Patients received ponatinib 30 to 45 mg/day. The primary end point was the rate of 6‐month complete cytogenetic response (CCyR). The study was held in June 2014 because of the risk of cardiovascular toxicity, requiring patients to change TKI. Results: Fifty‐one patients were treated with ponatinib (median dose, 45 mg/day). Median age was 48 years (range, 21–75); 30 (59%) had baseline cardiovascular comorbidities. Median treatment duration was 13 months (range, 2–25). Fourteen patients (28%) discontinued ponatinib because of toxicities, 36 (71%) after the Food and Drug Administration warning/study closure, and one for noncompliance. Dasatinib was the most frequently chosen second‐line TKI (n = 34; 66%). Among 46 patients evaluable at 6 months, 44 (96%) achieved CCyR, 37 (80%) major molecular response, 28 (61%) MR4, and 21 (46%) MR4.5. The cumulative 6‐month rates of CCyR, major molecular response, MR4, and MR4.5 were 96%, 78%, 50%, and 36%, respectively. Durable MR4 ≥24 or ≥60 months was observed in 67% and 51% of patients, respectively. The 24‐month event‐free survival rate was 97%. After a median follow‐up of 128 months, the 10‐year overall survival rate was 90%. Eight patients (16%) had serious grade 2 to 3 cardiovascular adverse events, leading to permanent discontinuation in five (10%). Conclusion: Ponatinib yielded high cytogenetic and molecular responses in newly diagnosed chronic myeloid leukemia in chronic phase. Its use in the frontline setting is hindered by arterio‐/vaso‐occlusive and other severe toxicities. Treatment with ponatinib in the frontline setting of chronic myeloid leukemia in chronic phase was associated with high molecular response rates, with 12‐month cumulative rates of major molecular response and MR4 of 82% and 72%, respectively. However, it was associated with an increased incidence of toxicity, in particular serious grade 2‐3 cardiovascular adverse events in 16% of the patients. [ABSTRACT FROM AUTHOR]

Understanding the mechanisms by which cancer cells switch between different adaptive states and evade therapeutic interventions is essential for clinical management. In this study, the in vivo cellular dynamics of a new chronic myeloid leukaemia cell line displaying altered phenotype and resistance to tyrosine kinase inhibitors were investigated in correlation with their parental cells for invasiveness/metastasis, angiogenic potential and population kinetics. We showed that the cells exhibiting drug resistance and plastic phenotype possess an increased capacity for invasion compared to their parental cells, that exposure to imatinib mesylate has the potential to enhance cellular motility and that in a leukaemic cell population, even a minority of plastic cells exhibit improved migratory ability. Furthermore, we show that these plastic cells have angiogenic and extravasation potential. The present study provides significant insights into the cellular dynamics displayed by a TKI‐resistant, phenotypically plastic CML cell line, using a zebrafish (Danio rerio) xenograft model. [ABSTRACT FROM AUTHOR]

Summary Superfine and regular grinding methods were used to mill mulberry leaves (ML), and the chemical composition and physical characteristics of the powders were investigated. Compared to regular grinding, superfine grinding reduced particle size from 121.44 μm to 18.69 μm. Compared to coarse mulberry leaf (CML), the fine mulberry leaf (FML) powder had a greater water solubility index, soluble dietary fibre content and 1‐deoxynojirimycin (DNJ) content. Both types of ML powders were substituted for flour at various percentages (3%, 6%, 9% and 12%), and their effects on the biscuits' textural qualities and sensory assessment were examined. The adhesiveness, cohesiveness and springiness of biscuit doughs were all reduced by ML powder addition, while their hardness was raised. The inclusion of ML powders increased the hardness of the biscuits significantly, whereas only the addition of FML powders decreased their fracturability. Additionally, the DNJ contents in FML biscuits were significantly higher than that in CML biscuits. The sensory assessment revealed that biscuits containing 9% FML powder received the best rating. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions In people with chronic‐phase chronic myeloid leukemia (CML) receiving imatinib and achieving major molecular response (MMR), dose reduction may decrease adverse events but may be associated with a loss of molecular response. Whether digital droplet polymerase chain reaction (ddPCR) can identify persons in whom dose reduction might be unsuccessful is unknown.Data from 716 consecutive subjects who achieved MMR after initial imatinib therapy (400 mg/day) were obtained. A total of 486 subjects remained on full‐dose imatinib, whereas 230 subjects had their dose reduced to 300 or 200 mg/day. The outcomes of these cohorts were compared via landmark and propensity score matching analyses.Imatinib dose reduction showed no significant effect on the subsequent achievement of deeper molecular responses (4‐ and 4.5‐log reductions in BCR::ABL1 transcripts; MR4 and MR4.5), maintenance of MMR, or attainment of therapy‐free remission when compared with subjects without dose reduction. In subjects achieving MR4, however, the probability of maintaining MR4 (p = .002) was lower in the reduced‐dose group. In multivariable analyses, failure to achieve MR4.5 as determined by ddPCR at the time of dose reduction was significantly associated with briefer MMR failure‐free survival (FFS; hazard ratio [HR], 10.3; 95% confidence interval [CI], 1.3–82.9; p = .03) and MR4 FFS (HR, 6.8; 95% CI, 2.6–18.0; p < .001).Imatinib dose reduction after achieving MMR does not adversely affect response deepening or MMR maintenance in chronic‐phase CML but compromises MR4 maintenance. The results of ddPCR may identify people who benefit from imatinib dose reduction. [ABSTRACT FROM AUTHOR]

BACKGROUND RESULTS CONCLUSION Nε‐carboxymethyllysine (CML), Nε‐carboxyethyllysine (CEL) and α‐aminoadipic acid (AAA) are important foodborne hazards and their intake can cause a variety of diseases in humans. It is extremely important to investigate the formation mechanism of CML, CEL and AAA, as well as their association with each other when aiming to control their production.A multi‐response kinetic model was developed within the glucose‐lysine Maillard reaction model system. The concentrations of glucose, lysine, glyoxal (GO), methylglyoxal (MGO), CML, CEL and AAA were quantified at different temperature (100–160 °C) and at different intervals (0–60 min). The experimental data were fitted to the proposed model to calculate kinetic parameters for the corresponding steps. The results indicated that the production of CML was primarily relied on the direct oxidative cleavage of the Amadori product, rather than the reaction between GO and Lys, whereas CEL and AAA were generated through the reaction of MGO with Lys. Significantly, the reaction between α‐dicarbonyl compounds and Lys preferentially generated CML and CEL, resulting in the lower concentrations of AAA compared to CML and CEL.The multi‐response kinetic model developed in the present study can be applied well to the Maillard reaction. The relationship between the formation mechanisms of CML, CEL and AAA is also explained. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Methods Results Conclusions The study aimed to evaluate the utilization of frontline TKI therapy in a large cohort of elderly CP‐CML patients.A retrospective analysis was conducted on 332 CP‐CML patients aged 75 years or older among 1929 diagnosed from January 2012 to December 2019 followed at 36 participating Hematology Centers involved in the “Campus CML” project.Among the patients analyzed, 85.8% received imatinib (IM) while 14.2% received second‐generation TKIs (2G‐TKI), 59.5% dasatinib, and 40.5% nilotinib. Most patients initiated IM at standard dose (67.3%) while 32.7% at reduced dose. A similar trend was observed with 2G‐TKIs. The cumulative incidence of permanent TKI discontinuation at 12 months was 28.4%, primarily due to primary resistance (10.1%) and extra‐hematologic toxicity (9.5%), with no significant difference between IM and 2G‐TKI groups. Following the introduction of generic IM in Italy in 2018, IM usage increased significantly compared with 2G‐TKIs.IM was in our Centers the preferred frontline therapy for older CP‐CML patients, with increasing utilization after the introduction of generic formulations. However, 2G‐TKIs are still used in a substantial proportion of patients, suggesting individualized physician assessments regarding patient suitability and expectations. Further investigation is needed to assess efficacy and safety of reduced TKI doses in this patient population. [ABSTRACT FROM AUTHOR]

Summary: Chronic myeloid leukaemia (CML) management is complicated by treatment‐emergent vascular adverse events seen with tyrosine kinase inhibitors (TKIs) such as nilotinib, dasatinib and ponatinib. Pleural effusion and pulmonary arterial hypertension (PAH) have been associated with dasatinib treatment. Endothelial dysfunction and impaired angiogenesis are hallmarks of PAH. In this study, we explored, at cellular and whole animal levels, the connection between dasatinib exposure and disruption of endothelial barrier integrity and function, leading to impaired angiogenesis. Understanding the mechanisms whereby dasatinib initiates PAH will provide opportunities for intervention and prevention of such adverse effects, and for future development of safer TKIs, thereby improving CML management. [ABSTRACT FROM AUTHOR]

Summary: Diagnosing chronic myeloid leukaemia (CML) during pregnancy is rare. Tyrosine kinase inhibitors (TKIs) have traditionally been contraindicated owing to their teratogenicity. Management decisions should consider the risks to mother and foetus of uncontrolled disease and teratogenic medications. Further cases are required to build upon the paucity of current literature. We report 22 cases of CML diagnosed during pregnancy from 2002 to date. Twenty‐one pregnancies resulted in healthy babies and one patient miscarried. Some patients remained untreated throughout pregnancy but the majority received one or both of interferon‐α and leucapheresis. One patient was started on imatinib at Week 26, and one on hydroxycarbamide in the third trimester. We report haematological parameters during pregnancy to provide clinicians with realistic expectations of management. There were no fetal abnormalities related to treatment during pregnancy. Seventeen patients achieved at least major molecular response on first‐line TKI. A diagnosis of CML during pregnancy can be managed without significant consequences for mother or child. Leucapheresis and interferon‐α are generally safe throughout pregnancy. Despite having been avoided previously, there is growing evidence that certain TKIs may be used in particular circumstances during the later stages of pregnancy. Future work should aim to further elucidate this safety profile. [ABSTRACT FROM AUTHOR]

Olverembatinib (HQP1351) is a BCR‐ABL1 tyrosine kinase inhibitor with promising clinical activity. It is approved in China for the treatment of patients with chronic myeloid leukemia harboring drug‐resistant mutations, such as T315I. In vitro studies suggested that metabolism of olverembatinib is primarily mediated by cytochrome P450 (CYP3A4). The effects of CYP3A4 inhibition and induction on the pharmacokinetics of olverembatinib were evaluated in an open‐label, 2‐part, fixed‐sequence study in healthy volunteers. In Part 1 of this study, 16 participants received a single oral dose of olverembatinib (20 mg) and the oral CYP3A4 inhibitor itraconazole (200 mg). In Part 2, 16 participants received a single oral dose of olverembatinib (40 mg) and the oral CYP3A4 inducer rifampin (600 mg). To measure pharmacokinetic parameters, serial blood samples were collected after administration of olverembatinib alone and combined with itraconazole or rifampin. Coadministration of olverembatinib with itraconazole increased the peak plasma concentration of olverembatinib, its area under the time‐concentration curve (AUC)0‐last, and AUC0‐inf by 75.63%, 147.06%, and 158.66%, respectively. Coadministration with rifampin decreased these same variables by 61.27%, 74.21%, and 75.19%, respectively. These results confirm that olverembatinib is primarily metabolized by CYP3A4 in humans, suggesting that caution should be exercised with concurrent use of olverembatinib and strong CYP3A4 inhibitors or inducers. [ABSTRACT FROM AUTHOR]

Background: To evaluate the outcomes of first‐line imatinib versus nilotinib treatment for chronic myeloid leukemia in the chronic phase (CML‐CP) in real‐world clinical practice. Methods: A propensity score analysis was performed to eliminate imbalances between the treatment groups. In the analysis, 163 patients in the nilotinib group and 163 patients in the matched imatinib group were retrospectively evaluated. Results: Nilotinib‐treated patients achieved complete cytogenetic response (CCyR) and major molecular response more rapidly than imatinib‐treated patients. However, there was no significant difference in 5‐year overall survival (OS) or progression‐free survival (PFS) between the two groups (OS: 94.3% vs. 90.5%, p = 0.602; PFS: 92.9% vs. 88.0%, p = 0.614). Nilotinib‐treated patients had a higher failure‐free survival (FFS) and event‐free survival (EFS) than imatinib‐treated patients (FFS: 71.7% vs. 54.3%, p = 0.040; EFS: 71.7% vs. 53.5%, p = 0.025). Conclusions: This retrospective analysis from clinical practice did not confirm any benefit of frontline nilotinib treatment for OS and PFS; however, it did demonstrate higher FFS and EFS in the nilotinib cohort. [ABSTRACT FROM AUTHOR]

This paper studies a novel time‐varying coefficient integer‐valued time series model driven by observation. The model is suitable for modeling negative integer‐valued time series based on the Poisson difference distribution and extended binomial thinning operator. Main methods used to estimate the parameters are the conditional least squares (CLS) and conditional maximum likelihood (CML) methods. This paper also discusses the consistency and asymptotic normality of the estimation results. Likelihood ratio tests are employed to examine the existence of covariate and observation. Numerical simulations are conducted to verify the accuracy and stability of the model. Finally, a real data application is presented to demonstrate the usefulness and adaptability of this newly proposed model. [ABSTRACT FROM AUTHOR]

Overexpression of matrix metalloproteinase‐2 (MMP‐2) possesses a correlation with leukemia especially chronic myeloid leukemia (CML). However, no such MMP‐2 inhibitor has come out in the market to date for treating leukemia. In this study, synthesis, biological evaluation, and molecular modeling studies of a set of biphenylsulfonamide derivatives as promising MMP‐2 inhibitors were performed, focusing on their potential applications as antileukemic therapeutics. Compounds DH‐18 and DH‐19 exerted the most effective MMP‐2 inhibition (IC50 of 139.45 nM and 115.16 nM, respectively) with potent antileukemic efficacy against the CML cell line K562 (IC50 of 0.338 µM and 0.398 µM, respectively). The lead molecules DH‐18 and DH‐19 reduced the MMP‐2 expression by 21.3% and 17.8%, respectively with effective apoptotic induction (45.4% and 39.8%, respectively) in the K562 cell line. Moreover, both these compounds significantly arrested different phases of the cell cycle. Again, both these molecules depicted promising antiangiogenic efficacy in the ACHN cell line. Nevertheless, the molecular docking and molecular dynamics (MD) simulation studies revealed that DH‐18 formed strong bidentate chelation with the catalytic Zn2+ ion through the hydroxamate zinc binding group (ZBG). Apart from that, the MD simulation study also disclosed stable binding interactions of DH‐18 and MMP‐2 along with crucial interactions with active site amino acid residues namely His120, Glu121, His124, His130, Pro140, and Tyr142. In a nutshell, this study highlighted the importance of biphenylsulfonamide‐based novel and promising MMP‐2 inhibitors to open up a new avenue for potential therapy against CML. [ABSTRACT FROM AUTHOR]

The therapeutic armamentarium of chronic myeloid leukemia (CML) has dramatically improved after small molecule tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 became available, with a life expectancy now close to that of the general population. Although highly effective, these drugs also have a toxicity profile that is often mild to moderate, but sometimes severe. Indeed, long‐term treatment with TKIs can lead to chronic adverse events that can negatively affect patients' quality of life and can promote significant morbidity and mortality, particularly in the case of second‐ or third‐generation TKIs. Treatment discontinuation has therefore become an emerging goal for CML patients and numerous studies have evaluated in off‐TKI subjects what requirements are appropriate for an attempt at treatment‐free remission (TFR). TFR eligibility is currently limited to a small population of subjects with both deep and sustained molecular responses to TKIs. For those attempting TFR, average success rates are promising, with 25%–30% of patients experiencing prolonged TFR. In case of failure to maintain sustained TFR, safety results to date are reassuring, with almost all patients responding successfully to resumption of TKIs, and advanced‐phase disease progression representing a very rare event. The purpose of this review is to discuss guidelines for TKI discontinuation, clinical advances from clinical trials and real‐life experiences, and describe areas of research, particularly regarding the biological factors capable of predicting the success of TFR. [ABSTRACT FROM AUTHOR]

Lombardy represents the largest region of Italy by population, with almost 10 million residents, a dimension similar to a medium size country like Sweden or Belgium. The CML subcommittee of the Lombardy Hematology Network (REL‐CML) conducted a study at the beginning of 2023. Prevalence was calculated by direct input from the 21 centers participating in REL‐CML. Tyrosine Kinase Inhibitors (TKI) prescription records collected from the ARIA regional registry were used to estimate the number of CML patients followed in smaller centers not participating in REL‐CML. A total of 2285 patients were registered, representing a prevalence of 0.23 ‰. These data were compared to a similar census conducted in 2005, at the beginning of the TKI era, where a prevalence of 0.029‰ was calculated. This indicates that an almost 10 times increase took place during this period of time. Imatinib represents the most frequently prescribed first‐line TKI; its use in 2022 still represented 75% of total first line prescriptions. An increased concentration of the care of CML patients in specialized REL centers with a decreased dispersion of patients in small centers was also evident over this 18 year period of time. Nineteen % of patients discontinued treatment, highlighting persisting logistical and biological challenges; one some recommendations on CML management are included to this aim. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cell therapy, a developing approach in cancer immunotherapy, involves isolating NK cells from peripheral blood. However, due to their limited number and activity, it is essential to significantly expand these primary NK cells and enhance their cytotoxicity. In this study, we investigated how Raddeanin A potentiate NK activity using KHYG‐1 cells. The results indicated that Raddeanin A increased the expression levels of cytolytic molecules such as perforin, granzymes A and granzymes B, granulysin and FasL in KHYG‐1 cells. Raddeanin A treatment increased CREB phosphorylation, p65 phosphorylation, NFAT1 and acetyl‐histone H3 expression. Raddeanin A elevated caspase 3 and PARP cleavage, increased t‐Bid expression, promoting apoptosis in K562 cells. Furthermore, it reduced the expression of HMGB2, SET and Ape1, impairing the DNA repair process and causing K562 cells to die caspase‐independently. Additionally, Raddeanin A increased ERK, p38 and JNK phosphorylation at the molecular level, which increased granzyme B production in KHYG‐1 cells. Raddeanin A treatment increased Ras, Raf phosphorylation, MEK phosphorylation, NKG2D, NKp44 and NKp30 expression in KHYG‐1 cells. Collectively, our data indicate that Raddeanin A enhances the cytotoxic activity of NK cells against different cancer cells. [ABSTRACT FROM AUTHOR]

Background: The dual inhibition of the BCR::ABL1 tyrosine kinase and BCL‐2 could potentially deepen the response rates of chronic myeloid leukemia in chronic phase (CML‐CP). This study evaluated the safety and efficacy of the combination of dasatinib and venetoclax. Methods: In this phase 2 trial, patients with CML‐CP or accelerated phase (clonal evolution) received dasatinib 50 mg/day for three courses; venetoclax was added in course 4 for 3 years. The initial venetoclax dose was 200 mg/day continuously but reduced later to 200 mg/day for 14 days, and to 100 mg/day for 7 days per course once a molecular response (MR)4.5 was achieved. After 3 years of combination, patients were maintained on single‐agent dasatinib. The primary end point was the rate of major molecular response (MMR) by 12 months of combination. Results: Sixty‐five patients were treated. Their median age was 46 years (range, 23–73). By 12 months of combination, the MMR, MR4, and MR4.5 rates were 86%, 53%, and 45%, respectively. After a median follow‐up of 42 months, the 4‐year event‐free and overall survival rates were 96% and 100%, respectively. Outcomes with the combination were comparable to historical outcomes with single‐agent dasatinib (cumulative 12‐months MMR rate of 79% with both strategies). The incidence of grade 3‐4 neutropenia was 22% with the combination and 11% with single‐agent dasatinib (p <.001). Conclusions: Treatment with dasatinib and venetoclax was safe and effective in CML‐CP. The cumulative response rates with the combination were similar to those with single‐agent dasatinib. Further follow‐up is needed to evaluate the rates of durable deep molecular response and treatment‐free remission. Treatment with dasatinib and venetoclax was effective and well‐tolerated. By 12 months of combination, 86% and 53% of patients achieved a major molecular response and a deep molecular response, respectively. [ABSTRACT FROM AUTHOR]

The article discusses the presence and characteristics of NFE2 mutations in myeloid neoplasms, including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and acute myeloid leukemia (AML). The study found that NFE2 mutations were most common in MPN and MDS, and were associated with elevated NFE2 mRNA expression levels in MPN. The mutations may also play a role in the development of bone marrow fibrosis in MPN and MDS. Further research is needed to fully understand the impact of NFE2 mutations on disease progression and transformation to leukemia. [Extracted from the article]

Aims: B lymphoblastic leukaemia/lymphoma (B‐ALL) is thought to originate from Pro/Pre‐B cells and the genetic aberrations largely reside in lymphoid‐committed cells. A recent study demonstrated that a proportion of paediatric B‐ALL patients have BCR::ABL1 fusion in myeloid cells, suggesting a chronic myeloid leukaemia (CML)‐like biology in this peculiar subset of B‐ALL, although it is not entirely clear if the CD19‐negative precursor compartment is a source of the myeloid cells. Moreover, the observation has not yet been extended to other fusion‐driven B‐ALLs. Methods and results: In this study we investigated a cohort of KMT2A‐rearranged B‐ALL patients with a comparison to BCR::ABL1‐rearranged B‐ALL by performing cell sorting via flow cytometry followed by FISH (fluorescence in situ hybridization) analysis on each of the sorted populations. In addition, RNA sequencing was performed on one of the sorted populations. These analyses showed that (1) multilineage involvement was present in 53% of BCR::ABL1 and 36% of KMT2A‐rearranged B‐ALL regardless of age, (2) multilineage involvement created pitfalls for residual disease monitoring, and (3) HSPC transcriptome signatures were upregulated in KMT2A‐rearranged B‐ALL with multilineage involvement. Conclusions: In summary, multilineage involvement is common in both BCR::ABL1‐rearranged and KMT2A‐rearranged B‐ALL, which should be taken into consideration when interpreting the disease burden during the clinical course. [ABSTRACT FROM AUTHOR]

In the treatment of chronic myeloid leukemia (CML), resistance to BCR‐ABL inhibitors makes it difficult to continue treatment and is directly related to life expectancy. Therefore, asciminib was introduced to the market as a useful drug for overcoming drug resistance. While combining molecular targeted drugs is useful to avoid drug resistance, the new BCR‐ABL inhibitor asciminib and conventional BCR‐ABL inhibitors should be used as monotherapy in principle. Therefore, we investigated the synergistic effect and mechanism of the combination of asciminib and imatinib. We generated imatinib‐resistant cells using the human CML cell line K562, examined the effects of imatinib and asciminib exposure on cell survival using the WST‐8 assay, and comprehensively analyzed genetic variation related to drug resistance using RNA‐seq and real‐time PCR. A synergistic effect was observed when imatinib and asciminib were combined with or without imatinib resistance. Three genes, GRRP1, ESPN, and NOXA1, were extracted as the sites of action of asciminib. Asciminib in combination with BCR‐ABL inhibitors may improve the therapeutic efficacy of conventional BCR‐ABL inhibitors and prevent the development of resistance. Its dosage may be effective even at minimal doses that do not cause side effects. Further verification of this mechanism of action is needed. Additionally, cross‐resistance between BCR‐ABL inhibitors and asciminib may occur, which needs to be clarified through further validation as soon as possible. [ABSTRACT FROM AUTHOR]

Many tumours are organised in a hierarchical structure with at its apex a cell that can maintain, establish, and repopulate the tumour—the cancer stem cell. The haematopoietic stem cell (HSC) is the founder cell for all functional blood cells. Like HSCs, the leukaemia stem cells (LSC) are hypothesised to be the leukaemia‐initiating cells, which have features of stemness such as self‐renewal, quiescence, and resistance to cytotoxic drugs. Immunophenotypically, CD34+CD38− defines HSCs by adding lineage negativity and CD90+CD45RA−. At which stage of maturation the further differentiation is blocked, determines the type of leukaemia, and determines the immunophenotype of the LSC specific to the leukaemia type. No apparent LSC phenotype has been described in lymphoid leukaemia, and it is debated if a specific acute lymphocytic leukaemia‐initiating cell is present, as all cells are capable of engraftment in a secondary mouse model. In chronic lymphocytic leukaemia, a B‐cell clone is responsible for uncontrolled proliferation, not a specific LSC. In chronic and acute myeloid leukaemia, LSC is described as CD34+CD38− with the expression of a marker that is aberrantly expressed (LSC marker), such as CD45RA, CD123 or in the case of chronic myeloid leukaemia CD26. In acute myeloid leukaemia, the LSC load had prognostic relevance and might be a biomarker that can be used for monitoring and as an addition to measurable residual disease. However, challenges such as the CD34‐negative immunophenotype need to be explored. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukaemia (CML) is a haematological malignancy characterized by the constitutive tyrosine kinase activity of the BCR‐ABL1 fusion protein. Flumatinib, a second‐generation tyrosine kinase inhibitor, has exhibited superior clinical efficacy compared to its precursor, imatinib. However, with increased clinical use, resistance to flumatinib has emerged as a significant challenge. To investigate the mechanisms of flumatinib resistance in CML, we induced the human CML cell line K562 using a flumatinib concentration gradient method in vitro, successfully establishing a flumatinib‐resistant K562/FLM cell line. This cell line exhibited cross‐resistance to imatinib and doxorubicin, but remained sensitive to the antiparasitic agent ivermectin, which possesses antitumoural effects. Through cellular experimentation, we explored the resistance mechanisms, which indicated that K562/FLM cells evade flumatinib cytotoxicity by enhancing autophagy, increasing the expression of membrane transport proteins, particularly P‐glycoprotein, ABCC1 and ABCC4, as well as enhancing phosphorylation of p‐EGFR, p‐ERK and p‐STAT3 proteins. Moreover, it was found that ivermectin effectively suppressed the expression of autophagy and transport proteins in K562/FLM cells, reduced the activity of the aforementioned phosphoproteins, and promoted apoptotic cell death. Collectively, the increased autophagy, higher expression of drug‐efflux proteins and hyperactivation of the EGFR/ERK/STAT3 signalling pathway were identified as pivotal elements promoting resistance to flumatinib. The significant effects of ivermectin might offer a novel therapeutic strategy to overcome flumatinib resistance and optimize the treatment outcomes of CML. [ABSTRACT FROM AUTHOR]

Dasatinib (DAS) is a second‐generation tyrosine kinase inhibitor used in the treatment of Philadelphia chromosome‐positive chronic myeloid leukemia and acute lymphoblastic leukemia. Nevertheless, this drug is hindered by poor gastrointestinal absorption and limited bioavailability, primarily attributable to its low aqueous solubility. To improve its properties, solid dispersions of DAS within a matrix of the hydrophilic polymer polyvinylpyrrolidone (PVP) are prepared by cogrinding in a vibrational ball mill at various drug‐to‐polymer ratios. The prepared solid dispersions are thoroughly characterized by several methods to verify the drug's amorphization and enhanced wettability as a result of successful mechanochemical activation. Fluidized bed melt granulation and traditional tableting are used to prepare tablets of 8 mm diameter with strictly defined aimed properties. Characterization of tablets includes testing their hardness, disintegration, and in vitro dissolution. The in vitro release profiles reveal a significant improvement in the release rate of DAS from tablets containing solid dispersion with the highest polymer ratio when compared with those containing untreated DAS or solid dispersions with a low polymer ratio. The results confirm the significant effect of the PVP ratio in solid dispersions on the surface characteristics and dissolution rate of DAS. [ABSTRACT FROM AUTHOR]

Summary: This prospective multicentre trial evaluated the safety and the efficacy of a thiotepa/melphalan‐based reduced intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT) in children and adolescents with chronic myeloid leukaemia (CML) in chronic phase (CP). Thirty‐two patients were transplanted from matched siblings or matched unrelated donors. In 22 patients, HSCT was performed due to insufficient molecular response or loss of response to first‐ or second‐generation tyrosine kinase inhibitor (TKI), with pretransplant BCR::ABL1 transcripts ranging between 0.001% and 33%. The protocol included a BCR::ABL1‐guided intervention with TKI retreatment in the first year and donor lymphocyte infusions (DLI) in the second‐year post‐transplant. All patients engrafted. The 1‐year transplant‐related mortality was 3% (confidence interval [CI]: 0%–6%). After a median follow‐up of 6.3 years, 5‐year overall survival and event‐free survival are 97% (CI: 93%–100%) and 91% (CI: 79%–100%) respectively. The current 5‐year leukaemia‐free survival with BCR::ABL1 <0.01% is 97% (CI: 88%–100%) and the current TKI‐ and DLI‐free survival is 95% (CI: 85%–100%). The incidence of chronic graft‐versus‐host disease (GvHD) was 32%, being severe in four patients (13%). At last follow‐up, 31 patients are GvHD‐free and have stopped immunosuppression. RIC HSCT following pretreatment with TKI is feasible and effective in children and adolescents with CP‐CML with an excellent disease‐free and TKI‐free survival. [ABSTRACT FROM AUTHOR]

Asciminib is a novel allosteric STAMP (specifically targets the ABL myristoyl pocket) inhibitor of the BCR::ABL1 oncogene. Real‐world clinical outcomes of patients with tyrosine kinase inhibitor (TKI)‐resistant/intolerant chronic myeloid leukaemia (CML) in Australia on the Managed Access Programme for asciminib showed higher molecular responses for those with intolerance versus resistance ± intolerance to their last TKI. There remains a clinical need to improve outcomes in patients with CML who have resistance to multiple TKIs, especially in the ponatinib‐pretreated cohort. [ABSTRACT FROM AUTHOR]

Summary: Allogeneic haematopoietic cell transplantation (allo‐HCT) remains an option for tyrosine kinase inhibitor‐resistant chronic myeloid leukaemia (CML) in first chronic phase (CP1) and high‐risk patients with advanced disease phases. In this European Society for Blood and Marrow Transplantation (EBMT) registry‐based study of 1686 CML patients undergoing first allo‐HCT between 2012 and 2019, outcomes were evaluated according to donor type, particularly focusing on mismatched related donors (MMRDs). Median age at allo‐HCT was 46 years (IQR 36–55). Disease status was CP1 in 43%, second CP (CP2) or later in 27%, accelerated phase in 12% and blast crisis in 18%. Donor type was matched related (MRD) in 39.2%, MMRD in 8.1%, matched unrelated (MUD) in 40.2%, and mismatched unrelated (MMUD) in 12.6%. In 4 years, overall survival (OS) for MRD, MMRD, MUD and MMUD was 61%, 56%, 63% and 59% (p = 0.21); relapse‐free survival (RFS) was 48%, 42%, 52% and 46% (p = 0.03); cumulative incidence of relapse (CIR) was 33%, 37%, 27% and 30% (p = 0.07); non‐relapse mortality (NRM) was 19%, 21%, 21% and 24% (p = 0.21); and graft‐versus‐host disease (GvHD)‐free/relapse‐free survival (GRFS) was 16%, 18%, 22% and 15% (p = 0.05) respectively. On multivariate analysis, MMRD use associated with longer engraftment times and higher risk of graft failure compared to MRD or MUD. There was no statistical evidence that MMRD use associated with different OS, RFS and incidence of GvHD compared to other donor types. [ABSTRACT FROM AUTHOR]

The article presents a case study of an 18-year-old female diagnosed with chronic myeloid leukemia (CML) who rapidly progressed to the blast phase despite treatment with tyrosine kinase inhibitors (TKIs). Topics discussed include the identification of recurrent fusion genes in CML-blast phase, their potential role in disease progression and drug resistance, and the need for further research to understand their prevalence and clinical implications.

The study's aim was to determine the effect of using sheep tail fat (STF) on carboxymethyl‐lysine (CML) content and other properties of heat‐treated sucuk (HTS), a type of semi‐dry fermented sausage. Three mixtures were prepared: 100% beef fat (BF), 50% BF + 50% STF, and 100% STF. After production (fermentation, heat treatment, and drying), the samples were cooked at 180°C for 0, 1, 3, and 5 min to determine the effect of cooking time on CML, thiobarbituric acid reactive substance (TBARS), total sulfhydryl, and carbonyl contents. The lowest pH value (5.50) was observed in the presence of STF. The most oleic acid (46.02%) was observed in the 100% STF group. The score of taste and general acceptability decreased with increasing STF. Using STF had no significant effect on TBARS, total sulfhydryl, carbonyl, or CML content. These parameters were affected by cooking time. The mean CML content increased from 55.77 to 72.90 μg/g after 5 min of cooking. CML correlated more strongly with TBARS than sulfhydryl or carbonyl. [ABSTRACT FROM AUTHOR]

The first‐generation tyrosine kinase inhibitor imatinib has revolutionized the development of targeted cancer therapy and remains among the frontline treatments, for example, against chronic myeloid leukemia. As a substrate of cytochrome P450 (CYP) 2C8, CYP3A4, and various transporters, imatinib is highly susceptible to drug–drug interactions (DDIs) when co‐administered with corresponding perpetrator drugs. Additionally, imatinib and its main metabolite N‐desmethyl imatinib (NDMI) act as inhibitors of CYP2C8, CYP2D6, and CYP3A4 affecting their own metabolism as well as the exposure of co‐medications. This work presents the development of a parent–metabolite whole‐body physiologically based pharmacokinetic (PBPK) model for imatinib and NDMI used for the investigation and prediction of different DDI scenarios centered around imatinib as both a victim and perpetrator drug. Model development was performed in PK‐Sim® using a total of 60 plasma concentration–time profiles of imatinib and NDMI in healthy subjects and cancer patients. Metabolism of both compounds was integrated via CYP2C8 and CYP3A4, with imatinib additionally transported via P‐glycoprotein. The subsequently developed DDI network demonstrated good predictive performance. DDIs involving imatinib and NDMI were simulated with perpetrator drugs rifampicin, ketoconazole, and gemfibrozil as well as victim drugs simvastatin and metoprolol. Overall, 12/12 predicted DDI area under the curve determined between first and last plasma concentration measurements (AUClast) ratios and 12/12 predicted DDI maximum plasma concentration (Cmax) ratios were within twofold of the respective observed ratios. Potential applications of the final model include model‐informed drug development or the support of model‐informed precision dosing. [ABSTRACT FROM AUTHOR]

While a pharmaceutically intriguing scaffold, 5,6‐dihydropyrrolo[2,1‐a]isoquinoline (DHPIQ), has precedently been prepared from diverse tetrahydroisoquinolines (THIQs) using elaborate conditions, convenient metal‐free methods were discovered from condensation of cyanomethylene‐THIQ (1) and α‐halo‐ketones or aldehydes (1a) to afford 15 DHPIQs (2–16) in moderate yields by employing unique reactivities of the secondary amine and α‐carbon to the nitrile of 1. Preliminary biological studies with chronic myelogenous leukemia K562 and adriamycin‐resistant K562 (K562/ADM) cells exhibited some of the DHPIQs tested were active in the both cell lines. In particular, cyclohexyl‐fused DHPIQ (10) showed GI50 values of 9.79 and 13.60 μM in K562 and K562/ADM cells, respectively. Based on the flow cytometry analysis of 10, the anti‐cancer activity could be from apoptosis‐related mechanisms. Overall, this DHPIQ scaffold may be further optimized to discover clinically meaningful anti‐leukemic agents overcoming adriamycin resistance. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusion Leukemic stem cells (LSCs) are the transcriptionally low/silent cells which are resistant to the tyrosine kinase inhibitor. These have been found to play a pivotal role in disease relapse in chronic myeloid leukemia (CML) cases. The present study evaluated the correlation of absolute CML‐LSC count in the peripheral blood (PB) at diagnosis and achievement of major molecular response (MMR) at 12 months in patients of CML‐CP.This was a prospective, observational, non‐interventional single center study including newly diagnosed adult (>18 yrs) CML‐CP patients. Absolute CD26 + CML‐LSC quantification was done by multiparametric flow cytometry. Patients were treated with Imatinib treatment and subsequently monitored at 3‐month intervals for BCR::ABL transcript levels. MMR was defined as a BCR::ABL1 transcript level of less than 0.1% on international scale.A total of 89 patients were enrolled in the study out of which 40.5% achieved MMR at 12 months. There was a significant difference in the median absolute CML‐LSC count of the patients who achieved MMR at 12 months as compared to those who did not (58.5 vs 368.1 cells/μL; p value <0.001). Using a ROC analysis, a count of <165.69 CML LSC/μL was identified to have a sensitivity of 83.8% and specificity of 72.4%, in predicting the MMR at 12 months.Absolute CML‐LSC count at diagnosis in the PB predicts the MMR achievement at 12 months. An absolute count of less than 165 cells/μL is highly predictive of achieving MMR at 12 months. [ABSTRACT FROM AUTHOR]

Background: The effects of novel non‐cytotoxic and immunotherapy drugs for cancer treatment on human testicular function have not been studied systematically. Objectives: The present study aimed to characterize effects of non‐cytotoxic and immunotherapy drugs in patients with cancers who had not been previously treated with gonadotoxic chemo‐ or radiotherapy. Materials and methods: This study involved 34 men, not previously treated with gonadotoxic regimens, in a mixed longitudinal (Cohort 1: 19 men about to start and approximately 1 year on non‐cytotoxic and immunotherapy treatment) and cross‐sectional (Cohort 2: 15 men already on non‐cytotoxic and immunotherapy treatment) study using data modeling to estimate within‐person time‐course changes in testicular exocrine and endocrine functions. Cohort 1 provided 45 paired semen and blood samples (34 prior to and nine during treatment) and Cohort 2 provided 45 sets of samples (15 pre‐treatment, 30 on treatment), including six men in Cohort 2 who had pre‐treatment spermatozoa cryostorage prior to the study. Men on non‐cytotoxic and immunotherapy treatment had undergone a median of 33.5 months long‐term treatment. Results: Spermatozoa output and concentration were reduced by about 50%, with corresponding increases in serum follicle‐stimulating hormone and decreases in serum inhibin B. Serum testosterone, luteinizing hormone, and sex hormone‐binding globulin were unaffected by non‐cytotoxic and immunotherapy treatment. Conclusion: Within limits of the present study of sample size and duration of on‐non‐cytotoxic and immunotherapy treatment, non‐cytotoxic and immunotherapy drugs have a modest effects on testicular exocrine function (sperm production) or its hormonal correlates (follicle‐stimulating hormone, inhibin B), with minimal impact on testicular endocrine (testosterone, luteinizing hormone) function. [ABSTRACT FROM AUTHOR]

Key Clinical Message: In a patient with de novo AML, co‐existing BCR::ABL1 p190 isoform and RUNX1::MECOM rearrangement is accompanied by a very poor prognosis including limited response to treatment and no molecular remission. It is essential to develop a consensus on the therapeutic modalities different from the current regimen. Acquisition of BCR::ABL1 fusion as a primary or secondary event and RUNX1::MECOM fusion independently is reported in de novo and therapy‐related MDS/AML, albeit with low frequency (<0.5%). Coexistence of BCR::ABL1 and MECOM translocation is known to cause leukemogenesis in animal models and progression towards blast crisis CML but not AML. Here we report a unique case of pediatric AML with concomitant BCR::ABL1 and RUNX1::MECOM fusion.Routine diagnostic work‐up included WBC manual differential, immunophenotype, morphology, qPCR, FISH, and NGS‐based CNV analyses. The patient presented with history of fever, dizziness, fatigue, gingival bleeding, and epistaxis associated with ecchymosis in right hand and heavy, prolonged menstrual period. At presentation, her hemoglobin was 5.3 g/dL, WBC 52.1(10*9/L), PLT 10(10*9/L), ESR 5 mm/h and LDH 2658 U/L. Bone marrow was hypercellular with 71% blasts, and flow cytometry showed myeloid markers including CD11c, CD33, CD34, and CD45 among others indicating AML with monocytic differentiation. FISH analyses showed variant t(9;22) (q34.1;q11.1), one additional copy each of chromosome 8 and Runx1 gene, while NGS‐based CNV analyses revealed a terminal and proximal pathogenic gain within 9q34.12q34.3 and 22q11.1q11.23, respectively, and gain of entire chromosome 8 and 12 in mosaic state. qPCR confirmed the presence of p190 and also revealed RUNX1::MECOM fusion. Patient received ADE (cytarabine, daunorubicin, and etoposide) induction regimen but required multiple ICU admissions due to sepsis, cardiac shock, acute myocarditis, and thyroiditis. Coexisting BCR::ABL1 and RUNX1::MECOM fusion is suggestive of poor prognosis, and a need for consensus on the treatment modalities other than the current regimen is warranted. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cell is a valuable tool for immunotherapy in cancer treatment, both the cultured cell line NK92 and primary NK cells are widely studied and used in research and clinical trials. Clinical observations witnessed the improvement of patients' NK cells in terms of cell counts and cytotoxic activity upon dasatinib treatment, an approved drug for chronic myeloid leukaemia and Ph+ acute lymphocytic leukaemia. Several studies supported the clinical observations, yet others argued a detrimental effect of dasatinib on NK cells. Due to the complex conditions in different studies, the definite influence of dasatinib on NK92 and primary NK cells remains to be settled. Here, we used a well‐defined in vitro system to evaluate the effects of dasatinib on NK92 cells and peripheral blood (PB)‐NK cells. By co‐culturing NK cells with dasatinib to test the cell counts and target cell‐killing activities, we surprisingly found that the chemical influenced oppositely on these two types of NK cells. While dasatinib suppressed NK92 cell proliferation and cytotoxic activity, it improved PB‐NK‐killing tumour cells. RNA sequencing analysis further supported this finding, uncovering several proliferating and cytotoxic pathways responding invertedly between them. Our results highlighted an intrinsic difference between NK92 and PB‐NK cells and may build clues to understand how dasatinib interacts with NK cells in vivo. [ABSTRACT FROM AUTHOR]

Destruction of erythropoiesis process leads to various diseases, including thrombocytopenia, anaemia, and leukaemia. miR‐429‐CT10 regulation of kinase‐like (CRKL) axis involved in development, progression and metastasis of cancers. However, the exact role of miR‐429‐CRKL axis in leukaemic cell differentiation are still unknown. The current work aimed to uncover the effect of miR‐429‐CRKL axis on erythropoiesis. In the present study, CRKL upregulation was negatively correlated with miR‐429 downregulation in both chronic myeloid leukaemia (CML) patient and CR patient samples. Moreover, CRKL expression level was significantly decreased while miR‐429 expression level was increased during the erythroid differentiation of K562 cells following hemin treatment. Functional investigations revealed that overexpression and knockdown of CRKL was remarkably effective in suppressing and promoting hemin‐induced erythroid differentiation of K562 cells, whereas, miR‐429 exhibited opposite effects to CRKL. Mechanistically, miR‐429 regulates erythroid differentiation of K562 cells by downregulating CRKL via selectively targeting CRKL‐3′‐untranslated region (UTR) through Raf/MEK/ERK pathway. Conversely, CRKII had no effect on erythroid differentiation of K562 cells. Taken together, our data demonstrated that CRKL (but not CRKII) and miR‐429 contribute to development, progression and erythropoiesis of CML, miR‐429‐CRKL axis regulates erythropoiesis of K562 cells via Raf/MEK/ERK pathway, providing novel insights into effective diagnosis and therapy for CML patients. [ABSTRACT FROM AUTHOR]

Heterocyclic compounds such as pyrrole and pyrrolidine derivatives have a broad spectrum of biological activity, being widely used as pharmacophore to design novel bioactive compounds. In this work, sixteen pyrrole and pyrrolidine derivatives were synthesized and evaluated for their growth inhibitory activity on two human cancer cells lines: breast cancer MDA‐MB‐231 and chronic myelogenous leukemia (K562). Eight compounds showed activity against at least one tumor cell line (IC50=49.15–195.9 μM). The compounds were tested in non‐cancerous human lung fibroblasts WI‐26VA4 to evaluate their selectivity index. In addition, Hierarchical Cluster Analysis (HCA) studies were carried out in attempt to establish a structure‐activity relationship. [ABSTRACT FROM AUTHOR]

In this paper, we designed, synthesized, and biologically screened a series of methyl‐piperidine‐phenyl‐nicotinamide derivatives with the aim of novel derivatives as effective anticancer agents. Compounds (9 a), (9 e) and (9 k) exhibited potent anticancer activity with an IC50 value of 5.9 μM, 5.9 μM and 5.0 μM, respectively using MV411 (Acute Myeloid Leukemia) and K562 (Chronic Myeloid Leukemia) cell line. Our docking studies show good binding affinity of these compounds for ABL1 kinase. Furthermore, these compounds exhibited a favourable in silico ADME profile with good solubility and low clearance in Human Liver Microsomes (HLM). These derivatives represent a promising approach to initiate the development of new anticancer drugs in oncology programs. [ABSTRACT FROM AUTHOR]

This article examines the relapse rates in chronic myelogenous leukemia (CML) patients after stopping tyrosine kinase inhibitor (TKI) treatment. The study found that relapse occurred faster in patients who had previously received the first-generation TKI imatinib compared to second-generation TKIs dasatinib or nilotinib. The study used standardized definitions of response and resistance and included patients from multiple centers. The findings suggest that the choice of TKI may affect the rate of relapse after treatment discontinuation. However, more research is needed to validate these findings in larger studies and clinical trials. [Extracted from the article]

Summary: Tyrosine kinase inhibitors (TKIs) have drastically improved the outcomes of pCML (paediatric CML) but data on long‐term off‐target toxicities of TKIs in children are scarce. In this single‐centre, retrospective cum prospective study of pCML in chronic phase, we report our experience of treating 173 children with imatinib and following them for long‐term toxicities. Mean (SD) time to attain CHR, CCyR and MMR were 3.05 (2.1), 10.6 (8.4) and 43.4 (31.8) months respectively. DMR was not attained in 59 (34%) patients at last follow‐up. Ten patients were switched to second‐generation TKIs (2G‐TKIs; nilotinib = 1/dasatinib = 9) due to poor/loss in response, of which seven had kinase domain mutations. Three patients progressed to the blastic phase. At a median follow‐up of 84 (3–261) months, the 5‐year EFS and OS for the entire cohort were 96.9% (95% CI: 93.4–100) and 98.7% (95% CI: 96.9–100) respectively. Screening for long‐term toxicities revealed low bone density and hypovitaminosis D in 70% and 80% respectively. Other late effects included short stature (27%), delayed puberty (15%), poor sperm quality (43%) and miscellaneous endocrinopathies (8%). Children younger than 5 years at diagnosis were more susceptible to growth and endocrine toxicities (p = 0.009). Regular monitoring for long‐term toxicities, timely intervention and trial of discontinuation whenever feasible are likely to improve the long‐term outlook of pCML. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Acute onset of vertigo and hearing loss is rare in leukemic disorders. MRI can diagnose intracochlear hemorrhage as the underlying cause. The hearing can improve but if severe hearing loss preserves, cochlear implantation can be considered. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Clinical presentation of leukemia cutis (LC) is polymorphic and can reveal a malignant hemopathy. More commonly described in cases of acute myeloid leukemia (AML), LC can also occur in case of chronic myeloid leukemia (CML). Leukemia cutis is a rare form of extramedullary feature of malignant hemopathy, seldom associated with CML. Its clinical presentation is pleiotropic and differential diagnosis is broad. It relies on clinical and typical histological and biomolecular concordance. Once confirmed, treatment is based on that of the primary condition. We present a case of a leukemia cutis revealing a relapse of a CML successfully treated by tyrosine kinase inhibitor. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Extramedullary involvement of the central nervous system (CNS) in Chronic Myeloid Leukemia (CML) is an uncommon relapse. In this case, we present a unique instance of a 43‐year‐old male diagnosed with CML experiencing a CNS blast crisis. [ABSTRACT FROM AUTHOR]

The document titled "Nomenclature for factors of the HLA system, update October, November and December 2023" provides a list of newly assigned sequences and confirmations of previously reported sequences for the Human Leucocyte Antigen (HLA) system. It includes accession numbers for each sequence, recent publications on new HLA sequences, and a list of individuals and organizations associated with specific genetic markers. The document is a valuable resource for library patrons conducting research on genetics and related topics. It also provides information on genetic codes, genetic samples, and genetic markers associated with immune response genes. The document includes researchers and locations from various countries, promoting diverse perspectives in genetic research. [Extracted from the article]

Nilotinib is a second‐generation BCR‐ABL tyrosine kinase inhibitor for the treatment of Philadelphia chromosome‐positive chronic myeloid leukemia in both adult and pediatric patients. The pharmacokinetics (PK) of nilotinib in specific populations such as pregnant and lactating people remain poorly understood. Therefore, the objectives of the current study were to develop a physiologically based pharmacokinetic (PBPK) model to predict nilotinib PK in virtual drug‐drug interaction (DDI) studies, as well as in pediatric, pregnant, and lactating populations. The nilotinib PBPK model was built in PK‐Sim, which is part of the free and open‐source software Open Systems Pharmacology. The observed clinical data for the validation of the nilotinib models were obtained from the literature. The model reasonably predicted nilotinib concentrations in the adult population; the DDIs between nilotinib and rifampin or ketoconazole in the adult population; and the PK in the pediatric, pregnant, and lactating populations, although in the latter 2 populations plasma concentrations were slightly underestimated. The ratio of predicted versus observed PK parameters for the adult model ranged from 0.71 to 1.11 for area under the concentration‐time curve and 0.55 to 0.95 for maximum concentration. For the DDI, the predicted area under the concentration‐time curve ratio and maximum concentration ratio fell within the Guest criterion. The current study demonstrated the utility of using PBPK modeling to understand the mechanistic basis of PK differences between adults and specific populations, such as pediatrics, and pregnant and lactating individuals, indicating that this technology can potentially inform or optimize dosing conditions in specific populations. [ABSTRACT FROM AUTHOR]

Background: Barely two per million Belgian children/adolescents are diagnosed with chronic myeloid leukemia (CML) annually. In this retrospective study, we aimed to investigate the diagnostic features, clinical and laboratory characteristics, and treatment outcome of this rare entity. Methods: Medical records of all pediatric CML patients (age ≤ 17 years) diagnosed at the University Hospitals Leuven between 1986 and 2021 were reviewed. Results: Fourteen patients (median age at diagnosis 12.5 years) were included, all presenting in chronic phase. Five patients were diagnosed before 2003; main therapy included hydroxyurea (n = 5/5), interferon‐alfa (n = 3/5) and allogeneic hematopoietic stem cell transplantation (allo‐Tx) (n = 3/5). Complete hematologic response (CHR), complete cytogenetic response (CCyR) and major molecular response (MMR) was reached in resp. 4/5, 4/5 and in 2/3 of evaluable patients. Three patients progressed to accelerated/blast phase (median time 19 months) and 1/5 is alive and disease‐free at last follow‐up. Nine patients were diagnosed after 2003 and were treated with first generation (1°G) tyrosine kinase inhibitors (TKI): 3/9 subsequently underwent an allo‐Tx, 4/9 were switched to 2°G TKI, one patient was additionally switched to 3°G TKI. CHR, CCyR and MMR was reached in 9/9, 9/9 and 8/9 of these patients. No progression to accelerated/blast phase was observed and none of these patients deceased. At last follow‐up, 7/9 patients were in MMR or disease free, the two remaining patients did not reach or lost MMR, both related to compliance issues. Conclusion: Our study confirmed that TKI significantly improved the prognosis of pediatric CML. However, drug compliance poses a considerable challenge. [ABSTRACT FROM AUTHOR]

This document presents the results of a study comparing blood cell counts in leukemoid reaction (LR) and chronic myeloid leukemia (CML). LR is characterized by an increase in white blood cells, particularly neutrophilic granulocytes, and can be difficult to distinguish from CML. The study analyzed peripheral blood smears from 33 LR cases and 28 CML cases and found that CML had higher percentages of immature forms of granulocytes compared to LR. The article suggests using a cutoff value of 45 x 10^9/L for white blood cell counts to differentiate between LR and CML, but advises that other laboratory results should also be considered for accurate assessment. The study provides useful information for pathologists and medical education, but its findings are limited by a small sample size and potential bias in participant selection. [Extracted from the article]