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In the present work, a new set of N‐(2‐((4‐(1,3‐diphenyl‐1H‐pyrazol‐4‐yl)pyridine sulfonamide derivatives was synthesized. Final target compounds were tested against JNK1 and JNK2 isoforms. Compounds 8f and 8d showed the highest activity over both JNK isoforms. They showed submicromolar activity over JNK1 (IC50 0.90 µM and 0.96 µM, respectively). They also showed excellent activity over JNK2 (IC50 0.62 µM and 1.07 µM, respectively). Moreover, the final target compounds were tested over HL‐60 and K‐562 cell lines for assessing the in vitro anticancer activity using sorafenib as a positive control. Compound 8f showed the highest potency at IC50 values of 6.21 and 7.43 µM, respectively. Furthermore, compounds 8e and 8g exhibited strong effects on both acute leukemia cancer cell lines with IC50 values of 13.83 and 10.02 µM, respectively, as well as chronic leukemia cancer cell line with IC50 of 12.65 and 9.51 µM, respectively. Compound 8f was also tested to examine its effect on the cell cycle. Finally, a molecular docking study was conducted to understand the plausible binding modes of the most active compounds 8d and 8f within the JNK1 and JNK2 binding sites. [ABSTRACT FROM AUTHOR]

Cell membrane nanoparticles have attracted increasing interest in nanomedicine because they allow to exploit the complexity of cell membrane interactions for drug delivery. Several methods are used to obtain plasma membrane to generate cell membrane nanoparticles. Here, an optimized method combining nitrogen cavitation in isotonic buffer and sucrose gradient fractionation is presented. The method allows to obtain cell membrane fractions of high purity from both suspension and adherent cells. Comparison with other common methods for membrane extraction, where mechanical lysis using cell homogenizers is performed in isotonic or hypotonic buffers, shows that the optimized procedure yields high purity membrane in a robust and reproducible way. Procedures to mix the purified membrane with synthetic lipids to obtain cell membrane liposomes (CMLs) are presented and indications on how to optimize these steps are provided. CMLs made using crude membrane isolates or the purified membrane fractions show different uptake by cells. The CMLs made with the optimized procedure and liposomes of the same composition but without cell membrane components are thoroughly characterized and compared for their size, zeta potential, bilayer and mechanical properties to confirm membrane protein inclusion in the CMLs. Cell uptake studies confirm that the inclusion of membrane components modifies liposome interactions with cells. [ABSTRACT FROM AUTHOR]

Summary This study retrospectively compared outcomes of various allogeneic haematopoietic cell transplantation (allo‐HCT) platforms in patients with adult T‐cell leukaemia/lymphoma. Platforms included human leukocyte antigen (HLA)‐haploidentical‐related donors using post‐transplant cyclophosphamide (PTCY), HLA‐matched related donors (MRD), HLA‐matched unrelated donors (MUD) and cord blood transplantation (CBT). Patients who underwent their first allo‐HCT between 2016 and 2021 were included. Outcomes analysed were overall survival (OS), relapse and non‐relapse mortality (NRM). Seven hundred patients were included (PTCY, n = 121; MRD, n = 91; MUD, n = 160; CBT, n = 328). With a median follow‐up of 794 days for survivors, 2‐year OS was 48.1% (PTCY), 48.8% (MRD), 48.4% (MUD) and 34.6% (CBT); the respective 2‐year cumulative incidence of relapse was 37.1%, 47.5%, 33.9% and 45.1% and that of NRM was 24.2%, 19.8%, 24.7% and 27.3%. PTCY was associated with delayed platelet engraftment relative to MRD and MUD. There was no increase in the incidence of severe acute or chronic graft‐versus‐host disease. In the PTCY group, poor performance status was a significant predictor of inferior OS, and infused CD34+ cell numbers of less than 5 × 106/kg were associated with delayed neutrophil and platelet engraftment. These results suggest that allo‐HCT with PTCY is a safe and effective platform for patients with adult T‐cell leukaemia/lymphoma. [ABSTRACT FROM AUTHOR]

Background: Approximately one‐third of US adults have a tattoo, and the prevalence is increasing. Tattooing can result in long‐term exposure to carcinogens and inflammatory and immune responses. Methods: We examined tattooing and risk of hematologic cancers in a population‐based case–control study with 820 cases diagnosed 2019–2021 and 8200 frequency‐matched controls, ages 18–79 years. We calculated odds ratios (OR) and 95% confidence intervals (CI) using multivariable‐adjusted logistic regression models. Results: The prevalence of tattooing was 22% among Hodgkin lymphoma (HL) cases, 11% among non‐Hodgkin lymphoma (NHL) cases, 16% among myeloid neoplasm cases, and 15% among controls. Though there were no clear patterns of associations between ever receiving a tattoo and risk of HL, NHL, or myeloid neoplasms overall, in analyses restricted to ages 20–60 years, ever receiving a tattoo (OR 2.06 [95% CI 1.01, 4.20]) and receiving a tattoo 10+ years prior (OR 2.64 [95% CI 1.23, 5.68]) were associated with an aggregated group of rarer mature B‐cell NHLs. We also observed elevated risks for a 10+ year latency for myelodysplastic syndromes and chronic myeloid leukemia (OR 1.48 [95% CI 0.40, 5.41], and OR 1.24 [95% CI 0.45, 3.43], respectively). Conclusions: Though estimates were imprecise, we found some suggestive evidence that tattooing may be associated with an increased risk of certain hematologic cancer subtypes. With an estimated 46% prevalence of tattooing in US individuals ages 30–49, additional studies are needed to understand the degree to which these exposures may be associated with hematologic cancer risk. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are common hematological malignancies in adults. Despite considerable research advances, the development of standard therapies, supportive care, and prognosis for the majority of AML and ALL patients remains poor and the development of new effective therapy is urgently needed. Here, it is reported that activation of thermogenic adipose tissues (TATs) by cold exposure or β3‐adrenergic receptor agonists markedly alleviated the development and progression of AML and ALL in mouse leukemia models. TAT activation (TATA) monotherapy substantially reduces leukemic cells in bone marrow and peripheral blood, and suppresses leukemic cell invasion, including hepatomegaly and splenomegaly. Notably, TATA therapy prolongs the survivals of AML‐ and ALL‐bearing mice. Surgical removal of thermogenic brown adipose tissue (BAT) or genetic deletion of uncoupling protein 1 (UCP1) largely abolishes the TATA‐mediated anti‐leukemia effects. Metabolomic pathway analysis demonstrates that glycolytic metabolism, which is essential for anabolic leukemic cell growth, is severely impaired in TATA‐treated leukemic cells. Moreover, a combination of TATA therapy with chemotherapy produces enhanced anti‐leukemic effects and reduces chemotoxicity. These data provide a new TATA‐based therapeutic paradigm for the effective treatment of AML, ALL, and likely other types of hematological malignancies. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusion α1‐Antitrypsin deficiency is characterized by elevated elastase activity and excessive elastin degradation, which may impact cancer development and progression. We tested the hypothesis that individuals with α1‐antitrypsin deficiency have increased susceptibility to cancer in the Danish population.In a nationwide nested study, we identified 2702 individuals with α1‐antitrypsin deficiency and 26,750 control subjects without α1‐antitrypsin deficiency matched on age, sex, and municipality. We recorded admissions due to cancer as outcomes during a median follow‐up of 62 years.Individuals with α1‐antitrypsin deficiency versus control subjects had an increased hazard of skin cancer (2.18, 95%CI: 1.81–2.63), leukemia (1.76, 1.12–2.79), liver cancer (3.91, 2.23–6.85), and cancer overall (1.25, 1.13–1.38). Corresponding hazard ratios when the entire Danish population was used as control group were 3.02 (2.55–3.58), 1.83 (1.19–2.81), 4.46 (2.74–7.28), and 1.45 (1.31–1.59). When the analysis was stratified according to comorbidities, the hazard for skin cancer was higher in those with chronic obstructive pulmonary disease (COPD) (3.59, 2.60–4.95) and skin disease (2.93, 2.19–3.92) but remained elevated in those without any of these diseases. Hazards for skin cancer in individuals with α1‐antitrypsin deficiency were similar when stratified by liver cirrhosis and ischemic heart disease (ps for interaction: ≥0.76). Hazards for liver cancer in individuals with α1‐antitrypsin deficiency versus control subjects were similar when stratified according to liver cirrhosis, COPD, skin disease, and ischemic heart disease (ps for interaction: ≥0.13).Individuals with α1‐antitrypsin deficiency have increased risks of skin cancer, leukemia, and liver cancer in the Danish population. [ABSTRACT FROM AUTHOR]

Introduction: Cancer constitutes the primary disease spectrum contributing to the Global Burden of Disease (GBD). Adolescents and young adults (AYA) aged 15–39 have received relatively less attention regarding tumor prevention, diagnosis, and treatment compared to older adults and children. This study aimed to analyze the changes in the disease burden of hematological malignancies among the global AYA over the past three decades based on the GBD database. Methods: The changes in the disease burden of hematological malignancies were analyzed among the AYA over the past three decades based on the information from the GBD database. The future trends were predicted using the Nordpred package in R. Results: Our results showed that leukemia ranked first as the leading tumor burden among AYA in 2019, but the incidence rate and mortality rate of leukemia decreased year by year, with a projected age‐standardized incidence rate (ASIR) of 1.65/100,000 for females and 2.40/100,000 for males by the year 2044. In addition, the incidence of non‐Hodgkin's lymphoma has been gradually increasing in recent years, with an ASIR of 1.73/100,000 from 2020 to 2024. The results may serve as a basis for developing strategies to reduce the burden of hematological malignancies in the AYA population in different regions. [ABSTRACT FROM AUTHOR]

Background: Leukemia is the tenth most common cause of cancer death worldwide and one of the most important causes of disability. To understand the current status and changing trends of the disease burden of leukemia at the global, regional, and national levels, and to provide a scientific basis for the development of leukemia prevention and treatment strategies. Methods: Based on open data from the Global Burden of Disease Study 2019 (GBD 2019), R software was used to calculate estimated annual percentage changes to estimate trends in the age‐standardized incidence (ASIR) and the age‐standardized disability‐adjusted life years (DALY) rate due to leukemia and its major subtypes from 1990 to 2019. Results: In 2019, globally, the number of incidences and DALYs of leukemia were 643.6 × 103 (587.0 × 103, 699.7 × 103) and 11,657.5 × 103 (10529.1 × 103, 12700.7 × 103), respectively. The ASIR (estimated annual percentage change (EAPC) = −0.37, 95%UI −0.46 to −0.28) and the age‐standardized DALY rate (EAPC = −1.72, 95%UI −1.80 to −1.65) of leukemia showed a decreasing trend from 1990 to 2019. The APC model analysis showed that the age effect of leukemia risk was a "U"‐shaped distribution of relative risk (RR) with increasing age from 1990 to 2019, globally. The time effect was an increase in incidence rate with increasing years but a decrease in DALY rate with increasing years. The cohort effects of both incidence and DALY rates tended to increase and then decrease with the development of the birth cohort. In 1990 and 2019, smoking, high body‐mass index, occupational exposure to benzene, and occupational exposure to formaldehyde were risk factors for DALY in leukemia, especially in areas with high SDI. Conclusions: From 1990 to 2019, the disease burden of leukemia showed a decreasing trend, but it is worth noting that its overall severity is still very high. The disease burden of leukemia varies greatly from region to region, and exclusive strategies for the prevention and treatment of leukemia should be developed according to the economic and cultural development of each region. [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]

B‐cell Acute Lymphoblastic Leukemia (B‐ALL) is the most common pediatric cancer, arising most often in children aged 2–5 years. This distinctive age distribution hints at an association between B‐ALL development and disrupted immune system function during a susceptible period during childhood, possibly triggered by early exposure to infection. While cure rates for childhood B‐ALL surpass 90% in high‐income nations, survivors suffer from diminished quality of life due to the side effects of treatment. Consequently, understanding the origins and evolution of B‐ALL, and how to prevent this prevalent childhood cancer, is paramount to alleviate this substantial health burden. This article provides an overview of our current understanding of the etiology of childhood B‐ALL and explores how this knowledge can inform preventive strategies. [ABSTRACT FROM AUTHOR]

The active form of vitamin D (VD) exerts hormonal effects by regulating the expression of genes involved in T‐cell activity, cell differentiation, and proliferation. Human T‐cell leukemia virus type 1 (HTLV‐1) is a causative agent of life‐threatening diseases, adult T‐cell leukemia (ATL) and HTLV‐1‐associated myelopathy (HAM). Among ATL patients, hypercalcemia is one of the most serious complications due to bone resorption. In this study, wild‐type mice administered UV‐irradiated HTLV‐1‐infected cells showed up to 47% decrease of plasma VD level compared with untreated mice. To clarify the effect of HTLV‐1 on plasma VD level, 315 samples registered in nationwide cohort study on ATL onset were measured. The VD level in HAM (14.98 ± 8.5 ng/mL) was significantly lower than those in asymptomatic carriers and ATL (p < 0.05). Upon comparing the VD levels in ATL stratified by disease subtypes, acute ATL showed a lower level (15.81 ± 12.0 ng/mL) than chronic and smoldering types (p < 0.05). In the longitudinal observation, VD levels were significantly higher in untreated spontaneous remission cases than in ATL progression cases, in which the VD levels decreased approximately 40% after onset. In cases of relapse after transplantation, the plasma VD level dropped to 38.7% of the pre‐relapse level, while in cases of complete remission, the VD level increased with improvement of the performance status. Taken together, these results suggest that plasma VD level is a potential indicator for the onset and relapse of HTLV‐1‐associated diseases. [ABSTRACT FROM AUTHOR]

Anti‐cancer peptides (ACPs) represent a promising potential for cancer treatment, although their mechanisms need to be further elucidated to improve their application in cancer therapy. Lycosin‐I, a linear amphipathic peptide isolated from the venom of Lycosa singorensis, shows significant anticancer potential. Herein, it is found that Lycosin‐I, which can self‐assemble into a nanosphere structure, has a multimodal mechanism of action involving lipid binding for the selective and effective treatment of leukemia. Mechanistically, Lycosin‐I selectively binds to the K562 cell membrane, likely due to its preferential interaction with negatively charged phosphatidylserine, and rapidly triggers membrane lysis, particularly at high concentrations. In addition, Lycosin‐I induces apoptosis, cell cycle arrest in the G1 phase and ferroptosis in K562 cells by suppressing the PI3K‐AKT‐mTOR signaling pathway and activating cell autophagy at low concentrations. Furthermore, intraperitoneal injection of Lycosin‐I inhibits tumor growth of K562 cells in a nude mouse xenograft model without causing side effects. Collectively, the multimodal effect of Lycosin‐I can provide new insights into the mechanism of ACPs, and Lycosin‐I, which is characterized by high potency and specificity, can be a promising lead for the development of anti‐leukemia drugs. [ABSTRACT FROM AUTHOR]

Summary: MLL‐rearranged (MLL‐r) leukaemia is observed in approximately 10% of acute myeloid leukaemia (AML) and is associated with a relatively poor prognosis, highlighting the need for new treatment regimens. MLL fusion proteins produced by MLL rearrangements recruit KDM4C to mediate epigenetic reprogramming, which is required for the maintenance of MLL‐r leukaemia. In this study, we used a combinatorial drug screen to selectively identify synergistic treatment partners for the KDM4C inhibitor SD70. The results showed that the drug combination of SD70 and MI‐503, a potent menin‐MLL inhibitor, induced synergistically enhanced apoptosis in MLL::AF9 leukaemia cells without affecting normal CD34+ cells. In vivo treatment with SD70 and MI‐503 significantly prolonged survival in AML xenograft models. Differential gene expression analysis by RNA‐seq following combined pharmacological inhibition of SD70 and MI‐503 revealed changes in numerous genes, with MYC target genes being the most significantly downregulated. Taken together, these data provide preclinical evidence that the combination of SD70 and MI‐503 is a potential dual‐targeted therapy for MLL::AF9 AML. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy is a promising treatment for pediatric patients with relapsed or refractory B cell acute lymphoblastic leukemia (R/R B ALL). Cytokine release syndrome (CRS) is a common toxicity after CAR T cell therapy and fever is often the first symptom. Differentiating CRS from infection after CAR T cell therapy can be challenging. Plasma microbial cell free DNA (mcfDNA) is a novel diagnostic tool which allows for qualitative and quantitative assessment of over 1000 organisms. This pilot study sought to characterize mcfDNA results in pediatric patients with R/R B ALL in the first 2 months after CAR T cell therapy. [ABSTRACT FROM AUTHOR]

Mammalian cells replicate ~ 3 × 109 base pairs per cell cycle. One of the key molecules that slows down the cell cycle and prevents excessive DNA damage upon DNA replication stress is the checkpoint kinase ataxia‐telangiectasia‐and‐RAD3‐related (ATR). Proteolysis‐targeting‐chimeras (PROTACs) are an innovative pharmacological invention to molecularly dissect, biologically understand, and therapeutically assess catalytic and non‐catalytic functions of enzymes. This work defines the first‐in‐class ATR PROTAC, Abd110/Ramotac‐1. It is derived from the ATR inhibitor VE‐821 and recruits the E3 ubiquitin‐ligase component cereblon to ATR. Abd110 eliminates ATR rapidly in human leukemic cells. This mechanism provokes DNA replication catastrophe and augments anti‐leukemic effects of the clinically used ribonucleotide reductase‐2 inhibitor hydroxyurea. Moreover, Abd110 is more effective than VE‐821 against human primary leukemic cells but spares normal primary immune cells. CRISPR‐Cas9 screens show that ATR is a dependency factor in 116 myeloid and lymphoid leukemia cells. Treatment of wild‐type but not of cereblon knockout cells with Abd110 stalls their proliferation which verifies that ATR elimination is the primary mechanism of Abd110. Altogether, our findings demonstrate specific anti‐leukemic effects of an ATR PROTAC. [ABSTRACT FROM AUTHOR]

In the last few decades, the increasing human life expectancy has led to the inflation of the elderly population and consequently the escalation of age‐related disorders. Biological aging has been associated with the accumulation of somatic mutations in the Hematopoietic Stem Cell (HSC) compartment, providing a fitness advantage to the HSCs leading to clonal hematopoiesis, that includes non‐malignant and malignant conditions (i.e. Clonal Hematopoiesis of Indeterminate Potential, Myelodysplastic Syndrome and Acute Myeloid Leukemia). The Janus Kinase‐Signal Transducer and Activator of Transcription (JAK–STAT) pathway is a key player in both normal and malignant hematopoiesis. STATs, particularly STAT3 and STAT5, are greatly implicated in normal hematopoiesis, immunity, inflammation, leukemia, and aging. Here, the pleiotropic functions of JAK–STAT pathway in age‐associated hematopoietic defects and of STAT3 and STAT5 in normal hematopoiesis, leukemia, and inflammaging are reviewed. Even though great progress has been made in deciphering the role of STATs, further research is required to provide a deeper understanding of the molecular mechanisms of leukemogenesis, as well as novel biomarkers and therapeutic targets for improved management of age‐related disorders. [ABSTRACT FROM AUTHOR]

This article discusses a rare case of CD10-negative adult B-lymphoblastic leukemia (B-LBL) with amplification of the KMT2A gene without rearrangement. The KMT2A gene is typically associated with myeloid neoplasms but rarely occurs in B-LBL. The patient in this case was a 70-year-old female who presented with pancytopenia and was found to have a high percentage of lymphoblasts in her bone marrow. The article provides detailed information about the patient's diagnosis, including flow cytometry, karyotyping, fluorescence in situ hybridization (FISH), and genetic analysis. The article also discusses the similarities and differences between B-LBL with KMT2A amplification and B-LBL with KMT2A rearrangements. The prognosis for patients with KMT2A amplification is generally poor, and this case was no exception, as the patient passed away shortly after diagnosis. Overall, this article provides valuable information about a rare and poorly understood form of B-LBL. [Extracted from the article]

The present study analyses the clinical characteristics of patients diagnosed with cutaneous fusarium through a systematic review of cases reported in literature. A total of 39 cases were included, of which 53% were men, 30% were women, and in 17% the sex was not specified. The age ranged from 5 to 85 years. Most cases were reported in Brazil, followed by Japan and United States of America. The most common agent was Fusarium solani, in 37.5% of the patients. Most of the affected individuals had acute myeloid leukaemia and some of the predisposing factors, which included induction chemotherapy, febrile neutropenia, and bone marrow transplantation. The clinical topography of the lesions was located in 27.5% and disseminated in 72.5%, with the most observed clinical feature outstanding the presence of papules and nodules with central necrosis in 47% of the cases. Longer survival was demonstrated in those treated with more than three antifungals. It is concluded that cutaneous fusarium is a complex and challenging clinical entity, infection in patients with leukaemias underscores the need for thorough care to decrease morbidity and mortality. [ABSTRACT FROM AUTHOR]

The Protein Data Bank (PDB) includes a carefully curated treasury of experimentally derived structural data on biological macromolecules and their various complexes. Such information is fundamental for a multitude of projects that involve large‐scale data mining and/or detailed evaluation of individual structures of importance to chemistry, biology and, most of all, to medicine, where it provides the foundation for structure‐based drug discovery. However, despite extensive validation mechanisms, it is almost inevitable that among the ∼215 000 entries there will occasionally be suboptimal or incorrect structure models. It is thus vital to apply careful verification procedures to those segments of the PDB that are of direct medicinal interest. Here, such an analysis was carried out for crystallographic models of l‐asparaginases, enzymes that include approved drugs for the treatment of certain types of leukemia. The focus was on the adherence of the atomic coordinates to the rules of stereochemistry and their agreement with the experimental electron‐density maps. Whereas the current clinical application of l‐asparaginases is limited to two bacterial proteins and their chemical modifications, the field of investigations of such enzymes has expanded tremendously in recent years with the discovery of three entirely different structural classes and with numerous reports, not always quite reliable, of the anticancer properties of l‐asparaginases of different origins. [ABSTRACT FROM AUTHOR]

Introduction: Nucleoporin 98 (NUP98) fusion proteins are recurrently found in leukemia and are associated with unfavorable clinical outcomes. They are distributed to the nucleus and contribute to leukemogenesis via aberrant transcriptional regulation. We previously identified NUP98‐BPTF (NB) fusion in patients with T‐cell acute lymphoblastic leukemia (T‐ALL) using next‐generation sequencing. The FG‐repeat of NUP98 and the PHD finger and bromodomain of bromodomain PHD finger transcription factor (BPTF) are retained in the fusion. Like other NUP98 fusion proteins, NB is considered to regulate genes that are essential for leukemogenesis. However, its target genes or pathways remain unknown. Materials and Methods: To investigate the potential oncogenic properties of the NB fusion protein, we lentivirally transduced a doxycycline‐inducible NB expression vector into mouse NIH3T3 fibroblasts and human Jurkat T‐ALL cells. Results: NB promoted the transformation of mouse NIH3T3 fibroblasts by upregulating the proto‐oncogene Pim1, which encodes a serine/threonine kinase. NB transcriptionally regulated Pim1 expression by binding to its promoter and activated MYC and mTORC1 signaling. PIM1 knockdown or pharmacological inhibition of mTORC1 signaling suppressed NB‐induced NIH3T3 cell transformation. Furthermore, NB enhanced the survival of human Jurkat T‐ALL cells by inactivating the pro‐apoptotic protein BCL2‐associated agonist of cell death (BAD). Conclusion: We demonstrated the pivotal role of NB in cell transformation and survival and identified PIM1as a key downstream target of NB. These findings propose a promising therapeutic strategy for patients with NB fusion‐positive leukemia. [ABSTRACT FROM AUTHOR]

Summary: We conducted a phase I trial in newly diagnosed acute myeloid leukaemia (AML) to investigate the combination of two novel targeted agents, gemtuzumab ozogamicin (GO) and midostaurin, with intensive chemotherapy in FLT3‐mutated AML and CBF leukaemia. Three dose levels of midostaurin and one to three sequential doses of 3 mg/m2 GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m2 GO on Days 1 + 4 and 100 mg midostaurin on Days 8–21 can be safely combined with IC in newly diagnosed AML. [ABSTRACT FROM AUTHOR]

Summary: The bendamustine–rituximab (BR) schedule is an efficient first‐line therapy in Waldenström macroglobulinaemia (WM). A previous analysis of 69 patients who received this treatment confirmed a high response rate and good progression‐free (PFS) and overall survival (OS). With a median follow‐up of 76.1 months (95% confidence interval [CI] 69.9–80.6), 5‐year outcome is still excellent at 66.63% (95% CI 56.09–79.17) for PFS and 80.01% (95% CI 70.82–90.41) for OS. The rate of secondary cancers is 17.66% (IQR 7.99–27.64) at 66 months. Relapsed patients who received ibrutinib as second‐line clearly benefited from this schedule. This confirms current recommendations suggesting BR long‐term efficacy as first‐line option in WM. [ABSTRACT FROM AUTHOR]

Objective: Cancer clinical trials (CCTs) provide access to emerging therapies and extra clinical care. We aimed to describe the volume and characteristics of CCTs available across Victoria, Australia, and identify factors associated with rural trial location. Methods: Quantitative analysis of secondary data from Cancer Council Victoria's Clinical Trials Management Scheme dataset. Design: A cross‐sectional study design was used. Setting: CCTs were available Victoria‐wide in 2018. Participants: There were 1669 CCTs and 5909 CCT participants. Main Outcome Measures: Rural CCT location was assessed as a binary variable with categories of 'yes' (modified Monash [MM] categories 2–7) and 'no' (MM category 1). MM categories were determined from postcodes. The highest ('least rural') MM category was used for postcodes with multiple MM categories. Results: Of 1669 CCTs, 168 (10.1%) were conducted in rural areas. Of 5909 CCT participants, 315 (5.3%) participated in rural CCTs. There were 526 CCTs (31.5%) with 1907 (32.3%) newly enrolled participants. Of 1892 newly enrolled participants with postcode data, 488 (25.8%) were rural residents. Of them, 368 (75.4%) participated in metropolitan CCTs. In a multivariable logistic regression analysis for all 1669 CCTs, odds of a rural rather than metropolitan CCT location were significantly (p‐value <0.05) lower for early‐phase than late‐phase trials and non‐solid than solid tumour trials but significantly (p‐value <0.05) higher for non‐industry than industry‐sponsored trials. Conclusions: In Victoria, 10% of CCTs are at rural sites. Most rural‐residing CCT participants travel to metropolitan sites, where there are more late‐phase, non‐solid‐tumour and industry‐sponsored trials. Approaches to increase the volume and variety of rural CCTs should be considered. [ABSTRACT FROM AUTHOR]

Calcium is a ubiquitous messenger that regulates a wide range of cellular functions, but its involvement in the pathophysiology of acute myeloid leukemia (AML) is not widely investigated. Here, we identified, from an analysis of The Cancer Genome Atlas and genotype‐tissue expression databases, stromal interaction molecule 2 (STIM2) as being highly expressed in AML with monocytic differentiation and negatively correlated with overall survival. This was confirmed on a validation cohort of 407 AML patients. We then investigated the role of STIM2 in cell proliferation, differentiation, and survival in two leukemic cell lines with monocytic potential and in normal hematopoietic stem cells. STIM2 expression increased at the RNA and protein levels upon monocyte differentiation. Phenotypically, STIM2 knockdown drastically inhibited cell proliferation and induced genomic stress with DNA double‐strand breaks, as shown by increased levels of phosphorylate histone H2AXγ (p‐H2AXγ), followed by activation of the cellular tumor antigen p53 pathway, decreased expression of cell cycle regulators such as cyclin‐dependent kinase 1 (CDK1)–cyclin B1 and M‐phase inducer phosphatase 3 (CDC25c), and a decreased apoptosis threshold with a low antiapoptotic/proapoptotic protein ratio. Our study reports STIM2 as a new actor regulating genomic stability and p53 response in terms of cell cycle and apoptosis of human normal and malignant monocytic cells. [ABSTRACT FROM AUTHOR]

Leukemia is a heterogeneous group of life‐threatening malignant disorders of the hematopoietic system. Immunotherapy, radiotherapy, stem cell transplantation, targeted therapy, and chemotherapy are among the approved leukemia treatments. Unfortunately, therapeutic resistance, side effects, relapses, and long‐term sequelae occur in a significant proportion of patients and severely compromise the treatment efficacy. The development of novel approaches to improve outcomes is therefore an unmet need. Recently, novel leukemia drug discovery strategies, including targeted protein degradation, have shown potential to advance the field of personalized medicine for leukemia patients. Specifically, PROteolysis‐TArgeting Chimeras (PROTACs) are revolutionary compounds that allow the selective degradation of a protein by the ubiquitin–proteasome system. Developed against a wide range of cancer targets, they show promising potential in overcoming many of the drawbacks associated with conventional therapies. Following the exponential growth of antileukemic PROTACs, this article reviews PROTAC‐mediated degradation of leukemia‐associated targets. Chemical structures, in vitro and in vivo activities, pharmacokinetics, pharmacodynamics, and clinical trials of PROTACs are critically discussed. Furthermore, advantages, challenges, and future perspectives of PROTACs in leukemia are covered, in order to understand the potential that these novel compounds may have as future drugs for leukemia treatment. [ABSTRACT FROM AUTHOR]

Lymphoma is one of the most common malignant neoplasms in cats. Historically, most feline lymphomas were associated with feline leukaemia virus infection, but due to routine vaccination against the virus, especially in developed countries, feline leukaemia virus‐associated cases are dramatically reduced in numbers. More recently, the most common lymphoma in cats is intestinal lymphoma, with most common type being the enteropathy‐associated T‐cell lymphomas. Follicular lymphoma is recognised in cats, but is very uncommon. Primary colorectal follicular lymphoma is rare in humans and has been reported in three dogs. In this case report, we describe a primary colorectal lymphoma with histological and immunohistochemical features of a follicular lymphoma in a Savannah cat. To the authors' knowledge, this is the first case report of a primary colorectal follicular lymphoma in cats, and differential diagnosis of tumours in the colorectal area in cats should include follicular lymphoma. [ABSTRACT FROM AUTHOR]

The treatment of acute myeloid leukaemia (AML) has changed fundamentally in the last decade with many new targeted therapies entering clinics. Some of the most interesting agents under development are Menin inhibitors which interfere with the interaction of Menin with wild‐type (wt) KMT2A or a KMT2A‐fusion protein and thereby downregulate the leukaemic gene expression (MEIS1, PBX3, HOX) in NPM1 mutant or KMT2A‐rearranged leukaemia. Other HOX and MEIS1 expressing leukaemias may also be sensitive to Menin inhibition. Following the encouraging results as monotherapy in refractory and relapsed AML, the combination of Menin inhibitors with chemotherapeutic agents and other targeted drugs is being investigated clinically. [ABSTRACT FROM AUTHOR]

Leukemia affects the body's blood‐forming tissues, especially the bone marrow and lymphatic system. Leukemia incidence varies between communities and between pathological kinds. Many treatment modalities exist for leukemia, such as chemotherapy, targeted therapy, radiation therapy, bone marrow transplantation, immunotherapy, and the engineering of immune cells to fight leukemia. Leukemia might be treated with a variety of pharmaceuticals, the most popular of which are imatinib (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), obinutuzumab (Gazyva), venetoclax (Venclexta), and so on. Thiazole is one of the scaffolds that are actively explored in leukemia. Derivatives having the thiazole nucleus have been surfacing as potent candidates in the treatment of leukemia for quite sometime now, but a consolidated report accumulating all these ventures is absent. Numerous naturally occurring substances, including flavones, alkaloids, anabolic steroids, and vitamin B1 (thiamine), include the basic thiazole molecule. Thiazole derivatives have been researched for their possible therapeutic effects in the treatment of leukemia. Thus, this review comprising reports regarding the effect of different thiazole‐based species in leukemia is a timely effort to the best of our knowledge. This review covers the chronological development of antileukemic thiazole‐based molecules, their synthesis, biological activity, and structure–activity relationships. [ABSTRACT FROM AUTHOR]

Background: B‐cell acute lymphoblastic leukemia (B‐ALL) is classified into subgroups based on known driver oncogenes and molecular lesions, including translocations and recurrent mutations. However, the current diagnostic tests do not identify subtypes or oncogenic lesions for all B‐ALL samples, creating a heterogeneous B‐ALL group of unknown subtypes. Methods: We sorted primary adult B‐ALL cells and performed transcriptome analysis by bulk RNA sequencing (RNA‐seq). Results: Transcriptomic analysis of an adult B‐ALL cohort allowed the classification of four patient samples with subtypes that were not previously revealed by standard gene panels. The leukemia of two patients were of the DUX4 subtype and two were CRLF2+ Ph‐like B‐ALL. Furthermore, single nucleotide variant analysis detected the oncogenic NRAS‐G12D, KRAS‐G12D, and KRAS‐G13D mutations in three of the patient samples, presenting targetable mutations. Additional oncogenic variants and gene fusions were uncovered, as well as multiple variants in the PDE4DIP gene across five of the patient samples. Conclusion: We demonstrate that RNA‐seq is an effective tool for precision medicine in B‐ALL by providing comprehensive molecular profiling of leukemia cells, identifying subtype and oncogenic lesions, and stratifying patients for appropriate therapy. [ABSTRACT FROM AUTHOR]

Objective: This study primarily focused on the diagnostic interval (DI), defined as the duration from the onset of leukemic symptoms to diagnosis. We investigated whether a prolonged DI is associated with the outcomes of pediatric leukemia. Methods: We retrospectively collected data of children with newly diagnosed pediatric leukemia at Okayama University Hospital from January 2007 to December 2022. Survival analyses were conducted using Kaplan–Meier methods, and an unadjusted analysis to compare differences in survival was performed using the log‐rank test. Results: In total, 103 children with leukemia were included in the analysis. The median DI was 20 days (interquartile range, 9.5–33.5 days). A prolonged DI (≥30 days) demonstrated no association with either 5‐year event‐free survival (70.1% for <30 days and 68.3% for ≥30 days, p =.99, log‐rank test) or overall survival (84.7% for <30 days and 89.4% for ≥30 days, p =.85, log‐rank test). Conclusions: A prolonged DI was not associated with the survival of children with leukemia. If a precise classification of leukemia biology is provided for pediatric patients, a prolonged DI may have little impact on the prognosis of these patients. [ABSTRACT FROM AUTHOR]

Key Clinical Message: A patient presented with cardiogenic shock, requiring the implantation of a left ventricular assist device (LVAD), and acute myeloblastic leukemia. This necessitated total body irradiation (TBI) while balancing dose reduction to the LVAD components to avoid potential radiation damage. Here we outline our treatment approach and dose estimates to the LVAD. This case report discusses the delivery of TBI to a patient with an LVAD. This treatment required radiation‐dose determinations and consequential reductions for the heart, LVAD, and an external controller connected to the LVAD. The patient was treated using a traditional 16MV anterior posterior (AP)/posterior anterior (PA) technique at a source‐to‐surface‐distance of 515 cm for 400 cGy in two fractions. A 3 cm thick Cerrobend block was placed on the beam spoiler to reduce dose to the heart and LVAD to 150 cGy. The external controller was placed in a 1 cm thick acrylic box to reduce neutron dose and positioned as far from the treatment fields as achievable. In vivo measurements were made using optically stimulated luminescence dosimeters (OSLDs) placed inside the box at distances of 2 cm, 8.5 cm, and 14 cm from the field edge, and on the patient along the central axis and centered behind the LVAD block. Further ion chamber measurements were made using a solid water phantom to more accurately estimate the dose delivered to the LVAD. Neutron dose measurements were also conducted. The total estimated dose to the controller ranged from 135.3 cGy to 91.5 cGy. The LVAD block reduced the surface dose to the patient to 271.6 cGy (68.1%). The block transmission factors of the 3 cm Cerrobend block measured in the phantom were 45% at 1 cm depth and decreased asymptotically to around 30% at 3 cm depth. Applying these transmission factors to the in vivo measurements yielded a dose of 120 cGy to the implanted device. The neutron dose the LVAD region is estimated around 0.46 cGy. Physical limitations of the controller made it impossible to completely avoid dose. Shielding is recommended. The block had limited dose reduction to the surface, due to secondary particles, but appropriately reduced the dose at 3 cm and beyond. More research on LVADs dose limits would be beneficial. [ABSTRACT FROM AUTHOR]

Venetoclax, a highly selective BCL‐2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine or decitabine, is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated venetoclax plus HMA in an inpatient setting owing to concerns of tumor lysis syndrome (TLS). This study (NCT03941964) evaluated the efficacy and safety of venetoclax plus HMA in a United States community–based outpatient setting in patients with ND AML (N = 60) who were treatment naïve for AML, ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed as appropriate candidates for outpatient initiation of venetoclax plus HMA by the investigator. Patients received venetoclax in combination with azacitidine (75 mg/m2) or decitabine (20 mg/m2) for up to 6 cycles during the study. With a median time on study of 18.3 weeks, the best response rate of composite complete remission was 66.7%, and the overall post‐baseline red blood cell (RBC) and platelet transfusion independence rate was 55.0%, consistent with results of studies in which treatment was initiated in an inpatient setting. Key adverse events included nausea, anemia, thrombocytopenia, neutropenia, and white blood cell count decrease of any grade (≥50% of patients). The observed safety profile was generally consistent with that of venetoclax plus HMA observed in inpatient AML studies. With close monitoring, 2 cases of TLS were identified, appropriately managed, and the patients were able to continue study treatment. Clinical Trials Registration: This study is registered at ClinicalTrials.gov. The registration identification number is NCT03941964. [ABSTRACT FROM AUTHOR]

The next‐generation sequencing technologies application discovers novel genetic alterations frequently in pediatric acute lymphoblastic leukemia (ALL). RAS signaling pathway mutations at the time of relapse ALL frequently appear as small subclones at the time of onset, which are considered as the drivers in ALL relapse. Whether subclones alterations in the RAS signaling pathway should be considered for risk group stratification of ALL treatment is not decided yet. In this work, we investigate the RAS signaling pathway mutation spectrum and the related prognosis in pediatric ALL. We employed an NGS panel comprising 220 genes. NGS results were collected from 202 pediatric ALL patients. 155 patients (76.7%) harbored at least one mutation. The incidences of RAS signaling pathway mutations are different significantly between T‐ALL and B‐ALL. In B‐ALL, the RAS pathway is mostly involved, and NRAS (17.6%), KRAS (22.7%), and PTPN11 (7.7%) were the three most frequently mutated genes. Co‐occurring mutations of CREBBP and NRAS, FLT3, or PTPN11 (p = 0.002, p = 0.009, and p = 0.003, respectively) were found in this cohort. The 3‐year RFS rates for the RAS signaling pathway mutation‐positive and negative cases was 76.5 % versus 89.7 % (p = 0.012). Four cases relapsed in the lately 3 years were RAS signaling pathway mutation‐positive. RAS signaling pathway mutation is an important biomarker for poorer relapse‐free survival in pediatric B‐ALL patients despite good early MRD levels. [ABSTRACT FROM AUTHOR]

Hyperpolarized carbon‐13 labeled compounds are increasingly being used in medical MR imaging (MRI) and MR imaging (MRI) and spectroscopy (MRS) research, due to its ability to monitor tissue and cell metabolism in real‐time. Although radiological biomarkers are increasingly being considered as clinical indicators, biopsies are still considered the gold standard for a large variety of indications. Bioreactor systems can play an important role in biopsy examinations because of their ability to provide a physiochemical environment that is conducive for therapeutic response monitoring ex vivo. We demonstrate here a proof‐of‐concept bioreactor and microcoil receive array setup that allows for ex vivo preservation and metabolic NMR spectroscopy on up to three biopsy samples simultaneously, creating an easy‐to‐use and robust way to simultaneously run multisample carbon‐13 hyperpolarization experiments. Experiments using hyperpolarized [1‐13C]pyruvate on ML‐1 leukemic cells in the bioreactor setup were performed and the kinetic pyruvate‐to‐lactate rate constants (kPL) extracted. The coefficient of variation of the experimentally found kPLs for five repeated experiments was CV=35%. With this statistical power, treatment effects of 30%–40% change in lactate production could be easily differentiable with only a few hyperpolarization dissolutions on this setup. Furthermore, longitudinal experiments showed preservation of ML‐1 cells in the bioreactor setup for at least 6 h. Rat brain tissue slices were also seen to be preserved within the bioreactor for at least 1 h. This validation serves as the basis for further optimization and upscaling of the setup, which undoubtedly has huge potential in high‐throughput studies with various biomarkers and tissue types. [ABSTRACT FROM AUTHOR]

The use of all‐trans retinoic acid and arsenic trioxide resulted in favourable therapeutic responses in standard‐risk acute promyelocytic leukaemia (APL) patients. However, resistance to these agents has made treating the high‐risk subgroup more problematic, and possible side effects limit their clinical dosages. Numerous studies have proven the cytotoxic properties of Gaillardin, one of the Inula oculus‐christi‐derived sesquiterpene lactones. Due to the adverse effects of arsenic trioxide on the high‐risk subgroup of APL patients, we aimed to assess the cytotoxic effect of Gaillardin on HL‐60 cells as a single or combined‐form approach. The results of the trypan blue and MTT assays outlined the potent cytotoxic properties of Gaillardin. The flow cytometric analysis and the mRNA expression levels revealed that Gaillardin attenuated the proliferative capacity of HL‐60 cells through cell cycle arrest and induced apoptosis via reactive oxygen species generation. Moreover, the results of synergistic experiments indicated that this sesquiterpene lactone sensitizes HL‐60 cells to the cytotoxic effects of arsenic trioxide. Taken together, the findings of the present investigation highlighted the antileukemic characteristics of Gaillardin by inducing G1 cell cycle arrest and triggering apoptosis. Gaillardin acts as an antileukemic metabolite against HL‐60 cells and this study provides new insight into treating APL patients, especially in the high‐risk subgroup. [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]

Objective(s): Hematologic malignancy involving the trachea is rare. It is even less common for tracheal involvement to be the initial manifestation of this disease. We present a case report highlighting an unusual diagnosis of acute myeloid leukemia (AML) that first presented with prominent tracheal manifestations. There have been only three other published case reports of extramedullary AML with involvement of the trachea. Methods: We discuss direct laryngoscopy and bronchoscopy findings, including pinkish‐white irregular lesions, which were similar to findings described in the available literature for tracheal AML. Results: Laboratory findings from our case are reported, including peripheral smear demonstrating 57% blasts and bone marrow biopsy confirming the diagnosis of AML, and the relevance of these findings is discussed. Conclusion: In patients with unusual airway lesions, laboratory testing and a comprehensive airway evaluation including biopsy are necessary to narrow the differential diagnosis. Level of Evidence: 5. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) is characterized by clonal heterogeneity, leading to frequent relapses and drug resistance despite intensive clinical therapy. Although AML's clonal architecture has been addressed in many studies, practical monitoring of dynamic changes in those subclones during relapse and treatment is still understudied. Method: Fifteen longitudinal bone marrow (BM) samples were collected from three relapsed and refractory (R/R) AML patients. Using droplet digital polymerase chain reaction (ddPCR), the frequencies of patient's leukemic variants were assessed in seven cell populations that were isolated from each BM sample based on cellular phenotypes. By quantifying mutant clones at the diagnosis, remission, and relapse stages, the distribution of AML subclones was sequentially monitored. Results: Minimal residual (MR) leukemic subclones exhibit heterogeneous distribution among BM cell populations, including mature leukocyte populations. During AML progression, these subclones undergo active phenotypic transitions and repopulate into distinct cell population regardless of normal hematopoiesis hierarchic order. Of these, MR subclones in progenitor populations of patient BM predominantly carry MR leukemic properties, leading to more robust expansion and stubborn persistence than those in mature populations. Moreover, a minor subset of MR leukemic subclones could be sustained at an extremely low frequency without clonal expansion during relapse. Conclusions: In this study, we observed treatment persistent MR leukemic subclones and their phenotypic changes during the treatment process of R/R AML patients. This underscores the importance of preemptive inhibition of clonal promiscuity in R/R AML, proposing a practical method for monitoring AML MR subclones. [ABSTRACT FROM AUTHOR]

Exosomes play a crucial role in intercellular communication and have emerged as significant vehicles for transporting disease‐specific biomarkers. This feature provides profound insights into the progression of diseases and the responses of patients to treatments. For example, in leukemia, exosomes convey critical information through the carriage of specific proteins and nucleic acids. In the case of human papillomavirus (HPV)‐mediated cervical cancer, exosomes are particularly useful for noninvasive detection as they transport high‐risk HPV DNA and specific biomolecules, which can be indicators of the disease. Despite their vast potential, there are several challenges associated with the use of exosomes in medical diagnostics. These include their inherent heterogeneity, the need for enhanced sensitivity in detection methods, the establishment of standardization protocols, and the requirement for cost‐effective scalability in their application. Addressing these challenges is crucial for the effective implementation of exosome‐based diagnostics. Future research and development are geared towards overcoming these obstacles. Efforts are concentrated on refining the processes of biomarker discovery, establishing comprehensive regulatory frameworks, developing convenient point‐of‐care devices, exploring methods for multimodal detection, and conducting extensive clinical trials. The ultimate goal of these efforts is to inaugurate a new era of precision diagnostics within healthcare. This would significantly improve patient outcomes and reduce the burden of diseases such as leukemia and HPV‐mediated cervical cancer. The integration of exosomes with cutting‐edge technology holds the promise of significantly reinforcing the foundations of healthcare, leading to enhanced diagnostic accuracy, better disease monitoring, and more personalized therapeutic approaches. [ABSTRACT FROM AUTHOR]

The growth of artificial intelligence (AI) in the healthcare industry tremendously increases the patient outcomes by reshaping the way we diagnose, treat and monitor patients. AI‐based innovation in healthcare include exploration of drugs, personalized medicine, clinical diagnosis investigations, robotic‐assisted surgery, verified prescriptions, pregnancy care for women, radiology, and reviewed patient information analytics. However, prediction of AI‐based solutions are depends mainly on the implementation of statistical algorithms and input data set. In this article, statistical performance review on various algorithms, Accuracy, Precision, Recall and F1‐Score used to predict the diagnosis of leukemia, glaucoma, and diabetes mellitus is presented. Review on statistical algorithms' performance, used for individual disease diagnosis gives a complete picture of various research efforts during the last two decades. At the end of statistical review on each disease diagnosis, we have discussed our inferences that will give future directions for the new researchers on selection of AI statistical algorithm as well as the input data set. [ABSTRACT FROM AUTHOR]

Exosomes have a significant impact on tumor survival, proliferation, metastasis, and recurrence. They also open up new therapeutic options and aid in the pathological identification and diagnosis of cancers. Exosomes have been shown in numerous studies to be essential for facilitating cell‐to‐cell communication. In B‐cell hematological malignancies, the proteins and RNAs that are encased by circulating exosomes are thought to represent prospective sources for therapeutic drugs as well as biomarkers for diagnosis and prognosis. Additionally, exosomes can offer a "snapshot" of the tumor and the metastatic environment at any given point in time. In this review study, we concluded that leukemia‐derived exosomes could be utilized as prognostic, diagnostic, and therapeutic biomarkers for individuals suffering from leukemia. Moreover, clinical studies have demonstrated that immune cells like dendritic cells create exosomes, which have the ability to activate the immune system against leukemia. Significant Statement: Exosomes have been observed in the treatment and diagnosis of a number of illnesses and diseases, particularly B‐cell disorders like leukemia, multiple sclerosis, and rheumatoid arthritis, because of their distinct biological properties. Exosomes have a significant impact on tumor survival, proliferation, metastasis, and recurrence. Increasing evidence has indicated that leukemia‐derived exosomes could be utilized as prognostic, diagnostic, and therapeutic biomarkers for individuals suffering from leukemia. In this regard, the importance of exosomes in terms of initiation and progression of leukemia was underlined in this study. [ABSTRACT FROM AUTHOR]

Summary: Obesity has taken the face of a pandemic with less direct concern among the general population and scientific community. However, obesity is considered a low‐grade systemic inflammation that impacts multiple organs. Chronic inflammation is also associated with different solid and blood cancers. In addition, emerging evidence demonstrates that individuals with obesity are at higher risk of developing blood cancers and have poorer clinical outcomes than individuals in a normal weight range. The bone marrow is critical for hematopoiesis, lymphopoiesis, and myelopoiesis. Therefore, it is vital to understand the mechanisms by which obesity‐associated changes in BM adiposity impact leukemia development. BM adipocytes are critical to maintain homeostasis via different means, including immune regulation. However, obesity increases BM adiposity and creates a pro‐inflammatory environment to upregulate clonal hematopoiesis and a leukemia‐supportive environment. Obesity further alters lymphopoiesis and myelopoiesis via different mechanisms, which dysregulate myeloid and lymphoid immune cell functions mentioned in the text under different sequentially discussed sections. The altered immune cell function during obesity alters hematological malignancies and leukemia susceptibility. Therefore, obesity‐induced altered BM adiposity, immune cell generation, and function impact an individual's predisposition and severity of leukemia, which should be considered a critical factor in leukemia patients. [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]

Several myeloid cell leukemia sequence 1 protein (MCL1) inhibitors including S64315 have undergone clinical testing for leukemia. Because of the toxicities after MCL1 inhibition, including hematopoietic, hepatic, and cardiac toxicities, there is substantial interest in finding agents that can sensitize leukemia cells to these MCL1 inhibitors. Melatonin is a chronobiotic that promotes chemo‐induced cancer cell death while protecting normal cells from cytotoxic effects. In this study, we found melatonin sensitizes over 10 leukemia cell lines to the MCL1 inhibitors S63845 (S64315 analog) and A‐1210477. Further studies demonstrate that melatonin sensitizes Jurkat cells to S63845 and A‐1210477 independent of melatonin receptors MT1 and MT2, but through multiple mechanisms, including upregulating the death receptor pathway, increasing mitochondrial reactive oxygen species (ROS), inhibiting nuclear factor‐κB (NF‐κB) signaling, and causing cell cycle arrest. First, death receptor pathway inhibition only slightly diminishes the melatonin sensitization of S63845, while inhibiting mitochondrial ROS partially reduces the S63845/melatonin combination‐induced apoptosis and depletion of the mitochondrial pathway totally abolishes it, indicating that both death receptor and mitochondrial apoptosis pathways are involved. Second, transcriptome sequencing analysis found that NF‐κB signaling is downregulated by melatonin that inhibition of NF‐κB signaling by parthenolide also dramatically sensitizes Jurkat cells to S63845. Third, melatonin induces G1 cell cycle arrest and upregulates NOXA while NOXA knockdown diminishes the sensitization to S63845 by melatonin. In addition, a xenograft model suggests that melatonin in combination with S63845 causes shrinkage of leukemic deposit while S63845 or melatonin monotherapy only has limited effects. Thus, our results demonstrate that melatonin efficiently sensitizes various leukemia to the MCL1 inhibitors, potentially allowing the usage of lower doses. [ABSTRACT FROM AUTHOR]

Objectives: Immunotherapies targeting natural killer (NK) cell receptors have shown promise against leukaemia. Unfortunately, cancer immunosuppressive mechanisms that alter NK cell phenotype prevent such approaches from being successful. The study utilises advanced cytometry to examine how cancer immunosuppressive pathways affect NK cell phenotypic changes in clinical samples. Methods: In this study, we conducted a high‐dimensional examination of the cell surface expression of 16 NK cell receptors in paediatric patients with acute myeloid leukaemia and acute lymphoblastic leukaemia, as well as in samples of non‐age matched adult peripheral blood (APB) and umbilical cord blood (UCB). An unsupervised analysis was carried out in order to identify NK cell populations present in paediatric leukaemias. Results: We observed that leukaemia NK cells clustered together with UCB NK cells and expressed relatively higher levels of the NKG2A receptor compared to APB NK cells. In addition, CD56dimCD16+CD57− NK cells lacking NKG2A expression were mainly absent in paediatric leukaemia patients. However, CD56br NK cell populations expressing high levels of NKG2A were highly represented in paediatric leukaemia patients. NKG2A expression on leukaemia NK cells was found to be positively correlated with the expression of its ligand, suggesting that the NKG2A‐HLA‐E interaction may play a role in modifying NK cell responses to leukaemia cells. Conclusion: We provide an in‐depth analysis of NK cell populations in paediatric leukaemia patients. These results support the development of immunotherapies targeting immunosuppressive receptors, such as NKG2A, to enhance innate immunity against paediatric leukaemia. [ABSTRACT FROM AUTHOR]

Aim: The survival rate after treatment for childhood leukaemia has greatly improved, but could result in protracted immune deficiency. This study examined the immune status of children after chemotherapy and evaluated their responses to immunisation. Methods: Subjects who had completed their treatment for acute lymphoblastic leukaemia at The Children's Hospital Reykjavík, Iceland, during 2011–2020 had blood drawn and were then immunised for influenza in October 2021. Blood was drawn again 4 weeks later and their humoral and cellular responses were measured with a haemagglutination inhibition assay and lymphocyte stimulation test. Antibodies to other immunisations were also evaluated. Results: We studied 18 patients (10 male) who had completed their treatment at 3.7–20.3 years of age (mean 9.1), 11–84 months (mean 36.9) before enrolment. Conventional immunological evaluation did not reveal notable abnormalities. The responses to several childhood vaccinations, including the pneumococcal conjugate vaccination, were adequate in most patients. Humoral responses to the influenza vaccine confirmed adequate reactions in all but one patient. Considerable variations were observed in the lymphocyte stimulations tests. Conclusion: Most patients reacted adequately to immunisation, especially against annual influenza and Streptococcus pneumoniae, reiterating the usefulness of vaccinations. The most appropriate timing for vaccination after treatment still needs to be determined. [ABSTRACT FROM AUTHOR]

This paper reports on the findings from a study that aimed to identify and characterize the constituents of Ocimum basilicum extract using gas chromatography–mass spectrometry (GC–MS) analysis, as well as assess the physicochemical properties and stability of nanoemulsions formulated with O. basilicum extract. The GC–MS analysis revealed that the O. basilicum extract contained 22 components, with Caryophyllene and Naringenin identified as the primary active constituents. The nanoemulsion formulation demonstrated excellent potential for use in the biomedical field, with a small and uniform particle size distribution, a negative zeta potential, and high encapsulation efficiency for the O. basilicum extract. The nanoemulsions exhibited spherical morphology and remained physically stable for up to 6 months. In vitro release studies indicated sustained release of the extract from the nanoemulsion formulation compared to the free extract solution. Furthermore, the developed nanoformulation exhibited enhanced anticancer properties against K562 cells while demonstrating low toxicity in normal cells (HEK293). The O. basilicum extract demonstrated antimicrobial activity against Pseudomonas aeruginosa, Candida albicans, and Staphylococcus epidermidis, with a potential synergistic effect observed when combined with the nanoemulsion. These findings contribute to the understanding of the constituents and potential applications of O. basilicum extract and its nanoemulsion formulation in various fields, including healthcare and pharmaceutical industries. Further optimization and research are necessary to maximize the efficacy and antimicrobial activity of the extract and its nanoformulation. Research Highlights: This study characterized the constituents of O. basilicum extract and assessed the physicochemical properties and stability of its nanoemulsion formulation.The O. basilicum extract contained 22 components, with Caryophyllene and Naringenin identified as the primary active constituents.The nanoemulsion formulation demonstrated excellent potential for biomedical applications, with sustained release of the extract, low toxicity, and enhanced anticancer and antimicrobial properties.The findings contribute to the understanding of the potential applications of O. basilicum extract and its nanoemulsion formulation in healthcare and pharmaceutical industries, highlighting the need for further optimization and research. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy that is associated with an increased risk of developing cutaneous malignancies. Clinical outcomes for these malignancies, including melanoma and keratinocyte cancers (KC), are worse for patients with CLL. Individuals with CLL develop an immunodeficiency of both the adaptive and innate immune system, which plays a role in the increased prevalence of skin cancers. This review focuses on the complex interplay between genetics, immunity, and pathogens that influence the cellular composition and biology of skin tumors and their microenvironment in CLL patients, and in comparison with other chronic hematological malignancies. It is paramount for dermatologists to be aware of the association between CLL (and chronic hematological malignancies more broadly) and cutaneous malignancies. This is a high‐risk population who require regular and vigorous dermatologic follow‐up. [ABSTRACT FROM AUTHOR]

Examination of central nervous system (CNS) involvement is not routine diagnostic practice in adult patients with acute myeloid leukemia (AML). Therefore, many asymptomatic patients with CNS involvement might go undetected. The effect of CNS involvement on the AML disease course is not well defined, with conflicting results regarding clinical outcome. This study aimed to determine the incidence of asymptomatic CNS involvement in AML estimated by multiparametric flow cytometry of cerebrospinal fluid (MFC‐CSF) at diagnosis, the related potential risk factors, and prognosis. In total, 645 patients with de novo AML were screened; 183 (28.4%) of them fulfilled institutional practice for MFC‐CSF analysis based on presence of CNS symptoms and/or clinical features. CNS symptoms and signs were observed in 8/183 (4.4%) patients, but most patients (175/183, 95.6%) were asymptomatic. In the asymptomatic group, 73/175 (41.7%) patients had positive or suspicious cerebrospinal fluid (CSF) findings categorized as CNS positive (CNSpos) and 102/175 (58.3%) had normal CNS findings categorized as CNS negative (CNSneg). The presence of leukemic blasts was confirmed in 81/183 (44.3%) patients; the total incidence of CNS involvement in the whole AML group was 12.6% (81/645). Compared with asymptomatic patients with CNSneg, those with CNSpos had a significantly higher frequency of lymphadenopathy, white blood cell count ≥30 × 109/L, presence of the monocytic phenotype, and a high percentage of bone marrow (BM) blasts. The multivariate logistic regression model identified monocytic phenotype (p = 0.047) and high percentage of BM blasts (p = 0.042) as predictors for CNSpos. CNSpos did not affect overall survival in patients with AML. There was a higher incidence of CNS involvement in asymptomatic adult patients with de novo AML, emphasizing possible undervalued rates of CNS disease at diagnosis. Prospective studies should determine whether diagnostic lumbar puncture for MFC‐CSF analysis and CNS prophylaxis could contribute to better selection and prognosis in this patient population. [ABSTRACT FROM AUTHOR]