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Acute Lymphoblastic Leukemia (ALL) is one of the most common cancers among children under the age of 15. An increasing awareness to detect early leukemia can be avoided preventable deaths from leukemia. Accurate leukemia cells image classification plays a crucial role in reducing health risks by enabling early diagnosis, which helps in mitigating the severity of the disease through timely and targeted treatment The detection of Acute Lymphoblastic Leukemia incurs significant costs in terms of time. We have developed an alternative method, A Modified EfficientNetV2-S to detect Acute Lymphoblastic Leukemia quickly, accurately, and affordably. We proposed a new architecture called Hybrid Kernel on EfficientNetV2-S. Our architecture integrates three convolutions with different kernels: regular convolution, dilated convolution, and depth-wise convolution. Three convolutions work together in one layer to provide detailed information about the object. The Network Encapsulation method uses convolution results to find object features from an image based on different locations and directions and provide combined convoluted information. We update the weight to customize the Networks Encapsulation feature map results iteratively. We continuously repeat this operation until the updated weight difference falls below the specified threshold. The approach we suggested is unique because it uses several kernels for convolutions to help capture various feature variations. We have evaluated our new architecture using the C-NMC-2019 dataset at three learning and epoch pairs: {0.001;5}, {0.0001;10}, and {0.00001;15}. We used 12,528 images to assess the reliability of our proposed new architecture. The results showed that the best accuracy, precision, recall, and F1-Score were 97.44%, 97.35%, 98.88%, and 97.48%, respectively. Our proposed method performance outperformed VGG19, Xception, RestNet50, and EfficientNetB0. [ABSTRACT FROM AUTHOR]

Objective: To describe the incidence, clinical characteristics, and long-term outcomes of cerebral sinus venous thrombosis in children with acute lymphoblastic leukemia. Methods: This was a retrospective cohort study comprising pediatric patients with newly diagnosed or first-relapse acute lymphoblastic leukemia who developed cerebral sinus venous thrombosis at Texas Children's Hospital from 2002 to 2019. Results: Nineteen cases (1.7%) with cerebral sinus venous thrombosis were identified in all pediatric patients with acute lymphoblastic leukemia (n = 1129). Increased risk of cerebral sinus venous thrombosis was observed with age >10 years (P =.006). Twelve cases (63%) occurred during the induction, 4 (21%) during maintenance, and 3 (16%) during the consolidation phases of leukemia therapy. Seizures (10/19) and headaches (9/19) were the most common presenting symptoms. After treatment with anticoagulation therapy, we observed full resolution of thrombosis in 10 (53%) and partial resolution in 8 patients (42%). Long-term neurologic outcomes at follow-up in the 14 patients who survived included normal neurologic examinations (n = 10), epilepsy (n = 3), and focal neurologic deficits (n = 2). The death occurred in 5 individuals. Conclusion: Cerebral sinus venous thrombosis is a notable complication of pediatric acute lymphoblastic leukemia therapy. Older age (>10 years) was a risk factor for developing cerebral sinus venous thrombosis. Despite variable patient presentations and treatment durations, favorable clinical outcomes were observed in most patients after the treatment with anticoagulation for a minimum of 3 months. [ABSTRACT FROM AUTHOR]

The present study assessed potential associations between vitamin intake and leukemia in a national sample of adults in the United States. A total of 5520 participants were included in this cross-sectional study to investigate the relationship between vitamin intake (including vitamins A, C, D, and E) and leukemia. Results revealed negative associations between vitamin C and E intake and leukemia, whereas associations between vitamin A and D and leukemia were not statistically significant. For vitamin C, compared with the first tertile, the odds ratio (OR) and corresponding 95% confidential interval (CI) was 0.90 (0.75–0.95) for the second tertile and 0.82 (0.61–0.90) for the third tertile (p < 0.01). For vitamin E, compared with the first tertile, the OR and 95% CI was 0.92 (0.80–0.96) for the second tertile and 0.86 (0.71–0.92) for the third tertile (p < 0.01). Furthermore, the inverse relationship between intake of vitamins C and E and leukemia were more evident for individuals ≥60 years of age and those with a body mass index >30 kg/m2. Results of this study provide evidence suggesting that intake of vitamin C and E intake may decrease the prevalence of leukemia; however, further large-scale prospective cohort studies are needed to verify these findings. [ABSTRACT FROM AUTHOR]

Background: Recent studies have reported an association between Cytotoxic T-lymphocyte antigen-4 (CTLA-4) polymorphisms and hematologic malignancy susceptibility, while the results remain inconsistent. Hence, we performed a meta-analysis to investigate the association between CTLA-4 polymorphisms with hematologic malignancy susceptibility. Methods: A comprehensive and systematic search of Cochrane Library, PubMed, Embase databases was performed up to Sep. 20, 2024. The pooled odds ratio (OR) and its 95% confidence interval (CI) were used to determine the strength of the association between CTLA-4 polymorphisms and hematologic malignancy susceptibility. Statistical analysis was performed in STATA 12.0. Results: A total of 13 studies concerning the CTLA-4 49A/G, CTLA-4 60A/G, CTLA-4 318T/C, CTLA-4 1661A/G, and CTLA-4 319C/T polymorphisms were included in the meta-analysis. The pooled results suggested the CTLA-4 49A/G polymorphism was significantly associated with an increased hematologic malignancy risk (AA vs. GA+GG: OR = 1.77, 95% CI = 1.56-2.02), especially in NHL, multiple myeloma, and leukemia. Similarly, CTLA-4 319C/T polymorphism was found to be associated with decreased chronic lymphocytic leukemia risk. There was no significant association between the CTLA-4 60A/G, 318T/C, and 1661A/G polymorphism and hematologic malignancy risk. Conclusion: CTLA-4 49A/G and 319C/T polymorphisms were associated with hematologic malignancy susceptibility. [ABSTRACT FROM AUTHOR]

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]

Boesenbergia rotunda, commonly known as fingerroot, is a medicinal and culinary plant native to the Indochina Peninsula. We found that panduratin A (Pan-A), one of the compounds present in the rhizome extract of fingerroot, inhibited cell proliferation, induced apoptosis, and promoted cell cycle arrest at G0/G1 phase in multiple hematologic malignant cell lines including leukemia and lymphoma lines. Pan-A inhibited these activities in leukemia and lymphoma cells in a concentration-dependent manner. High-throughput transcriptome analysis indicated that Pan-A is involved in the cell cycle, cellular senescence, apoptosis, and multiple canonical signaling pathways in lymphoma cells. The Forkhead box O (FOXO) transcription factor family was identified as a potential target of Pan-A. Western blot showed elevated caspase 7 and cPARP/PARP in the B-cell lymphoma cells after treatment with Pan-A. The inhibitory effects were accompanied by stimulation of Akt signaling and phosphorylation of FOXO3. Immunohistochemistry of tissues from patients with B-cell lymphoma revealed detectable levels of FOXO3 protein specifically in neoplastic B cells. Overall, our results highlight FOXO3 as a player underlying antileukemia/lymphoma effects of Pan-A. [ABSTRACT FROM AUTHOR]

Erythropoiesis is regulated by the differential expression of many genes. Besides being transcriptionally regulated, these genes are also with the oath of epigenetic regulation by the microRNAs (miRNAs), in particular. Various miRNAs appear to be very important for the normal process of erythropoiesis and various hematological abnormalities in humans. Therefore, the review aims to summarize the significance of miRNAs in erythropoiesis and different hematological diseases with clinical importance. Our analysis indicates that specific miRNAs regulate erythropoiesis in a stage-specific manner from hematopoietic stem cells to differentiated erythrocytes. Further, many miRNAs have been reported to be linked with various hematological diseases. The importance of miRNAs as biomarkers or therapeutic drug targets for various hematological disorders like anemia, β-thalassemia, and leukemia has been revealed through various clinical studies and clinical trials. The miR-34a mimic and miR-155 inhibitor demonstrate promising therapeutic effects in various hematological malignancies. Additionally, miR-34a, miR-538e, miR-193e, and miR-198 exhibit diagnostic potential in acute myeloid leukemia, while miR-451, miR-151-5p, and miR-1290 show diagnostic potential in B-cell acute lymphoblastic leukemia. Thus, this review encompasses the latest observations and implications of specific miRNAs in erythropoiesis and various hematological disorders. However, challenges persist in developing safe and efficient delivery strategies to target miRNAs specifically, minimizing off-target effects and enhancing therapeutic outcomes. Future mechanistic pre-clinical and clinical research would contribute to overcoming these challenges. [ABSTRACT FROM AUTHOR]

Simple Summary: Drug repurposing offers a valuable approach for utilizing FDA-approved drugs to address new diseases, including cancer, while significantly reducing the time and cost associated with drug development. In this review, we highlight the anticancer potential of anthelmintic benzimidazole derivatives, such as mebendazole (MBZ), fenbendazole (FBZ), flubendazole (FLBZ), and albendazole (ABZ), with a particular focus on their efficacy against blood cancers. These compounds operate through multiple mechanisms, including disrupting microtubule formation, regulating the cell cycle, inducing cellular differentiation, and modulating key signaling pathways involved in cancer progression. The ability of benzimidazoles to exert these diverse effects on malignant cells suggests their promise as therapeutic agents for hematological cancers. Furthermore, investigating their use in combination with standard-of-care treatments may lead to the development of novel, more effective therapeutic strategies, offering new avenues of hope for patients with blood malignancies. Drug repurposing is a strategy to discover new therapeutic uses for existing drugs, which have well-established toxicity profiles and are often more affordable. This approach has gained significant attention in recent years due to the high costs and low success rates associated with traditional drug development. Drug repositioning offers a more time- and cost-effective path for identifying new treatments. Several FDA-approved non-chemotherapy drugs have been investigated for their anticancer potential. Among these, anthelmintic benzimidazoles (such as albendazole, mebendazole, and flubendazole) have garnered interest due to their effects on microtubules and oncogenic signaling pathways. Blood cancers, which frequently develop resistance and have high mortality rates, present a critical need for effective therapies. This review highlights the recent advances in repurposing benzimidazoles for blood malignancies. These compounds induce cell cycle arrest, differentiation, tubulin depolymerization, loss of heterozygosity, proteasomal degradation, and inhibit oncogenic signaling to exert their anticancer effects. We also discuss current limitations and strategies to overcome them, emphasizing the potential of combining benzimidazoles with standard therapies for improved treatment of hematological cancers. [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]

Background: Leukemia is a prevalent pediatric life-threatening hematologic malignancy with a poor prognosis. Targeting immune checkpoints (ICs) to reverse T cell exhaustion is a potentially effective treatment for leukemia. Tissue resident memory T (TRM) cells have been found to predict the efficacy of programmed death receptor-1 inhibitor (anti-PD-1) therapy in solid tumors. However, the IC characteristics of TRM cells in leukemia and their relationship with prognosis remain unclear. Methods: We employed multi-color flow cytometry to evaluate the frequencies of CD103+CD4+ and CD103+CD8+ T cells in the peripheral blood (PB) of patients with acute myeloid leukemia and B-cell acute lymphoblastic leukemia compared to healthy individuals. We examined the expression patterns of PD-1 and T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) within the circulating CD103+ T cell subsets affected by leukemia. To further elucidate the immunological landscape, we assessed the differentiation status of CD103+ T cells across various disease states in patients with leukemia. Results: Our findings showed a significant increase in the frequency of CD103+CD8+ T cells in the PB of patients with leukemia who had achieved complete remission (CR) compared to those in the de novo (DN) and relapsed/refractory (RR) stages. This increase was accompanied by a notable decrease in the expression levels of PD-1 and TIGIT in CD103+CD8+ T cells in the CR stage. Additionally, our analysis revealed a higher proportion of CD103+CD8+ T cells in the central memory (TCM) and effector memory (TEM) subsets of the immune profile. Notably, the proportions of CD103+ naïve T cells, CD103+ TEM, and CD103+ terminally differentiated T cells within the CD8+ T cell population were significantly elevated in patients with CR compared to those in the DN/RR stages. Conclusion: The data indicate that circulating higher frequency of CD103+CD8+ T cells with lower expression of PD-1 and TIGIT are associated with favorable outcomes in patients with leukemia. This suggests a potential role of TRM cells in leukemia prognosis and provides a foundation for developing targeted immunotherapies. [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]

Background: Leukemia is a prevalent pediatric life-threatening hematologic malignancy with a poor prognosis. Targeting immune checkpoints (ICs) to reverse T cell exhaustion is a potentially effective treatment for leukemia. Tissue resident memory T (TRM) cells have been found to predict the efficacy of programmed death receptor-1 inhibitor (anti-PD-1) therapy in solid tumors. However, the IC characteristics of TRM cells in leukemia and their relationship with prognosis remain unclear. Methods: We employed multi-color flow cytometry to evaluate the frequencies of CD103+CD4+ and CD103+CD8+ T cells in the peripheral blood (PB) of patients with acute myeloid leukemia and B-cell acute lymphoblastic leukemia compared to healthy individuals. We examined the expression patterns of PD-1 and T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) within the circulating CD103+ T cell subsets affected by leukemia. To further elucidate the immunological landscape, we assessed the differentiation status of CD103+ T cells across various disease states in patients with leukemia. Results: Our findings showed a significant increase in the frequency of CD103+CD8+ T cells in the PB of patients with leukemia who had achieved complete remission (CR) compared to those in the de novo (DN) and relapsed/refractory (RR) stages. This increase was accompanied by a notable decrease in the expression levels of PD-1 and TIGIT in CD103+CD8+ T cells in the CR stage. Additionally, our analysis revealed a higher proportion of CD103+CD8+ T cells in the central memory (TCM) and effector memory (TEM) subsets of the immune profile. Notably, the proportions of CD103+ naïve T cells, CD103+ TEM, and CD103+ terminally differentiated T cells within the CD8+ T cell population were significantly elevated in patients with CR compared to those in the DN/RR stages. Conclusion: The data indicate that circulating higher frequency of CD103+CD8+ T cells with lower expression of PD-1 and TIGIT are associated with favorable outcomes in patients with leukemia. This suggests a potential role of TRM cells in leukemia prognosis and provides a foundation for developing targeted immunotherapies. [ABSTRACT FROM AUTHOR]

Background: We here report the first case of leukemic lung infiltration diagnosed by transbronchial lung cryobiopsy (TBLC). TBLC is likely to be a superior method to transbronchial forceps biopsy because TBLC can get larger specimens, resulting in a higher chance of containing the leukemic cells infiltrated tissues. TBLC is generally considered a superior diagnostic method compared to transbronchial lung forceps biopsy (TBLB) because it utilizes cryotechnology to obtain larger specimens, increasing the likelihood of capturing tissues infiltrated with leukemic cells. Case presentation: A 69-year-old male patient with acute myeloid leukemia presented with a fever. His initial chest CT scans revealed consolidative lesions, raising suspicion of fungal infection such as angioinvasive aspergillosis or mucormycosis. TBLC and TBLB were conducted to achieve a precise diagnosis, and eventually, leukemic lung infiltration was identified exclusively in the tissues obtained from TBLC. Two cycles of chemotherapy was administrated to patient, showing improvements in symptoms and chest CT findings. Conclusions: TBLC has greater potential as a differential diagnostic method for pulmonary lesions than TBLB in leukemia patients facing therapeutic challenges due to its higher diagnostic yield. [ABSTRACT FROM AUTHOR]

Isolated ocular relapses of leukemia are rare and typically present as infiltrative lesions of the optic nerve. This report presents a case of an isolated ocular relapse of leukemia in a female patient, characterized by occult infiltrative optic neuropathy. Despite the absence of leukemic cell infiltration on MRI, a 33-year-old female patient presented with optic neuritis, which resolved after intrathecal administration of chemotherapeutic agents. However, due to her non-compliance with the treatment regimen, leukemia progressed to infiltrative optic neuropathy. She refused radiation therapy, and while intrathecal injections provided temporary stabilization, they were insufficient for sustained disease control. This case uniquely documents the extended progression of an isolated ocular relapse of leukemia, evolving from an occult infiltrative lesion initially presenting as optic neuritis to a more pronounced infiltrative lesion. It suggests that leukemic optic nerve infiltration can occur in patients with leukemia even in the absence of MRI-detectable abnormalities. Radiation therapy emerges as a critical modality in the management of infiltrative lesions of the optic nerve. [ABSTRACT FROM AUTHOR]

Background: We here report the first case of leukemic lung infiltration diagnosed by transbronchial lung cryobiopsy (TBLC). TBLC is likely to be a superior method to transbronchial forceps biopsy because TBLC can get larger specimens, resulting in a higher chance of containing the leukemic cells infiltrated tissues. TBLC is generally considered a superior diagnostic method compared to transbronchial lung forceps biopsy (TBLB) because it utilizes cryotechnology to obtain larger specimens, increasing the likelihood of capturing tissues infiltrated with leukemic cells. Case presentation: A 69-year-old male patient with acute myeloid leukemia presented with a fever. His initial chest CT scans revealed consolidative lesions, raising suspicion of fungal infection such as angioinvasive aspergillosis or mucormycosis. TBLC and TBLB were conducted to achieve a precise diagnosis, and eventually, leukemic lung infiltration was identified exclusively in the tissues obtained from TBLC. Two cycles of chemotherapy was administrated to patient, showing improvements in symptoms and chest CT findings. Conclusions: TBLC has greater potential as a differential diagnostic method for pulmonary lesions than TBLB in leukemia patients facing therapeutic challenges due to its higher diagnostic yield. [ABSTRACT FROM AUTHOR]

Background: Bleeding events are common complications in critically ill patients with haematological malignancies. The objective of this study was to assess the incidence and identify determinants of ICU-acquired severe bleeding events in critically ill patients with haematological malignancies. We conducted a single-center retrospective study including all adult patients with a history of haematological malignancy requiring unplanned ICU admission over a 12-year period (2007–2018). The primary endpoint was the occurrence of ICU-acquired (i.e. after the first 24 h in the ICU) severe bleeding events, as defined as grades 3 or 4 of the World Health Organization classification. Results: A total of 1012 patients were analysed, mainly with a diagnosis of lymphoma (n = 434, 42.9%) and leukaemia or myelodysplastic syndrome (n = 266, 26.3%). Most patients were recently diagnosed (n = 340, 33.6%) and under active cancer treatment within the last 3 months (n = 604, 59.7%). The main cause for admission was infection (n = 479, 47.3%), but a significant proportion of patients were admitted for a primary haemorrhage (n = 99, 10%). ICU-acquired severe bleeding events occurred in 109 (10.8%) patients after 3.0 days [1.0–7.0] in the ICU. The main source of bleeding was the gastrointestinal tract (n = 44, 40.3%). Patients experiencing an ICU-acquired severe bleeding event displayed prolonged in-ICU length of stay (9.0 days [1.0–6.0] vs. 3.0 [3.5–15.0] in non-bleeding patients, p < 0.001) and worsened outcomes with increased in-ICU and in-hospital mortality rates (55% vs. 18.3% and 65.7% vs. 33.1%, respectively, p < 0.001). In multivariate analysis, independent predictors of ICU-acquired severe bleeding events were chronic kidney disease (cause-specific hazard 2.00 [1.19–3.31], p = 0.008), a primary bleeding event present at the time of ICU admission (CSH 4.17 [2.71–6.43], p < 0.001), non-platelet SOFA score (CSH per point increase 1.06 [1.01–1.11], p = 0.02) and prolonged prothrombin time (CSH per 5-percent increase 0.90 [0.85–0.96], p = 0.001) on the day prior to the event of interest. Conclusions: Major bleeding events are common complications in critically ill patients with haematological malignancies and are associated with a worsened prognosis. We identified relevant risk factors of bleeding which may prompt closer monitoring or preventive measures. [ABSTRACT FROM AUTHOR]

Objective: Rare coexistence of disease or pathology. Background: Simultaneous occurrence of chronic lymphocytic leukemia (CLL) and plasma cell myeloma (PCM) is an uncommon hematological condition, with most patients presenting in late adult life. When these diagnoses occur concurrently, it often poses diagnostic challenges to the pathologist, with other important differential diagnoses including lymphoplasmacytic lymphoma, marginal-zone lymphoma, and chronic lymphocytic leukemia with plasmacytoid differentiation. Ancillary studies are indispensable in arriving at a reliable diagnosis in this clinical scenario. Case Reports: We present 2 cases of simultaneous CLL and PCM that were diagnosed in our facility. The bone marrow in these patients showed increased plasma cells with a separate population of neoplastic lymphoid cells. Bone marrow examination and ancillary studies (immunohistochemistry, fluorescence in situ hybridization, and molecular studies) were performed in both cases to arrive at the diagnosis and rule out other important differential diagnoses. While the first patient was still being observed at the time of writing this report, and found to be clinically stable during his last clinic visit, the second patient succumbed to the disease as a result of gram-negative sepsis. Conclusions: CLL and PCM can occasionally co-exist, posing diagnostic challenges to the pathologist. Ancillary diagnostic techniques are important in making a correct diagnosis. Making an accurate diagnosis is vital as this will guide appropriate treatment strategies. Whenever these 2 conditions occur simultaneously, patients often succumb as a result of progression of PCM. [ABSTRACT FROM AUTHOR]

Background: Disease trajectories in leukemia are often unpredictable and recurrent, and patients' experiences can impact their quality of life. Studies in the literature often do not explore gender-related illness experiences from an intersectional approach and throughout the illness trajectory. This comprehensive study aims to explore the full spectrum of experiences lived by women with leukemia throughout the disease trajectory, from diagnosis to treatments and post-stem cell transplant follow-up. Method: A grounded theory approach was meticulously developed to analyze semi-structured interviews with 13 women with leukemia in the post-transplant follow-up phase at a hospital in Northern Italy. The data analysis was an iterative process, conducted concurrently using a constant comparative method. Data collection concluded when data saturation was reached. Results: The core category identified is women's inner strength during the disease trajectory, which was identified for its recurrence and cross-cutting nature, according to the women. This core category interconnects with five main categories: 1. Facing the disease: Between resistance and surrender. 2. Living for today and moving forward. 3. Unexpected elements in relationships. 4. Changes that shape women. 5. Demystifying the body and embracing 'diminished beauty'. Conclusions: An explanatory model of the disease trajectory of women with leukemia was defined as: 'Women with leukemia, between inner strength and fighting prejudice'. An in-depth analysis of the disease experiences revealed aspects that are not easily understood through a purely biological perspective of gender differences, often overlooking the psycho-social and relational peculiarities of women. [ABSTRACT FROM AUTHOR]

T-cell acute lymphoblastic leukemia (T-ALL) is a challenging childhood cancer to treat, with limited therapeutic options and high relapse rates. This study explores deamidated triosephosphate isomerase (dTPI) as a novel therapeutic target. We hypothesized that selectively inhibiting dTPI could reduce T-ALL cell viability without affecting normal T lymphocytes. Computational modeling and recombinant enzyme assays revealed that disulfiram (DS) and curcumin (CU) selectively bind and inhibit dTPI activity without affecting the non-deamidated enzyme. At the cellular level, treatment with DS and CU significantly reduced Jurkat T-ALL cell viability and endogenous TPI enzymatic activity, with no effect on normal T lymphocytes, whereas the combination of sodium dichloroacetate (DCA) with DS or CU showed synergistic effects. Furthermore, we demonstrated that dTPI was present and accumulated only in Jurkat cells, confirming our hypothesis. Finally, flow cytometry confirmed apoptosis in Jurkat cells after treatment with DS and CU or their combination with DCA. These findings strongly suggest that targeting dTPI represents a promising and selective target for T-ALL therapy. [ABSTRACT FROM AUTHOR]

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Globally, overall survival (OS) of older patients with AML continues to be suboptimal with very little data from India. In a multicenter registry analysis, we evaluated 712 patients with AML older than 55 years. Only 323 (45.3%) underwent further treatment, of which 239 (74%) received HMAs, and 60 (18%) received intensive chemotherapy (IC). CR was documented in 39% of those receiving IC and 42% after HMAs. Overall, 100 (31%) patients died within 60 days of diagnosis, most commonly due to progressive disease (47%) or infections (30%). After a median follow-up of 176 days, 228 (76%) of patients had discontinued treatment. At one year from diagnosis, 211 (65%) patients had died, and the median OS was 186 days (IQR, 137–234). Only 12 (3.7%) patients underwent stem cell transplantation. Survival was significantly lower for those older than 60 years (p < 0.001). Patients who died had a higher median age (p =.027) and baseline WBC counts (p =.006). Our data highlights suboptimal outcomes in older AML patients, which are evident from 55 years of age onwards, making it necessary to evaluate HMA and targeted agent combinations along with novel consolidation strategies to improve survival in this high-risk population. [ABSTRACT FROM AUTHOR]

The primary treatment for chronic myeloid leukemia (CML) involves first- and second-generation tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, bosutinib, and dasatinib. However, these medications are ineffective against mutations in the kinase domain of the ABL1 protein, particularly in the protein with the T315I mutation. To address this, ponatinib (PNT), a third-generation inhibitor, was developed. Despite its efficacy in treating the BCR-ABL1T315I mutation, the use of PNT was briefly suspended in 2013 due to serious adverse effects but was subsequently reintroduced to the market. During the drug discovery and development process, it is rare to consolidate all information into a single article, as is the case with ponatinib. This review aims to compile and chronologically organize the research on the discovery of ponatinib using medicinal chemistry tools and computational methods. It includes in silico calculations, such as the octanol/water partition coefficient (cLogP) via SwissAdme, and 2D maps of intermolecular interactions through molecular docking. This approach enhances understanding for both specialists and those interested in medicinal chemistry and pharmacology, while also contextualizing future directions for further optimizations of ponatinib, facilitating the development of new analogs of this crucial inhibitor for the treatment of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). [ABSTRACT FROM AUTHOR]

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Copyright of Gazi Medical Journal is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

6-thioguanine (6-TG) is an antimetabolite drug of purine structure, approved by the FDA for the treatment of acute myeloid lesukemia, and it is of interest in treating other diseases. The interaction of drugs with matrices is of interest to achieving a delayed, sustained, and local release. The interaction of 6-TG with an aluminum metal–organic framework (Al-MOF) DUT-4 is studied using a novel experimental approach, namely, mechano-chemistry by liquid-assisted grinding (LAG). The bonding of 6-TG to the DUT-4 matrix in the composite (6-TG)(DUT-4) was studied using ATR-FTIR spectroscopy and XRD. This interaction involves amino groups and C and N atoms of the heterocyclic ring of 6-TG, as well as the carboxylate COO− and (Al)O-H groups of the matrix, indicating the formation of the complex. Next, an in vitro delayed release of 6-TG was studied from composite powder versus pure 6-TG in phosphate buffered saline (PBS) at 37 °C. Herein, an automated drug dissolution apparatus with an autosampler was utilized, and the molar concentration of the released 6-TG was determined using an HPLC–UV analysis. Pure 6-TG shows a quick (<300 min) dissolution, while the composite gives the dissolution of non-bonded 6-TG, followed by a significantly (factor 6) slower release of the bonded drug. Each step of the release follows the kinetic pseudo-first-order rate law with distinct rate constants. Then, a pharmaceutical shaped body was prepared from the composite, and it yields a significantly delayed release of 6-TG for up to 10 days; a sustained release is observed with the 6-TG concentration being within the therapeutically relevant window. Finally, the composite shows a time-dependent (up to 9 days) stronger inhibition of leukemia MV-4-11 cell colonies than 6-TG. [ABSTRACT FROM AUTHOR]

Simple Summary: This article examines the significance of β-chemokines, γ-chemokines, and δ-chemokines in acute myeloid leukemia (AML). It focuses on the effects of these chemotactic cytokines on both leukemic cells and non-leukemic cells within the tumor niche in the bone marrow. This article emphasizes the substantial impact of certain chemokines on tumorigenic processes in AML, highlighting the correlation between chemokine expression and patient prognosis. However, the mechanisms underlying this relationship remain poorly understood. The lack of comprehensive understanding of the role of chemokines in AML impedes the development of new anti-leukemic drugs targeting these chemokines and their receptors. Background/Objectives: Acute myeloid leukemia (AML) is a type of leukemia with a very poor prognosis. Consequently, this neoplasm is extensively researched to discover new therapeutic strategies. One area of investigation is the study of intracellular communication and the impact of the bone marrow microenvironment on AML cells, with chemokines being a key focus. The roles of β-chemokines, γ-chemokines, and δ-chemokines in AML processes have not yet been sufficiently characterized. Methods: This publication summarizes all available knowledge about these chemotactic cytokines in AML and myelodysplastic neoplasm (MDS) processes and presents potential therapeutic strategies to combat the disease. The significance of β-chemokines, γ-chemokines, and δ-chemokines is detailed, including CCL2 (MCP-1), CCL3 (MIP-1α), CCL5 (RANTES), CCL23, CCL28, and CX3CL1 (fractalkine). Additionally, the importance of atypical chemokine receptors in AML is discussed, specifically ACKR1, ACKR2, ACKR4, and CCRL2. Results/Conclusions: The focus is on the effects of these chemokines on AML cells, particularly their influence on proliferation and resistance to anti-leukemic drugs. Intercellular interactions with non-AML cells, such as mesenchymal stem cells (MSC), macrophages, and regulatory T cells (Treg), are also characterized. The clinical aspects of chemokines are thoroughly explained, including their effect on overall survival and the relationship between their blood levels and AML characteristics. [ABSTRACT FROM AUTHOR]

Transcription factors control genes to maintain normal hemopoiesis, and dysregulation of some factors can lead to acute lymphoblastic leukemia (ALL). Mycoviruses are known to alter the genetics of their fungal host. The present study evaluates the effects of the products of a mycovirus-containing Aspergillus flavus (MCAF), isolated from the home of a patient with ALL, on certain transcription factors of normal and ALL cell lines. Our published studies have shown that ALL patients have antibodies to MCAF, and that exposure of the mononuclear leukocytes of patients in complete remission to its products, unlike controls, results in the re-development of genetic and cell surface phenotypes characteristic of ALL. For the present study, normal, pre-B, and B-cell leukemia cell lines were exposed to the culture of MCAF. Pre- and post-exposure levels of PAX5, Ikaros, and NF-κB were assessed. Exposure to MCAF resulted in apoptosis, cell cycle changes, and complete downregulation of all transcription factors in normal cell lines. In acute leukemia cell lines, cellular apoptosis and alterations in the cell cycle were also noted; however, while there was downregulation of all tested transcription factors, residual levels were retained. The noted alterations in the transcription factors caused by MCAF are novel findings. The possible role of MCAF in leukemogenesis needs to be further investigated. Mycovirus-containing Aspergillus flavus was initially isolated from a leukemia patient's home. Our prior published studies have illuminated intriguing associations of this organism with leukemia. Unlike controls, patients diagnosed with acute lymphoblastic leukemia (ALL) harbor antibodies to this organism. Furthermore, the exposure of mononuclear cells from patients with ALL in complete remission to the products of this organism reproduced genetic and cell phenotypes characteristic of ALL. These findings underscore the potential role of environmental factors in leukemogenesis and hint at novel avenues for therapeutic intervention and preventive strategies. [ABSTRACT FROM AUTHOR]

Drug resistance is one of the major obstacles to the clinical use of doxorubicin, an extensively used chemotherapeutic drug to treat various cancers, including leukemia. Inhibition of the nuclear factor erythroid 2-related factor 2 (NRF2) seems a promising strategy to reverse chemoresistance in cancer cells. NRF2 is a transcription factor that regulates both antioxidant defense and drug detoxification mechanisms. In this study, we investigated the potential of three inhibitors of NRF2—K67, retinoic acid and ML-385—to overcome doxorubicin resistance in promyelocytic leukemia HL-60 cells. For this purpose, low-dose doxorubicin was used to establish doxorubicin-resistant HL-60/DR cells. The expression of NRF2 and its main repressor, Kelch-like ECH-associated protein 1 (KEAP1), at mRNA and protein levels was examined. HL-60/DR cells overexpressed NRF2 at mRNA and protein levels and down-regulated KEAP1 protein compared to drug-sensitive HL-60 cells. The effects of NRF2 inhibitors on doxorubicin-resistant HL-60/DR cell viability, apoptosis, and intracellular reactive oxygen species (ROS) levels were analyzed. We observed that NRF2 inhibitors significantly sensitized doxorubicin-resistant HL-60/DR cells to doxorubicin, which was associated with increased intracellular ROS levels and the expression of CAS-9, suggesting the participation of the mitochondrial-dependent apoptosis pathway. Furthermore, ML-385 inhibitor was used to study the expression of NRF2–KEAP1 pathway genes. NRF2 gene and protein expression remained unchanged; however, we noted the down-regulation of KEAP1 protein upon ML-385 treatment. Additionally, the expression of NRF2-regulated antioxidant and detoxification genes including SOD2, HMOX2, and GSS was maintained upon ML-385 treatment. In conclusion, our results demonstrated that all the studied inhibitors, namely K67, retinoic acid, and ML-385, increased the efficacy of doxorubicin in doxorubicin-resistant HL-60/DR cells, and suggested a potential strategy of combination therapy using NRF2 inhibitors and doxorubicin in overcoming doxorubicin resistance in leukemia. [ABSTRACT FROM AUTHOR]

Hematologic malignancies (HMs), including leukemia, lymphoma, and multiple myeloma, involve the uncontrolled proliferation of abnormal blood cells, posing significant clinical challenges due to their heterogeneity and varied treatment responses. Despite recent advancements in therapies that have improved survival rates, particularly in chronic lymphocytic leukemia and acute lymphoblastic leukemia, treatments like chemotherapy and stem cell transplantation often disrupt gut microbiota, which can negatively impact treatment outcomes and increase infection risks. This review explores the complex, bidirectional interactions between gut microbiota and cancer treatments in patients with HMs. Gut microbiota can influence drug metabolism through mechanisms such as the production of enzymes like bacterial β-glucuronidases, which can alter drug efficacy and toxicity. Moreover, microbial metabolites like short-chain fatty acids can modulate the host immune response, enhancing treatment effectiveness. However, therapy often reduces the diversity of beneficial bacteria, such as Bifidobacterium and Faecalibacterium, while increasing pathogenic bacteria like Enterococcus and Escherichia coli. These findings highlight the critical need to preserve microbiota diversity during treatment. Future research should focus on personalized microbiome-based therapies, including probiotics, prebiotics, and fecal microbiota transplantation, to improve outcomes and quality of life for patients with hematologic malignancies. [ABSTRACT FROM AUTHOR]

Copyright of Saudi Medical Journal is the property of Saudi Medical Journal and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Non-Hodgkin lymphoma (NHL) is one of the most common hematological cancers in the United States. The mortality rate of NHL in the United States is the sixth highest among all cancers. Our cross-sectional study aims to examine the trends and disparity in NHL mortality. We analyzed death certificate data from the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) United States to determine the NHL mortality trends among the U.S. population aged ø15 years. NHL (ICD-10 C82-85) was listed as the underlying cause of death. Age-adjusted mortality rates (AAMRs) per 100,000 individuals and joinpoint trend analysis were performed to determine the average annual percent change (AAPC) in AAMR trends. From 1999 to 2020, NHL accounted for 457,143 deaths in the United States, of which 54% are men and 46% are women. The NHL AAMR decreased significantly from 10.59 to 6.21 per 100,000 individuals with an AAPC of 22.55. Men had a higher AAMR than women (10.10 vs 6.29 per 100,000 individuals). Whites recorded the highest AAMR (8.43 per 100,000 individuals), followed by Hispanics (6.32 per 100,000 individuals), Blacks (5.71 per 100,000 individuals), American Indians (5.31 per 100,000 individuals), and Asians (5.10 per 100,000 individuals). Those who lived in the Midwest and the rural areas had the highest AAMR at 8.60 and 8.35 per 100,000 individuals respectively. Despite the declining NHL mortality rate, this study calls for targeted intervention to improve outcomes for susceptible individuals affected by NHL. [ABSTRACT FROM AUTHOR]

Context: The MEIS proteins, originally described as the "helper groups" of HOX proteins, are now becoming recognized as significant and incredibly diverse controllers of cellular behavior. The MEIS agents can incorporate a variety of epigenetic modulators into chromatin to aid in embryonic growth or tissue homeostasis by adult stem cells. The MEIS gene's expression, binding, stability, post-translational protein modification, and controlled intracellular availability are all fully regulated, and they all react to external stimuli. Objectives: We explored the diverse roles of MEIS proteins in cellular behavior and epigenetic regulation and investigated the potential of MEIS proteins as diagnostic and therapeutic biomarkers in cancers. Results: The MEIS proteins can be diagnostic and therapeutic biomarkers for cancer. The MEIS-PBX heterotrimeric is involved in neurogenesis processes, and the formation of the MEIS2 heterodimer with PAX6 and DLX2 can proliferate periplomerular dopaminergic neurons in the olfactory bulb. The estrogen receptor in breast cancer upregulates MEIS1 and FOXP3. The estrogen receptor pathway's cancer-related genes can express themselves more strongly when MEIS1-FOXP3 interacts with a positive feedback mechanism. Because MEIS1 expression is decreased in clear renal cell carcinoma (ccRCC) cell lines, MEIS1 may function as a tumor suppressor in the development of ccRCC. Conclusions: MEIS1 is recognized as one of the main contributors to the development of leukemias. The MEIS proteins influence the c-MYC signaling pathway, cell proliferation, and invasion of PC by contributing to its development. [ABSTRACT FROM AUTHOR]

Acalabrutinib (ACL) was approved in the United States in the year of 2017 and 2019 for the treatment of chronic lymphocytic leukemia (CLL) and relapsed mantle cell lymphoma (MCL). Low-energy method was employed to curate nanoemulsion (NE) for which various components were screened through solubility study and optimization was done through a pseudo-ternary phase diagram. The NE was evaluated for its droplet size, polydispersity index (PDI), transmittance, morphology, rheology, robustness to dilution, the effect of pH, storage stability, and ex vivo permeation study. The optimized ACL-NE demonstrated an appropriate droplet size (94.35 ± 0.3 nm), PDI (0.27 ± 0.03), and an entrapment efficiency of 67.38 ± 2.69%. It showed non-Newtonian (shear thinning behavior) due to reduced viscosity with an increasing shear rate. The apparent permeability was 3.09-fold higher for ACL-NE than ACL suspension. An in vitro drug release study depicted a higher release of ACL (71.10 ± 10.99%) from the optimized NE in a sustained fashion than the suspension (49.01 ± 1.65%). A dose-dependent cytotoxicity was observed in MOLT-4 and HH-cell lines where the IC50 values of ACL were 5.62- and 16.49-fold reduced when encapsulated in oil globules for the respective cell lines. Blank-NE did cause a reduction in cellular toxicity at higher doses. A 7.31- and 5.1-fold increase in Cmax and bioavailability was noted between ACL suspension and ACL-NE. [ABSTRACT FROM AUTHOR]

Objective: The objective was to evaluate the efficacy/safety of pirtobrutinib in the treatment of B-cell malignancies and distinguish it from other available Bruton's tyrosine kinase (BTK) inhibitors. Data sources: A literature search of PubMed (January 2021 through November 2023) and Clinicaltrials.gov was conducted using terms pirtobrutinib, Jaypirca, and LOXO 305. Licensing trials of available BTK inhibitors were also reviewed. Study selection and data extraction: Relevant English-language clinical trials were evaluated. Data synthesis: Pirtobrutinib was approved by the US Food and Drug Administration for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) based largely on a phase 1/2 study in B-cell malignancies. Pirtobrutinib demonstrated a 73% overall response rate (ORR) in the CLL population and 58% in MCL. Pirtobrutinib has activity in patients resistant to earlier-generation, covalent BTK inhibitors. In fact, the ORRs were similar in BTK-pretreated and naïve patients. Adverse effects include fatigue, diarrhea, bleeding, and infection. Atrial fibrillation, a class effect of BTK inhibitors, may be less common with pirtobrutinib. Relevance to patient care and clinical practice in comparison with existing drugs: Compared with earlier-generation BTK inhibitors, pirtobrutinib is more selective for BTK and binds noncovalently to the receptor. Ongoing studies are evaluating pirtobrutinib's use in multiple B-cell malignancies and comparing it with other BTK inhibitors. Conclusion: The characteristics of pirtobrutinib render it useful in the treatment of B-cell malignancies no longer responding to a previous BTK inhibitor, and results from ongoing clinical trials may support future expanded use. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the utilization of drugs with pharmacogenomic guidelines (PGx-drugs) for personalized dosing in pediatric leukemia. A retrospective observational study of pediatric leukemia patients admitted between 2009–2019 at a single-center academic children's hospital was conducted to determine PGx-drug exposure within 3 years of diagnosis. Along with baseline demographic and clinical characteristics of these patients, data regarding dates of diagnosis, relapse, death were collected. During the study period, inclusion criteria were met by 714 patients. The most frequently given medications were ondansetron (96.1%), morphine (92.2%), and allopurinol (85.3%) during the study period. In this cohort, 82% of patients received five or more PGx-drugs. Patients diagnosed with acute myeloid leukemia and leukemia unspecified were prescribed more PGx-drugs than other types of leukemia. There was a significant relationship between age at diagnosis and the number of PGx-drugs prescribed. Adolescents and adults both received a median of 10 PGx-drugs, children received a median of 6 PGx-drugs, and infants received a median of 7 PGx-drugs (p < 0.001). Patients with recurrent leukemia had significantly more PGx-drugs prescribed compared to those without recurrent disease, 10 drugs and 6 drugs, respectively (p < 0.001). Patients diagnosed with childhood leukemia are high utilizers of PGx-drugs. There is a vital need to understand how PGx testing may be utilized to optimize treatment and enhance quality of life. Preemptive PGx testing is a tool that aids in optimization of drug therapy and decreases the need for later treatment modifications. This can result in financial savings from decreased health-care encounters. [ABSTRACT FROM AUTHOR]

Acute leukemia is characterized by abnormal white blood cell proliferation with rapid onset and severe complications. Natural compounds, which are alternative treatments, are widely used in cancer treatment. Piperine, an alkaloid compound from black pepper, exerts anticancer effects through the cell death signaling pathway. Autophagy and senescence signaling pathways are considered target signaling pathways for cancer treatment. In this study, we investigated the effects of piperine via autophagy and senescence signaling pathways in NB4 and MOLT-4 cells. The MTT assay results demonstrated that piperine significantly decreased the viability of NB4 and MOLT-4 cells. Piperine induced autophagy by increasing LC3, Beclin-1 and ULK1 and decreasing mTOR and NF-κB1 expression in NB4 and MOLT-4 cells. In addition, piperine increased senescence-associated beta-galactosidase fluorescence intensity by increasing p21 and IL-6 expression while decreasing CDK2 expression in NB4 and MOLT-4 cells. In conclusion, our study provides additional information about the induction of autophagy and senescence by piperine in acute leukemia. [ABSTRACT FROM AUTHOR]

Leukemia is a form of cancer that affects the bone marrow and lymphatic system, and it requires complex treatment strategies that vary with each subtype. Due to the subtle morphological differences among these types, monitoring gene expressions is crucial for accurate classification. Manual or pathological testing can be time-consuming and expensive. Therefore, data-driven methods and machine learning algorithms offer an efficient alternative for leukemia classification. This study introduced a novel super learning model that leverages heterogeneous machine learning models to analyze gene expression data and classify leukemia cells. The proposed approach incorporates an entropy-based feature importance technique to identify the gene profiles most significant to the labeling process. The strength of this super learning model lies in its final super learner, Random Forest, which effectively classifies cross-validated data from the candidate learners. Validation on a gene expression monitoring dataset demonstrates that this model outperforms other state-of-the-art models in predictive accuracy. The study contributes to the knowledge regarding the use of advanced machine learning techniques to improve the accuracy and reliability of leukemia classification using gene expression data, addressing the challenges of traditional methods that rely on clinical features and morphological examination. [ABSTRACT FROM AUTHOR]

Acute leukemia is a proliferation of white blood cells that originates in the bone marrow and impinges on the working of the lymphatic system. Due to the abrupt and aggressive nature of spreading, it requires prompt medical attention. The procedure adopted by hematologists for evaluating morphological features and counting the cells is quite time-consuming, cumbersome, and error-prone. Thus, automatic methods are recommended to overcome the limitations of manual segmentation. The motive of this systematic review is to investigate the various automatic segmentation techniques of acute leukemia using blood and bone marrow smear images. The guidelines of PRISMA have been adopted for systematic review. For the identification of the papers, three online databases are used, namely PubMed, Science Direct, and Google Scholar. A query has been used to find the relevant research article. Inclusion and exclusion criteria are used to scrutinize the papers, and four research questions have been framed to explore the literature to investigate further. In the preview of four different questions, the various methods have been compared based on accuracy, and the various challenges have been highlighted with respect to the methods and distinct datasets of blood and bone marrow smear images. This systematic review summarizes the various automated segmentation techniques under the pretext of framed research questions based on the PRISMA Model. The different types of datasets, performance evaluation parameters, and various obstacles with future scope have also been discussed. [ABSTRACT FROM AUTHOR]

Background: The non-viral production of CAR-T cells through electroporation of transposon DNA plasmids is an alternative approach to lentiviral/retroviral methods. This method is particularly suitable for early-phase clinical trials involving novel types of CAR-T cells. The primary disadvantage of non-viral methods is the lower production efficiency compared to viral-based methods, which becomes a limiting factor for CAR-T production, especially in chemotherapy-pretreated lymphopenic patients. Methods: We describe a good manufacturing practice (GMP)-compliant protocol for producing CD19 and CD123-specific CAR-T cells based on the electroporation of transposon vectors. The lymphocytes were purified from the blood of patients undergoing chemotherapy for B-NHL or AML and were electroporated with piggyBac transposon encoding CAR19 or CAR123, respectively. Electroporated cells were then polyclonally activated by anti-CD3/CD28 antibodies and a combination of cytokines (IL-4, IL-7, IL-21). The expansion was carried out in the presence of irradiated allogeneic blood-derived mononuclear cells (i.e., the feeder) for up to 21 days. Results: Expansion in the presence of the feeder enhanced CAR-T production yield (4.5-fold in CAR19 and 9.3-fold in CAR123). Detailed flow-cytometric analysis revealed the persistence of early-memory CAR-T cells and a low vector-copy number after production in the presence of the feeder, with no negative impact on the cytotoxicity of feeder-produced CAR19 and CAR123 T cells. Furthermore, large-scale manufacturing of CAR19 carried out under GMP condi tions using PBMCs obtained from B-NHL patients (starting number=200x10e6 cells) enabled the production of >50x10e6 CAR19 in 7 out of 8 cases in the presence of the feeder while only in 2 out of 8 cases without the feeder. Conclusions: The described approach enables GMP-compatible production of sufficient numbers of CAR19 and CAR123 T cells for clinical application and provides the basis for non-viral manufacturing of novel experimental CAR-T cells that can be tested in early-phase clinical trials. This manufacturing approach can complement and advance novel experimental immunotherapeutic strategies against human hematologic malignancies. [ABSTRACT FROM AUTHOR]

Background: Evidence from multiple observational studies suggests that ankylosing spondylitis (AS) is associated with leukemia and lymphocytic malignancies. However, the obtained results are inconsistent, and the causal relationship still needs to be determined. In this context, we utilized two-sample Mendelian randomization (MR) to investigate potential causal associations between AS and leukemia and lymphocytic malignancies. Methods: The analysis was conducted through published genome-wide association studies (GWAS). We obtained genetic data on AS as the exposure and leukemia, including lymphocytic leukemia, myeloid leukemia, and lymphocytic malignancies including lymphoma, multiple myeloma (MM) as the endpoint. The main method to evaluate causality in this analysis was the inverse variance weighting (IVW) technique. Additionally, we employed the weighted mode, weighted median, and MR-Egger regression for supplementary analyses. Finally, heterogeneity tests, sensitivity analyses, and multi-effect analyses are carried out. Results: In a random-effects IVW analysis, we found that genetic susceptibility to AS was associated with an increased risk of leukemia (OR = 1.002; 95%CI, 1.001-1.003; p = 0.003) and an increased risk of lymphocytic leukemia [OR = 1.001; 95% CI, (1.000-1.002), p = 0.008]. There was no evidence that AS was associated with lymphoma, myeloid leukemia, and MM. Conclusion: Our research indicates that AS was associated with an elevated risk of leukemia, and further analysis of specific types of leukemia showed that the risk of lymphocytic leukemia was associated with AS. Our findings highlight the importance of active intervention and monitoring to mitigate leukemia, especially lymphocytic leukemia risk in patients with AS. [ABSTRACT FROM AUTHOR]

We evaluated by comparing the performance of three pneumatically-driven bioreactors in the production of L-asparaginase (L-ASNase), an enzyme used to treat leukaemia and lymphoma. A two-step screening process was conducted to detect Cunninghamella spp. strains producing L-ASNase. Cunninghamella echinulata DSM1905 produced the highest levels of L-ASNase during screening assays. Subsequently, fermentations were performed in bubble column (BCR), airlift (ALR), and hybrid fixed-bed airlift (FB-ALR) bioreactors to determine the best upstream bioprocess. Mycelial biomass production was higher in BCR than in ALR and FB-ALR (p ≤ 0.0322). The activity of L-ASNase produced in FB-ALR, in which the fungus grew as a consistent biofilm, was significantly higher (p ≤ 0.022) than that from ALR, which was higher than that of BCR (p = 0.036). The specific activity of ALR and FB-ALR presented no differences (p = 0.073), but it was higher than that of BCR (p ≤ 0.032). In conclusion, C. echinulata DSM1905, grown under the biofilm phenotype, produced the highest levels of L-ASNase, and FB-ALR was the best upstream system for enzyme production. [ABSTRACT FROM AUTHOR]

Background: Several fusion oncogenes showing a higher incidence in pediatric acute myeloid leukemia (AML) are associated with heterogeneous megakaryoblastic and other myeloid features. Here we addressed how developmental mechanisms influence human leukemogenesis by ETO2::GLIS2, associated with dismal prognosis. Methods: We created novel ETO2::GLIS2 models of leukemogenesis through lentiviral transduction and CRISPR-Cas9 gene editing of human fetal and post-natal hematopoietic stem/progenitor cells (HSPCs), performed in-depth characterization of ETO2::GLIS2 transformed cells through multiple omics and compared them to patient samples. This led to a preclinical assay using patient-derived-xenograft models to test a combination of two clinically-relevant molecules. Results: We showed that ETO2::GLIS2 expression in primary human fetal CD34+ hematopoietic cells led to more efficient in vivo leukemia development than expression in post-natal cells. Moreover, cord blood-derived leukemogenesis has a major dependency on the presence of human cytokines, including IL3 and SCF. Single cell transcriptomes revealed that this cytokine environment controlled two ETO2::GLIS2-transformed states that were also observed in primary patient cells. Importantly, this cytokine sensitivity may be therapeutically-exploited as combined MEK and BCL2 inhibition showed higher efficiency than individual molecules to reduce leukemia progression in vivo. Conclusions: Our study uncovers an interplay between the cytokine milieu and transcriptional programs that extends a developmental window of permissiveness to transformation by the ETO2::GLIS2 AML fusion oncogene, controls the intratumoral cellular heterogeneity, and offers a ground-breaking therapeutical opportunity by a targeted combination strategy. [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]

Leukemia is a prevalent pediatric cancer with significant challenges, particularly in relapsed or refractory cases. Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a personalized cancer treatment, modifying patients' T cells to target and destroy resistant cancer cells. This study reviews the current therapeutic options of CAR-T therapy for leukemia, addressing the primary obstacles such as antigen escape and T-cell exhaustion. We explore dual-targeting strategies and their potential to improve treatment outcomes by preventing the loss of target antigens. Additionally, we examine the mechanisms of T-cell exhaustion and strategies to enhance CAR-T persistence and effectiveness. Despite remarkable clinical successes, CAR-T therapy poses risks such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Our findings highlight the need for ongoing research to optimize CAR-T applications, reduce toxicities, and extend this innovative therapy to a broader range of hematologic malignancies. This comprehensive review aims to provide valuable insights for improving leukemia treatment and advancing the field of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Human endogenous retroviruses (HERVs) are retroviral sequences integrated into 8% of the human genome resulting from ancient exogenous retroviral infections. Unlike endogenous retroviruses of other mammalian species, HERVs are mostly replication and retro-transposition defective, and their transcription is strictly regulated by epigenetic mechanisms in normal cells. A significant addition to the growing body of research reveals that HERVs' aberrant activation is often associated with offsetting diseases like autoimmunity, neurodegenerative diseases, cancers, and chemoresistance. Adult T-cell leukemia/lymphoma (ATLL) is a very aggressive and chemoresistant leukemia caused by the human T-cell leukemia virus type 1 (HTLV-1). The prognosis of ATLL remains poor despite several new agents being approved in the last few years. In the present study, we compare the expression of HERV genes in CD8+-depleted PBMCs from HTLV-1 asymptomatic carriers and patients with acute ATLL. Herein, we show that HERVs are highly upregulated in acute ATLL. Our results further demonstrate that the oncoprotein Fra-2 binds the LTR region and activates the transcription of several HERV families, including HERV-H and HERV-K families. This raises the exciting possibility that upregulated HERV expression could be a key factor in ATLL development and the observed chemoresistance, potentially leading to new therapeutic strategies and significantly impacting the field of oncology and virology. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T (CAR T) cell therapy has shown remarkable success in treating various leukemias and lymphomas. Cellular kinetic (CK) and pharmacodynamic (PD) behavior of CAR T cell therapy is distinct from other therapies due to its living nature. CAR T CK is typically characterized by an exponential expansion driven by target binding, fast initial decline (contraction), and slow long-term decline (persistence). Due to the dependence of CK on target binding, CK and PD of CAR T therapies are inherently and bidirectionally linked. In this work, we develop a semi-mechanistic model of CAR T CK/PD, incorporating molecular-scale binding, T cell dynamics with multiple phenotypes, and tumor growth and killing. We calibrate this model to published CK and PD data for a CD19-targeting CAR T cell therapy. Using sensitivity analysis, we explore variability in response due to patient- and drug-specific properties. We further explore the impact of tumor characteristics on CAR T-cell expansion and efficacy through individual- and population-level parameter scans. [ABSTRACT FROM AUTHOR]

Leukemia is a malignant tumor with high heterogeneity and a complex evolutionary process. It is difficult to resolve the heterogeneity and clonal evolution of leukemia cells by applying traditional bulk sequencing techniques, thus preventing a deep understanding of the mechanisms of leukemia development and the identification of potential therapeutic targets. However, with the development and application of single-cell sequencing technology, it is now possible to investigate the gene expression profile, mutations, and epigenetic features of leukemia at the single-cell level, thus providing a new perspective for leukemia research. In this article, we review the recent applications and advances of single-cell sequencing technology in leukemia research, discuss its potential for enhancing our understanding of the mechanisms of leukemia development, discovering therapeutic targets and personalized treatment, and provide reference guidelines for the significance of this technology in clinical research. [ABSTRACT FROM AUTHOR]

Background: Maintaining the dose-intensity of cancer treatment is an important prognostic factor of aggressive hematological malignancies. The objective of this study was to assess the long-term outcomes of intensive care unit (ICU) survivors with acute myeloid leukemia (AML) or aggressive B-cell non-Hodgkin lymphoma (B-NHL) with emphasis on the resumption of the intended optimal regimen of cancer treatment. Patients and methods: We conducted a retrospective (2013–2021) single-center observational study where we included patients with AML and B-NHL discharged alive from the ICU after an unplanned admission. The primary endpoint was the change in the intended optimal cancer treatment following ICU discharge. Secondary endpoints were 1-year progression-free survival and overall survival rates. Determinants associated with modifications in cancer treatment were assessed through multivariate logistic regression. Results: Over the study period, 366 patients with AML or B-NHL were admitted to the ICU, of whom 170 survivors with AML (n = 92) and B-NHL (n = 78) formed the cohort of interest. The hematological malignancy was recently diagnosed in 68% of patients. The admission Sequential Organ Failure Assessment (SOFA) score was 5 (interquartile range 4–8). During the ICU stay, 30 patients (17.6%) required invasive mechanical ventilation, 29 (17.0%) vasopressor support, and 16 (9.4%) renal replacement therapy. The one-year survival rate following ICU discharge was 59.5%. Further modifications in hematologic treatment regimens were required in 72 patients (42%). In multivariate analysis, age > 65 years (odds ratio (OR) 3.54 [95%-confidence interval 1.67–7.50], p < 0.001), ICU-discharge hyperbilirubinemia > 20 µmol/L (OR 3.01 [1.10–8.15], p = 0.031), and therapeutic limitations (OR 16.5 [1.83–149.7], p = 0.012) were independently associated with modifications in cancer treatment. Post-ICU modifications of cancer treatment had significant impact on in-hospital, 1-year overall survival and progression-free survival. Conclusion: The intended cancer treatment could be resumed in 58% of ICU survivors with aggressive hematological malignancies. At the time of ICU discharge, advanced age, persistent liver dysfunction and decisions to limit further life-support therapies were independent determinants of cancer treatment modifications. These modifications were associated with worsened one-year outcomes. [ABSTRACT FROM AUTHOR]

Background. Lysine methyltransferase 2A (KMT2A) rearrangements are commonly found in juvenile acute myeloid leukaemia (AML). Although distinct diseases, there is a known clinical overlap between KMT2A‐rearranged AML and juvenile myelomonocytic leukaemia (JMML). Both occur in infancy or early childhood and present with abnormal monocytosis. Case Report. We report a case of a 20‐month‐old girl, who presented with lethargy, recurrent infections, bruising, and marked hepatosplenomegaly. JMML was suspected after initial work‐up, revealing an abnormal monocytosis without blast excess on immunophenotyping. The additional cytogenetic and molecular diagnostics, revealing a KMT2A rearrangement, was decisive for the confirmation of AML. Conclusion. This case highlights the challenges of diagnosing KMT2A‐rearranged monocytic AML and the importance of careful morphological assessment in partnership with cytogenetic and molecular diagnostics to distinguish between KMT2A‐rearranged AML and JMML. Moreover, the emerging role of molecular monitoring in AML is highlighted. [ABSTRACT FROM AUTHOR]

This article explores the role of O-GlcNAcylation in regulating the immune system. O-GlcNAcylation is a post-translational modification that affects cell signaling, metabolism, and development. It has been linked to immune dysfunction and the development of autoimmune, inflammatory, and allergic diseases, as well as immune cell malignancies. The article includes original research articles and comprehensive reviews that cover various aspects of O-GlcNAcylation in the immune system, such as its impact on leukemia, immune cell infiltration, and inflammation. The collection of articles provides a comprehensive overview of O-GlcNAcylation's role in the immune system, highlighting the potential for therapeutic interventions and improved disease diagnoses. [Extracted from the article]