Relationships of Prodiginins Mechanisms and Molecular Structures to their Antiproliferative Effects.

The Prodiginins (PGs) natural pigments are secondary metabolites produced by a broad spectrum of gram-negative and gram-positive bacteria, notably by species within the Serratia and Streptomyces genera. These compounds exhibit diverse and potent biological activities, including anticancer, immunosuppressive, antimicrobial, antimalarial, and antiviral effects. Structurally, PGs share a common tripyrrolic core but possess variable side chains and undergo cyclization, resulting in structural diversity. Studies have investigated their antiproliferative effects on various cancer cell lines, with some PGs advancing to clinical trials for cancer treatment. This review aims to illuminate the molecular mechanisms underlying PG-induced apoptosis in cancer cells and explore the structure-activity relationships pertinent to their anticancer properties. Such insights may serve as a foundation for further research in anticancer drug development, potentially leading to the creation of novel, targeted therapies based on PGs or their derivatives.

Ameliorative effects of gallic acid on tebuconazole-induced adverse effects in the cerebellum of adult albino rats: histopathological and immunohistochemical evidence.

Tebuconazole (TEB) is a common triazole sterol demethylation inhibitor fungicide utilized to manage a variety of diseases in crops like cereals, fruits, and vegetables. The aim of this work was to assess the effects of TEB on the structure of the cerebellum in adult albino rats and possible protective impact of co-administration of Gallic acid (GA). Four groups of forty adult male albino rats were randomly selected, and the rats in group I received corn oil through daily gavage for 4 weeks. Group II received GA dissolved in the normal saline at a dose of 100 mg/kg through daily gavage for 4 weeks, group III administered with TEB dissolved in corn oil at its acceptable daily intake dose (0.02 mg/kg body weight) through daily gavage for 4 weeks, group IV rats received both TEB and GA. For light microscopic, ultrastructural, and immunohistochemical investigations, cerebellar specimens were prepared. TEB exposure led to neuronal damage in the form of degenerated Purkinje cells with vacuolated cytoplasm, areas of lost Purkinje cells, the basket cells appeared vacuolated with degenerated neuropil, the granule cells clumped with congested areas between them, dilated cerebellar islands, weak positive bcl2 immunoreactions in the Purkinje cells, and numerous GFAP-positive astrocytes. GA mitigated TEB-mediated histological changes in the cerebellar cortex. We concluded that TEB caused Purkinje neurons in the rat cerebellar cortex to degenerate and undergo apoptosis. GA had a neuroprotective benefit against TEB toxicity in the rat cerebellar cortex.

Mathematical modelling of Alzheimer's disease biomarkers: Targeting Amyloid beta, Tau protein, Apolipoprotein E and Apoptotic pathways.

Introduction: The kinetics of brain cell death in Alzheimer's disease (AD) is being studied using mathematical models. These mathematical models utilize techniques like differential equations, stochastic processes, and network theory to explore crucial signalling pathways and interactions between different cell types. One crucial area of research is the intentional cell death known as apoptosis, which is crucial for the nervous system. The main purpose behind the mathematical modelling of this is for identification of which biomarkers and pathways are most influential in the progression of AD. In addition, we can also predict the natural history of the disease, by which we can make early diagnosis. Mathematical modelling of AD: Current mathematical models include the Apolipoprotein E (APOE) Gene Model, the Tau Protein Kinetics Model, and the Amyloid Beta Peptide Kinetic Model. The Bcl-2 and Bax apoptosis theories postulate that the balance of pro- and anti-apoptotic proteins in cells determines whether a cell experiences apoptosis, where the Bcl-2 model, depicts the interaction of pro- and anti-apoptotic proteins, it is also being used in research on cell death in a range of cell types, including neurons and glial cells. How peptides are produced and eliminated in the brain is explained by the Amyloid beta Peptide (Aß) Kinetics Model. The tau protein kinetics model focuses on production, aggregation, and clearance of tau protein processes, which are hypothesized to be involved in AD. The APOE gene model investigates the connection between the risk of Alzheimer's disease and the APOE gene. These models have been used to predict how Alzheimer's disease would develop and to evaluate how different inhibitors will affect the illness's course. Conclusion: These mathematical models reflect physiological meaningful characteristics and demonstrates robust fits to training data. Incorporating biomarkers like Aß, Tau, APOE and markers of neuronal loss and cognitive impairment can generate sound predictions of biomarker trajectories over time in Alzheimer's disease.

Clinical, Pathological, and Immunohistochemical Predictors of Cause-Specific Mortality in Papillary Thyroid Cancer: Multivariate Analysis.

The association of clinical, pathological, and immunohistochemical characteristics of papillary thyroid cancer with cause-specific mortality was analyzed in a case-control study within a cohort of patients from the Altai Regional Oncology Center. According to multivariate analysis, the independent predictors of fatal outcome within 10 years after surgery in patients living in Altai region are nuclear pattern of Hsp70 expression, thyroid capsular invasion, Ki-67 expression index >7%, and patient's age >45 years for men and >50 years for women. The prognostic model based on these features contributes to a significant improvement in the individual prognostic performance for papillary thyroid cancer in the modeling sample. The model has high statistical significance (χ2=64.73; p<0.001) and discriminative power (AUC=0.950, prediction accuracy 88.5%).

miR-29a expression negatively correlates with Bcl-2 levels in colorectal cancer and is correlated with better prognosis.

MicroRNAs (miRNAs) are a class of small non-coding RNAs that act as important regulators of gene expression, involved in various biological pathways. Aberrant miRNAs expression is associated with the onset and progression of colorectal cancer (CRC). The aim of this study was to investigate the correlation between five miRNAs (miR-29a, miR-101, miR-125b, miR-146a, and miR-155), found to be deregulated in tissue samples of CRC patients, and clinicopathological characteristics and histological markers. Analysis of histological markers was performed by immunohistochemical staining of tumour tissues with Ki-67, p53, CD34, and Bcl-2. Our findings revealed a significant negative correlation between miR-29a expression and Bcl-2 levels. Furthermore, high miR-29a expression was associated with a lower incidence of distant metastasis in CRC patients. We observed negative correlations between miR-101 expression and the number of lymph nodes with metastasis, as well as the size of the largest metastasis; miR-125b expression and lymphovascular invasion; and miR-155 expression and mucus presence. Our survival analysis demonstrated that high miR-29a expression correlated with better progression-free survival of CRC patients, underscoring its potential as a prognostic marker. Our study unveiled intricate relationships between specific miRNA expressions and clinicopathological features in CRC, highlighting the potential utility of miR-29a as a valuable prognostic biomarker.

Analysis of Co-expression of HSP 70 and BCL 2 in Oral Precancer and Cancer Patients Using Immunohistochemistry.

Introduction: Understanding of molecular model of oral carcinogenesis has carried cancer chemotherapy far forward from conventional drug therapies. Small molecule inhibitors have gained acceptance as it has fewer adverse effects and also provide targeted drug therapy. The association of HSP 70 (Heat Shock Protein 70) and BCL 2 (B-cell lymphoma 2) proteins with oral precancer and cancer is already established. However, the complex interaction between these two proteins and how they affect each other's expression is still not understood completely. In our study, we aimed to correlate the expression of HSP 70 and BCL 2 with different histopathological grades of oral precancer and cancer tissue samples using tissue immunohistochemistry. Materials and Methods: Tissue samples were taken from a total of 250 patients (100 OPMDs and 150 OSCCs) and subjected to immunohistochemistry using anti-human mouse monoclonal antibodies to HSP70 and BCL2. Immunostaining was done, and the immunostaining intensity distribution (IID) index was calculated. Results and Discussion: Immunoreactivity scores for both HSP 70 and BCL 2 correlated with different grades of dysplasia. However, only HSP 70 had a statistically significant association (p = 0.066). We also found that HSP 70 showed an inverse correlation, with higher expression majorly seen in well-differentiated OSCCs. Conclusion: Our study unveiled the HSP 70-BCL 2 interaction and provides insights about how this might affect drug designing and help overcome therapeutic lags. However, further studies are needed to provide a comprehensive review of such interactions among various small molecules.

Venetoclax combined with azacitidine in blastic plasmacytoid dendritic cell neoplasm: a case report and comprehensive review on the current and future treatment.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare hematological malignancy with a highly aggressive behavior and median survival of <2 years. Especially, most BPDCN patients present with extensive and non-specific skin lesions, usually leading to misdiagnosis as a skin disease and delay therapy. As for treatment, most patients with BPDCN experience relapse shortly after treatment with the traditional regimens. The alleviation of skin symptoms reflects the effects of clinical treatments. Herein, we report a case of a 71-year-old man with intermittent and gradually expanding skin lesions over his chest, abdomen, and back for 1 year. On admission, physical examination revealed extensive skin lesions and multiple enlarged lymph nodes. Laboratory examinations showed pancytopenia and numerous malignant cells in the peripheral blood smear (60%), bone marrow aspirate smear (73.5%). Immunophenotyping using flow cytometry and immunohistochemistry presented large numbers of BPDCN cells in the bone marrow, cervical lymph nodes and dermal tissue. PET/CT revealed multiple enlarged lymph nodes and splenomegaly. Once the diagnosis was identified as BPDCN, the patient began treatment with the oral BCL2 inhibitor venetoclax and subcutaneously administered azacitidine. After the first course, skin lesions reduced markedly and complete remission was achieved in the bone marrow. Our study and current cumulative data according to reviewing systematically suggest that venetoclax combined with azacitidine is safe, effective, and applicable in the treatment of BPDCN, especially for elderly relapsed/refractory patients. This study, therefore, significantly contributes to the literature on the current and future treatment for BPDCN.

Chronic Lymphocytic Leukemia: Prognostic Factors in the Era of Novel Drugs.

Novel drugs have profoundly changed the outcomes in chronic lymphocytic leukemia (CLL) patients, and the traditional prognostic factors that were identified in the era of chemoimmunotherapy need to be validated in the context of these new targeted therapies. Currently, the most important prognostic genetic biomarkers are the immunoglobulin heavy chain variable (IGHV) mutational status, genetic aberrations including del(17p)/TP53 abnormalities, and the complex karyotype. In this review, we discuss the prognostic role of these genomic markers in relation to novel treatments. Moreover, we present and discuss new scoring systems that were elaborated and validated in the era of new drugs. In routine clinical practice, the application of an extensive genomic work-up with validated prognostic markers could improve the identification of "very high-risk" CLL patients who could benefit from novel, more effective targeted treatments.

The Role of Erythropoietin in Bovine Sperm Physiology.

Erythropoietin (EPO), a hormone secreted mainly by the kidney, exerts its biological function by binding to its cell-surface receptor (EpoR). The presence of EPO and EpoR in the male and female reproductive system has been verified. Therefore, some of the key properties of EPO, such as its antioxidant and antiapoptotic effects, could improve the fertilizing capacity of spermatozoa. In the present study, the effect of two different concentrations of EPO (10 mIU/µL and 100 mIU/µL) on bovine sperm-quality parameters was evaluated during a post-thawing 4-h incubation at 37 °C. EPO had a positive effect on sperm motility, viability, and total antioxidant capacity. Moreover, EPO inhibited apoptosis, as it reduced both BCL2-associated X apoptosis regulator (Bax)/B-cell lymphoma 2 (Bcl-2) ratio and cleaved cysteine-aspartic proteases (caspases) substrate levels in a dose-dependent manner. In addition, EPO induced sperm capacitation and acrosome reaction in spermatozoa incubated in capacitation conditioned medeia. These results establish a foundation for the physiological role of EPO in reproductive processes and hopefully will provide an incentive for further research in order to fully decipher the role of EPO in sperm physiology and reproduction.

Correlation between the Long Head of the Biceps Microscopic Degeneration and Extent of Apoptotic Process.

Objectives: The purpose of this study was to determine the correlation between microscopic degeneration in the long head of the biceps tendon (LHBT) and the apoptotic process. Methods: This study included 26 consecutive patients who had undergone arthroscopic biceps tenodesis or tenotomy for symptomatic LHBT with or without concomitant rotator cuff tears (RCTs). Histological examination of the specimens under a light microscope was conducted after staining with hematoxylin, eosin, and the Alcian blue. Histopathological changes were assessed using the original Bonar score and the modified Bonar score and then correlated with the expression of the subsequent apoptosis markers: activated caspase-3 (casp3), tumor protein p53 (p53), and B-cell lymphoma 2 (BCL-2). Results: The mean original Bonar score was 8.65 (range 5-11), while the modified Bonar score was 7.61. There was no correlation between the original Bonar score and the age of the patients, but a positive correlation was found between the modified Bonar score and the age of the patients (p = 0.0022). There was no correlation between the age of patients and the expression indexes of BCL-2 and casp3. However, the expression of the p53 index showed a positive correlation with patient aging (p = 0.0441). Furthermore, there was no correlation observed between the expression of apoptotic indexes and both the original and modified Bonar scale. Conclusions: In LHB tendinopathy, the expression of apoptosis does not seem to directly correlate with the extent of degeneration, particularly in the late stages of tendinopathy. However, the transformations observed in collagen and ground substance were significantly associated with age, as well as tendinous tissue degeneration quantified according to modified Bonar score. The age of patients was also linked with the expression of the p53 index, as an increased apoptosis in the studied population.

Discovery and development of thiazolidine-2,4-dione derivatives as Bcl-2/Mcl-1 dual inhibitors.

Increasing the levels of antiapoptotic Bcl-2 proteins is an important way that cancer cells utilize to get out of apoptosis, underscoring their significance as promising targets for anticancer therapies. Lately, a primary compound 1 bearing thiazolidine-2,4-dione was discovered to exhibit comparable Mcl-1 inhibitory activity in comparison to WL-276. Herein, thirty-nine thiazolidine-2,4-dione analogs were yielded through incorporating different biphenyl moieties (R1), amino acid side chains (R2) and sulfonamides (R3) on 1. The findings indicated that certain compounds exhibited favorable inhibitory effects against Bcl-2/Mcl-1, while demonstrating limited or negligible binding affinity towards Bcl-xL. In particular, compounds 16 and 20 exhibited greater Bcl-2/Mcl-1 inhibition compared to AT-101, WL-276 and 1. Moreover, they demonstrated notable antiproliferative effects and significantly induced apoptosis in U937 cells. The western blot and co-immunoprecipitation assays confirmed that 20 could induce alterations in the expression of apoptosis-associated proteins to result in apoptosis through on-target Bcl-2 and Mcl-1 inhibition. In addition, 20 exhibited favorable stability profiles in both rat plasma and rat liver microsomes. In total, 20 could be used as a promising compound to discover Bcl-2/Mcl-1 dual inhibitors with favorable therapeutic properties.

Nano-emulsion based on Santolina chamaecyparissus essential oil potentiates the cytotoxic and apoptotic effects of Doxorubicin: an in vitro study.

AIM: This study was aimed at investigating the cytotoxic effect of a novel combination of doxorubicin (DOX) and nano-formulation of Santolina chamaecyparissus L. essential oil (SCEO-NANO) on hepatic (HepG2) and colon (HT29) cancer cell lines. METHODS: A nano-emulsion was prepared by high-pressure homogenisation, then analysed by zetasizer and Fourier transform infrared spectroscopy. HepG2 and HT29 cells were used in in vitro tests for apoptosis detection. RESULTS: Formulated droplet size increased in DOX@SCEO-NANO/DOX to 11.54 ± 0.02 with uniform distribution (PDI = 0.13 ± 0.01), when compared with SCEO-NANO (size: 8.91 ± 0.02 nm; PDI = 0.1 ± 0.02). In both cells, DOX@SCEO-NANO/DOX led to a considerable reduction in colony formation. Compared to DOX, apoprotein proteins were overexpressed in HepG2 cells, showing increases of 8.66-fold for caspase-3 and 4.24-fold for the Bax/Bcl-2 ratio. In HT29 cells, ROS-dependent necrosis and apoptosis were seen. Comparing DOX@SCEO-NANO/DOX versus DOX, greater levels of caspase-3 and the Bax/Bcl-2 ratio were observed. CONCLUSION: The DOX@SCEO-NANO/DOX formulation showed potential for targeted eradication of colon adenocarcinoma and hepatocellular carcinoma cells.

Combining the novel FLT3 and MERTK dual inhibitor MRX-2843 with venetoclax results in promising antileukemic activity against FLT3-ITD AML.

FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately one third of acute myeloid leukemia (AML) patients. FLT3-Internal tandem duplication (FLT3-ITD) mutations are the most common FLT3 mutations and are associated with a poor prognosis. Gilteritinib is a FLT3 inhibitor that is US FDA approved for treating adult patients with relapsed/refractory AML and a FLT3 mutation. While gilteritinib monotherapy has improved patient outcome, few patients achieve durable responses. Combining gilteritinib with venetoclax (VEN) appears to make further improvements, though early results suggest that patients with prior exposure to VEN fair much worse than those without prior exposure. MRX-2843 is a promising inhibitor of FLT3 and MERTK. We recently demonstrated that MRX-2843 is equally potent as gilteritinib in FLT3-ITD AML cell lines in vitro and primary patient samples ex vivo. In this study, we investigated the combination of VEN and MRX-2843 against FLT3-ITD AML cells. We found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-mutated AML cell lines and primary patient samples. Importantly, we found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-ITD AML cells with acquired resistance to cytarabine (AraC) or VEN+AraC. VEN and MRX-2843 significantly reduce colony-forming capacity of FLT3-ITD primary AML cells. Mechanistic studies show that MRX-2843 decreases Mcl-1 and c-Myc protein levels via transcriptional regulation and combined MRX-2843 and VEN significantly decreases oxidative phosphorylation in FLT3-ITD AML cells. Our findings highlight a promising combination therapy against FLT3-ITD AML, supporting further in vitro and in vivo testing.

Favorable Radiographic Response in a Patient With an Oligodendroglioma Treated With Azacitidine and Venetoclax for Acute Myeloid Leukemia.

The standard chemotherapy for treating oligodendrogliomas consists of a combination of procarbazine, lomustine, and vincristine (PCV). The combination of hypomethylating agents like azacitidine and BCL2 inhibitors like venetoclax has not been formally studied in the treatment of glial tumors. The combination of these two drugs is commonly used to treat acute myeloid leukemia (AML), with IDH-mutant disease being a particularly sensitive subtype. The use of azacitidine for the treatment of IDH-mutant gliomas has been reported in the literature, with mixed results that might suggest at least some benefits in a subtype of patients. It is also reported in the literature that the BCL2 gene is associated with treatment resistance and tumor recurrence in gliomas. Here, we present a patient with an oligodendroglioma who was treated with a conventional chemotherapy regimen for AML and, at the same time, had a favorable radiographic response to his brain tumor.

Topical application of a BCL-2 inhibitor ameliorates imiquimod-induced psoriasiform dermatitis by eliminating senescent cells.

BACKGROUND: Psoriasis is an inflammatory skin disease with unclear pathogenesis and unmet therapeutic needs. OBJECTIVE: To investigate the role of senescent CD4+ T cells in psoriatic lesion formation and explore the application of senolytics in treating psoriasis. METHODS: We explored the expression levels of p16INK4a and p21, classical markers of cellular senescence, in CD4+ T cells from human psoriatic lesions and imiquimod (IMQ)-induced psoriatic lesions. We prepared a senolytic gel using B-cell lymphoma 2 (BCL-2) inhibitor ABT-737 and evaluated its therapeutic efficacy in treating psoriasis. RESULTS: Using multispectrum immunohistochemistry (mIHC) staining, we detected increased expression levels of p16INK4a and p21 in CD4+ T cells from psoriatic lesions. After topical application of ABT-737 gel, significant alleviation of IMQ-induced psoriatic lesions was observed, with milder pathological alterations. Mechanistically, ABT-737 gel significantly decreased the percentage of senescent cells, expression of T cell receptor (TCR) α and ß chains, and expression of Tet methylcytosine dioxygenase 2 (Tet2) in IMQ-induced psoriatic lesions, as determined by mIHC, high-throughput sequencing of the TCR repertoire, and RT-qPCR, respectively. Furthermore, the severity of psoriatic lesions in CD4creTet2f/f mice was milder than that in Tet2f/f mice in the IMQ-induced psoriasis model. CONCLUSION: We revealed the roles of senescent CD4+ T cells in developing psoriasis and highlighted the therapeutic potential of topical ABT-737 gel in treating psoriasis through the elimination of senescent cells, modulation of the TCR αß repertoire, and regulation of the TET2-Th17 cell pathway.

Prognostic Significance of Bcl-2 Expression in Non-germinal Center B-cell-Like Diffuse Large B-cell Lymphoma.

INTRODUCTION: Diffuse large B-cell lymphomas (DLBCLs) are a group of malignant neoplasms with extensive clinical and molecular heterogeneity. Several key genetic aberrations have been identified, such as those involving the MYC, BCL6, and BCL2 genes. Prior studies on the prognostic significance of Bcl-2 protein expression in DLBCL have been contradictory, with some suggesting it has an adverse effect, while others have shown no such association. Bcl-2 is known to be more highly expressed in the non-germinal center B-cell-like (non-GCB) subtype compared to germinal center B-cell-like (GCB) DLBCL. Non-GCB status is associated with a less favorable prognosis. This study aimed to investigate whether the expression of Bcl-2 protein in non-GCB DLBCL influences response to treatment, progression-free survival, or overall survival. METHODS: In this retrospective study, we investigated whether there was a difference in the clinical outcomes of non-GCB DLBCL cases (n = 97) that were confirmed by immunochemistry to demonstrate high levels of Bcl-2 protein expression (>50% neoplastic cells stained) when compared to those who were deemed negative based on this criterion. Response to rituximab-based induction immunochemotherapy, five-year progression-free survival, and five-year overall survival were assessed. RESULTS: There was no statistically significant difference in response to treatment, five-year progression-free survival, or five-year overall survival between the patients who were positive for Bcl-2 (n = 70) compared to those who were considered Bcl-2 negative (n = 27). CONCLUSION: High levels of Bcl-2 protein expression do not appear to be of prognostic significance in non-GCB DLBCL and therefore Bcl-2 may not be a key therapeutic target in the treatment and improvement of clinical outcome in such cases.

Waldenström Macroglobulinemia - A State-of-the-Art Review: Part 1: Epidemiology, Pathogenesis, Clinicopathologic Characteristics, Differential Diagnosis, Risk Stratification, and Clinical Problems.

Waldenström macroglobulinemia (WM) is an infrequent variant of lymphoma, classified as a B-cell malignancy identified by the presence of IgM paraprotein, infiltration of clonal, small lymphoplasmacytic B cells in the bone marrow, and the MYD88 L265P mutation, which is observed in over 90% of cases. The direct invasion of the malignant cells into tissues like lymph nodes and spleen, along with the immune response related to IgM, can also lead to various health complications, such as cytopenias, hyperviscosity, peripheral neuropathy, amyloidosis, and Bing-Neel syndrome. Chemoimmunotherapy has historically been considered the preferred treatment for WM, wherein the combination of rituximab and nucleoside analogs, alkylating drugs, or proteasome inhibitors has exhibited notable efficacy in inhibiting tumor growth. Recent studies have provided evidence that Bruton Tyrosine Kinase inhibitors (BTKI), either used independently or in conjunction with other drugs, have been shown to be effective and safe in the treatment of WM. The disease is considered to be non-curable, with a median life expectancy of 10 to 12 years.

Reverse aging to treat lupus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multifaceted pathogenetic processes, including abnormalities of T-cell subset distribution and function. Accumulation of senescent CD4+ T cells has been found to contribute to the development of the disease. In this issue, Jiang et al. provide compelling evidence that links an expanded pool of CD4+CD57+ senescent T cells in patients with SLE to disease activity favored by interleukin-15. Importantly, treatment of lupus-prone mice with a senolytic drug resulted in decreased autoimmune pathology. The findings of this study suggest possible novel therapeutics to treat patients with SLE.

Potential impact of NOTCH1 activation on venetoclax sensitivity in chronic lymphocytic Leukaemia: In vitro insights and clinical implications.

Despite significant progress in treating chronic lymphocytic leukaemia (CLL), resistance to therapy remains challenging. NOTCH1 activation, common in CLL, confers adverse prognosis. This study explores the impact of NOTCH1 signalling on venetoclax sensitivity in vitro. Although NOTCH1 activation minimally impaired the susceptibility of CLL cells to venetoclax, ex vivo cell competition studies reveal that cells with constitutive NOTCH1 activation outgrew their wild-type counterparts in the presence of ongoing venetoclax exposure. Our findings suggest that while NOTCH1 activation is insufficient to confer venetoclax refractoriness, there is enhanced potential for cells with NOTCH1 activation to escape and thus become fully resistant to venetoclax.