Steroid-free combination of 5-azacytidine and venetoclax for the treatment of multiple myeloma.

Multiple myeloma (MM) is an incurable plasma cell malignancy that, despite an unprecedented increase in overall survival, lacks truly risk-adapted or targeted treatments. A proportion of patients with MM depend on BCL-2 for survival, and, recently, the BCL-2 antagonist venetoclax has shown clinical efficacy and safety in t(11;14) and BCL-2 overexpressing MM. However, only a small proportion of MM patients rely on BCL-2 (approx. 20%), and there is a need to broaden the patient population outside of t(11;14) that can be treated with venetoclax. Therefore, we took an unbiased screening approach and screened epigenetic modifiers to enhance venetoclax sensitivity in 2 non-BCL-2 dependent MM cell lines. The demethylase inhibitor 5-azacytidine was one of the lead hits from the screen, and the enhanced cell killing of the combination was confirmed in additional MM cell lines. Using dynamic BH3 profiling and immunoprecipitations, we identified the potential mechanism of synergy is due to increased NOXA expression, through the integrated stress response. Knockdown of PMAIP1 or PKR partially rescues cell death of the venetoclax and 5-azacytidine combination treatment. The addition of a steroid to the combination treatment did not enhance the cell death, and, interestingly, we found enhanced death of the immune cells with steroid addition, suggesting that a steroid-sparing regimen may be more beneficial in MM. Lastly, we show for the first time in primary MM patient samples that 5-azacytidine enhances the response to venetoclax ex vivo across diverse anti-apoptotic dependencies (BCL-2 or MCL-1) and diverse cytogenetic backgrounds. Overall, our data identify 5-azacytidine and venetoclax as an effective treatment combination, which could be a tolerable steroid-sparing regimen, particularly for elderly MM patients.

Lmo2 expression defines tumor cell identity during T-cell leukemogenesis.

The impact of LMO2 expression on cell lineage decisions during T-cell leukemogenesis remains largely elusive. Using genetic lineage tracing, we have explored the potential of LMO2 in dictating a T-cell malignant phenotype. We first initiated LMO2 expression in hematopoietic stem/progenitor cells and maintained its expression in all hematopoietic cells. These mice develop exclusively aggressive human-like T-ALL In order to uncover a potential exclusive reprogramming effect of LMO2 in murine hematopoietic stem/progenitor cells, we next showed that transient LMO2 expression is sufficient for oncogenic function and induction of T-ALL The resulting T-ALLs lacked LMO2 and its target-gene expression, and histologically, transcriptionally, and genetically similar to human LMO2-driven T-ALL We next found that during T-ALL development, secondary genomic alterations take place within the thymus. However, the permissiveness for development of T-ALL seems to be associated with wider windows of differentiation than previously appreciated. Restricted Cre-mediated activation of Lmo2 at different stages of B-cell development induces systematically and unexpectedly T-ALL that closely resembled those of their natural counterparts. Together, these results provide a novel paradigm for the generation of tumor T cells through reprogramming in vivo and could be relevant to improve the response of T-ALL to current therapies.

Anti-CD20-interleukin-21 fusokine targets malignant B cells via direct apoptosis and NK-cell-dependent cytotoxicity.

In spite of newly emerging therapies and the improved survival of patients with non-Hodgkin lymphoma (NHL), relapses or primary refractory disease are commonly observed and associated with dismal prognosis. Although discovery of the anti-CD20 antibody rituximab has markedly improved outcomes in B-cell NHL, rituximab resistance remains an important obstacle to successful treatment of these tumors. To improve the efficacy of CD20-targeted therapy, we fused interleukin 21 (IL-21), which induces direct lymphoma cytotoxicity and activates immune effector cells, to the anti-CD20 antibody (αCD20-IL-21 fusokine). We observed substantially enhanced IL-21R-mediated signaling by the fusokine compared with native IL-21 at equimolar concentrations. Fusokine treatment led to direct apoptosis of lymphoma cell lines and primary tumors that otherwise were resistant to native IL-21 treatment. In addition to direct cytotoxicity, the fusokine enhanced NK cell activation, effector functions, and interferon γ production, resulting in greater antibody-dependent cell-mediated cytotoxicity compared with IL-21 and/or anti-CD20 antibody treatments. Further, the αCD20-IL-21 fusokine stabilizes IL-21 and prolongs its half-life. In vivo αCD20-IL-21 therapy resulted in a significant tumor control in the rituximab-resistant A20-huCD20 tumors. Collectively, the dual functional ability of the αCD20-IL-21 fusokine to induce direct apoptosis and activate immune effector cells may provide benefit over existing treatments for NHL.

Direct and immune-mediated cytotoxicity of interleukin-21 contributes to antitumor effects in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a distinct subtype of non-Hodgkin lymphoma characterized by overexpression of cyclin D1 in 95% of patients. MCL patients experience frequent relapses resulting in median survival of 3 to 5 years, requiring more efficient therapeutic regimens. Interleukin (IL)-21, a member of the IL-2 cytokine family, possesses potent antitumor activity against a variety of cancers not expressing the IL-21 receptor (IL-21R) through immune activation. Previously, we established that IL-21 exerts direct cytotoxicity on IL-21R-expressing diffuse large B-cell lymphoma cells. Herein, we demonstrate that IL-21 possesses potent cytotoxicity against MCL cell lines and primary tumors. We identify that IL-21-induced direct cytotoxicity is mediated through signal transducer and activator of transcription 3-dependent cMyc upregulation, resulting in activation of Bax and inhibition of Bcl-2 and Bcl-XL. IL-21-mediated cMyc upregulation is only observed in IL-21-sensitive cells. Further, we demonstrate that IL-21 leads to natural killer (NK)-cell-dependent lysis of MCL cell lines that were resistant to direct cytotoxicity. In vivo treatment with IL-21 results in complete FC-muMCL1 tumor regression in syngeneic mice via NK- and T-cell-dependent mechanisms. Together, these data indicate that IL-21 has potent antitumor activity against MCL cells via direct cytotoxic and indirect, immune-mediated effects.

Effect of GSTP1 and ABCC4 gene polymorphisms on response and toxicity of cyclophosphamide-epirubicin-5-fluorouracil-based chemotherapy in Bangladeshi breast cancer patients.

The most important cytotoxic drug namely, cyclophosphamide used in breast cancer along with epirubicin and 5-fluorouracil, is transported by ABCC transporters and detoxified by glutathione S-transferases (GSTs). The activities of these enzymes and transporters may vary in different population due to the presence of genetic polymorphisms. This study was aimed to evaluate the effects of GSTP1rs1695 and ABCC4rs9561778 polymorphisms on the response and toxicities produced by chemotherapy used in the treatment of Bangladeshi breast cancer patients. A total of 200 and 56 patients with invasive breast cancers were recruited from different public and private hospitals of Bangladesh of which 117 patients received neoadjuvant chemotherapy to examine the response as well as the toxicity, and another 139 patients received adjuvant chemotherapy to evaluate only the toxicity. Genetic polymorphisms of the mentioned genes were detected by using Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR RFLP). Patients carrying AG and AG plus GG genotype of GSTP1rs1695 were more likely to have a good response, whereas no association of ABCC4rs9561778 was found with the chemotherapy response. Patients carrying GT and GT plus TT genotypes of ABCC4rs9561778 were found to be associated with anemia, neutropenia, leukopenia, and gastrointestinal toxicities when compared with GG genotype whereas no association was found with thrombocytopenia. GSTP1rs1695 was not associated with any type of toxicities investigated. Our result indicates that GSTP1rs1695 polymorphism was strongly associated with the response of chemotherapy, whereas ABCC4rs9561778 polymorphism was significantly related with chemotherapy-induced toxicities.

Performance evaluation of nanofluid-based photovoltaic thermal (PVT) system with regression analysis.

The recent global energy crisis has shocked Bangladesh's power sectors, and experts recommend using alternative energy sources to conserve natural gas, fossil fuels, and electricity. Numerous investigations on the photovoltaic thermal (PVT) system have been carried out to get the source efficiently. As a result, a parametric evaluation of the PVT system's efficiency in Dhaka, Bangladesh, is investigated numerically using CNT nanofluid as a coolant. The numerical simulation is performed using the Galerkin weighted residual based finite element method. For accurate computations, the meteorological data for Dhaka, Bangladesh, is taken from open sources of Renewables.ninja. The effect of regulating parameters Reynolds number (200 ≤ Re ≤ 1000), solar irradiation (200 W/m2 ≤ G ≤ 1000 W/m2), and the monthly influence on performance such as cell temperature, fluid domain exit temperature, efficiencies, and energy are discussed. In addition, regression analyses of electrical efficiency and thermal efficiency are discussed for the input variables Reynolds number and solar irradiation. After postprocessing, empirical results are compiled and presented as 3D surface graphs, tables, and line diagrams. As the Reynolds number increased, the cell temperature and discharge temperature decreased, resulting in increased efficiency. However, the opposite situation is found for solar irradiation. Month-to-month variation also has a considerable impact on photovoltaic thermal performance. This research will help to improve the efficacy of PVTs in Dhaka, Bangladesh, by identifying useful alternative renewable energy sources.

Population-based survey of the prevalence and types of glaucoma in Bangladesh.

BACKGROUND: To delineate the epidemiological landscape of glaucoma using a population-based sample representative of Bangladesh. METHODS: Using multistage stratified cluster random sampling, households were selected to identify individuals ≥35 years across all 8 divisions of Bangladesh. Sampling frames were derived from the 2011 national census. Fifty-eight study examination sites were set up for comprehensive eye evaluations, including intraocular pressure, gonioscopy and visual field testing when indicated. International Society for Geographic and Epidemiological Ophthalmology definitions were used to define glaucoma and glaucoma suspect cases. RESULTS: One hundred forty clusters (89 rural and 51 urban) were randomly selected, and 13 791 residential households were visited. We invited 17 002 individuals ≥35 years for on-site examination, of which 12 000 (71%) complied, with a male-to-female ratio of 1:1. The prevalence of glaucoma was 3.2% (95% CI 2.79% to 3.64%), and glaucoma suspect was 10.1% (95% CI 9.05% to 11.12%). The majority (78%) had primary open-angle glaucoma (POAG), while angle closure was seen in 16%. Of the POAG, 83% (n=251) were normal-tension glaucoma. Multivariable logistic regression showed increasing age (OR=1.01 for every 5-year increment, 95% CI 1 to 1.01) and male gender (OR=1.43, 95% CI 1.15 to 1.77) to be associated with an increased risk of glaucoma. CONCLUSIONS: The prevalence of glaucoma in Bangladesh is 3.2% in ≥35-year-old individuals with older men most at risk. Extrapolating the results, we estimate about 2 million patients with glaucoma. Though normal-tension variety was the most common type, caution should be exercised in generalising these results to other populations.

Impact of ALDH1A1 and NQO1 gene polymorphisms on the response and toxicity of chemotherapy in Bangladeshi breast cancer patients.

PURPOSE: Cyclophosphamide, Epirubicin/Doxorubicin, 5-fluorouracil (CEF or CAF) chemotherapy has long been a standard first-line treatment for breast cancer. The genetic variations of enzymes that are responsible for the metabolism of these drugs have been linked to altered treatment response and toxicity. Two drug-metabolizing enzymes ALDH1A1 and NQO1 are critically involved in the pathways of CEF/CAF metabolism. This study aimed to evaluate the effect of ALDH1A1 (rs13959) and NQO1 (rs1800566) polymorphisms on treatment response and toxicities caused by adjuvant (ACT) and neoadjuvant chemotherapy (NACT) where CEF/CAF combination was used to treat Bangladeshi breast cancer patients. METHODS: A total of 330 patients were recruited from various hospitals, with 150 receiving neoadjuvant chemotherapy and 180 receiving adjuvant chemotherapy. To extract genomic DNA, a non-enzymatic simple salting out approach was adopted. The polymerase chain reaction-restriction fragment length polymorphism method was used to detect genetic polymorphisms. Unconditional logistic regression was used to derive odds ratios (ORs) with 95% confidence intervals (CIs) to study the association between genetic polymorphisms and clinical outcome and toxicity. RESULTS: A statistically significant association was observed between ALDH1A1 (rs13959) polymorphism and treatment response (TT vs. CC: aOR = 6.40, p = 0.007; recessive model: aOR = 6.38, p = 0.002; allele model: p = 0.032). Patients with the genotypes TT and CT + TT of the NQO1 (rs1800566) polymorphism had a significantly higher risk of toxicities such as anemia (aOR = 0.34, p = 0.006 and aOR = 0.58, p = 0.021), neutropenia (aOR = 0.42, p = 0.044 and aOR = 0.57, p = 0.027), leukopenia (aOR = 0.33, p = 0.010 and aOR = 0.46, p = 0.005), and gastrointestinal toxicity (aOR = 0.30, p = 0.02 and aOR = 0.38, p = 0.006) when compared to the wild CC genotype, while patients with the genotype CT had a significant association with gastrointestinal toxicity (aOR = 0.42, p = 0.02) and leukopenia (aOR = 0.52, p = 0.010). The TT and CT + TT genotypes of rs13959 had a significantly higher risk of anemia (aOR = 2.00, p = 0.037 and aOR = 1.68, p = 0.029). There was no significant association between rs1800566 polymorphism and treatment response. CONCLUSION: Polymorphisms in ALDH1A1 (rs13959) and NQO1 (rs1800566) may be useful in predicting the probability of treatment response and adverse effects from CEF or CAF-based chemotherapy in breast cancer patients.

Targeting conditioned media dependencies and FLT-3 in chronic lymphocytic leukemia.

The importance of the stromal microenvironment in chronic lymphocytic leukemia (CLL) pathogenesis and drug resistance is well established. Despite recent advances in CLL therapy, identifying novel ways to disrupt interactions between CLL and its microenvironment may identify new combination partners for the drugs currently in use. To understand the role of microenvironmental factors on primary CLL cells, we took advantage of an observation that conditioned media (CM) collected from stroma was protective of CLL cells from spontaneous cell death ex vivo. The cytokine in the CM-dependent cells that most supports CLL survival in short-term ex vivo culture was CCL2. Pretreatment of CLL cells with anti-CCL2 antibody enhanced venetoclax-mediated killing. Surprisingly, we found a group of CLL samples (9/23 cases) that are less likely to undergo cell death in the absence of CM support. Functional studies revealed that CM-independent (CMI) CLL cells are less sensitive to apoptosis than conventional stroma-dependent CLL. In addition, a majority of the CMI CLL samples (80%) harbored unmutated immunoglobulin heavy-chain variable (IGHV) region. Bulk-RNA sequence analysis revealed upregulation of the focal adhesion and RAS signaling pathways in this group, along with expression of fms-like tyrosine kinase 3 (FLT3) and CD135. Treatment with FLT3 inhibitors caused a significant reduction in cell viability among CMI samples. In summary, we were able to discriminate and target 2 biologically distinct subgroups of CLL based on CM dependence with distinct microenvironmental vulnerabilities.

IKAROS and MENIN coordinate therapeutically actionable leukemogenic gene expression in MLL-r acute myeloid leukemia.

Acute myeloid leukemia (AML) remains difficult to treat and requires new therapeutic approaches. Potent inhibitors of the chromatin-associated protein MENIN have recently entered human clinical trials, opening new therapeutic opportunities for some genetic subtypes of this disease. Using genome-scale functional genetic screens, we identified IKAROS (encoded by IKZF1) as an essential transcription factor in KMT2A (MLL1)-rearranged (MLL-r) AML that maintains leukemogenic gene expression while also repressing pathways for tumor suppression, immune regulation and cellular differentiation. Furthermore, IKAROS displays an unexpected functional cooperativity and extensive chromatin co-occupancy with mixed lineage leukemia (MLL)1-MENIN and the regulator MEIS1 and an extensive hematopoietic transcriptional complex involving homeobox (HOX)A10, MEIS1 and IKAROS. This dependency could be therapeutically exploited by inducing IKAROS protein degradation with immunomodulatory imide drugs (IMiDs). Finally, we demonstrate that combined IKAROS degradation and MENIN inhibition effectively disrupts leukemogenic transcriptional networks, resulting in synergistic killing of leukemia cells and providing a paradigm for improved drug targeting of transcription and an opportunity for rapid clinical translation.

Metabolic perturbations sensitize triple-negative breast cancers to apoptosis induced by BH3 mimetics.

Cancer cells have differential metabolic dependencies compared to their nonmalignant counterparts. However, few metabolism-targeting compounds have been successful in clinical trials. Here, we investigated the metabolic vulnerabilities of triple-negative breast cancer (TNBC), particularly those metabolic perturbations that increased mitochondrial apoptotic priming and sensitivity to BH3 mimetics (drugs that antagonize antiapoptotic proteins). We used high-throughput dynamic BH3 profiling (HT-DBP) to screen a library of metabolism-perturbing small molecules, which revealed inhibitors of the enzyme nicotinamide phosphoribosyltransferase (NAMPT) as top candidates. In some TNBC cells but not in nonmalignant cells, NAMPT inhibitors increased overall apoptotic priming and induced dependencies on specific antiapoptotic BCL-2 family members. Treatment of TNBC cells with NAMPT inhibitors sensitized them to subsequent treatment with BH3 mimetics. The combination of a NAMPT inhibitor (FK866) and an MCL-1 antagonist (S63845) reduced tumor growth in a TNBC patient-derived xenograft model in vivo. We found that NAMPT inhibition reduced NAD+ concentrations below a critical threshold that resulted in depletion of adenine, which was the metabolic trigger that primed TNBC cells for apoptosis. These findings demonstrate a close interaction between metabolic and mitochondrial apoptotic signaling pathways and reveal that exploitation of a tumor-specific metabolic vulnerability can sensitize some TNBC to BH3 mimetics.

Multifunctional barcoding with ClonMapper enables high-resolution study of clonal dynamics during tumor evolution and treatment.

Lineage-tracing methods have enabled characterization of clonal dynamics in complex populations, but generally lack the ability to integrate genomic, epigenomic and transcriptomic measurements with live-cell manipulation of specific clones of interest. We developed a functionalized lineage-tracing system, ClonMapper, which integrates DNA barcoding with single-cell RNA sequencing and clonal isolation to comprehensively characterize thousands of clones within heterogeneous populations. Using ClonMapper, we identified subpopulations of a chronic lymphocytic leukemia cell line with distinct clonal compositions, transcriptional signatures and chemotherapy survivorship trajectories; patterns that were also observed in primary human chronic lymphocytic leukemia. The ability to retrieve specific clones before, during and after treatment enabled direct measurements of clonal diversification and durable subpopulation transcriptional signatures. ClonMapper is a powerful multifunctional approach to dissect the complex clonal dynamics of tumor progression and therapeutic response.

Activation of Notch and Myc Signaling via B-cell-Restricted Depletion of Dnmt3a Generates a Consistent Murine Model of Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by disordered DNA methylation, suggesting these epigenetic changes might play a critical role in disease onset and progression. The methyltransferase DNMT3A is a key regulator of DNA methylation. Although DNMT3A somatic mutations in CLL are rare, we found that low DNMT3A expression is associated with more aggressive disease. A conditional knockout mouse model showed that homozygous depletion of Dnmt3a from B cells results in the development of CLL with 100% penetrance at a median age of onset of 5.3 months, and heterozygous Dnmt3a depletion yields a disease penetrance of 89% with a median onset at 18.5 months, confirming its role as a haploinsufficient tumor suppressor. B1a cells were confirmed as the cell of origin of disease in this model, and Dnmt3a depletion resulted in focal hypomethylation and activation of Notch and Myc signaling. Amplification of chromosome 15 containing the Myc gene was detected in all CLL mice tested, and infiltration of high-Myc-expressing CLL cells in the spleen was observed. Notably, hyperactivation of Notch and Myc signaling was exclusively observed in the Dnmt3a CLL mice, but not in three other CLL mouse models tested (Sf3b1-Atm, Ikzf3, and MDR), and Dnmt3a-depleted CLL were sensitive to pharmacologic inhibition of Notch signaling in vitro and in vivo. Consistent with these findings, human CLL samples with lower DNMT3A expression were more sensitive to Notch inhibition than those with higher DNMT3A expression. Altogether, these results suggest that Dnmt3a depletion induces CLL that is highly dependent on activation of Notch and Myc signaling. SIGNIFICANCE: Loss of DNMT3A expression is a driving event in CLL and is associated with aggressive disease, activation of Notch and Myc signaling, and enhanced sensitivity to Notch inhibition.

Report: analgesic activities of ethanol extract of leaf, stem and their different fractions of Swertia chirata.

The purpose of the present study was to investigate the analgesic activity of ethanol extract of leaf, stem, and their different fractions i.e. pet-ether, dichloromethane, and methanol fraction of Swertia chirata (Family-Gentianaceae) on Swiss albino mice. Acetic acid induced writhing in mice was used as the process to evaluate the analgesic activity. The ethanol extract of leaf and stem of Swertia chirata showed moderate inhibition (p<0.001) of writhing. Among different fractions pet-ether fraction showed significant inhibition (p<0.0001) of writhing where as methanol fraction showed moderate inhibition (p<0.003) of writhing as well. The inhibition of writhing was calculated in respective to control (vehicle). The test samples were administered at a dose of 200 mg/kg body weight of experimental animals where diclofenac sodium at a dose of 25 mg/kg body weight was used as standard drug in this study.

Combined EZH2 and Bcl-2 inhibitors as precision therapy for genetically defined DLBCL subtypes.

Molecular alterations in the histone methyltransferase EZH2 and the antiapoptotic protein Bcl-2 frequently co-occur in diffuse large B-cell lymphoma (DLBCL). Because DLBCL tumors with these characteristics are likely dependent on both oncogenes, dual targeting of EZH2 and Bcl-2 is a rational therapeutic approach. We hypothesized that EZH2 and Bcl-2 inhibition would be synergistic in DLBCL. To test this, we evaluated the EZH2 inhibitor tazemetostat and the Bcl-2 inhibitor venetoclax in DLBCL cells, 3-dimensional lymphoma organoids, and patient-derived xenografts (PDXs). We found that tazemetostat and venetoclax are synergistic in DLBCL cells and 3-dimensional lymphoma organoids that harbor an EZH2 mutation and an IGH/BCL2 translocation but not in wild-type cells. Tazemetostat treatment results in upregulation of proapoptotic Bcl-2 family members and priming of mitochondria to BH3-mediated apoptosis, which may sensitize cells to venetoclax. The combination of tazemetostat and venetoclax was also synergistic in vivo. In DLBCL PDXs, short-course combination therapy resulted in complete remissions that were durable over time and associated with superior overall survival compared with either drug alone.

Leukemia Cell of Origin Influences Apoptotic Priming and Sensitivity to LSD1 Inhibition.

The cell of origin of oncogenic transformation is a determinant of therapeutic sensitivity, but the mechanisms governing cell-of-origin-driven differences in therapeutic response have not been delineated. Leukemias initiating in hematopoietic stem cells (HSC) are less sensitive to chemotherapy and highly express the transcription factor MECOM (EVI1) compared with leukemias derived from myeloid progenitors. Here, we compared leukemias initiated in either HSCs or myeloid progenitors to reveal a novel function for EVI1 in modulating p53 protein abundance and activity. HSC-derived leukemias exhibit decreased apoptotic priming, attenuated p53 transcriptional output, and resistance to lysine-specific demethylase 1 (LSD1) inhibitors in addition to classical genotoxic stresses. p53 loss of function in Evi1 lo progenitor-derived leukemias induces resistance to LSD1 inhibition, and EVI1hi leukemias are sensitized to LSD1 inhibition by venetoclax. Our findings demonstrate a role for EVI1 in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in chemoresistant EVI1 hi acute myeloid leukemia. SIGNIFICANCE: We demonstrate that the cell of origin of leukemia initiation influences p53 activity and dictates therapeutic sensitivity to pharmacologic LSD1 inhibitors via the transcription factor EVI1. We show that drug resistance could be overcome in HSC-derived leukemias by combining LSD1 inhibition with venetoclax.See related commentary by Gu et al., p. 1445.This article is highlighted in the In This Issue feature, p. 1426.

LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL.

Deficiency in DNA double-strand break (DSB) repair mechanisms has been widely exploited for the treatment of different malignances, including homologous recombination (HR)-deficient breast and ovarian cancers. Here we demonstrate that diffuse large B cell lymphomas (DLBCLs) expressing LMO2 protein are functionally deficient in HR-mediated DSB repair. Mechanistically, LMO2 inhibits BRCA1 recruitment to DSBs by interacting with 53BP1 during repair. Similar to BRCA1-deficient cells, LMO2-positive DLBCLs and T cell acute lymphoblastic leukemia (T-ALL) cells exhibit a high sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Furthermore, chemotherapy and PARP inhibitors synergize to inhibit the growth of LMO2-positive tumors. Together, our results reveal that LMO2 expression predicts HR deficiency and the potential therapeutic use of PARP inhibitors in DLBCL and T-ALL.

Association of BRCA1, BRCA2, RAD51, and HER2 gene polymorphisms with the breast cancer risk in the Bangladeshi population.

PURPOSE: Breast cancer is considered as the most frequent female malignancy. Altered gene expressions due to genetic polymorphisms in the BRCA1, BRCA2, RAD51, and HER2 contribute toward the development of breast cancer, and yet, no such type of study has been conducted in the Bangladeshi population. This study was designed to evaluate the role of BRCA1rs80357713, BRCA1rs80357906, BRCA2rs11571653, RAD51rs1801320, and HER2rs1136201 polymorphisms as risk factors in the development of breast cancer in the Bangladeshi population. METHODS: A total 310 patients with invasive breast cancers were recruited as cases from different public and private hospitals of Bangladesh, and 250 Bangladeshi healthy women matching age with the patients were recruited as controls. Polymerase chain reaction-restriction fragment length polymorphism method was used to analyze the genetic polymorphisms. RESULTS: Patients carrying BRCA1/2 mutations, GC and GC plus CC genotypes of RAD51rs1801320, and AG plus GG genotype of HER2rs1136201 polymorphisms were found to be associated with breast cancer. In subgroup analysis, AG plus GG genotype of HER2rs1136201 was found to be associated with the breast cancer risk in the patients younger than 45 years of age compared with the older patients having more than 45 years of age, and RAD51rs1801320 was related to the tumor size and tumor aggressiveness (higher graded tumor). CONCLUSION: Our results indicate that BRCA1/BRCA2, RAD51rs1801320 and HER2rs1136201 polymorphisms were associated with breast cancer in the studied population.

Finite element analysis of double-diffusive natural convection in a porous triangular enclosure filled with Al2O3 -water nanofluid in presence of heat generation.

The problem of double-diffusive natural convection of Al2O3 -water nanofluid in a porous triangular enclosure in presence of heat generation has been studied numerically in this paper. The bottom wall of the cavity is heated isothermally, the left inclined wall is non-isothermal and the right inclined wall is considered to be cold. The concentration is higher at bottom wall, lower at right inclined wall and non-isoconcentration at left inclined wall of the cavity. The governing equations are transformed to the dimensionless form and solved numerically using Galerkin weighted residual technique of finite element method. The results are obtained in terms of streamlines, isotherms, isoconcentrations, average Nueeslt number (Nu) and average Sherwood number (Sh) for the parameters thermal Rayleigh number (RaT ), dimensionless heat generation parameter (λ), solid volume fraction (ϕ) and Lewis number (Le) while Prandtl number (Pr), Buoyancy ratio (N) and Darcy number (Da) are considered to be fixed. It is observed that flow pattern, temperature fields and concentration fields are affected by the variation of above considered parameters.