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Literature on photovoltaic thermal (PV/T) system has developed significantly over the last decades. Besides a few review papers, no study has examined their citations using the most popular citation mapping technique — bibliometric. This study, for the first time, reviews total 1659 published documents from Scopus database on PV/T system from 1981 until August 20, 2021, using bibliometric analysis. For data analysis and graphical presentation, the bibliometrix package in R software and the VOSviewer software are implemented. The results of theme mapping, trend topics, bibliometric coupling, and co-occurrence networks have been used to identify potential research fields for the future. The results indicate that the photovoltaic thermal system literature has advanced after 2000 at a pace of 16.28 percent per year. Results also identify the most influential parts of the literature in terms of most cited topic, articles, authors, and keywords. Results reveals that application of artificial neural networks analysis on PV/T, multiphase flow integrated photovoltaic thermal systems, and magnetic effects with photovoltaic have potential literature gap.

shRNA screen hits

Bliss synergy scores for in vitro venetoclax/IMG-7289 combination treatment

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 Evi1lo 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 EVI1hi 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

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Background: Glaucoma is a progressive optic neuropathy that is significantly related to Ocular Surface Disease. The ocular surface includes the cornea, conjunctiva, eyelids, and lacrimal glands; hence the ocular surface disease directs damage to the surface layers of the eye. Methods: This study is a cross-sectional study, conducted in Anwer khan Modern Medical College Hospital, Dhaka, at the Department of Ophthalmology. The study was conducted during the period from December 2020- to November 2021. The sample size was 121. Result: In the age group51-61, there were highest participation 33(27.3%) and among the participants males were 62 (51.2%) and females were 59(48.8%). Mean time for glaucoma or ocular hypertension diagnosis(years) was 8.11±7.42. Open-angle glaucoma was most frequent, 97(95.1%). Mean IOP assessment- Right eye(mmHg) was 15.87±3.97 and Men IOP assessment - Left eye(mmHg) was 15.84±3.94. Conjunctival hyperemia was controlled in 13(10.8%), mild in 49(40.8%), moderate in 27(22.5%), and severe in 32(26.7%) cases which was quite high. When the OSD grade was severe in (˃12 dB) 37(30.6%), the glaucoma stage was also severe (˃12 dB) in 27(22.3%) cases. Conclusion: Glaucoma had affected millions of patients around the world and chronic use of topical glaucoma medications may negatively impact the patient’s ocular surface. There is a strong association between OSD and quality of life in medically treated glaucoma patients.

The current work performs the heatline revelation for combined convection of nanofluid within an enclosure with two moving walls at several thermal conductivity ratios plus heat generation parameter. A solid obstacle that produces uniform heat q per unit area is positioned at the middle of the domain. Sliding lids are assigned to the opposite side walls. Two cases: (I) vertical lids are moving in the same directions and (II) horizontal lids are moving in the opposite directions are analyzed. The computational fluid throughout the enclosed space is water-alumina nanofluid. The Finite Element Method of Galerkin’s weighted residual technique is used to solve the governing nonlinear partial differential equations. Numerical estimations are conducted for a wide range of solid fluid thermal conductivity ratio (0.2 ≤ K ≤ 50) and heat generation parameter (1 ≤ Q ≤ 4) for both cases. Outcomes are obtained as streamlines, isothermal lines, heatlines, heat transfer rate and average heat flow. The results show that the heat flux magnitude is higher for case II than case I but the rate of heat transfer stays nearly same for both cases which increase for the increment of Q and decrement of K. Finally, correlations have been established between the heatfunction with parameters K and Q. There exist strong correlations between the variables which measured from the R-squared values.

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.

The present work mainly focuses on analyzing an unsteady laminar incompressible two-phase flow in a rectangular curved duct. The corresponding governing equations are represented by the Navier-Stokes equations and Level set equation with the boundary conditions. Fluid flow through curved rectangular ducts is influenced by the centrifugal action arising from duct curvature and has a unique behavior different from fluid flow through straight ducts. Centrifugal force-induced secondary flow vortices and produce spiraling fluid motion within curved ducts.This paper shows the vector plot of the field flow, velocity contours,axial flow velocity and fluid volume fractions visualization graphically. The effect of curvature, Dean number and aspect ratio is also displayed. A comparison of two-phase flow between different fluids is also shown. The results reveal that the unstable behavior of the flow reduces for the increasing values of curvature, Dean number, and high viscosity flow.

For the best structure and reliable maintenance, two- or multiphase flow is becoming more and more essential in engineering systems. However, a variety of different of biological organisms and natural phenomena that exhibit two-phase situations can be explored to improve our knowledge of this. This is so because current industrial technology does not place these limitations. This research aims to investigate the effect of an external magnetic field on unsteady laminar incompressible two-phase flow in a porous medium via a rectangular curved duct. The relevant governing equations are represented by the Navier-Stokes equations and by the Level set equation with boundary conditions. Fluid flow through curved rectangular ducts behaves differently from fluid flow through straight ducts due to the centrifugal action generated by duct curvature. Within curved ducts, centrifugal force is generated secondary flow vortices and spiraling fluid motion. This analysis graphically depicts the fluid phase distribution, the Dean vortex, velocity contours, and fluid volume fractions. Furthermore, displayed are the effects of the aspect ratio, porosity, Dean number, radius of curvature, and Hartmann number. Additionally, a comparison of two-phase flow between various fluids is presented.

In recent years, a good number of research works have been conducted to elucidate the different aspects of photovoltaic thermal (PV/T) technology. However, in order to take a technology to its maturity level, it is important to explore its internal physics and identify the factors that control system performance. With this view, in the present research, thermal and heat transfer characterization, and pressure drop phenomena inside a parallel-plate PV/T collector have been examined numerically to portray the thermo-fluid physiognomy of the system. A three-dimensional mathematical model of the PV/T system has been developed, and the model is used to build a computer simulation of the system in COMSOL Multiphysics® software. Hence, the simulation model has been validated by outdoor experimental results and was found to be in good agreement. Thus, the simulation program is employed to produce temperature distribution and heat flow plots throughout the flow channel, wherein results have been evaluated for two different channel materials, e.g., aluminum and copper. Results show that heat flowrate through both aluminum and copper channels is virtually the same. On the other hand, pressure drop, thereby pumping power required to maintain flow, is greater for an aluminum channel. The developed heat transfer simulation model can be extended for other PV modules with diverse designs and materials of the heat exchanger.

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.

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. Wu and colleagues develop a barcoding tool, ClonMapper, which permits single-cell lineage tracing and clonal isolation and demonstrate its utility to study clonal dynamics in human CLL cells in the context of chemotherapy treatment and resistance.

Photovoltaic thermal (PV/T) collectors that supply both electricity and heat are growingly becoming popular in household and other applications. However, efficient heat removal from backside of PV module is still a challenge that hampers its electrical as well as thermal performance. In the present research, an absorber-plate less thermal collector has been introduced and mathematical model of such a PV/T system has been developed, which is employed in COMSOL Multiphysics® software to simulate the heat transfer phenomenon in the system. Effect of different flow parameters on heat transfer and PV/T performance is thus studied numerically in the developed simulation model. Also, the effect of irradiation level and depth of the flow channel has been examined on the thermal as well as electrical performance of the module. Results reveal that PV/T electrical and thermal efficiency increase with both of Reynolds and Prandtl number. Heat transfer rate is observed to increase as high as 25.5% with increasing Reynolds number. A maximum reduction in cell temperature of 10.2 °C is obtained by increasing the channel depth. Elimination of absorber plate from thermal collector simplified the design reducing its weight and cost as well.

Interaction between CLL and its microenvironment is a major factor in drug resistance. Bone marrow derived stroma cells provide a protective and supportive niche to allow CLL cells to survive drug-induced apoptosis. Therefore, a current challenge is to develop new strategies to target the microenvironment. To understand the role of tumor microenvironment in CLL survival, we studied conditioned media (CM) derived from NKTert cells. Human NKTert stroma cells provide a survival advantage to primary CLL cells by protecting them from spontaneous apoptosis in ex-vivo culture. We identified three cytokines (IL6, IL8 and CCL2) from CM as candidates for mediating survival. We exposed CLL cells to neutralizing antibodies against each cytokine and found significant decrease in CLL viability in presence of anti-CCL2 suggesting its role in CLL survival. BH3 profiling revealed an increase in apoptotic priming with anti-CCL2 treatment as well. Using dynamic BH3 profiling (DBP), we found that anti-CCL2 increased dependence on BCL-2 as well as BCL-xL in primary CLL cells suggesting a potential role of CCL2 on CLL survival. To our surprise, we also identified a CLL group (CM independent, CMI) that were resilient to cell death in the absence of stroma support in ex-vivo culture. In addition to this, anti-CCL2 antibody showed no effect on their survival. Next, we exposed CMI CLL cells to venetoclax and found that these CLL cells were less sensitive to apoptosis compared to the CLL samples that are stroma dependent (CM dependent, CMD). BH3 profiling showed that CMI CLL cells are less primed for apoptosis. Consistent with our findings, DBP with anti-CCL2, venetoclax or the combination didn’t increase any drug induced apoptotic priming in CMI CLL samples. In our study, 80% of CMI harbor unmutated IgHV. To provide additional insight to the molecular mechanism, we performed western blot analyses for BCL-2 family proteins and found decreased BAX ad BCL-2 expression in CMI samples. This result suggests altered BCL-2 family proteins expression might be a mechanism for differential priming. Bulk RNA seq analysis revealed upregulation of focal adhesion genes and Ras signaling pathway in CMI samples. In summary, our study suggest that in the CMD subset of CLL, anti-CCL2 therapy enhances apoptotic priming and venetoclax efficacy. Furthermore, we have also functionally defined two biologically distinct CLL subgroups based on stroma dependence. Citation Format: Salma Parvin, Aditi Aryal, Shanye Yin, Matthew S. Davids, Geoffrey G. Fell, Catherine J. Wu, Anthony Letai. Targeting tumor-microenvironmental dependencies as a therapeutic approach in Chronic Lymphocytic Leukemia (CLL) [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A39.

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.

Cancer cells have differential metabolic dependencies compared to their non-malignant counterparts. However, few metabolism-targeting compounds have been successful in clinical trials. Here, we investigated the metabolic vulnerabilities of triple-negative breast cancer (TNBC), in particular those metabolic perturbations that increased mitochondrial apoptotic priming and sensitivity to BH3 mimetics (drugs that antagonize anti-apoptotic 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 non-malignant cells, NAMPT inhibitors increased overall apoptotic priming and induced dependencies on specific anti-apoptotic 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.

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.

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 Evi1lo 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 EVI1hi 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

The laminar natural convection flow and heat transfer inside a trapezoidal cavity filled with air and containing a rectangular block is investigated numerically. The left and right walls of the cavity are cold, the top and bottom walls are adiabatic and the rectangular body is heated uniformly. Finite Element Method of Galerkin’s weighted residual scheme is used to solve the transport equations with appropriate boundary conditions. The main objective of this study is to explore the influence of pertinent parameters such as Rayleigh number, Hartmann number and orientation of the magnetic field on the flow and heat transfer performance of the fluid while the Prandtl number is considered fixed. Results indicate that the heat transfer rate is significantly affected by increasing the mentioned parameters.

Richter's syndrome (RS) represents one of the foremost challenges in CLL management, and its pathogenesis remains largely undefined. We recently leveraged CRISPR-Cas9 in vivo gene editing to develop mouse models of RS by engineering multiplexed loss-of-function lesions typical of CLL (Atm, Trp53, Chd2, Birc3, Mga, Samhd1) in early stem and progenitor cells [Lineage - Sca-1 + c-kit + (LSK)] from MDR-Cd19Cas9 donor mice. These animals express Cas9-GFP in a B-cell restricted fashion and the leukemogenic MDR lesion, which mimics del(13q) when the sgRNA-transduced LSK cells are transplanted in CD45.1 immunocompetent recipients. Through these methods, we observed not only development of CLL, but also transformation into RS, and even captured a stage where CLL and RS were co-existing in the same animal (CLL/RS). We hypothesized that the molecular events underlying RS development would be markedly distinct from those of CLL and performed transcriptome analysis of FACS-sorted CLL and/or RS cells (5 CLL, 4 CLL/RS, 10 RS) and normal B cell controls from 4 age-matched wild type MDR-Cd19Cas9 mice. We identified a unique transcriptional profile of RS (ANOVA, FDR We asked whether these oncogenic circuitries would be recapitulated in human RS. By correlating the differentially expressed genes in murine RS with those of 7 human RS cases (compared to matched CLL), we identified similar pathway dysregulations with >100 commonly altered genes including upregulated cell cycle regulators (CDK1, CCNA2) and downregulated signaling adapters (ITPKB, MAP3K9). To further dissect gene regulatory networks driving transformation in the mouse, we profiled one CLL and one RS case by single cell ATAC sequencing (scATAC-seq). Consistent with the RNA-seq profiles, we detected increased chromatin accessibility of MYC-family associated transcription factor motifs (MAX, MYCN), and reduced accessibility of the pro-inflammatory STAT2 motif in RS (-log10adjP>50). Functionally, decreased interferon gamma responses were confirmed by the reduced ability of RS cells to phosphorylate STAT1 and STAT3 at 5' and 15' after IFN-gamma stimulation, compared to CLL and normal B cells (Western Blot). To define the genetic landscape underlying these changes, we performed whole genome sequencing analysis, and identified loss of chr12 and chr16 as recurrent events in RS (6/8 cases) and CLL/RS (2/2), but not in CLL cases (0/5). Among the genes encoded by these chromosomes, we identified several epigenetic drivers (Dnmt3a, Crebbp, Setd3/4), MAP kinase family members (Map4k5, Mapk1), cytoskeletal regulators (Hcls1, Rhoj), and interferon family receptors (Ifnar1/2, Ifngr2), suggesting that broad epigenetic modifications together with loss of BCR and interferon signaling molecules represent key events of transforming disease. RS cases were also characterized by a significantly higher number of full chromosome amplifications or deletions (median=6; range: 2-9), as compared to CLL or CLL/RS (1; 0-5, P=0.0008), consistent with the high degree of genomic instability observed in human disease. Finally, we asked whether the observed changes would impact RS therapeutic vulnerabilities, and exposed 15 primary murine RS splenocyte samples to 20 drugs in vitro for 24 hours, followed by CellTiter-Glo assessment of cellular viability. We observed strong sensitivity to the BRD4 inhibitor JQ1 and the mTOR inhibitor everolimus (both reported to interfere with MYC signaling, P In conclusion, we define the evolutionary trajectories and therapeutic vulnerabilities of RS in a mouse model, with unique transcriptional, genetic, and epigenetic features, indicative of broad changes in MYC, IFN and BCR signaling pathways and remarkable similarities with human disease. In-depth analyses of BCR signaling and in vivo treatment studies are underway and will refine mechanistic insights into the biology of RS. Disclosures Davids: Surface Oncology: Research Funding; Eli Lilly and Company: Consultancy; Genentech: Consultancy, Research Funding; Takeda: Consultancy; MEI Pharma: Consultancy; Janssen: Consultancy; Verastem: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Merck: Consultancy; Adaptive Biotechnologies: Consultancy; Research to Practice: Consultancy; AbbVie: Consultancy; MEI Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy; BeiGene: Consultancy. Letai: Dialectic Therapeutics: Other: equity holding member of the scientific advisory board; Flash Therapeutics: Other: equity holding member of the scientific advisory board; Zentalis Pharmaceuticals: Other: equity holding member of the scientific advisory board. Neuberg: Madrigal Pharmaceuticals: Other: Stock ownership; Pharmacyclics: Research Funding. Wu: Pharmacyclics: Research Funding; BioNTech: Current equity holder in publicly-traded company.

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.

The paper executes the laminar natural convection flow and heat transfer inside a prismatic enclosure with non-uniform temperature distribution maintained at the bottom wall. The side walls are insulated and the remaining walls are cooled at temperature T c . A magnetic field of strength B 0 is applied horizontally normal to the side walls. The water- Al 2 O 3 nanofluid is used as the heat transfer medium through the enclosure. Finite Element Method of Galerkin's weighted residual scheme is used to solve the transport equations with appropriate boundary conditions. The effect of Hartman number Ha (0 to 50) for nanofluid as well as for the base fluid on isotherms, streamlines and heat lines, local and average heat transfer are presented graphically. The calculations have been performed for Prandtl number Pr = 6.2. Results indicate that the heat transfer rate is significantly affected by increasing the mentioned parameter.

In the present study, double-diffusive natural convection flow inside a window shaped cavity containing multiple obstacles filled with nanofluid is studied numerically. Water base nanofluid containing various nanoparticles including Ag, Cu and Al 2 O 3 are considered as working fluid. The left and right inclined walls of the cavity are maintained at a relatively low temperature and low concentration while the vertical walls are adiabatic and impermeable. The non-uniform temperature and concentration are imposed along the bottom 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 influence of pertinent parameters such as thermal Rayleigh number and Lewis number and volume fraction of nanoparticles on the heat and mass transfer and fluid flow is studied. The results are obtained in terms of streamlines, isotherms, isoconcentrations, average Nusselt number and average Sherwood number for the considered parameters and it is observed that the flow pattern, temperature and concentration fields are affected by the variation of the parameters.

Despite the recent advances in chronic lymphocytic leukemia (CLL) treatment with the development of novel targeted agents such as Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and the BCL2 antagonist Venetoclax, the disease remains incurable for most patients, and resistance mechanisms to these novel agents have already been identified. Therefore, identifying new therapeutic vulnerabilities to treat and prevent resistant tumors is of great importance. Stromal cells provide CLL cells a protective niche which increases resistance to drug-induced apoptosis. Therefore, a current challenge is to develop new strategies by targeting not only CLL cells, but also the microenvironment. We found that soluble factors can recapitulate much of the protective function of stromal cells. To understand the role of microenvironmental factors on CLL cells, we took advantage of the conditioned media (CM) collected from the stromal cell line NK-tert, which protects CLL cells from spontaneous cell death. First, we identified three major cytokines (IL6, IL8, CCL2) from the conditioned media using Proteome Profiler Human XL Cytokine Array. Next, we evaluated the effect of each cytokine on peripheral blood (PB) CLL survival (n=5, treatment naïve, unselected regarding genetic background). CLL cells were cultured ex-vivo in CM and treated with neutralizing antibody against either Il6, IL8 or CCL2 for 48hrs and found a significant decrease in cell viability in presence of anti-CCL2 antibody (median % decrease in cell viability over isotype control is 50%, p BH3 profiling quantifies apoptotic signaling based on cytochrome c loss as a measure of mitochondrial outer membrane permeabilization (MOMP) by flow cytometry in response to BH3-only synthetic peptides that mimic pro-apoptotic BCL-2 family proteins, applied to digitonin permeabilized cells. We performed BH3 profile on PB derived -CLL samples (n=5, treatment naive) cultured in CM and exposed to either isotype control or anti-CCL2 antibody. Anti-CCL2 treated CLL samples showed an increase in MOMP in response to BIM, PUMA, MS1 and HRK peptides compared to CLL samples exposed to isotype control. This suggests that CCL2 suppresses apoptotic signaling in CLL cells. Furthermore, Dynamic BH3 profiling (DBP), a measure of drug-induced apoptotic signaling as previously described (Montero et al., Cell, 2015) showed that a combination of anti-CCL2 and venetoclax increased dependence on BCL-2 (BAD peptide)MCL-1(MS1 peptide) as well as BCL-xL (HRK peptide) in CLL cells. To our surprise, we also found a subgroup of treatment naive PB-CLL samples (CM independent) that undergo minimal spontaneous cell death in the absence of stroma support. In addition to this, IL-6, IL8, CCL2 neutralizing antibodies showed no effect on their survival. These CM independent CLL samples(n=5) are less sensitive to venetoclax treatment compared to the CLL samples that need stroma support (CM dependent). Moreover, baseline BH3 profile showed that CM independent CLL cells are less primed for apoptosis compared to CM dependent CLL cells, and exposure to venetoclax and anti-CCL2 antibody did not increase any drug-mediated apoptotic priming. Next, we checked mRNA expression level of the CCL2 receptor, CCR2 from CM dependent and CM independent CLL samples and found that CM dependent CLL cells have higher expression of CCR2, suggesting a distinct signature discriminating CM dependent and independent patients. In summary, our study shows that CCL2 may serve as a novel biomarker to target in CLL, especially in relapsed/refractory patients. Disclosures Davids: Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Surface Oncology: Research Funding; MEI Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Gilead Sciences: Consultancy; Merck: Consultancy; Bristol Myers Squibb: Research Funding; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Eli Lilly: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; Ascentage Pharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy; Zentalis: Consultancy; Sunesis: Consultancy; Syros Pharmaceuticals: Consultancy; Research to Practice: Honoraria. Letai:Chugai: Other: Lecture Fees; Novartis: Research Funding; AbbVie: Consultancy; AstraZeneca: Consultancy; Zentalis: Membership on an entity's Board of Directors or advisory committees; Flash Therapeutics: Membership on an entity's Board of Directors or advisory committees; Dialectic: Membership on an entity's Board of Directors or advisory committees.

Rabindranath Tagore’s Chokher Bali and D.H Lawrence’s Sons and Lovers are two famous novels in the early 20th century from two different social culture. Both these novels have particular important issues in them to be discussed. As in Chokher Bali we find Tagore has presented his idea in feminism, man-woman relationship, woeful condition of widow in his contemporary society etc. In the same way in Sons and Lovers Lawrence has talked about critical mother-son relationship, social bondage among the characters, description of nature, problems in the lives of working class etc. Though Chokher Bali and Sons and Lovers are from different social context but they can be compared through the commonly discussed issue in them that is complex mother-son relationship and the impact of motherhood to the sons. This paper is going to discuss the impact of excessive motherly affection to the life of son, similarities and dissimilarities in mother-son relationship in Chokher Bali and Sons and Lovers.

Mixed convective flow and heat transfer characteristics of nanofluid inside a double lid driven cavity with a square heat generating block is analyzed numerically based on heatline approach. The upper and lower lids of the cavity are kept adiabatic and are moving in opposite direction while the other two boundaries are kept fixed at uniform temperature Tc. The water-alumina nanofluid is chosen as the operational fluid through the enclosure. The governing differential equations with proper boundary conditions are solved by Finite Element Method using Galerkin’s weighted residual scheme. Calculations are performed for different Reynolds number such as 20, 50, 100 and 150. Results are shown in terms of stream lines, isothermal lines, heatlines, average Nusselt number and average temperature. An enhancement in heat transfer rate is observed with the variation of Reynolds number.

A finite element Fluid-Structure-Interaction (FSI) model is developed and validated for hemodynamic pulsatile blood flow through a stenosed artery under the effect of an applied magnetic field. The two-layered blood flow is considered with a core layer of suspension of all erythrocytes assumed to be a non-Newtonian Casson fluid and a peripheral layer of plasma, free from cells, as a Newtonian fluid. The model is considered for the 2D idealized elastic arteries. The blood flow is characterized as a steady, laminar, incompressible and unidirectional flow velocity at the inflow and various values of blood-pressure at the outflow, while the arterial walls as well as the surrounding muscles are modeled as a hyperelastic neo-Hookean material and results are obtained for axial velocities, total flow rate, pressure gradient and wall shear stresses (WSS) and solid displacement due to blood pulse. The result shows significant strengthened WSS at the stenotic regions and weakened WSS at the distal side of stenosis neck. It is found that the increase of stenosis size (height) increases the pressure drop and WSS, whereas velocity and flow rate decreases. The wall deformation and WSS may play an important role in the flow mechanics of blood in the stenotic vessel. It is also observed that the fluid velocity and flow rate were reduced when the magnetic field was introduced as well as when its intensity was increased, while WSS was increased with the increase of Hartmann number (Ha) as well as Reynolds number (Re). This work may enhance to work upon the strength of magnetic field to regulate the blood flow in hypertensive patients and those who have blockage in their arteries.

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., This work was supported by grant 1R01CA233945 from the National Cancer Institute, Florida Health Bankhead-Coley Cancer Research Award AWD-005151 and the Intramural Funding Program from the University of Miami SCCC (to R.E.V. and I.S.L.). I.S.L. is supported by the Dwoskin and Anthony Rizzo Families Foundations and Jaime Erin Follicular Lymphoma Research Consortium. R.E.V. is supported by R01GM121595 from the National Institute of General Medical Sciences and funds from the University of Miami SCCC.

In this research, a non-Newtonian model for blood flow within a stenosed artery is investigated numerically. Finite Element Method of Galerkin’s weighted residual scheme is used to solve the transport equations with appropriate boundary conditions. The main objective of this study is to explore the influence of magnetic field on the blood flow. The numerical results are presented in terms of the velocity, pressure distribution and shear rate of the stenosed artery.

Molecular alterations in the histone methyltransferase EZH2 and the antiapoptotic protein BCL2 frequently co-occur in diffuse large B-cell lymphoma (DLBCL). We hypothesized that EZH2 inhibition and BCL2 inhibition would be synergistic in DLBCL. To test this, we evaluated the EZH2 inhibitor tazemetostat and the BCL2 inhibitor venetoclax in DLBCL cells, 3D lymphoma organoids, and patient-derived xenografts (PDXs). We found that tazemetostat and venetoclax are synergistic in DLBCL cells that harbor both an EZH2 mutation and a BCL2/IGH translocation, as demonstrated by CI values Citation Format: Hanna Scholze, Regan E. Stephenson, Raymond Reynolds, Shivem Shah, Rishi Puri, Matthew R. Teater, Herman van Besien, Destini Gibbs-Curtis, Hideki Ueno, Salma Parvin, Anthony G. Letai, Susan Mathew, Ankur Singh, Ethel Cesarman, Ari Melnick, Lisa Giulino-Roth. Combined EZH2 and BCL2 inhibitors as precision therapy for genetically defined DLBCL subtypes [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-53.

A numerical attempt of the two-phase (non-homogeneous) nanofluid approach towards the convection heat transfer within a 3D wavy direct absorber solar collector is reported. The solar collector is permeated by a water-Al2O3 nanofluid and contains a wavy glass top surface that is exposed to the ambient atmosphere and a flat steel bottom surface. The left and right surfaces are maintained adiabatic. The governing equations of the Navier&ndash, Stokes and energy equations for the nanofluid are transformed into a dimensionless pattern and then solved numerically using the Galerkin weighted residual finite-element technique. Validations with experimental and numerical data are performed to check the validity of the current code. Impacts of various parameters such as the number of oscillations, wave amplitude, Rayleigh number and the nanoparticles volume fraction on the streamlines, isotherms, nanoparticle distribution, and heat transfer are described. It is found that an augmentation of the wave amplitude enhances the thermophoresis and Brownian influences which force the nanoparticles concentration to display a nonuniform trend within the examined region. Furthermore, the heat transfer rate rises midst the growing wave amplitude and number of oscillations. More importantly, such enhancement is observed more significantly with the variation of the wave amplitude.

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., J.H. has been supported by the German Cancer Aid (Project 110997 and Translational Oncology Program 70112951), the German Jose Carreras Leukemia Foundation (DJCLS 02R/2016), Deutsches Konsortium für Translationale Krebsforschung (DKTK), Joint funding (Targeting MYC L*10), the Kinderkrebsstiftung (2016/17), and the “Elterninitiative Kinderkrebsklinik e.V. Düsseldorf”. SG has been supported by a scholarship of the Hochschule Bonn-Rhein-Sieg. AB has been supported by the German Children's Cancer Foundation and the Federal Ministry of Education and Research, Bonn, Germany. Research in ISG group is partially supported by FEDER and by MINECO (SAF2012-32810, SAF2015-64420-R, and Red de Excelencia Consolider OncoBIO SAF2014-57791-REDC), Instituto de Salud Carlos III (PIE14/00066), ISCIII- Plan de Ayudas IBSAL 2015 Proyectos Integrados (IBY15/00003), by Junta de Castilla y León (BIO/SA51/15, CSI001U14, UIC-017, and CSI001U16), Fundacion Inocente Inocente, and by the ARIMMORA project (European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 282891). ISG Lab is a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program. AB and ISG have been supported by the German Carreras Foundation (DJCLS R13/26). IGR was supported by BES-Ministerio de Economía y Competitividad (BES-2013-063789). AML and GRH were supported by FSE-Conserjería de Educación de la Junta de Castilla y León (CSI001-13, CSI001-15). Research in CVD group is partially supported by FEDER, “Miguel Servet” Grant (CP14/00082—AES 2013-2016) from the Instituto de Salud Carlos III (Ministerio de Economía y Competitividad), “Fondo de Investigaciones Sanitarias/Instituto de Salud Carlos III” (PI17/00167), and by the Lady Tata International Award for Research in Leukaemia 2016–2017.