scholarly journals Knockdown of NRMT enhances sensitivity of retinoblastoma cells to cisplatin through upregulation of the CENPA/Myc/Bcl2 axis

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Zhongrui Li ◽  
Lan Zhang ◽  
Dongrui Liu ◽  
Zhanghui Yang ◽  
Di Xuan ◽  
...  
Keyword(s):  
Chromatin Condensation ◽  
Protein A ◽  
Chemotherapy Resistance ◽  
B Cell Lymphoma ◽  
Loss Of Function ◽  
Retinoblastoma Cell ◽  
In Vivo Experiments ◽  
Centromere Protein A ◽  
Retinoblastoma Cells

AbstractChemotherapy resistance of tumor cells causes failure in anti-tumor therapies. Recently, N-terminal regulator of chromatin condensation 1 methyltransferase (NRMT) is abnormally expressed in different cancers. Hence, we speculate that NRMT may pay a crucial role in the development of chemosensitivity in retinoblastoma. We characterized the upregulation of NRMT in the developed cisplatin (CDDP)-resistant retinoblastoma cell line relative to parental cells. Loss-of-function experiments demonstrated that NRMT silencing enhanced chemosensitivity of retinoblastoma cells to CDDP. Next, NRMT was identified to enrich histone-H3 lysine 4 trimethylation in the promoter of centromere protein A (CENPA) by chromatin immunoprecipitation assay. Rescue experiments suggested that CENPA reduced chemosensitivity by increasing the viability and proliferation and reducing apoptosis of CDDP-resistant retinoblastoma cells, which was reversed by NRMT. Subsequently, CENPA was witnessed to induce the transcription of Myc and to elevate the expression of B cell lymphoma-2. At last, in vivo experiments confirmed the promotive effect of NRMT knockdown on chemosensitivity of retinoblastoma cells to CDDP in tumor-bearing mice. Taken together, NRMT is an inhibitor of chemosensitivity in retinoblastoma. Those findings shed new light on NRMT-targeted therapies for retinoblastoma.

scholarly journals Characterization of SOX2, OCT4 and NANOG in Ovarian Cancer Tumor-Initiating Cells

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 262
Author(s):  
Mikella Robinson ◽  
Samuel F. Gilbert ◽  
Jennifer A. Waters ◽  
Omar Lujano-Olazaba ◽  
Jacqueline Lara ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Chemotherapy Resistance ◽  
Tumor Initiating Cells ◽  
In Vivo Experiments ◽  
Nanog Expression ◽  
Ovarian Cancer Cell Lines ◽  
Cancer Tumor ◽  
Early Tumor ◽  
Cycle Regulation

The identification of tumor-initiating cells (TICs) has traditionally relied on surface markers including CD133, CD44, CD117, and the aldehyde dehydrogenase (ALDH) enzyme, which have diverse expression across samples. A more reliable indication of TICs may include the expression of embryonic transcription factors that support long-term self-renewal, multipotency, and quiescence. We hypothesize that SOX2, OCT4, and NANOG will be enriched in ovarian TICs and may indicate TICs with high relapse potential. We evaluated a panel of eight ovarian cancer cell lines grown in standard 2-D culture or in spheroid-enriching 3-D culture, and correlated expression with growth characteristics, TIC marker expression, and chemotherapy resistance. RNA-sequencing showed that cell cycle regulation pathways involving SOX2 were elevated in 3-D conditions. HGSOC lines had longer doubling-times, greater chemoresistance, and significantly increased expression of SOX2, OCT4, and NANOG in 3-D conditions. CD117+ or ALDH+/CD133+ cells had increased SOX2, OCT4, and NANOG expression. Limiting dilution in in vivo experiments implicated SOX2, but not OCT4 or NANOG, with early tumor-initiation. An analysis of patient data suggested a stronger role for SOX2, relative to OCT4 or NANOG, for tumor relapse potential. Overall, our findings suggest that SOX2 may be a more consistent indicator of ovarian TICs that contribute to tumor repopulation following chemotherapy. Future studies evaluating SOX2 in TIC biology will increase our understanding of the mechanisms that drive ovarian cancer relapse.

scholarly journals miR-26a/HOXC9 Dysregulation Promotes Metastasis and Stem Cell-Like Phenotype of Gastric Cancer

2018 ◽  
Vol 49 (4) ◽  
pp. 1659-1676 ◽  
Author(s):  
Xudong Peng ◽  
Qingjie Kang ◽  
Rui Wan ◽  
Ziwei Wang
Keyword(s):  
Gastric Cancer ◽  
Stem Cell ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Promoting Effect ◽  
In Vivo Experiments ◽  
Direct Target ◽  
Cancer Tissues

Background/Aims: Previous studies demonstrated that HOXC9 acts as an oncogene in several tumors. The aim of this study was to explore whether HOXC9 promotes gastric cancer (GC) progression and elucidate the underlying molecular mechanisms. Methods: HOXC9 expression in GC tissues and adjacent non-cancer tissues was detected by quantitative RT-PCR (qRT-PCR) and immunohistochemistry. The functional effects of HOXC9 on proliferation, metastasis and stem cell-like phenotype were evaluated by relevant experiments in GC cells. The effect of miR-26a on HOXC9 was investigated by gain- and loss-of-function assays and luciferase reporter assay. Nude mouse models were established to test the effect of miR-26a and HOXC9 on tumorigenesis and metastasis of GC cells in vivo. Results: Herein, we showed that HOXC9 was upregulated in GC tissues and associated with a poor prognosis. HOXC9 knockdown inhibited the metastasis and stem cell-like phenotype of GC cells without significant effects on cell proliferation. In addition, we identifed HOXC9 as a direct target of miR-26a. Restoration of miR-26a in GC cells downregulated HOXC9 and reversed its promoting effect on metastasis and self-renewal, whereas miR-26a silencing upregulated HOXC9. In vivo experiments showed that HOXC9 knockdown suppressed tumorigenesis and lung metastasis of GC cells in nude mice, and these effects were mimicked by restoration of miR-26a. Conclusion: The present study demonstrates that HOXC9 promotes the metastasis and stem cell-like phenotype of GC cells, and this phenomenon can be reversed by restoration of miR-26a.

scholarly journals Exposure to Mites Sensitizes Intestinal Stem Cell Maintenance, Splenic Marginal Zone B Cell Homeostasis, And Heart Development to Notch Dosage and Cooperativity

2020 ◽  
Author(s):  
Francis M. Kobia ◽  
Kristina Preusse ◽  
Quanhui Dai ◽  
Nicholas Weaver ◽  
Praneet Chaturvedi ◽  
...  
Keyword(s):  
B Cell ◽  
Heart Development ◽  
Marginal Zone ◽  
B Cell Lymphoma ◽  
Mite Infestation ◽  
List Type ◽  
Loss Of Function ◽  
B Cell Homeostasis

AbstractCooperative DNA binding is a key feature of transcriptional regulation. Here we examined the role of cooperativity in Notch signaling by CRISPR-mediated engineering of mice in which neither Notch1 nor Notch2 can homo- or heterodimerize, essential for cooperative binding to sequence paired sites (SPS) located near many Notch-regulated genes. While most known Notch-dependent phenotypes were unaffected in Notch1/2 dimer-deficient mice, a subset of tissues proved highly sensitive to loss of cooperativity. These phenotypes include heart development, compromising viability in combination with low gene dose, and the gut, developing ulcerative colitis in response to 1% DSS. The most striking phenotypes – gender imbalance and splenic marginal zone B cell lymphoma – emerged in combination with dose reduction or when challenged by chronic fur mite infestation. This study highlights the role of the environment in malignancy and colitis, and is consistent with Notch-dependent anti-parasite immune responses being compromised in the dimer deficient animals.HighlightsNotch dimerization has an in vivo role in contributing to intestinal homeostasisLoss of cooperativity can manifest as Notch gain or loss of function phenotypesMite infestation exacerbates all phenotypes, triggers MZB hyperproliferation in mutant animalsMite-infested mutant mice develop SMZL with age

scholarly journals Cardamonin Promotes the Apoptosis and Chemotherapy Sensitivity to Gemcitabine of Pancreatic Cancer Through Modulating the FOXO3a-FOXM1 Axis

Dose-Response ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. 155932582110421
Author(s):  
Huapeng Sun ◽  
Na Zhang ◽  
Yiqiang Jin ◽  
Haisheng Xu
Keyword(s):  
Pancreatic Cancer ◽  
Biological Activities ◽  
Cell Counting ◽  
Loss Of Function ◽  
Chemotherapy Sensitivity ◽  
In Vivo Experiments ◽  
Pathway Expression ◽  
Foxm1 Expression

Cardamonin (CAR), a flavone existing in the Alpinia plant, has been found to modulate multiple biological activities, including antioxidant, anti-inflammatory, and anti-tumor effects. Nevertheless, the influence of CAR on pancreatic cancer (PC) is less understood. Here, we conducted in vitro and in vivo experiments to explore the functions of CAR on PC cells’ proliferation, apoptosis and chemosensitivity to gemcitabine (GEM). The growth of PC cells (including PANC-1 and SW1990) was evaluated by the cell counting kit-8 assay, colony formation assay and xenograft tumor experiment. Besides, the apoptosis was determined by flow cytometry and western blot (WB). Moreover, the FOXO3a-FOXM1 pathway expression was tested by reverse transcription-polymerase chain reaction and WB. Our data suggested that CAR restrained cell proliferation, growth and expedited apoptosis both in vitro and in vivo. Moreover, CAR sensitized PC cells to GEM. Mechanistically, CAR heightened FOXO3a while repressed FOXM1. Further loss-of-function assays revealed that down-regulating FOXO3a markedly dampened the anti-tumor effect induced by CAR and accelerated the FOXM1 expression. Our data confirmed that CAR exerted an anti-tumor function in PC dependently by modulating the FOXO3a-FOXM1 axis.

Two chloroplastic PLGG1 isoforms function together to transport photorespiratory glycolate and glycerate in rice

2021 ◽  
Author(s):  
Lili Cui ◽  
Chuanling Zhang ◽  
Zhichao Li ◽  
Tuxiu Xian ◽  
Limin Wang ◽  
...  
Keyword(s):  
Rice Genome ◽  
Direct Interaction ◽  
Crop Productivity ◽  
Chloroplast Envelope ◽  
Starch Accumulation ◽  
Loss Of Function ◽  
In Planta ◽  
In Vivo Experiments

Abstract The photorespiratory pathway is highly compartmentalized. As such, metabolite shuttles between organelles are critical to ensure efficient photorespiratory carbon flux. Arabidopsis PLGG1 has been reported as a key chloroplastic glycolate/glycerate transporter. Two homologous genes OsPLGG1a and OsPLGG1b have been identified in the rice genome, although their distinct functions and relationships remain unknown. Herein, our analysis of exogenous expression in oocytes and yeast shows that both OsPLGG1a and OsPLGG1b have the ability to transport glycolate and glycerate. Furthermore, we demonstrate in planta, that the perturbation of OsPLGG1a or OsPLGG1b expression leads to extensive accumulation of photorespiratory metabolites, especially glycolate and glycerate. Under ambient CO2 conditions, loss-of-function osplgg1a or osplgg1b mutant plants exhibited significant decreases in photosynthesis efficiency, starch accumulation, plant height, and crop productivity. These morphological defects were almost entirely recovered when the mutant plants were grown under elevated CO2 conditions instead. In contrast to osplgg1a, osplgg1b mutant alleles produced a mild photorespiratory phenotype and had reduced accumulation of photorespiratory metabolites. Subcellular localization analysis showed that OsPLGG1a and OsPLGG1b are located in the inner and outer membranes of the chloroplast envelope, respectively. In vitro and in vivo experiments revealed that OsPLGG1a and OsPLGG1b have a direct interaction. Our results indicate that both OsPLGG1a and OsPLGG1b are chloroplastic glycolate/glycerate transporters required for photorespiratory metabolism and plant growth, and that they may function as a singular complex.

In Vitro and In Vivo Anti Lymphoma Effect of GX15-070 in Mantle Cell Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4756-4756 ◽  
Author(s):  
Gwyn Bebb ◽  
Huong Muzik ◽  
Sophia Nguyen ◽  
Don Morris ◽  
Douglas A. Stewart
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Line ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cytotoxic Agents ◽  
In Vivo Experiments ◽  
Mantle Cell

Abstract Introduction Mantle cell lymphoma (MCL), an incurable B cell lymphoma, consistently over expresses bcl-2 despite not carrying the t(14;18). The attenuation of apoptosis by bcl-2 is thought to contribute to the malignant process and increase resistance to some cytotoxic agents. We recently demonstrated that GX15-070, a small molecular inhibitor of the BH3 binding groove of bcl-2, has activity against MCL cell lines in vitro. We set out to assess the effect of GX15-070 alone and in combination with Vincristine on the viability of MCL cells in vitro and in vivo. Methods 3 previously characterized bcl-2 over expressing MCL cell lines (JVM-2, Hbl-2, granta) were used. Cells were grown in standard media and exposed to a range of concentrations of GX15-070 with and without Vincristine. Dose-response was assessed by measuring viability at 48 hours using the WST-1 assay. In vivo experiments were conducted on immune deficient mice in which 5×106 cells were injected in the flank then treated IV with GX15-070 (q 2days × 5 doses), Vincristine (q4 days × 3 doses) or both starting 5 days later. Tumours were measured three times weekly. Results All three MCL cell lines over-expressed bcl-2 by western blot. Each MCL cell line showed sensitivity to GX15-070 at a range of concentrations. The addition of GX15-070 to low dose Vincristine (10−6) caused significant growth inhibition of each MCL cell line (see table 1). Discussion Our results demonstrate that using GX15-070 to target bcl-2 is an effective anti neoplastic approach against MCL cell lines in vitro. In addition, our results suggest that combining Vincristine and GX15-070 is a promising strategy in treating MCL. In vivo experiments to confirm this additive activity are still ongoing and will be presented in full. Initial impressions suggest that there is a rationale for the addition of GX15-070 to current cytotoxic regimens used to treat MCL in the setting of clinical trials. Table 1: Effect of Vincristine and GX15-070 on in vitro growth of 3 MCL cell lines Growth as % age of Control Cell Line JVM-2 HBL-2 Granta Vincristine alone (10-6 mg/ml) 92% 48% 89% GX15-070 alone (0.08 uM) 75% 76% 60% Vincristine 10-6 mg/ml and GX15-070 0.08 uM 52% 24% 52%

scholarly journals Functional Complementation of Human Centromere Protein A (CENP-A) by Cse4p from Saccharomyces cerevisiae

2004 ◽  
Vol 24 (15) ◽  
pp. 6620-6630 ◽  
Author(s):  
Gerhard Wieland ◽  
Sandra Orthaus ◽  
Sabine Ohndorf ◽  
Stephan Diekmann ◽  
Peter Hemmerich
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Budding Yeast ◽  
Protein A ◽  
Human Cells ◽  
Cycle Arrest ◽  
Centromere Protein ◽  
Centromere Protein A

ABSTRACT We have employed a novel in vivo approach to study the structure and function of the eukaryotic kinetochore multiprotein complex. RNA interference (RNAi) was used to block the synthesis of centromere protein A (CENP-A) and Clip-170 in human cells. By coexpression, homologous kinetochore proteins from Saccharomyces cerevisiae were then tested for the ability to complement the RNAi-induced phenotypes. Cse4p, the budding yeast CENP-A homolog, was specifically incorporated into kinetochore nucleosomes and was able to complement RNAi-induced cell cycle arrest in CENP-A-depleted human cells. Thus, Cse4p can structurally and functionally substitute for CENP-A, strongly suggesting that the basic features of centromeric chromatin are conserved between yeast and mammals. Bik1p, the budding yeast homolog of human CLIP-170, also specifically localized to kinetochores during mitosis, but Bik1p did not rescue CLIP-170 depletion-induced cell cycle arrest. Generally, the newly developed in vivo complementation assay provides a powerful new tool for studying the function and evolutionary conservation of multiprotein complexes from yeast to humans.

scholarly journals MiR-613 suppresses retinoblastoma cell proliferation, invasion, and tumor formation by targeting E2F5

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769167 ◽  
Author(s):  
Yiting Zhang ◽  
Xinyue Zhu ◽  
Xiaomin Zhu ◽  
Yan Wu ◽  
Yajun Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Formation ◽  
Migration And Invasion ◽  
The Novel ◽  
Aberrant Expression ◽  
Retinoblastoma Cell ◽  
Cycle Arrest ◽  
Retinoblastoma Cells

Retinoblastoma is a common intraocular malignancy that occurs during childhood. MicroRNAs play critical roles in the regulation of retinoblastoma initiation and progression, and aberrant expression of miR-613 had been reported in various types of cancer. However, the role and mechanism of its function in retinoblastoma are still unclear. In this study, we found that miR-613 was downregulated in retinoblastoma tissues and cell lines. Overexpression of miR-613 suppressed retinoblastoma cell proliferation, migration, and invasion and induced cell cycle arrest in vitro. Additionally, overexpressed miR-613 also inhibited tumor formation of retinoblastoma cells in vivo. We further identified E2F5 as a direct target of miR-613. Reintroduction of E2F5 without 3′-untranslated region reversed the inhibitory effects of miR-613 on cell proliferation and invasion. Our data collectively indicate that miR-613 functions as a tumor suppressor in retinoblastoma through downregulating E2F5, supporting the targeting of the novel miR-613/E2F5 axis as a potentially effective therapeutic approach for retinoblastoma.

scholarly journals Hypoxia-induced up-regulation of miR-27a promotes paclitaxel resistance in ovarian cancer

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
Lanlan Feng ◽  
Fangrong Shen ◽  
Jinhua Zhou ◽  
Yan Li ◽  
Rong Jiang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Regulatory Mechanism ◽  
Chemotherapy Resistance ◽  
Paclitaxel Resistance ◽  
In Vivo Experiments ◽  
Hypoxic Environment ◽  
Skov3 Cells

Abstract Ovarian cancer (OC) is a malignant tumor with high mortality in women. Although cancer patients initially respond to paclitaxel chemotherapy following surgery, most patients will relapse after 12–24 months and gradually die from chemotherapy resistance. In OC, cancer cells become resistant to paclitaxel chemotherapy under hypoxic environment. The miR-27a has been identified as an oncogenic molecular in ovarian cancer, prostate cancer, liver cancer etc. In addition, the miR-27a is involved in hypoxia-induced chemoresistance in various cancers. However, the role of miR-27a in hypoxia-induced OC resistance remains unclear. The aim of the present study was to investigate the regulatory mechanism of miR-27a in hypoxia-induced OC resistance. The expression of HIF-1α induced Hypoxia overtly up-regulated. At the same time, hypoxia increased viability of Skov3 cells and decreased cell apoptosis when treated with paclitaxel. The expression of the miR-27a was obviously up-regulated under hypoxia and involved in hypoxia-induced paclitaxel resistance. Follow-up experiments portray that miR-27a improved paclitaxel resistance by restraining the expression of APAF1 in OC. Finally, we further elucidated the important regulatory role of the miR-27a-APAF1 axis in OC through in vivo experiments. According to our knowledge, we first reported the regulation of miR-27a in hypoxia-induced chemoresistance in OC, providing a possible target for chemoresistance treatment of OC.

The SMAC Mimetic Lcl-161 Augments the in Vitro and in Vivo anti-Tumor Activity of Rituximab and Chemotherapy in Rituximab Relapse/Refractory Lymphoma Models

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3110-3110 ◽  
Author(s):  
Kyle L. Runckel ◽  
Joseph Skitzki ◽  
Francisco Hernandez ◽  
Myron S. Czuczman
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Chemotherapy Resistance ◽  
B Cell Lymphoma ◽  
Over Expression ◽  
Tail Vein Injection ◽  
Refractory Lymphoma ◽  
Anti Tumor Activity

Abstract The addition of rituximab to front-line therapy regimens in diffuse large B-cell lymphoma (DLBCL) has greatly improved clinical outcomes, but is also associated with a disease that is more resistant to salvage chemotherapy in the second-line setting, reinforcing the need for new therapies targeted at the overlapping resistance pathways between rituximab and chemotherapy. To better understand the mechanisms responsible for rituximab/chemotherapy cross-resistance we developed several rituximab resistance cell lines which exhibited significant concurrent chemotherapy resistance. These multi-therapy resistant cell lines (TRCL) exhibit decreased expression of the pro-apoptotic Bcl-2 family proteins Bak and Bak, along with over-expression of several anti-apoptotic proteins, including the inhibitor of apoptosis proteins (IAP) survivin and livin (determined by Western blot). High IAP expression has been associated with inferior clinical outcomes in a range of hematological malignancies, and solid tumors. To determine the impact of IAP over-expression on TRCL rituximab/chemotherapy resistance we utilized a transient siRNA knockdown of both survivn and livin. TRCLs with livin knockdown had a statistically significant improvement in response to several chemotherapy agents including doxorubicin, vincristine, and the proteasome inhibitor carfilzomib (measured at 48 hours with the Cell Titer-Glo viability assay). These results support livin over-expression as a key lymphoma therapy resistance mechanism, and establish IAPs as potential therapeutic targets. Small molecule IAP inhibitors, like LCL-161 (obtained from Novartis), are chemical mimetics of the endogenous IAP antagonist termed the second mitochondrial inhibitor of caspases (SMAC). Western blot analysis indicated that TRCLs treated in vitro with LCL-161 exhibited a dose dependent decrease in the expression of several IAPs, including livin. In addition, LCL-161 increased rates of TRCL apoptosis, and produced synergistic anti-tumor activity when combined with cytarabine, gemcitabine, and carfilzomib in vitro. LCL-161 also enhanced the ex vivo anti-tumor activity of carfilzomib against primary tumor cells isolated from lymphoma patients with both de novo, and relapse/refractory disease. Cell viability and apoptosis induction were determined at 48 hours with CellTiter-Glo viability assays and flow cytometry respectively. To evaluate the anti-tumor effect of LCL-161 in vivo severe combined immunodeficiency (SCID) mice were inoculated with the TRCL Raji-4RH via tail vein injection (iv), and assigned to observation or treatment arms 7 days after inoculation. Treatments were LCL-161 alone (60mg/kg), the combination of rituximab: 10mg/kg, gemcitabine: 120mg/kg, and vinorelbine: 8mg/kg (RGV), or LCL-161 and RGV together. LCL-161 was administered on day 7 as one dose given p.o. by gavage; RGV was also administered on day 7 as a single i.v. dose given by tail vein injection. Differences in survival (measured as the time to the development of limb paralysis) were evaluated with the Log-rank, Breslow, and Tarone-Ware tests across treatment arms. As a single agent LCL-161 was ineffective in controlling Raji-4RH tumor growth in vivo. However, the combination of LCL-161 with RGV (median survival 133 days) resulted in a statistically significant (P=0.002 with each test) improvement in overall survival when compared to RGV alone (median survival 53 days). In summary, IAPs, especially livin, contribute to rituximab/chemotherapy resistance in relapse/refractory B-cell lymphoma models. However, the IAP inhibitor LCL-161 can disrupt this resistance and augment the effect of chemotherapy in resistant lymphoma cell line models, as well as relapse/refractory lymphoma patient samples. In addition, LCL-161 can improve the anti-tumor activity of the RGV chemotherapy regimen, and increase overall survival in a mouse in vivo model of human rituximab/chemotherapy resistant lymphoma. Our data supports the continued investigation of LCL-161 as a novel and effective targeted agent for the treatment of aggressive rituximab relapse/refractory B-cell lymphomas. (Supported by a NHI SPORE Lymphoma grant: 5 P50 CA130805-04, a NIH grant R01 CA136907-01A1 and The Eugene and Connie Corasanti Lymphoma Research Fund) Disclosures No relevant conflicts of interest to declare.

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