scholarly journals Ginsenoside Rg1 Suppresses Type 2 PRRSV Infection via NF-κB Signaling Pathway In Vitro, and Provides Partial Protection against HP-PRRSV in Piglet

Viruses ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1045 ◽  
Author(s):  
Yu ◽  
Yi ◽  
Ma ◽  
Wei ◽  
Cai ◽  
...  
Keyword(s):  
Respiratory Syndrome Virus ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Ginsenoside Rg1 ◽  
Virus Attachment ◽  
Current Vaccine ◽  
Anti Oxidant ◽  
Signaling Activation

Porcine reproductive and respiratory syndrome virus (PRRSV) is a huge threat to the modern pig industry, and current vaccine prevention strategies could not provide full protection against it. Therefore, exploring new anti-PRRSV strategies is urgently needed. Ginsenoside Rg1, derived from ginseng and notoginseng, is shown to exert anti-inflammatory, neuronal apoptosis-suppressing and anti-oxidant effects. Here we demonstrate Rg1-inhibited PRRSV infection both in Marc-145 cells and porcine alveolar macrophages (PAMs) in a dose-dependent manner. Rg1 treatment affected multiple steps of the PRRSV lifecycle, including virus attachment, replication and release at concentrations of 10 or 50 µM. Meanwhile, Rg1 exhibited broad inhibitory activities against Type 2 PRRSV, including highly pathogenic PRRSV (HP-PRRSV) XH-GD and JXA1, NADC-30-like strain HNLY and classical strain VR2332. Mechanistically, Rg1 reduced mRNA levels of the pro-inflammatory cytokines, including IL-1β, IL-8, IL-6 and TNF-α, and decreased NF-κB signaling activation triggered by PRRSV infection. Furthermore, 4-week old piglets intramuscularly treated with Rg1 after being challenged with the HP-PRRSV JXA1 strain display moderate lung injury, decreased viral load in serum and tissues, and an improved survival rate. Collectively, our study provides research basis and supportive clinical data for using Ginsenoside Rg1 in PRRSV therapies in swine.

scholarly journals ent-Epiafzelechin-(4α→8)-epiafzelechin extracted from Cassia javanica inhibits herpes simplex virus type 2 replication

2006 ◽  
Vol 55 (2) ◽  
pp. 201-206 ◽  
Author(s):  
Hua-Yew Cheng ◽  
Chien-Min Yang ◽  
Ta-Chen Lin ◽  
Den-En Shieh ◽  
Chun-Ching Lin
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Inhibitory Effect ◽  
Human Populations ◽  
Dependent Manner ◽  
Virus Attachment ◽  
Life Threatening ◽  
Simplex Virus

Herpes simplex virus (HSV) is a ubiquitous organism that causes infections in human populations throughout the world. It causes a variety of diseases ranging in severity from mild to life-threatening. In this study, ent-epiafzelechin-(4α→8)-epiafzelechin (EEE) extracted from the fresh leaves of Cassia javanica L. agnes de Wit (Leguminosae) was investigated for its in vitro anti-HSV-2 activity using XTT and plaque reduction assays. Results showed that EEE inhibited HSV-2 replication in a dose-dependent manner. The IC50 value was 83·8±10·9 and 166·8±12·9 μM for XTT and plaque reduction assays, respectively. EEE did not affect the viability and the proliferation of cells at antiviral concentrations. Mechanistic studies demonstrated that EEE prevented HSV-2 from penetrating the cell and also interfered with HSV-2 replication at the late stage of its life cycle. It also disturbed virus attachment but the inhibitory effect was minor. In summary, the conclusion of this study was that EEE exhibits various modes of action in suppressing HSV-2 multiplication.

scholarly journals Platycodin D Suppresses Type 2 Porcine Reproductive and Respiratory Syndrome Virus In Primary and Established Cell Lines

Viruses ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 657 ◽  
Author(s):  
Mingxin Zhang ◽  
Taofeng Du ◽  
Feixiang Long ◽  
Xia Yang ◽  
Yankuo Sun ◽  
...  
Keyword(s):  
Virus Production ◽  
In Vivo Studies ◽  
Progeny Virus ◽  
Respiratory Syndrome Virus ◽  
Dependent Manner ◽  
Triterpenoid Saponins ◽  
Platycodin D

Porcine reproductive and respiratory syndrome virus (PRRSV) is a continuous threat to the pork industry as it continues to cause significant economic loss worldwide. Currently, vaccination strategies provide very limited protection against PRRSV transmission. Consequently, there is an urgent need to develop new antiviral strategies. Platycodin D (PD) is one of the major bioactive triterpenoid saponins derived from Platycodon grandiflorum, a traditional Chinese medicine used as an expectorant for pulmonary diseases and a remedy for respiratory disorders. Here, we demonstrate that PD exhibits potent activity against PRRSV infection in Marc-145 cells and primary porcine alveolar macrophages. PD exhibited broad-spectrum inhibitory activities in vitro against high pathogenic type 2 PRRSV GD-HD strain and GD-XH strain as well as classical CH-1a and VR2332 strains. PD at concentrations ranging 1–4 μM significantly inhibited PRRSV RNA synthesis, viral protein expression and progeny virus production in a dose-dependent manner. EC50 values of PD against four tested PRRSV strains infection in Marc-145 cells ranged from 0.74 to 1.76 μM. Mechanistically, PD inhibited PRRSV replication by directly interacting with virions therefore affecting multiple stages of the virus life cycle, including viral entry and progeny virus release. In addition, PD decreased PRRSV- and LPS-induced cytokine (IFN-α, IFN-β, IL-1α, IL-6, IL-8 and TNF-α) production in PAMs. Altogether, our findings suggested that PD is a potent inhibitor of PPRSV infection in vitro. However, further in vivo studies are necessary to confirm PD as a potential novel and effective PPRSV inhibitor in swine.

scholarly journals Evaluation of the Inhibitory Effects of (E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(naphthalen-1-yl)prop-2-en-1-one (DiNap), a Natural Product Analog, on the Replication of Type 2 PRRSV In Vitro and In Vivo

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 887
Author(s):  
Amina Khatun ◽  
Sun Park ◽  
Nadeem Shabir ◽  
Salik Nazki ◽  
A-Rum Kang ◽  
...  
Keyword(s):  
Natural Product ◽  
Control Measure ◽  
Virus Transmission ◽  
Pharmacological Intervention ◽  
Respiratory Syndrome Virus ◽  
Dependent Manner ◽  
Swine Industry

DiNap [(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(naphthalen-1-yl)prop-2-en-1-one], an analog of a natural product (the chalcone flavokawain), was synthesized and characterized in this study. Porcine reproductive and respiratory syndrome virus (PRRSV) is the most challenging threat to the swine industry worldwide. Currently, commercially available vaccines are ineffective for controlling porcine reproductive and respiratory syndrome (PRRS) in pigs. Therefore, a pharmacological intervention may represent an alternative control measure for PRRSV infection. Hence, the present study evaluated the effects of DiNap on the replication of VR2332 (a prototype strain of type 2 PRRSV). Initially, in vitro antiviral assays against VR2332 were performed in MARC-145 cells and porcine alveolar macrophages (PAMs). Following this, a pilot study was conducted in a pig model to demonstrate the effects of DiNap following VR2332 infection. DiNap inhibited VR2332 replication in both cell lines in a dose-dependent manner, and viral growth was completely suppressed at concentrations ≥0.06 mM, without significant cytotoxicity. Consistent with these findings, in the pig study, DiNap also reduced viral loads in the serum and lungs and enhanced the weight gain of pigs following VR2332 infection, as indicated by comparison of the DiNap-treated groups to the untreated control (NC) group. In addition, DiNap-treated pigs had fewer gross and microscopic lesions in their lungs than NC pigs. Notably, virus transmission was also delayed by approximately 1 week in uninfected contact pigs within the same group after treatment with DiNap. Taken together, these results suggest that DiNap has potential anti-PRRSV activity and could be useful as a prophylactic or post-exposure treatment drug to control PRRSV infection in pigs.

scholarly journals In Vitro Studies on the Antioxidant Property and Inhibition of α-Amylase, α-Glucosidase, and Angiotensin I-Converting Enzyme by Polyphenol-Rich Extracts from Cocoa (Theobroma cacao) Bean

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Ganiyu Oboh ◽  
Ayokunle O. Ademosun ◽  
Adedayo O. Ademiluyi ◽  
Olasunkanmi S. Omojokun ◽  
Esther E. Nwanna ◽  
...  
Keyword(s):  
Enzyme Activities ◽  
Theobroma Cacao ◽  
Antioxidant Property ◽  
Cocoa Bean ◽  
Dependent Manner ◽  
Converting Enzyme ◽  
Angiotensin I Converting Enzyme ◽  
Dose Dependent

Background. This study sought to investigate the antidiabetic and antihypertensive mechanisms of cocoa (Theobroma cacao) bean through inhibition of α-amylase, α-glucosidase, angiotensin-1 converting enzyme, and oxidative stress. Methodology. The total phenol and flavonoid contents of the water extractable phytochemicals from the powdered cocoa bean were determined and the effects of the extract on α-amylase, α-glucosidase, and angiotensin-1 converting enzyme activities were investigated in vitro. Furthermore, the radicals [1,1-diphenyl-2 picrylhydrazyl (DPPH), 2,2..-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS), hydroxyl (OH), and nitric oxide (NO)] scavenging ability and ferric reducing antioxidant property of the extract were assessed. Results. The results revealed that the extract inhibited α-amylase (1.81 ± 0.22 mg/mL), α-glucosidase (1.84 ± 0.17 mg/mL), and angiotensin-1 converting enzyme (0.674 ± 0.06 mg/mL [lungs], 1.006 ± 0.08 mg/mL [heart]) activities in a dose-dependent manner and also showed dose-dependent radicals [DPPH (16.94 ± 1.34 mg/mL), NO (6.98 ± 0.886 mg/mL), OH (3.72 ± 0.26 mg/mL), and ABTS (15.7 ± 1.06 mmol/TEAC·g] scavenging ability. Conclusion. The inhibition of α-amylase, α-glucosidase, and angiotensin-1 converting enzyme activities by the cocoa bean extract could be part of the possible mechanism by which the extract could manage and/or prevent type-2 diabetes and hypertension.

scholarly journals Estrogen Up-Regulates Hepatic Expression of Suppressors of Cytokine Signaling-2 and -3 in Vivo and in Vitro

Endocrinology ◽  
2004 ◽  
Vol 145 (12) ◽  
pp. 5525-5531 ◽  
Author(s):  
Gary M. Leong ◽  
Sofia Moverare ◽  
Jesena Brce ◽  
Nathan Doyle ◽  
Klara Sjögren ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Hepatoma Cells ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Wild Type ◽  
Hepatic Expression ◽  
Suppressors Of Cytokine Signaling

Abstract Suppressors of cytokine signaling (SOCS) are important negative regulators of cytokine action. We recently reported that estrogen stimulates SOCS-2 expression and inhibits GH signaling in kidney cells. The effects of estrogen on SOCS expression in other tissues are unclear. The aim of this study was to investigate in vivo and in vitro whether estrogen affected SOCS expression in the liver, a major target organ of GH. The in vivo hepatic effects of estrogen on ovariectomized mice lacking estrogen receptor (ER)-α, ERβ, or both and their wild-type littermates were examined by DNA microarray analysis. In vitro, the effects of estrogen on SOCS expression in human hepatoma cells were examined by reverse transcription quantitative PCR. Long-term (3 wk) estrogen treatment induced a 2- to 3-fold increase in hepatic expression of SOCS-2 and -3 in wild-type and ERβ knockout mice but not in those lacking ERα or both ER subtypes. Short-term treatment (at 24 h) increased the mRNA level of SOCS-3 but not SOCS-2. In cultured hepatoma cells, estrogen increased SOCS-2 and -3 mRNA levels by 2-fold in a time- and dose-dependent manner (P < 0.05). Estrogen induced murine SOCS-3 promoter activity by 2-fold (P < 0.05) in constructs containing a region between nucleotides −1862 and −855. Moreover, estrogen and GH had additive effects on the SOCS-3 promoter activity. In summary, estrogen, via ERα, up-regulated hepatic expression of SOCS-2 and -3, probably through transcriptional activation. This indicates a novel mechanism of estrogen regulation of cytokine action.

scholarly journals Tumor-Stroma Crosstalk Enhances REG3A Expressions that Drive the Progression of Hepatocellular Carcinoma

2020 ◽  
Vol 21 (2) ◽  
pp. 472 ◽  
Author(s):  
Yuri Cho ◽  
Min Ji Park ◽  
Koeun Kim ◽  
Jae-Young Park ◽  
Jihye Kim ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Microarray Analysis ◽  
Cdna Microarray ◽  
Tumor Stroma ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Cdna Microarray Analysis ◽  
Hcc Cells

Abstract: Background: Crosstalk between tumors and their microenvironment plays a crucial role in the progression of hepatocellular carcinoma (HCC). However, there is little existing information about the key signaling molecule that modulates tumor-stroma crosstalk. Methods: Complementary DNA (cDNA) microarray analysis was performed to identify the key molecule in tumor-stroma crosstalk. Subcutaneous xenograft in vivo murine model, immunoblotting, immunofluorescence, and real-time polymerase chain reaction using HCC cells and tissues were performed. Results: The key molecule, regenerating gene protein-3A (REG3A), was most significantly enhanced when coculturing HCC cells and activated human hepatic stellate cells (HSCs) (+8.2 log) compared with monoculturing HCC cells using cDNA microarray analysis. Downregulation of REG3A using small interfering RNA significantly decreased the proliferation of HSC-cocultured HCC cells in vitro and in vivo, and enhanced deoxycholic acid-induced HCC cell apoptosis. Crosstalk-induced REG3A upregulation was modulated by platelet-derived growth factor ββ (PDGF-ββ) in p42/44-dependent manner. REG3A mRNA levels in human HCC tissues were upregulated 1.8-fold compared with non-tumor tissues and positively correlated with PDGF-ββ levels. Conclusions: REG3A/p42/44 pathway/PDGF-ββ signaling plays a significant role in hepatocarcinogenesis via tumor-stroma crosstalk. Targeting REG3A is a potential novel therapeutic target for the management of HCCs by inhibiting crosstalk between HCC cells and HSCs.

scholarly journals Human Proximal Tubule Epithelial Cells (HK-2) as a Sensitive In Vitro System for Ochratoxin A Induced Oxidative Stress

Toxins ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 787
Author(s):  
Enrique García-Pérez ◽  
Dojin Ryu ◽  
Hwa-Young Kim ◽  
Hae Dun Kim ◽  
Hyun Jung Lee
Keyword(s):  
Oxidative Stress ◽  
Ochratoxin A ◽  
Cell Lines ◽  
Time Dependent ◽  
Mrna Levels ◽  
Dependent Manner ◽  
In Vitro System ◽  
Glutathione Peroxidase 1 ◽  
Glucose 6 Phosphate Dehydrogenase

Ochratoxin A (OTA) is a mycotoxin that is potentially carcinogenic to humans. Although its mechanism remains unclear, oxidative stress has been recognized as a plausible cause for the potent renal carcinogenicity observed in experimental animals. The effect of OTA on oxidative stress parameters in two cell lines of LLC-PK1 and HK-2 derived from the kidneys of pig and human, respectively, were investigated and compared. We found that the cytotoxicity of OTA on LLC-PK1 and HK-2 cells was dose- and time-dependent in both cell lines. Furthermore, increased intracellular reactive oxygen species (ROS) induced by OTA in both cell lines were observed in a time-dependent manner. Glutathione (GSH) was depleted by OTA at >48 h in HK-2 but not in LLC-PK1 cells. While the mRNA levels of glucose-6-phosphate dehydrogenase (G6PD) and glutathione peroxidase 1 (GPX1) in LLC-PK1 were down-regulated by 0.67- and 0.66-fold, respectively, those of catalase (CAT), glutathione reductase (GSR), and superoxide dismutase 1 (SOD) in HK-2 were up-regulated by 2.20-, 2.24-, and 2.75-fold, respectively, after 72 h exposure to OTA. Based on these results, we conclude that HK-2 cells are more sensitive to OTA-mediated toxicity than LLC-PK1, and OTA can cause a significant oxidative stress in HK-2 as indicated by changes in the parameter evaluated.

scholarly journals Antiviral Effect of Lithium Chloride and Diammonium Glycyrrhizinate on Porcine Deltacoronavirus In Vitro

Pathogens ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 144 ◽  
Author(s):  
Xiaofeng Zhai ◽  
Shilei Wang ◽  
Mengyan Zhu ◽  
Wei He ◽  
Zhongzhou Pan ◽  
...  
Keyword(s):  
Lithium Chloride ◽  
Early Stage ◽  
Antiviral Effect ◽  
Antiviral Drugs ◽  
New Drugs ◽  
Interspecies Transmission ◽  
Dependent Manner ◽  
Virus Attachment ◽  
Induced Apoptosis

Porcine deltacoronavirus (PDCoV) is an emerging global swine virus that has a propensity for interspecies transmission. It was identified in Hong Kong in 2012. Given that neither specific antiviral drugs nor vaccines are available for newly emerging porcine deltacoronavirus, searching for effective antiviral drugs is a high priority. In this study, lithium chloride (LiCl) and diammonium glycyrrhizinate (DG), which are host-acting antivirals (HAAs), were tested against PDCoV. We found that LiCl and DG inhibited PDCoV replication in LLC-PK1 cells in a dose-dependent manner. The antiviral effects of LiCl and DG occurred at the early stage of PDCoV replication, and DG also inhibited virus attachment to the cells. Moreover, both drugs inhibited PDCoV-induced apoptosis in LLC-PK1 cells. This study suggests LiCl and DG as new drugs for the treatment of PDCoV infection.

scholarly journals Wnt/β-catenin signaling contributes to articular cartilage homeostasis through lubricin induction in the superficial zone

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Fengjun Xuan ◽  
Fumiko Yano ◽  
Daisuke Mori ◽  
Ryota Chijimatsu ◽  
Yuji Maenohara ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Mechanical Loading ◽  
Cartilage Degeneration ◽  
Mrna Levels ◽  
Superficial Zone ◽  
Gain Of Function ◽  
Wnt Ligands ◽  
Signaling Activation ◽  
Signaling Activity

Abstract Background Both loss- and gain-of-function of Wnt/β-catenin signaling in chondrocytes result in exacerbation of osteoarthritis (OA). Here, we examined the activity and roles of Wnt/β-catenin signaling in the superficial zone (SFZ) of articular cartilage. Methods Wnt/β-catenin signaling activity was analyzed using TOPGAL mice. We generated Prg4-CreERT2;Ctnnb1fl/fl and Prg4-CreERT2;Ctnnb1-ex3fl/wt mice for loss- and gain-of-function, respectively, of Wnt/β-catenin signaling in the SFZ. Regulation of Prg4 expression by Wnt/β-catenin signaling was examined in vitro, as were upstream and downstream factors of Wnt/β-catenin signaling in SFZ cells. Results Wnt/β-catenin signaling activity, as determined by the TOPGAL reporter, was high specifically in the SFZ of mouse adult articular cartilage, where Prg4 is abundantly expressed. In SFZ-specific β-catenin-knockout mice, OA development was significantly accelerated, which was accompanied by decreased Prg4 expression and SFZ destruction. In contrast, Prg4 expression was enhanced and cartilage degeneration was suppressed in SFZ-specific β-catenin-stabilized mice. In primary SFZ cells, Prg4 expression was downregulated by β-catenin knockout, while it was upregulated by β-catenin stabilization by exon 3 deletion or treatment with CHIR99021. Among Wnt ligands, Wnt5a, Wnt5b, and Wnt9a were highly expressed in SFZ cells, and recombinant human WNT5A and WNT5B stimulated Prg4 expression. Mechanical loading upregulated expression of these ligands and further promoted Prg4 transcription. Moreover, mechanical loading and Wnt/β-catenin signaling activation increased mRNA levels of Creb1, a potent transcription factor for Prg4. Conclusions We demonstrated that Wnt/β-catenin signaling regulates Prg4 expression in the SFZ of mouse adult articular cartilage, which plays essential roles in the homeostasis of articular cartilage.

ZAP-70 Expression Is Associated with Increased Migration to SDF-1 in Chronic Lymphocytic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 587-587
Author(s):  
Yuji Miura ◽  
Elinor Lee ◽  
Federica Gibellini ◽  
Therese White ◽  
Gerald Marti ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cxcr4 Expression ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Short Exposure ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Western Blots ◽  
Stroma Cell

Abstract Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature B lymphocytes in the peripheral blood (PB), lymph nodes (LN) and bone marrow (BM). Increasing evidence suggests that CLL cells depend on survival and proliferation signals provided by stroma cells in LN and BM. The chemokine receptor CXCR4 (CD184) and its ligand stromal cell-derived factor-1 (SDF-1) play an important role in trafficking of lymphocytes and may guide CLL cells to stroma cell niches. ZAP70 expression has prognostic value in CLL but the functional consequences of ZAP70 expression remain incompletely defined. Given that ZAP70 has been implicated in CXCR4 signaling its expression could enhance migration to SDF-1 and thereby promote interactions with stroma cells. As measured by flow cytometry, CXCR4 expression on leukemic cells obtained from different anatomic sites differed; cells from the PB (n=24, median 71% above isotype control) expressed CXCR4 more strongly than cells from BM (n=21, median 39%) and from LN (n=9, median 24%). Expression of CD69, an activation marker, followed a reverse pattern with cells from LN and BM typically showing higher expression than cells from PB, albeit with not detectable difference in expression in several patients. In vitro CLL cells from PB migrated in a dose dependent manner to SDF-1, and cells that had migrated down-modulated CXCR4 expression (89% before migration - 54% after migration). After exposure to SDF-1 CXCR4 expression decreased rapidly and remained virtually absent for at least 24 hours. Several mechanisms apparently decrease CXCR4 expression after contact with SDF-1, including internalization (given rapid re-expression of CXCR4 when SDF-1 is washed off after short exposure), protein degradation or inhibition of translation (evidenced by a decrease in total CXCR4 protein on Western blots), and mRNA degradation or transcriptional inhibition (decrease in mRNA levels more than 6 hours from SDF-1 exposure). In vitro migration of ZAP70(+) CLL cells toward SDF-1 through a 5μm membrane (Migration Index [MI] of 12.0, n=5) was significantly increased compared to ZAP70(−) CLL cells (MI of 2.9, n=4, p<0.05). To exclude effects of contaminating cells we repeated these assays with purified CLL cells (negative selection) with similar results. To model the complex interactions of CLL cells with stroma, we cultured PB derived leukemic cells with or without murine marrow stroma cells (S17). CXCR4 expression on CD19+ cells decreased from 90% without S17 to 50% when cultured on S17 cells, consistent with the known SDF-1 secretion by the murine stroma cell line. Conversely, CD69 expression increased from 58% without S17 to 71% with S17 cells. In addition, culturing of CLL cells on an S17 stroma cell layer extended their survival by several weeks when compared to cultures without S17 cells. Our data is consistent with a model in which CLL cells migrate along an SDF-1 gradient to stroma cell niches in BM and LN where they are activated. ZAP70 expression is associated with more effective migration in an SDF-1 gradient and thereby may facilitate access to growth and survival signals which then could contribute to the more progressive nature of ZAP70(+) CLL. The interaction between leukemic cells and stroma may represent a novel target for therapy of patients with CLL.

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