scholarly journals Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell–like spheroids, and tumor xenografts through multiple cell signaling pathways

2017 ◽  
Vol 127 (6) ◽  
pp. 1219-1230 ◽  
Author(s):  
Khadijeh Bijangi-Vishehsaraei ◽  
M. Reza Saadatzadeh ◽  
Haiyan Wang ◽  
Angie Nguyen ◽  
Malgorzata M. Kamocka ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Cell Survival ◽  
Apoptotic Cell ◽  
Primary Cultures ◽  
In Vivo Studies ◽  
Dna Breaks ◽  
Early Passage ◽  
Established Cell

OBJECTIVEDefects in the apoptotic machinery and augmented survival signals contribute to drug resistance in glioblastoma (GBM). Moreover, another complexity related to GBM treatment is the concept that GBM development and recurrence may arise from the expression of GBM stem cells (GSCs). Therefore, the use of a multifaceted approach or multitargeted agents that affect specific tumor cell characteristics will likely be necessary to successfully eradicate GBM. The objective of this study was to investigate the usefulness of sulforaphane (SFN)—a constituent of cruciferous vegetables with a multitargeted effect—as a therapeutic agent for GBM.METHODSThe inhibitory effects of SFN on established cell lines, early primary cultures, CD133-positive GSCs, GSC-derived spheroids, and GBM xenografts were evaluated using various methods, including GSC isolation and the sphere-forming assay, analysis of reactive oxygen species (ROS) and apoptosis, cell growth inhibition assay, comet assays for assessing SFN-triggered DNA damage, confocal microscopy, Western blot analysis, and the determination of in vivo efficacy as assessed in human GBM xenograft models.RESULTSSFN triggered the significant inhibition of cell survival and induced apoptotic cell death, which was associated with caspase 3 and caspase 7 activation. Moreover, SFN triggered the formation of mitochondrial ROS, and SFN-triggered cell death was ROS dependent. Comet assays revealed that SFN increased single- and double-strand DNA breaks in GBM. Compared with the vehicle control cells, a significantly higher amount of γ-H2AX foci correlated with an increase in DNA double-strand breaks in the SFN-treated samples. Furthermore, SFN robustly inhibited the growth of GBM cell–induced cell death in established cell cultures and early-passage primary cultures and, most importantly, was effective in eliminating GSCs, which play a major role in drug resistance and disease recurrence. In vivo studies revealed that SFN administration at 100 mg/kg for 5-day cycles repeated for 3 weeks significantly decreased the growth of ectopic xenografts that were established from the early passage of primary cultures of GBM10.CONCLUSIONSThese results suggest that SFN is a potent anti-GBM agent that targets several apoptosis and cell survival pathways and further preclinical and clinical studies may prove that SFN alone or in combination with other therapies may be potentially useful for GBM therapy.

scholarly journals Novel estradiol analogue induces apoptosis and autophagy in esophageal carcinoma cells

2014 ◽  
Vol 19 (1) ◽  
Author(s):  
Elize Wolmarans ◽  
Thandi Mqoco ◽  
Andre Stander ◽  
Sandra Nkandeu ◽  
Katherine Sippel ◽  
...  
Keyword(s):  
Cell Death ◽  
Esophageal Carcinoma ◽  
Ex Vivo ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Carcinoma Cells ◽  
In Vivo Studies ◽  
Apoptotic Pathway

AbstractCancer is the second leading cause of death in South Africa. The critical role that microtubules play in cell division makes them an ideal target for the development of chemotherapeutic drugs that prevent the hyperproliferation of cancer cells. The new in silico-designed estradiol analogue 2-ethyl-3-O-sulfamoylestra-1,3,5(10)16-tetraene (ESE-16) was investigated in terms of its in vitro antiproliferative effects on the esophageal carcinoma SNO cell line at a concentration of 0.18 μM and an exposure time of 24 h. Polarization-optical differential interference contrast and triple fluorescent staining (propidium iodide, Hoechst 33342 and acridine orange) revealed a decrease in cell density, metaphase arrest, and the occurrence of apoptotic bodies in the ESE-16-treated cells when compared to relevant controls. Treated cells also showed an increase in the presence of acidic vacuoles and lysosomes, suggesting the occurrence of autophagic processes. Cell death via autophagy was confirmed using the Cyto-ID autophagy detection kit and the aggresome detection assay. Results showed an increase in autophagic vacuole and aggresome formation in ESE-16 treated cells, confirming the induction of cell death via autophagy. Cell cycle progression demonstrated an increase in the sub-G1 fraction (indicative of the presence of apoptosis). In addition, a reduction in mitochondrial membrane potential was also observed, which suggests the involvement of apoptotic cell death induced by ESE-16 via the intrinsic apoptotic pathway. In this study, it was demonstrated that ESE-16 induces cell death via both autophagy and apoptosis in esophageal carcinoma cells. This study paves the way for future investigation into the role of ESE-16 in ex vivo and in vivo studies as a possible anticancer agent.

scholarly journals Protective Effect of Panaxynol Isolated from Panax vietnamensis against Cisplatin-Induced Renal Damage: In Vitro and In Vivo Studies

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 890
Author(s):  
Dahae Lee ◽  
Jaemin Lee ◽  
Kim Long Vu-Huynh ◽  
Thi Hong Van Le ◽  
Thi Hong Tuoi Do ◽  
...  
Keyword(s):  
Cell Death ◽  
Protective Effect ◽  
Renal Damage ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
Body Weight Loss ◽  
Apoptotic Cell Death ◽  
In Vivo Studies

Polyacetylenic compounds isolated from Panax species are comprised of non-polar C17 compounds, exhibiting anti-inflammatory, antitumor, and antifungal activities. Panaxynol represents the major component of the essential oils of ginseng. We investigated whether panaxynol isolated from Panax vietnamensis (Vietnamese ginseng, VG) could prevent cisplatin-induced renal damage induced in vitro and in vivo. Cisplatin-induced apoptotic cell death was observed by staining with annexin V conjugated with Alexa Fluor 488, and western blotting evaluated the molecular mechanism. Panaxynol at concentrations above 0.25 μM prevented cisplatin-induced LLC-PK1 porcine renal proximal tubular cell death. LLC-PK1 cells treated with cisplatin demonstrated an increase in apoptotic cell death, whereas pretreatment with 2 and 4 μM panaxynol decreased this effect. Cisplatin demonstrated a marked increase in the phosphorylation of c-Jun N-terminal kinase (JNK), P38, and cleaved caspase-3. However, pretreatment with 2 and 4 μM panaxynol reversed the upregulated phosphorylation of JNK, P38, and the expression of cleaved caspase-3. We confirmed that the protective effect of panaxynol isolated from P. vietnamensis in LLC-PK1 cells was at least partially mediated by reducing the cisplatin-induced apoptotic damage. In the animal study, panaxynol treatment ameliorated body weight loss and blood renal function markers and downregulated the mRNA expression of inflammatory mediators.

Autophagy Is a Relevant Cellular Process In CLL and Contributes to Drug Resistance of Flavopiridol

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 691-691
Author(s):  
Emilia Mahoney ◽  
Amy J. Johnson ◽  
Amy J. Wagner ◽  
Joshua Hessler ◽  
Sneha V. Gupta ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Er Stress ◽  
Cell Survival ◽  
Calcium Flux ◽  
Immunofluorescent Staining ◽  
Death Process ◽  
Potential Contribution

Abstract Abstract 691 Autophagy is an active process of intracellular degradation that occurs via sequestration of intracytoplasmic components (proteins, organelles) inside double membrane vesicles termed “autophagosomes”, followed by enzymatic degradation upon fusion with lysosomes. Autophagy is an adaptive process induced by cellular starvation but also contributes to development, aging, and pathogenesis of infections, neurodegenerative disease, atherosclerosis and cancer. In cancer, autophagy can function either as a cell survival signal or death response (i.e. type II cell death). To date, autophagy has not been characterized in chronic lymphocytic leukemia (CLL). The aim of our study is to investigate the presence and the role of autophagy in CLL and the potential contribution it may have to cell death or drug resistance with common therapeutics used in CLL. Our initial studies demonstrated that the essential cellular machinery for autophagy was present. CLL cells have a basal low level of autophagy when cultured in standard media that is actively promoted by cellular starvation or treatment with rapamycin. Given the potential contribution of autophagy in the death process or mechanism of drug resistance, we examined the influence of different therapeutics currently approved for CLL including chlorambucil, fludarabine, rituximab and dexamethasone. Cells were exposed to the drugs for four hours and examined by immunofluorescent staining of endogenous LC3 protein, an established marker of autophagy that becomes conjugated with phosphatydylethanolamine and recruited to the autophagosome membrane. Similar to rapamycin, fludarabine promotes autophagosome accumulation in all CLL samples tested, whereas dexamethasone caused this effect only in a subset. In contrast, no autophagosome accumulation was observed with chlorambucil or rituximab plus cross-linking.To determine the influence of this autophagic response on CLL cell survival, we next examined if chloroquine, which inhibits autophagy via preventing fusion of autophagosomes with lysosomes, affected fludarabine-mediated cell death at concentrations attainable in patients. Although chloroquine inhibited autophagy under these conditions as noted by confocal microscopy showing lack of co-localization between LC3 (autophagosome marker) and LAMP-2 (lysosome marker), it had no effect on fludarabine-mediated cell death. Subsequent studies showed that investigational agents including inhibitors of PI3-kinase, HSP-90, and cyclin-dependent kinases (CDK) each induced autophagy, while inhibitors of histone deacetylases (HDACs) did not. Notably, chloroquine enhanced cytotoxicity mediated by the CDK inhibitor flavopiridol in all patient samples examined, while it produced no effect on the cytotoxicity of the remaining agents. This sensitization to flavopiridol was most striking in CLL samples with the greatest viability after four hours of in vitro treatment with flavopiridol, as assessed by annexin/PI flow cytometry. Given that endoplasmic reticulum (ER) stress induces autophagy in normal cells, we examined this pathway in flavopiridol-treated CLL patient cells. These studies demonstrated that in a subset of samples, flavopiridol, but not fludarabine, promotes early intracellular ER-derived calcium flux, concomitant with the appearance of ER stress evidenced by quantitative real-time PCR showing increased gene expression of specific markers (XBP1, IRE1, Grp78) and standard PCR showing XBP1 splicing. To determine if this finding was relevant to the in vivo setting, we subsequently examined samples obtained serially from CLL patients during treatment with flavopiridol as part of two completed clinical trials at our institution. Similar to our in vitro studies, we found that flavopiridol actively induces autophagy in vivo through an ER stress-directed pathway. Collectively, our data demonstrate that autophagy is relevant to CLL biology and may serve as a pharmacodynamic marker of targeted therapy in CLL. Furthermore, induction of autophagy appears to contribute to flavopiridol resistance in CLL, whereas its role with other therapeutics is unclear. This work is supported by the Leukemia and Lymphoma Society, the D. Warren Brown Foundation, and the National Cancer Institute (CLL Research Consortium and OSU Leukemia SPORE). Disclosures: No relevant conflicts of interest to declare.

scholarly journals Functional Interaction of Hypoxia-Inducible Factor 2-Alpha and Autophagy Mediates Drug Resistance in Colon Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 755 ◽  
Author(s):  
Abril Saint-Martin ◽  
Jacobo Martínez-Ríos ◽  
M. Cristina Castañeda-Patlán ◽  
Miguel Angel Sarabia-Sánchez ◽  
Nydia Tejeda-Muñoz ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Drug Resistance ◽  
Cell Death ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Malignant Cells ◽  
Colon Cancer Cells ◽  
Mtor Inhibition

Hypoxia and the accumulation of hypoxia-inducible factors (HIFs) in tumors have been associated with therapeutic resistance and with autophagy establishment. We examined the effects of stable knockdown of HIF-1α or HIF-2α expression on autophagy and drug resistance in colon cancer cells. We found that under normoxic conditions, malignant cells exhibit increased basal levels of autophagy, compared with non-malignant cells, in addition to the previously reported coexpression of HIF-1α and HIF-2α. Knockdown of HIF-1α or HIF-2α expression resulted in increased autophagic and apoptotic cell death, indicating that the survival of cells is HIF-dependent. Cytotoxic-induced cell death was significantly increased by knockdown of HIFs but not by autophagy inhibition. Strikingly, although malignancy-resistant cells were sensitized to death by nutrient stress, the combination with HIF-2α depletion, but not with HIF-1α depletion, induced severe cell death. Oxidative stress levels were significantly increased as a result of HIF-2α specific inhibition or silencing suggesting that this may contribute to sensitize cells to death. The in vitro results were confirmed in vivo using a xenograft mouse model. We found that coordinated autophagy and mTOR inhibition enhanced cell death and induced tumor remission only in HIF-2α-silenced cells. Finally, using a specific HIF-2α inhibitor alone or in combination with drugs in patient-derived primary colon cancer cells, overcame their resistance to 5-FU or CCI-779, thus emphasizing the crucial role played by HIF-2α in promoting resistance and cell survival.

scholarly journals KUS121 attenuates the progression of monosodium iodoacetate-induced osteoarthritis in rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sachiko Iwai ◽  
Hanako O. Ikeda ◽  
Hisashi Mera ◽  
Kohei Nishitani ◽  
Motoo Saito ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Apoptotic Cell ◽  
Intraperitoneal Administration ◽  
Atp Depletion ◽  
Knee Joints ◽  
Cellular Protection ◽  
Monosodium Iodoacetate

AbstractCurrently there is no effective treatment available for osteoarthritis (OA). We have recently developed Kyoto University Substances (KUSs), ATPase inhibitors specific for valosin-containing protein (VCP), as a novel class of medicine for cellular protection. KUSs suppressed intracellular ATP depletion, endoplasmic reticulum (ER) stress, and cell death. In this study, we investigated the effects of KUS121 on chondrocyte cell death. In cultured chondrocytes differentiated from ATDC5 cells, KUS121 suppressed the decline in ATP levels and apoptotic cell death under stress conditions induced by TNFα. KUS121 ameliorated TNFα-induced reduction of gene expression in chondrocytes, such as Sox9 and Col2α. KUS121 also suppressed ER stress and cell death in chondrocytes under tunicamycin load. Furthermore, intraperitoneal administration of KUS121 in vivo suppressed chondrocyte loss and proteoglycan reduction in knee joints of a monosodium iodoacetate-induced OA rat model. Moreover, intra-articular administration of KUS121 more prominently reduced the apoptosis of the affected chondrocytes. These results demonstrate that KUS121 protects chondrocytes from stress-induced cell death in vitro and in vivo, and indicate that KUS121 is a promising novel therapeutic agent to prevent the progression of OA.

scholarly journals Pancreatic islet cell survival following islet isolation: the role of cellular interactions in the pancreas

1999 ◽  
Vol 161 (3) ◽  
pp. 357-364 ◽  
Author(s):  
A Ilieva ◽  
S Yuan ◽  
RN Wang ◽  
D Agapitos ◽  
DJ Hill ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Islet Cell ◽  
Apoptotic Cell ◽  
Specific Cell ◽  
Cellular Interactions ◽  
Pancreatic Islet Cell ◽  
Beneficial Result ◽  
Trophic Effect ◽  
Ductal Epithelium

The purpose of this study was to characterize the trophic effect of pancreatic duct cells on the islets of Langerhans. Ductal epithelium and islets were isolated from hamster pancreata. In addition, duct-conditioned medium (DCM) was prepared from primary duct cultures that had been passaged twice to remove other cellular elements. Three experimental groups were then established: Group 1, 100 islets alone; Group 2, 100 islets+80 duct fragments; and Group 3, 100 islets in 25% DCM. All tissues were embedded in rat tail collagen for up to 12 days and the influence of pancreatic ductal epithelium on islet cell survival was examined. By day 12, 20.6+/-3. 0% (S.E.M.) of the islets cultured alone developed central necrosis, compared with 6.7+/-2.0% of the islets co-cultured with ducts and 5.6+/-1.5% of the islets cultured in DCM (P<0.05). The presence of apoptotic cell death was determined by a TdT-mediated dUTP-biotin nick end labelling (TUNEL) assay and by a specific cell death ELISA. DNA fragmentation in islets cultured alone was significantly increased compared with islets cultured either in the presence of duct epithelium or in DCM (P<0.05). More than 80% of TUNEL-positive cells were situated in the inner 80% of the islet area, suggesting that most were beta-cells. DCM was analysed for known growth factors. The presence of a large amount of IGF-II (34 ng/ml) and a much smaller quantity of nerve growth factor (4 ng/ml) was identified. When the apoptosis studies were repeated to compare islets alone, islets+DCM and islets+IGF-II, the cell death ELISA indicated that IGF-II produced the same beneficial result as DCM when compared with islets cultured alone. We conclude that pancreatic ductal epithelium promotes islet cell survival. This effect appears to be mediated in a paracrine manner by the release of IGF-II from cells in the ductal epithelium.

Kinase cascades regulating entry into apoptosis

1997 ◽  
Vol 61 (1) ◽  
pp. 33-46
Author(s):  
P Anderson
Keyword(s):  
Cell Death ◽  
Cell Surface ◽  
Cell Survival ◽  
Tyrosine Kinases ◽  
Uv Light ◽  
Apoptotic Cell ◽  
Paracrine Factors ◽  
Surface Receptors ◽  
Promote Cell Survival ◽  
Necrosis Factor

All cells are constantly exposed to conflicting environment cues that signal cell survival or cell death. Survival signals are delivered by autocrine or paracrine factors that actively suppress a default death pathway. In addition to survival factor withdrawal, cell death can be triggered by environmental stresses such as heat, UV light, and hyperosmolarity or by dedicated death receptors (e.g., FAS/APO-1 and tumor necrosis factor [TNF] receptors) that are counterparts of growth factor or survival receptors at the cell surface. One of the ways that cells integrate conflicting exogenous stimuli is by phosphorylation (or dephosphorylation) of cellular constituents by interacting cascades of serine/threonine and tyrosine protein kinases (and phosphatases). Survival factors (e.g., growth factors and mitogens) activate receptor tyrosine kinases and selected mitogen-activated, cyclin-dependent, lipid-activated, nucleic acid-dependent, and cyclic AMP-dependent kinases to promote cell survival and proliferation, whereas environmental stress (or death factors such as FAS/APO-1 ligand and TNF-alpha) activates different members of these kinase families to inhibit cell growth and, under some circumstances, promote apoptotic cell death. Because individual kinase cascades can interact with one another, they are able to integrate conflicting exogenous stimuli and provide a link between cell surface receptors and the biochemical pathways leading to cell proliferation or cell death.

Overexpression of human Hsp27 inhibits serum-induced proliferation in airway smooth muscle myocytes and confers resistance to hydrogen peroxide cytotoxicity

2007 ◽  
Vol 293 (5) ◽  
pp. L1194-L1207 ◽  
Author(s):  
Sonemany Salinthone ◽  
Mariam Ba ◽  
Lisa Hanson ◽  
Jody L. Martin ◽  
Andrew J. Halayko ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Cell Death ◽  
Smooth Muscle ◽  
Cell Survival ◽  
Airway Smooth Muscle ◽  
Apoptotic Cell ◽  
Airway Remodeling ◽  
Small Heat Shock Protein ◽  
Nonmuscle Cells ◽  
Myocyte Proliferation

Airway smooth muscle (ASM) hypertrophy and hyperplasia are characteristics of asthma that lead to thickening of the airway wall and obstruction of airflow. Very little is known about mechanisms underlying ASM remodeling, but in vascular smooth muscle, it is known that progression of atherosclerosis depends on the balance of myocyte proliferation and cell death. Small heat shock protein 27 (Hsp27) is antiapoptotic in nonmuscle cells, but its role in ASM cell survival is unknown. Our hypothesis was that phosphorylation of Hsp27 may regulate airway remodeling by modifying proliferation, cell survival, or both. To test this hypothesis, adenoviral vectors were used to overexpress human Hsp27 in ASM cells. Cells were infected with empty vector (Ad5) or wild-type Hsp27 (AdHsp27 WT), and proliferation and death were assessed. Overexpressing Hsp27 WT caused a 50% reduction in serum-induced proliferation and increased cell survival after exposure to 100 μM hydrogen peroxide (H2O2) compared with mock-infected controls. Overexpression studies utilizing an S15A, S78A, and S82A non-phosphorylation mutant (AdHsp27 3A) and an S15D, S78D, and S82D pseudo-phosphorylation mutant (AdHsp27 3D) showed phosphorylation of Hsp27 was necessary for regulation of ASM proliferation, but not survival. Hsp27 provided protection against H2O2-induced cytotoxicity by upregulating cellular glutathione levels and preventing necrotic cell death, but not apoptotic cell death. The results support the notion that ASM cells can be stimulated to undergo proliferation and death and that Hsp27 may regulate these processes, thereby contributing to airway remodeling in asthmatics.

scholarly journals The Importance of Exosomal PD-L1 in Cancer Progression and Its Potential as a Therapeutic Target

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3247
Author(s):  
Lingxiao Ye ◽  
Zhengxin Zhu ◽  
Xiaochuan Chen ◽  
Haoran Zhang ◽  
Jiaqi Huang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cancer Progression ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Escape ◽  
Tumor Treatment

Binding of programmed cell death ligand 1 (PD-L1) to its receptor programmed cell death protein 1 (PD-1) can lead to the inactivation of cytotoxic T lymphocytes, which is one of the mechanisms for immune escape of tumors. Immunotherapy based on this mechanism has been applied in clinic with some remaining issues such as drug resistance. Exosomal PD-L1 derived from tumor cells is considered to play a key role in mediating drug resistance. Here, the effects of various tumor-derived exosomes and tumor-derived exosomal PD-L1 on tumor progression are summarized and discussed. Researchers have found that high expression of exosomal PD-L1 can inhibit T cell activation in in vitro experiments, but the function of exosomal PD-L1 in vivo remains controversial. In addition, the circulating exosomal PD-L1 has high potential to act as an indicator to evaluate the clinical effect. Moreover, therapeutic strategy targeting exosomal PD-L1 is discussed, such as inhibiting the biogenesis or secretion of exosomes. Besides, some specific methods based on the strategy of inhibiting exosomes are concluded. Further study of exosomal PD-L1 may provide an effective and safe approach for tumor treatment, and targeting exosomal PD-L1 by inhibiting exosomes may be a potential method for tumor treatment.

scholarly journals Plasmodium vivax and Drug Resistance

2021 ◽  
Author(s):  
Puji Budi Setia Asih ◽  
Din Syafruddin
Keyword(s):  
Drug Resistance ◽  
Molecular Basis ◽  
Indirect Evidence ◽  
Antimalarial Drugs ◽  
In Vivo Studies ◽  
In Vitro Cultivation ◽  
Radical Cure ◽  
The Status

Resistance to antimalarial drugs is a threat to global efforts to eliminate malaria by 2030. Currently, treatment for vivax malaria uses chloroquine or ACT for uncomplicated P. vivax whereas primaquine is given to eliminate latent liver stage infections (a method known as radical cure). Studies on P. vivax resistance to antimalarials and the molecular basis of resistance lags far behind the P. falciparum as in vitro cultivation of the P. vivax has not yet been established. Therefore, data on the P. vivax resistance to any antimalarial drugs are generated through in vivo studies or through monitoring of antimalarial treatments in mixed species infection. Indirect evidence through drug selective pressure on the parasites genome, as evidenced by the presence of the molecular marker(s) for drug resistance in areas where P. falciparum and P. vivax are distributed in sympatry may reflect, although require validation, the status of P. vivax resistance. This review focuses on the currently available data that may represent the state-of-the art of the P. vivax resistance status to antimalarial to anticipate the challenge for malaria elimination by 2030.

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