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Retrospective study of treatment patterns and outcomes post-lenalidomide for multiple myeloma in Canada.

Eur J Haematol 2021 Jun 15. Epub 2021 Jun 15.

Cross Cancer Institute, University of Alberta, Canada.

Lenalidomide is an important component of initial therapy in newly-diagnosed multiple myeloma, either as maintenance therapy post-autologous stem cell transplantation (ASCT) or as first-line therapy with dexamethasone for patients' ineligible for ASCT (non-ASCT). This retrospective study investigated treatment patterns and outcomes for ASCT-eligible and -ineligible patients who relapsed after lenalidomide as part of first-line therapy, based on data from the Canadian Myeloma Research Group Database for patients treated between January 2007 and April 2019. Among 256 patients who progressed on lenalidomide maintenance therapy, 28. Read More

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Daratumumab provides a survival benefit in relapsed and refractory Multiple Myeloma, independent of baseline clinical characteristics: A meta-analysis.

Pharmacol Res Perspect 2021 Aug;9(4):e00797

Radiology Department, The People's Hospital of Pingyi County, Linyi, China.

Daratumumab was approved in patients with relapsed or refractory multiple myeloma (MM) who previously received proteasome inhibitors or immunomodulatory drugs. However, the efficacy and safety of the addition of daratumumab in subpopulations of patients with relapsed or refractory MM is still unknown. We systematically searched MEDLINE, EMBASE, and Cochrane for randomized controlled trials (inception to September 2020). Read More

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Prognostic impact of resistance to bortezomib and/or lenalidomide in carfilzomib-based therapies for relapsed/refractory multiple myeloma: The Kyoto Clinical Hematology Study Group, multicenter, pilot, prospective, observational study in Asian patients.

Cancer Rep (Hoboken) 2021 Jun 14:e1476. Epub 2021 Jun 14.

Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background: Combinatory strategies with carfilzomib (CFZ), a second-generation proteasome inhibitor, plus dexamethasone (DEX) with or without lenalidomide (LEN) have shown promising efficacy for patients with relapsed/refractory multiple myeloma (RRMM) in pivotal clinical trials. However, their effects on patients who were resistance to bortezomib (BTZ) and/or LEN have not been fully evaluated in a daily practice setting.

Aims: To evaluate the real-world efficacy and safety of CFZ-based treatments; that is, CFZ with LEN plus DEX (KRD therapy) and CFZ with DEX (KD therapy), in Asian patients, we conducted a multicenter pilot prospective observational study in the Kyoto Clinical Hematology Study Group. Read More

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Natural Phytochemicals as Novel Therapeutic Strategies to Prevent and Treat Parkinson's Disease: Current Knowledge and Future Perspectives.

Oxid Med Cell Longev 2021 25;2021:6680935. Epub 2021 May 25.

Department of Applied Life Science, Graduate School, BK21 Program, Konkuk University, Chungju 27478, Republic of Korea.

Parkinson's disease (PD) is the second-most common neurodegenerative chronic disease affecting both cognitive performance and motor functions in aged people. Yet despite the prevalence of this disease, the current therapeutic options for the management of PD can only alleviate motor symptoms. Research has explored novel substances for naturally derived antioxidant phytochemicals with potential therapeutic benefits for PD patients through their neuroprotective mechanism, targeting oxidative stress, neuroinflammation, abnormal protein accumulation, mitochondrial dysfunction, endoplasmic reticulum stress, neurotrophic factor deficit, and apoptosis. Read More

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Venetoclax for the Treatment of Multiple Myeloma: Outcomes Outside of Clinical Trials.

Am J Hematol 2021 Jun 11. Epub 2021 Jun 11.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester.

Introduction: Multiple myeloma (MM) remains an incurable disease despite incorporation of novel agents. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor is approved for some hematologic malignancies but not yet for MM, although clinical trials have shown efficacy in patients with MM particularly those harboring t(11;14).

Methods: We reviewed the medical records of relapsed and/or refractory MM patients to study the efficacy and safety of venetoclax used outside of clinical trials at Mayo Clinic between December 2016 and March 2019. Read More

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Efficacy of Qingre Huayu Fang on atherosclerotic vulnerable plaque in apolipoprotein E knockout mice: proteasome pathway involvement.

J Tradit Chin Med 2021 Jun;41(3):432-437

Department of Cardiology, Guizhou Provincial People's Hospital, Guiyang 520000, China.

Objective: To investigate the efficacy and mechanism of the Qingre Huayu Fang () on atherosclerotic vulnerable plaque in apolipoprotein E (ApoE) knockout mice through the ubiquitin proteasome pathway.

Methods: Sixty 8-week-old C57BL/6J ApoE knockout mice were fed a high-fat for 12 weeks and randomly divided into four treatment groups (n = 15 each): high-fat control, bortezomib (a proteasome inhibitor), bortezomib combined with Qingre Huayu Fang, and Qingre Huayu Fang alone. Aortic sections were examined for plaque development, inflammatory cell infiltration, type Ⅰ/Ⅲ collagen expression and immunohistochemical staining of CD40L, nuclear factor-kappa B (NF-κB)/P65 and ubiquitin. Read More

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The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma.

Ther Adv Hematol 2021 31;12:20406207211019622. Epub 2021 May 31.

Clinical Hematology Department and Clinical Trial Unit, Institut Català d'Oncologia at Hospital Germans Trias i Pujol, Badalona, Spain.

The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Read More

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Belantamab Mafodotin for the Treatment of Multiple Myeloma: An Overview of the Clinical Efficacy and Safety.

Drug Des Devel Ther 2021 2;15:2401-2415. Epub 2021 Jun 2.

Clinica di Ematologia Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Ancona, Ancona, Italy.

Despite the introduction of immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and, more recently, monoclonal antibodies (mAbs), in the chemotherapy regimens for newly diagnosed (NDMM) and relapsed/refractory MM (RRMM), the occurrence of drug resistance remains a challenge in MM patients. This is mainly in the advanced stage of the disease when treatments are limited, and the prognosis is abysmal. Nevertheless, novel molecules and therapeutic approaches are rapidly moving through the several phases of drug development and could address the need for new treatment options. Read More

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Anti-plasma cell treatment in refractory autoimmune hemolytic anemia in a child with multivisceral transplant.

Pediatr Transplant 2021 Jun 6:e14045. Epub 2021 Jun 6.

MedStar Georgetown University Hospital, Transplant Institute, Washington, DC, USA.

Background: Warm-antibody AIHA is known to complicate solid organ (SOT) and HSCT, the disease maybe refractory to standard therapy. Immunosuppressive therapies as well as IVIG, and rituximab have been the main stay of treatment. Over the past decade, B-lymphocyte targeted, anti-CD-20 antibody has been recognized in the treatment of autoimmune diseases and utilized in AIHA. Read More

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Ubiquitin-proteasome System Is a Promising Target for Killing Cisplatin-resistant Bladder Cancer Cells.

Anticancer Res 2021 Jun;41(6):2901-2912

Department of Urology, National Defense Medical College, Tokorozawa, Japan;

Background/aim: Activation of the ubiquitin-proteasome system (UPS) has been shown to be associated with drug resistance in cancer. Using bladder cancer cells, we investigated the association between UPS activation and cisplatin resistance and also the efficacy of UPS-targeting drugs.

Materials And Methods: We established cisplatin-resistant bladder cancer cells (J82-cisR, T24-cisR) and examined the activation status of the UPS and the efficacy of MLN7243, oprozomib, ixazomib, and RTS-V5. Read More

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Propensity-score matched analysis of the efficacy of maintenance/continuous therapy in newly diagnosed patients with multiple myeloma: a multicenter retrospective collaborative study of the Japanese Society of Myeloma.

J Cancer Res Clin Oncol 2021 Jun 2. Epub 2021 Jun 2.

Department of Hematology/Oncology, Higashi Nagoya National Hospital, Nagoya, Japan.

Background: Maintenance ± consolidation or continuous therapy is considered a standard of care for both transplant-eligible and -ineligible patients with multiple myeloma (MM). However, long-term benefits of such therapy have not yet been clarified in the context of clinical practice.

Purpose: To clarify the efficacy of maintenance/continuous approach, we retrospectively analyzed the cohort data of newly diagnosed MM patients by propensity-score matching based on age, gender, revised International Staging System (R-ISS) stage, and implementation of transplantation to reduce the bias due to confounding variables. Read More

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Evaluation of a First-in-Class Proteasome Inhibitor in Patients With Moderate to Severe Rosacea.

J Drugs Dermatol 2021 Jun;20(6):660-664

Background: Novel, effective, affordable therapies for rosacea are needed. Innovative methods of assessing response for rosacea treatments are needed as well. This trial was designed to evaluate efficacy and safety of ACU-D1, a novel inhibitor of the 26S protea-some for the treatment of moderate to severe rosacea in a first in human pilot study. Read More

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Respiratory syncytial virus induces β-adrenergic receptor dysfunction in human airway smooth muscle cells.

Sci Signal 2021 Jun 1;14(685). Epub 2021 Jun 1.

Departments of Pediatrics, Biochemistry and Molecular Biology, Tulane School of Medicine, New Orleans, LA 70112, USA.

Pharmacologic agonism of the β-adrenergic receptor (βAR) induces bronchodilation by activating the enzyme adenylyl cyclase to generate cyclic adenosine monophosphate (cAMP). βAR agonists are generally the most effective strategy to relieve acute airway obstruction in asthmatic patients, but they are much less effective when airway obstruction in young patients is triggered by infection with respiratory syncytial virus (RSV). Here, we investigated the effects of RSV infection on the abundance and function of βAR in primary human airway smooth muscle cells (HASMCs) derived from pediatric lung tissue. Read More

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NBM-BMX, an HDAC8 Inhibitor, Overcomes Temozolomide Resistance in Glioblastoma Multiforme by Downregulating the β-Catenin/c-Myc/SOX2 Pathway and Upregulating p53-Mediated MGMT Inhibition.

Int J Mol Sci 2021 May 31;22(11). Epub 2021 May 31.

Ph.D. Program in Environmental and Occupational Medicine, College of Medicine, Kaohsiung Medical University and National Health Research Institutes, Kaohsiung 807, Taiwan.

Although histone deacetylase 8 (HDAC8) plays a role in glioblastoma multiforme (GBM), whether its inhibition facilitates the treatment of temozolomide (TMZ)-resistant GBM (GBM-R) remains unclear. By assessing the gene expression profiles from short hairpin RNA of HDAC8 in the new version of Connectivity Map (CLUE) and cells treated by NBM-BMX (BMX)-, an HDAC8 inhibitor, data analysis reveals that the Wnt signaling pathway and apoptosis might be the underlying mechanisms in BMX-elicited treatment. This study evaluated the efficacy of cotreatment with BMX and TMZ in GBM-R cells. Read More

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Rapid Progress in Immunotherapies for Multiple Myeloma: An Updated Comprehensive Review.

Authors:
Hiroko Nishida

Cancers (Basel) 2021 May 31;13(11). Epub 2021 May 31.

Department of Pathology, Keio University, School of Medicine, Tokyo 160-8582, Japan.

Despite rapid advances in treatment approaches of multiple myeloma (MM) over the last two decades via proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs), their efficacies are limited. MM still remains incurable, and the majority of patients shortly relapse and eventually become refractory to existing therapies due to the genetic heterogeneity and clonal evolution. Therefore, the development of novel therapeutic strategies with different mechanisms of action represents an unmet need to achieve a deep and highly durable response as well as to improve patient outcomes. Read More

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Insight into Bortezomib Focusing on Its Efficacy against P-gp-Positive MDR Leukemia Cells.

Int J Mol Sci 2021 May 23;22(11). Epub 2021 May 23.

Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dúbravská cesta 9, 84505 Bratislava, Slovakia.

In this paper, we compared the effects of bortezomib on L1210 (S) cells with its effects on P-glycoprotein (P-gp)-positive variant S cells, which expressed P-gp either after selection with vincristine (R cells) or after transfection with a human gene encoding P-gp (T cells). Bortezomib induced the death-related effects in the S, R, and T cells at concentrations not exceeding 10 nM. Bortezomib-induced cell cycle arrest in the G2/M phase was more pronounced in the S cells than in the R or T cells and was related to the expression levels of cyclins, cyclin-dependent kinases, and their inhibitors. Read More

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Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model.

Int J Mol Sci 2021 May 25;22(11). Epub 2021 May 25.

Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany.

Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the first targeted alpha therapy approved, specifically targets bone metastases, where it disrupts the activity of both tumor cells and tumor-supporting bone cells in mouse models of breast and prostate cancer bone metastasis. Read More

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Targeting Reactive Oxygen Species Metabolism to Induce Myeloma Cell Death.

Cancers (Basel) 2021 May 17;13(10). Epub 2021 May 17.

Normandie University, INSERM, Université de Caen, F-14000 Caen, France.

Multiple myeloma (MM) is a common hematological disease characterized by the accumulation of clonal malignant plasma cells in the bone marrow. Over the past two decades, new therapeutic strategies have significantly improved the treatment outcome and patients survival. Nevertheless, most MM patients relapse underlying the need of new therapeutic approaches. Read More

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Role of Oxidative Stress and Nrf2/KEAP1 Signaling in Colorectal Cancer: Mechanisms and Therapeutic Perspectives with Phytochemicals.

Antioxidants (Basel) 2021 May 7;10(5). Epub 2021 May 7.

College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam 13488, Korea.

Colorectal cancer still has a high incidence and mortality rate, according to a report from the American Cancer Society. Colorectal cancer has a high prevalence in patients with inflammatory bowel disease. Oxidative stress, including reactive oxygen species (ROS) and lipid peroxidation, has been known to cause inflammatory diseases and malignant disorders. Read More

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Single Amino Acid Deletion at N-Terminus of the Target Antigen in DNA Vaccine Induces Altered CD8 T Cell Responses against Tumor Antigen.

Authors:
Takashi Imai

Vaccines (Basel) 2021 May 21;9(6). Epub 2021 May 21.

Department of Microbiology and Immunology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Since CD8 T cells have immunological memory and can eliminate tumor or infected cells, antigen-specific CD8 T cell inducing DNA vaccines are potential next-generation vaccines. However, the relationship between single amino acid deletion of target antigens in plasmid DNA vaccines and vaccine efficacy is not completely understood. To address this knowledge disparity and improve DNA vaccine development, two constructs cytosolic form of ovalbumin, pOVAv (346 amino acids) and pOVAy (345 amino acids) were constructed and compared. Read More

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Morphology, clearing efficacy, and mTOR dependency of the organelle autophagoproteasome.

Eur J Histochem 2021 Jun 1;65(s1). Epub 2021 Jun 1.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa; IRCCS Neuromed, Pozzilli (IS).

The interplay between autophagy (ATG) and ubiquitin proteasome (UP) cell-clearing systems was recently evidenced at biochemical and morphological levels, where subunits belonging to both pathways co-localize within a novel organelle named autophagoproteasome (APP). We previously documented that APP occurs at baseline conditions, while it is hindered by neurotoxicant administration. This is bound to the activity of the mechanistic target of rapamycin (mTOR), since APP is stimulated by mTOR inhibition, which in turn, is correlated with cell protection. Read More

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Shifting the paradigm in treating multi-factorial diseases: polypharmacological co-inhibitors of HDAC6.

RSC Med Chem 2021 Mar 11;12(2):178-196. Epub 2020 Dec 11.

Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy 20 N Pine St Baltimore MD 21201 USA

Multi-factorial diseases are illnesses that exploit multiple cellular processes, or stages within one process, and thus highly targeted therapies often succumb to the disease, losing efficacy as resistance sets in. Combination therapies have become a mainstay to battle these diseases, however these regimens are plagued with caveats. An emerging avenue to treat multi-factorial diseases is polypharmacology, wherein a single drug is rationally designed to bind multiple targets, and is widely touted to be superior to combination therapy by inherently addressing the latter's shortcomings, which include poor patient compliance, narrow therapeutic windows and spiraling healthcare costs. Read More

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M3258 is a selective inhibitor of the immunoproteasome subunit LMP7 (β5i) delivering efficacy in multiple myeloma models.

Mol Cancer Ther 2021 May 27. Epub 2021 May 27.

Merck KGaA, Biopharma Research & Development, Frankfurter Str. 250, 64293 Darmstadt, Germany.

Large multifunctional peptidase 7 (LMP7/β5i/PSMB8) is a proteolytic subunit of the immunoproteasome, which is predominantly expressed in normal and malignant hematolymphoid cells, including multiple myeloma (MM), and contributes to the degradation of ubiquitinated proteins. Described herein for the first time is the preclinical profile of M3258; an orally-bioavailable, potent, reversible and highly-selective LMP7 inhibitor. M3258 demonstrated strong antitumor efficacy in MM xenograft models, including a novel model of the human bone niche of MM. Read More

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Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL-AF4 fusion protein.

Sci Rep 2021 May 25;11(1):10883. Epub 2021 May 25.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, PRB, 720 S. Donahue Dr., Auburn, AL, 36849, USA.

Proteasome inhibitors bortezomib and carfilzomib are approved for the treatment of multiple myeloma and mantle cell lymphoma and have demonstrated clinical efficacy for the treatment of acute lymphoblastic leukemia (ALL). The t(4;11)(q21;q23) chromosomal translocation that leads to the expression of MLL-AF4 fusion protein and confers a poor prognosis, is the major cause of infant ALL. This translocation sensitizes tumor cells to proteasome inhibitors, but toxicities of bortezomib and carfilzomib may limit their use in pediatric patients. Read More

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Aldehyde Dehydrogenase 2 Mediates Alcohol-Induced Colorectal Cancer Immune Escape through Stabilizing PD-L1 Expression.

Adv Sci (Weinh) 2021 05 24;8(10):2003404. Epub 2021 Mar 24.

Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Esophageal Cancer Institute Guangzhou 510060 China.

Despite the great success of immunotherapy in a small subset of cancer patients, most colorectal cancer (CRC) patients do not respond to programmed cell death receptor 1 (PD-1) blockade immunotherapy. There is an urgent medical need to elucidate how cancer cells evade immune response and to develop novel means to boost the efficacy of immune checkpoint inhibitors. In this study, alcohol induces ligand programmed cell death receptor 1 (PD-L1) expression of CRC cells in vitro and in vivo. Read More

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Lenalidomide enhances the efficacy of anti-BCMA CAR-T treatment in relapsed/refractory multiple myeloma: a case report and revies of the literature.

Cancer Immunol Immunother 2021 May 18. Epub 2021 May 18.

Department of Hematology, Henan Province Hospital of Traditional Chinese Medicine (The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine), Institute of Hematology, Henan University of Traditional Chinese Medicine, Zhengzhou, 450002, China.

We report successful clinical experience using anti-BCMA CAR-T combined with lenalidomide in a patient who was refractory to a previous CAR-T treatment. The patient was a 51-year-old man, and was diagnosed with IgD-λ multiple myeloma(MM) in October 2015. 10 courses of chemotherapy including immunomodulators and proteasome inhibitors were used for remission and autologous hematopoietic stem cell transplantation was performed. Read More

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A phase II trial of continuous ixazomib, thalidomide and dexamethasone for relapsed and/or refractory multiple myeloma: the Australasian Myeloma Research Consortium (AMaRC) 16-02 trial.

Br J Haematol 2021 May 15. Epub 2021 May 15.

Alfred Health-Monash University, Melbourne, Victoria, Australia.

We evaluated the efficacy and tolerability of continuous ixazomib-thalidomide-dexamethasone (ITd: 4 mg, day 1, 8, 15; 100 mg daily; and 40 mg weekly). A total of 39 patients with relapsed/refractory multiple myeloma (RRMM) aged ≥18 years with one to three prior lines of therapy were enrolled from two tertiary centres in Victoria and South Australia, Australia. The overall response rate (ORR) was 56·4% with a clinical benefit rate of 71·8%. Read More

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Pegfilgrastim for primary prophylaxis of febrile neutropenia in multiple myeloma.

Support Care Cancer 2021 May 14. Epub 2021 May 14.

Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori "Dino Amadori" (IRST), IRCCS, Via Piero Maroncelli 40, Meldola, (FC), 47014, Italy.

Multiple myeloma (MM) survival rates have been substantially increased thanks to novel agents that have improved survival outcomes and shown better tolerability than treatments of earlier years. These new agents include immunomodulating imide drugs (IMiD) thalidomide and lenalidomide, the proteasome inhibitor bortezomib (PI), recently followed by new generation IMID pomalidomide, monoclonal antibodies daratumumab and elotuzumab, and next generation PI carfilzomib and ixazomib. However, even in this more promising scenario, febrile neutropenia remains a severe side effect of antineoplastic therapies and can lead to a delay and/or dose reduction in subsequent cycles. Read More

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Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis.

Drugs 2021 May 13. Epub 2021 May 13.

San Diego VA Medical Center (SDVAMC), San Diego, CA, USA.

Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that exerts its actions by engaging 5 G-protein-coupled receptors (S1PR1-S1PR5). S1P receptors are involved in several cellular and physiological events, including lymphocyte/hematopoietic cell trafficking. An S1P gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, regulates lymphocyte trafficking. Read More

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A Proteasome Mutation Sensitizes Cam3.II K13 Parasites to DHA and OZ439.

ACS Infect Dis 2021 May 10. Epub 2021 May 10.

Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.

Artemisinin-based combination therapies (ACTs), the World Health Organization-recommended first-line therapy for uncomplicated falciparum malaria, has led to significant decreases in malaria-associated morbidity and mortality in the past two decades. Decreased therapeutic efficacy of artemisinins, the cornerstone of ACTs, is threatening the gains made against this disease. As such, novel therapeutics with uncompromised mechanisms of action are needed to combat parasite-mediated antimalarial resistance. Read More

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