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Glutaminolysis-induced mTORC1 activation drives non-alcoholic steatohepatitis progression.

J Hepatol 2021 May 4. Epub 2021 May 4.

Universitat Rovira i Virgili, Department of Medicine and Surgery, Reus, Spain; Unitat de Recerca Biomèdica (URB-CRB), Hospital Universitari de Sant Joan, Institut d'Investigacio Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain; The Campus of International Excellence Southern Catalonia, Tarragona, Spain. Electronic address:

Background & Aims: A holistic insight on the relationship between obesity and metabolic dysfunction-associated fatty liver disease is an unmet clinical need. Omics investigations can be used to investigate the multifaceted role of altered mitochondrial pathways to promote nonalcoholic steatohepatitis, a major risk factor for liver disease-associated death. There are no specific treatments but remission via surgery might offer an opportunity to examine the signaling processes that govern the complex spectrum of chronic liver diseases observed in extreme obesity. Read More

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Ilex kudingcha C.J. Tseng Mitigates Phenotypic Characteristics of Human Autism Spectrum Disorders in a Drosophila Melanogaster Rugose Mutant.

Neurochem Res 2021 May 5. Epub 2021 May 5.

Center for Supporting Pharmaceutical Education, Daiichi University of Phamacy, Fukuoka, 815-8511, Japan.

Autism spectrum disorders (ASD) have heterogeneous etiologies involving dysfunction of central nervous systems, for which no effective pan-specific treatments are available. Ilex kudingcha (IK) C.J. Read More

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Conformational interconversion of MLKL and disengagement from RIPK3 precede cell death by necroptosis.

Nat Commun 2021 04 13;12(1):2211. Epub 2021 Apr 13.

Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

Phosphorylation of the MLKL pseudokinase by the RIPK3 kinase leads to MLKL oligomerization, translocation to, and permeabilization of, the plasma membrane to induce necroptotic cell death. The precise choreography of MLKL activation remains incompletely understood. Here, we report Monobodies, synthetic binding proteins, that bind the pseudokinase domain of MLKL within human cells and their crystal structures in complex with the human MLKL pseudokinase domain. Read More

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Nrf2 as a potential target for Parkinson's disease therapy.

J Mol Med (Berl) 2021 Apr 12. Epub 2021 Apr 12.

The Institute of Medicine, Qiqihar Medical University, 333 BuKui Street, JianHua District, Qiqihar, 161006, China.

Parkinson's disease (PD) is a complex neurodegenerative disorder featuring both motor and nonmotor symptoms associated with a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Conventionally, PD treatment options have focused on dopamine replacement and provide only symptomatic relief. However, disease-modifying therapies are still unavailable. Read More

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Bruton's tyrosine kinase: an emerging targeted therapy in myeloid cells within the tumor microenvironment.

Cancer Immunol Immunother 2021 Apr 5. Epub 2021 Apr 5.

Department of Surgery, Division of Surgical Oncology, Tzagournis Medical Research Facility, The Ohio State University, Columbus, OH, USA.

Bruton's tyrosine kinase (BTK) is a non-receptor kinase belonging to the Tec family of kinases. The role of BTK in B cell receptor signaling is well defined and is known to play a key role in the proliferation and survival of malignant B cells. Moreover, BTK has been found to be expressed in cells of the myeloid lineage. Read More

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5-Aryl-1-Arylideneamino-1-Imidazole-2(3)-Thiones: Synthesis and In Vitro Anticancer Evaluation.

Molecules 2021 Mar 18;26(6). Epub 2021 Mar 18.

Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Port Said University, Port Said 42526, Egypt.

A novel series of arylidene amino imidazole-2-thiones were synthesized, identified using IR, H-NMR, and C-NMR spectral data. Cytotoxic effect of the prepared compounds was carried out utilizing three cancer cell lines; MCF-7 breast cancer, HepG2 liver cancer, and HCT-116 colon cancer cell lines. Imidazole derivative was the most potent of all against three cell lines. Read More

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Distinct Regulation of Dopamine D3 Receptor in the Basolateral Amygdala and Dentate Gyrus during the Reinstatement of Cocaine CPP Induced by Drug Priming and Social Stress.

Int J Mol Sci 2021 Mar 18;22(6). Epub 2021 Mar 18.

Group of Cellular and Molecular Pharmacology, Department of Pharmacology, University of Murcia, 30120 Murcia, Spain.

Relapse in the seeking and intake of cocaine is one of the main challenges when treating its addiction. Among the triggering factors for the recurrence of cocaine use are the re-exposure to the drug and stressful events. Cocaine relapse engages the activity of memory-related nuclei, such as the basolateral amygdala (BLA) and the hippocampal dentate gyrus (DG), which are responsible for emotional and episodic memories. Read More

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Sofosbuvir Selects for Drug-Resistant Amino Acid Variants in the Zika Virus RNA-Dependent RNA-Polymerase Complex In Vitro.

Int J Mol Sci 2021 Mar 6;22(5). Epub 2021 Mar 6.

Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy.

The nucleotide analog sofosbuvir, licensed for the treatment of hepatitis C, recently revealed activity against the Zika virus (ZIKV) in vitro and in animal models. However, the ZIKV genetic barrier to sofosbuvir has not yet been characterized. In this study, in vitro selection experiments were performed in infected human hepatoma cell lines. Read More

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Centriole-less pericentriolar material serves as a microtubule organizing center at the base of C. elegans sensory cilia.

Curr Biol 2021 Mar 24. Epub 2021 Mar 24.

Department of Biology, Stanford University, 371 Serra Mall, Stanford, 94305, CA, USA. Electronic address:

During mitosis in animal cells, the centrosome acts as a microtubule organizing center (MTOC) to assemble the mitotic spindle. MTOC function at the centrosome is driven by proteins within the pericentriolar material (PCM), however the molecular complexity of the PCM makes it difficult to differentiate the proteins required for MTOC activity from other centrosomal functions. We used the natural spatial separation of PCM proteins during mitotic exit to identify a minimal module of proteins required for centrosomal MTOC function in C. Read More

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CXCL2 benefits acute myeloid leukemia cells in hypoxia.

Int J Lab Hematol 2021 Apr 1. Epub 2021 Apr 1.

Department of Hematology, The First Affiliated Hospital of Lanzhou University, Lanzhou, China.

Introduction: Drug resistance and relapse of acute myeloid leukemia (AML) is still an important problem in the treatment of leukemia. Leukemia outbreak causes severe hypoxia in bone marrow (BM), remolding BM microenvironment (niche), and transforming hematopoietic stem cell (HSC) niche into leukemia stem cell (LSC) niche. AML cells and the microenvironment usually conduct "cross-talk" through cytokines to anchor resistant AML cells into LSC niche, thus supporting their survival. Read More

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Molecular changes of Arabidopsis thaliana plastoglobules facilitate thylakoid membrane remodeling under high light stress.

Plant J 2021 Mar 30. Epub 2021 Mar 30.

Department of Biochemistry and Molecular Biology, Plant Resilience Institute, Michigan State University, East Lansing, MI, USA.

Plants require rapid responses to adapt to environmental stresses. This includes dramatic changes in the size and number of plastoglobule lipid droplets within chloroplasts. Although the morphological changes of plastoglobules are well documented, little is known about the corresponding molecular changes. Read More

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Thymulin and peroxiredoxin 6 have protective effects against streptozotocin-induced type 1 diabetes in mice.

Int J Immunopathol Pharmacol 2021 Jan-Dec;35:20587384211005645

Institute of Cell Biophysics of the Russian Academy of Sciences, PSCBR RAS, Pushchino, Moscow Region, Russia.

Protective effects of peroxiredoxin 6 (PRDX6) in RIN-m5F β-cells and of thymulin in mice with alloxan-induced diabetes were recently reported. The present work was aimed at studying the efficiency of thymulin and PRDX6 in a type 1 diabetes mellitus model induced by streptozotocin in mice. Effects of prolonged treatment with PRDX6 or thymic peptide thymulin on diabetes development were evaluated. Read More

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WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity.

Science 2021 03;371(6536)

Mount Sinai Hospital, Toronto, Ontario, Canada.

Cytoskeletal regulatory protein dysfunction has been etiologically linked to inherited diseases associated with immunodeficiency and autoimmunity, but the mechanisms involved are incompletely understood. Here, we show that conditional ablation in T cells causes severe autoimmunity associated with increased mammalian target of rapamycin (mTOR) activation and metabolic reprogramming that engender spontaneous activation and accelerated differentiation of peripheral T cells. These mice also manifest diminished antigen-specific T cell responses associated with increased inhibitory receptor expression, dysregulated mitochondrial function, and reduced cell survival upon activation. Read More

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PADI2-Catalyzed MEK1 Citrullination Activates ERK1/2 and Promotes IGF2BP1-Mediated SOX2 mRNA Stability in Endometrial Cancer.

Adv Sci (Weinh) 2021 Mar 29;8(6):2002831. Epub 2021 Jan 29.

State Key Laboratory of Reproductive Medicine Nanjing Medical University Nanjing Jiangsu 211166 China.

Peptidylarginine deiminase II (PADI2) converts positively charged arginine residues to neutrally charged citrulline, and this activity has been associated with the onset and progression of multiple cancers. However, a role for PADI2 in endometrial cancer (EC) has not been previously explored. This study demonstrates that PADI2 is positively associated with EC proregression. Read More

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CDK4/6 inhibitors as adjuvant treatment for hormone receptor-positive, HER2-negative early breast cancer: a systematic review and meta-analysis.

ESMO Open 2021 Apr 18;6(2):100091. Epub 2021 Mar 18.

Academic Trials Promoting Team, Institut Jules Bordet and l'Université Libre de Bruxelles (ULB), Brussels, Belgium.

Background: The combination of cyclin-dependent kinases 4/6 inhibitors (CDK4/6is) and endocrine therapy (ET) is standard of care for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (BC). However, studies evaluating adjuvant CDK4/6is provided contradictory results thus far.

Materials And Methods: We conducted a systematic review and meta-analysis to assess if the addition of CDK4/6is to adjuvant ET impacts on survival's outcomes and safety of patients with HR+/HER2- early BC (EBC). Read More

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First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer.

Cochrane Database Syst Rev 2021 03 18;3:CD010383. Epub 2021 Mar 18.

Institute of Translational Medicine, University of Liverpool, Bebington, UK.

Background: Epidermal growth factor receptor (EGFR) mutation positive (M+) non-small cell lung cancer (NSCLC) is an important subtype of lung cancer comprising 10% to 15% of non-squamous tumours. This subtype is more common in women than men, is less associated with smoking, but occurs at a younger age than sporadic tumours.

Objectives: To assess the clinical effectiveness of single-agent or combination EGFR therapies used in the first-line treatment of people with locally advanced or metastatic EGFR M+ NSCLC compared with other cytotoxic chemotherapy (CTX) agents used alone or in combination, or best supportive care (BSC). Read More

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(3α)-3-(tiglinoyloxy)-ent-kaur-16-en-19-oic acid, isolated from Wedelia trilobata L., exerts an anti-inflammatory effect via the modulation of NF-κB, MAPK and mTOR pathway and autophagy in LPS-stimulated macrophages.

Toxicol In Vitro 2021 Jun 9;73:105139. Epub 2021 Mar 9.

School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Engineering Research Center for Lead Compounds & Drug Discovery, Guangzhou 510006, China. Electronic address:

(3α)-3-(tiglinoyloxy)-ent-kaur-16-en-19-oic acid (WT-26) is an ent-kaurane dieterpenoid extracted from Wedelia trilobata L., a widely cultivated ornamental plant with several scientific reports supporting its anti-inflammatory activity. WT-26 has better anti-inflammatory activity than its analog Kaurenoic acid (ent-kaur-16-en-19-oic acid). Read More

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The Role of Genetic Testing for Parkinson's Disease.

Curr Neurol Neurosci Rep 2021 03 8;21(4):17. Epub 2021 Mar 8.

Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.

Purpose Of Review: To describe current practices and attitudes about genetic testing for Parkinson's disease (PD) among neurologists, highlight the changing scene of genetic testing for PD, and provide guidance on facilitating PD genetic testing in a clinical practice.

Recent Findings: Since the 1990s, researchers have discovered several major gene variants contributing to PD etiology. A large body of literature now exists supporting the frequency of these variants in different populations and their effects on phenotype and clinical course. Read More

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Oncogenic functions and therapeutic targeting of EphA2 in cancer.

Oncogene 2021 Apr 8;40(14):2483-2495. Epub 2021 Mar 8.

Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.

More than 25 years of research and preclinical validation have defined EphA2 receptor tyrosine kinase as a promising molecular target for clinical translation in cancer treatment. Molecular, genetic, biochemical, and pharmacological targeting strategies have been extensively tested in vitro and in vivo, and drugs like dasatinib, initially designed to target SRC family kinases, have been found to also target EphA2 activity. Other small molecules, therapeutic targeting antibodies, and peptide-drug conjugates are being tested, and more recently, approaches harnessing antitumor immunity against EphA2-expressing cancer cells have emerged as a promising strategy. Read More

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Integrin Regulation in Immunological and Cancerous Cells and Exosomes.

Int J Mol Sci 2021 Feb 23;22(4). Epub 2021 Feb 23.

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-City 514-8507, Mie, Japan.

Integrins represent the biologically and medically significant family of cell adhesion molecules that govern a wide range of normal physiology. The activities of integrins in cells are dynamically controlled via activation-dependent conformational changes regulated by the balance of intracellular activators, such as talin and kindlin, and inactivators, such as Shank-associated RH domain interactor (SHARPIN) and integrin cytoplasmic domain-associated protein 1 (ICAP-1). The activities of integrins are alternatively controlled by homotypic lateral association with themselves to induce integrin clustering and/or by heterotypic lateral engagement with tetraspanin and syndecan in the same cells to modulate integrin adhesiveness. Read More

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February 2021

Barrier-to-autointegration-factor (Banf1) modulates DNA double-strand break repair pathway choice via regulation of DNA-dependent kinase (DNA-PK) activity.

Nucleic Acids Res 2021 04;49(6):3294-3307

Queensland University of Technology (QUT), Cancer & Ageing Research Program, Centre for Genomics and Personalised Health at the Translational Research Institute (TRI), Brisbane, Australia.

DNA repair pathways are essential to maintain the integrity of the genome and prevent cell death and tumourigenesis. Here, we show that the Barrier-to-Autointegration Factor (Banf1) protein has a role in the repair of DNA double-strand breaks. Banf1 is characterized as a nuclear envelope protein and mutations in Banf1 are associated with the severe premature aging syndrome, Néstor-Guillermo Progeria Syndrome. Read More

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New Insights into the Mechanisms of Polyphenol from Plum Fruit Inducing Apoptosis in Human Lung Cancer A549 Cells Via PI3K/AKT/FOXO1 Pathway.

Plant Foods Hum Nutr 2021 Mar 27;76(1):125-132. Epub 2021 Feb 27.

School of Aerospace Medicine, Fourth Military Medical University, No. 169, Changle-West road, Xi'an, 710032, Shaanxi, China.

Recent studies have been found that polyphenols from plums fruits can inhibit the proliferation of multiple cancer cells, while the molecular mechanism was unclear. This study aimed to investigate the molecular mechanism underlying the pro-apoptotic effect of purified plum polyphenols (PPP) on human lung cancer A549 cells. Quercitrin (quercetin-3-O-glucoside, 814. Read More

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E3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3.

Nat Commun 2021 02 19;12(1):1194. Epub 2021 Feb 19.

Clinical Cancer Institute, Center for Translational Medicine, Second Military Medical University, Shanghai, 200433, China.

Ubiquitination is one of the most prevalent protein posttranslational modifications. Here, we show that E3 ligase Nedd4l positively regulates antiviral immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3. Deficiency of Nedd4l significantly impairs type I interferon and proinflammatory cytokine production induced by virus infection both in vitro and in vivo. Read More

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February 2021

Transcription activation by a sliding clamp.

Nat Commun 2021 02 18;12(1):1131. Epub 2021 Feb 18.

Department of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Transcription activation of bacteriophage T4 late genes is accomplished by a transcription activation complex containing RNA polymerase (RNAP), the promoter specificity factor gp55, the coactivator gp33, and a universal component of cellular DNA replication, the sliding clamp gp45. Although genetic and biochemical studies have elucidated many aspects of T4 late gene transcription, no precise structure of the transcription machinery in the process is available. Here, we report the cryo-EM structures of a gp55-dependent RNAP-promoter open complex and an intact gp45-dependent transcription activation complex. Read More

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February 2021

Cost-Effective Trap qPCR Approach to Evaluate Telomerase Activity: an Important Tool for Aging, Cancer, and Chronic Disease Research.

Clinics (Sao Paulo) 2021 5;76:e2432. Epub 2021 Feb 5.

Laboratorio de Dermatologia e Imunodeficiencias (LIM56), Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, BR.

Objectives: Telomeres are a terminal "DNA cap" that prevent chromosomal fusion and degradation. However, aging is inherent to life, and so is the loss of terminal sequences. Telomerase is a specialized reverse transcriptase encoded by self-splicing introns that counteract chromosome erosion. Read More

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Partial Prion Cross-Seeding between Fungal and Mammalian Amyloid Signaling Motifs.

mBio 2021 02 9;12(1). Epub 2021 Feb 9.

Non-Self Recognition in Fungi, Institut de Biochimie et de Génétique Cellulaire (CNRS UMR 5095), Université de Bordeaux, Bordeaux, France

In filamentous fungi, NLR-based signalosomes activate downstream membrane-targeting cell death-inducing proteins by a mechanism of amyloid templating. In the species , two such signalosomes, NWD2/HET-S and FNT1/HELLF, have been described. An analogous system involving a distinct amyloid signaling motif, termed PP, was also identified in the genome of the species and studied using heterologous expression in The PP motif bears resemblance to the RIP homotypic interaction motif (RHIM) and to RHIM-like motifs controlling necroptosis in mammals and innate immunity in flies. Read More

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February 2021

Interleukin (IL)-7 Signaling in the Tumor Microenvironment.

Adv Exp Med Biol 2021 ;1290:9-49

Department of Medical Biochemistry, Wroclaw Medical University, Wroclaw, Poland.

Interleukin (IL)-7 plays an important immunoregulatory role in different types of cells. Therefore, it attracts researcher's attention, but despite the fact, many aspects of its modulatory action, as well as other functionalities, are still poorly understood. The review summarizes current knowledge on the interleukin-7 and its signaling cascade in context of cancer development. Read More

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February 2021

Prostaglandin E receptor PTGER4-expressing macrophages promote intestinal epithelial barrier regeneration upon inflammation.

Gut 2021 Feb 7. Epub 2021 Feb 7.

Department of Microbiology and Immunology and Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea

Objective: Dysfunctional resolution of intestinal inflammation and altered mucosal healing are essential features in the pathogenesis of inflammatory bowel disease (IBD). Intestinal macrophages are vital in the process of inflammation resolution, but the mechanisms underlying their mucosal healing capacity remain elusive.

Design: We investigated the role of the prostaglandin E (PGE) receptor PTGER4 on the differentiation of intestinal macrophages in patients with IBD and mouse models of intestinal inflammation. Read More

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February 2021

Mechanisms of Coronavirus Nsp1-Mediated Control of Host and Viral Gene Expression.

Cells 2021 02 2;10(2). Epub 2021 Feb 2.

Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555-1019, USA.

Many viruses disrupt host gene expression by degrading host mRNAs and/or manipulating translation activities to create a cellular environment favorable for viral replication. Often, virus-induced suppression of host gene expression, including those involved in antiviral responses, contributes to viral pathogenicity. Accordingly, clarifying the mechanisms of virus-induced disruption of host gene expression is important for understanding virus-host cell interactions and virus pathogenesis. Read More

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February 2021

Protein kinase C-β-dependent changes in the glucose metabolism of bone marrow stromal cells of chronic lymphocytic leukemia.

Stem Cells 2021 Feb 4. Epub 2021 Feb 4.

Department of Medicine 5-Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

Survival of chronic lymphocytic leukemia (CLL) cells critically depends on the support of an adapted and therefore appropriate tumor microenvironment. Increasing evidence suggests that B-cell receptor-associated kinases such as protein kinase C-β (PKCβ) or Lyn kinase are essential for the formation of a microenvironment supporting leukemic growth. Here, we describe the impact of PKCβ on the glucose metabolism in bone marrow stromal cells (BMSC) upon CLL contact. Read More

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February 2021