Rob 895 / OxyPharma - LARVOL DELTA

"Hope you get one @fabiopss @MorrowYash @Kumaarsunil @nmamtf1 @Raejo101 @GiorgioJackson0 @PiTelegram @MuneshBhargava @chrischoitweets @zmfflem @sdfaydnsdf @hoanggiang19011 @MrPenny3ags @JeffinManuel @MELORDYx_design @robo895 @cryptocafetero @cryptoantifudd @hsyn_akinci" (@RobCar77)

Genetic Modeling and Therapeutic Targeting of ETV6-NTRK3 with Loxo-101 in Acute Lymphoblastic Leukemia (ASH 2016) - "Compared to crizotinib (IC50 205 nM), LOXO-101 was 10 times more potent against BaF3-ETV6-NTRK3 cells (IC5017 nM), and had no effect on other kinase fusions (ABL1, ABL2, CSF1R, FLT3, JAK2) up to 10µM. Pathological analysis using hematoxylin and eosin and B220 staining showed infiltration of leukemic cells into the bone marrow, spleen, liver and lung. Notably, treatment with dexamethasone had a modest effect against this tumor (average 55.3% bone marrow blasts and spleen weight 134mg, n=5). We have described the first genetically engineered mouse model of Ph-like ALL with an ETV6-NTRK3 fusion, and reported remarkable efficacy of LOXO-101 against the NTRK3 fusion, with complete suppression of leukemic cell proliferation when administered as a monotherapy. These findings warrant screening for ETV6-NTRK3 in newly diagnosed ALL patients, and testing the efficacy of LOXO-101 in combination with chemotherapy regimens."

Acute Lymphocytic Leukemia • Biosimilar • Breast Cancer • Hematological Malignancies • Leukemia • Oncology • Sarcoma

Short-term consumption of n-3 PUFAs increases murine IL-5 levels, but IL-5 is not the mechanistic link between n-3 fatty acids and changes in B-cell populations. (PubMed) - J Nutr Biochem - "N-3 PUFA supplementation as ethyl esters to obesogenic diets did not alter circulating IL-5 levels. Altogether, the data establish that n-3 PUFAs as fish oil can increase circulating IL-5 in lean mice, which has implications for several disease end points, but this increase in IL-5 is not the mechanistic link between n-3 PUFAs and changes in B-cell populations."

Journal • Biosimilar • Obesity

TAK-659, a dual SYK/FLT3 inhibitor, leads to complete and sustained tumor regression and immune memory against tumor cells upon combination with anti-PD-1 agent (EORTC-NCI-AACR 2016) - "TAK-659 is an inhibitor of Spleen Tyrosine Kinase (SYK) that is being evaluated in hematological malignancies in multiple clinical trials. Our pre-clinical data has shown a decrease in MDSC’s or B220+ B-Cells following treatment with TAK-659 in the CT-26 syngeneic colon cancer model. Similar combination efficacy and vaccinal memory effect has been observed in other syngeneic models as well. Taken together, TAK-659 treatment in combination with anti-PD-1 resulted in complete tumor growth suppression, prolonged tumor free survival and potential immune memory against tumor cells supporting the rationale for examining the addition of TAK-659 to anti-PD-1 therapy in the clinic."

Myeloid-derived suppressor cells • Tumor microenvironment • Biosimilar • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Leukemia • Oncology

Alum Adjuvant Enhances Protection against Respiratory Syncytial Virus but Exacerbates Pulmonary Inflammation by Modulating Multiple Innate and Adaptive Immune Cells. (PubMed) - "Alum adjuvant in the FI-RSV-A was found to be mainly responsible for inducing high levels of RSV-specific IFN-γ-IL4+, IFN-γ-TNF-α+ CD4+ T cells, and proinflammatory cytokines IL-6 and IL-4 as well as B220+ plasmacytoid and CD4+ dendritic cells, and inhibiting the induction of IFN-γ+CD8 T cells. This study suggests that alum adjuvant in FI-RSV vaccines increases immunogenicity and viral clearance but also induces atypical T helper CD4+ T cells and multiple inflammatory dendritic cell subsets responsible for vaccine-enhanced severe RSV disease."

Journal • Biosimilar • Immunology • Inflammation

Leukemogenic Pathway of MLL-AF4 Fusion-Positive Acute Lymphoblastic Leukemia (ASH 2017) - "...The MLL-AF4-expressing Tie2-positive cells with insertional mutagenesis showed clonal expansion and formed mostly extra-medullary tumors with B220 expression, but did not fully develop into tumors of hematopoietic organs...Considering the in utero formation of MLL-AF4 harboring pre-leukemic stem cells in ALL, hematopoietic progenitor cells or immature fetal cells may be potential targets of leukemic transformation. Immature hematopoietic cells such as the Tie2-positive cells derived from ES cells could be suitable candidates for transformation with MLL-AF4. Clonal expansion of MLL-AF4-positive cells after introduction of retroviral insertional mutagenesis suggests the necessity of additional genetic change(s) that activate certain target gene(s) in leukemogenesis with MLL-AF4."

Acute Lymphocytic Leukemia • Biosimilar • Gene Therapies • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Metabolic Disorders • Obesity • Oncology

A population of innate myelolymphoblastoid effector cell expanded by inactivation of mTOR complex 1 in mice. (PubMed, Elife) - "...Mouse IMLECs are CD3-B220-NK1.1-Ter119- CD11clow/-CD115-F4/80low/-Gr-1- CD11b+, but surprisingly express high levels of PD-L1...Importantly, IMLECs broadly overexpress pattern-recognition receptors and their expansion causes systemic inflammation in response to Toll-like receptor ligands in mice. Our data unveil a novel leukocyte population and an unrecognized role of Raptor/mTORC1 in innate immune tolerance."

Journal • Biosimilar • Immunology

B cells are required for sunlight protection of mice from a CNS-targeted autoimmune attack. (PubMed) - J Autoimmun - "Indeed, UV-protection from EAE was dependent on UV activation of lymph node B cells because UV could not protect mice from EAE who were pharmacologically depleted of B cells using antibodies. Thus, UV maintenance of a pool of unique regulatory B cells in peripheral lymph nodes appears to be essential to prevent an autoimmune attack on the central nervous system."

Journal • Biosimilar • Immunology • Inflammation • Multiple Sclerosis

Somatic drivers of B-ALL in a model of ETV6-RUNX1; Pax5 (+/-) leukemia. (PubMed) - "Powerful synergies exists in our model suggesting STAT pathway activation and mutation of Trp53 are potent drivers of B-ALL in the context of Etv6-RUNX1;Pax5 (+/-) ."

Journal • Acute Lymphocytic Leukemia • Biosimilar • Hematological Malignancies • Leukemia • Oncology

Presentation of high Ag-dose by splenic B220(lo) B cells fosters a feedback loop between Th2 memory and antibody isotype switching. (PubMed) - Immunology - "The memory Th2 cells supported the production of antibodies by effector B cells and promoted isotype switching to IgG1. Moreover, among the B cell subsets tested for induction of Th2 memory, the splenic but not peritoneal B220(lo) cells were most effective in sustaining Th2 memory development as well as Ig isotype switching, and this function involved a tight control by PD1-PD-L2 interactions."

Journal • Biosimilar

The Age of the Hematopoietic Microenvironment Specifies Lineage Commitment in MLL-Rearranged Leukemia (ASH 2017) - "...We found that leukemia developing in neonates contained a small (3.5 ± 1%) population of cells expressing the B-cell marker B220, which were not present in pure AML developing in adults...We attribute this to inhibition of B-lymphoid output from multipotent progenitor-like LICs by Ccl5 from adult bone marrow stroma. These findings connect normal maturation and aging of the hematopoietic system and its microenvironment to the age specificity of leukemia."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Biosimilar • Hematological Malignancies • Leukemia • Oncology

Resistance of novel mouse strains different in MHC class I and the NKC domain to the development of experimental tumors. (PubMed) - Int J Oncol - "The changes in the T-cell population were represented mainly by the prevalence of T helper cells reflected by grown CD4/CD8 ratio, most prominent in the b+d-NK1.1neg strain. The results of the present study imply usefulness of the two novel mouse strains as an experimental model for further studies of tumor resistance mechanisms."

Journal • Biosimilar • Colorectal Cancer • Gastrointestinal Cancer • Graft versus Host Disease • Melanoma • Oncology

Differential effects of FTY720 on the B cell compartment in a mouse model of multiple sclerosis. (PubMed, J Neuroinflammation) - "The data suggest differential effects of FTY720 on the B cell compartment in MP4-induced EAE."

Journal • Biosimilar • CNS Disorders • Immunology • Multiple Sclerosis

Germinal Center-Derived Lymphomas and Plasmacytomas in Mice with Targeted Deletion of MiR-15a/16-1 in Activated B Cells (ASH 2016) - "Two distinct patterns of B220+BCL6+BCL2- B-cell lymphomas were identified after detailed analysis. The comparison of lymphomas arising in AID-Cre+/-; miR-15a/16-1fl/fl mice and CD19-Cre+/-; miR-15a/16-1fl/fl mice corroborated that deletion of miR-15a/16-1 at different stages of B-cell development leads to distinct subtypes of B-cell malignancies. Finally, we investigated miR-15a/16-1 expression in human FL and PC and showed that miR-15a/16-1 abundance is significantly decreased in those malignancies when compared with nodal B-cells in reactive GCs and normal plasma cells in interfollicular areas respectively, suggesting that miR-15a/16-1 may play important roles in normal GC B-cell development as well as in the pathogenesis of FL and PC in humans."

Biosimilar • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Indolent Lymphoma • Leukemia • Non-Hodgkin’s Lymphoma • Oncology

Deletion or inhibition of Fc gamma receptor 2B (CD32) prevents FVIII-specific activation of memory B cells in vitro. (PubMed) - "We conclude that CD32 is a crucial regulator of FVIII-specific B cells and is required for the differentiation of MBCs into ASCs. Inhibition of CD32 could potentially improve the efficacy of FVIII in the context of ITT."

Journal • Biosimilar • Hemophilia

Expansion of Age Associated B Cells in Murine Lupus Is Regulated By DEF6 and Its Homologue Swap-70 (ACR-ARHP 2016) - "Methods: Presence of CD11c+CD11b+B220+CD19+ B cells (ABCs) was evaluated by FACS in WT and DKO mice as well as in DKO mice concomitantly lacking either IL-21 or SAP. We also show that accumulation of ABCs in murine lupus is dependent on T-B cell interactions and IL-21. Finally, we demonstrate that ABCs may contribute to SLE pathogenesis by producing high levels of anti-dsDNA IgG2a/c antibodies."

Preclinical • Biosimilar • Dry Eye Disease • Gene Therapies • Immunology • Lupus • Ophthalmology

Beneficial Immune Modulation Post-Cardiac Infarction in Mice (AHA 2017) - "Hearts isolated from mice treated with FTY720 showed a slight decrease in total cardiac leukocytes (CD45+), however the most significant change was in the marked decrease in number of B cells isolated at both day 2 and day 7 (B220+ cells). There was a trend towards a slight decrease in total macrophage numbers and towards changes in Ly6C expression on F4/80 high cells in the FTY720 treated group. Our study suggests that FTY720 can improve myocardial function and survival in mice following myocardial infarction in a permanent ligation model and that FTY720 induces changes in cardiac immune cell infiltration and/or proliferation that likely contributed to the beneficial outcomes in mice that received FTY720 post-infarction treatment."

Preclinical • Acute Coronary Syndrome • Cardiovascular • Reperfusion Injury

Hematopoietic Stem Cells in Neural-crest Derived Bone Marrow. (PubMed) - Sci Rep - "Mandibular HSCs showed a consistent deficiency in lymphoid differentiation, including significantly fewer CD229 + fractions, PreProB, ProB, PreB and B220 + slgM cells. Thus, lymphoid deficiency of mandibular HSCs may be accounted by putative niche regulating genes. HSCs in craniofacial bones have functional implications in homeostasis, osteoclastogenesis, immune functions, tumor metastasis and infections such as osteonecrosis of the jaw."

Journal • Biosimilar • Immunology • Oncology

Suppression of Plasmacytoid Dendritic Cell Migrating to Isolated Lymphoid Follicles in Colon Exert Protective Effects Against a Murine Experimental Colitis (DDW 2019) - "...The colonic cryosections were stained with anti-mouse B220 and anti-mouse CD11c and quantitated with Image J software...Accord- ingly, pDC migration to the ILFs contributes to the development of the colitis. Suppressor of pDC migration has a therapeutic potential against colonic inflammation such as Crohn's disease and ulcerative colitis."

Preclinical