Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD38 is overexpressed by multiple myeloma cells and has emerged as a target for therapeutic antibodies. Nanobodies are soluble single domain antibody fragments derived from the VHH variable domain of heavy chain antibodies naturally occurring in camelids. We previously identified distinct llama nanobodies that recognize three non-overlapping epitopes of the extracellular domain of CD38. Here, we fused these VHH domains to the hinge, CH2, and CH3 domains of human IgG1, yielding highly soluble chimeric llama/human heavy chain antibodies (hcAbs). We analyzed the capacity of these hcAbs to mediate complement-dependent cytotoxicity (CDC) to CD38-expressing human multiple myeloma and Burkitt lymphoma cell lines. Combinations of two hcAbs that recognize distinct, non-overlapping epitopes of CD38 mediated potent CDC, in contrast to the hcAb monotherapy with only weak CDC capacity. Similarly, combining daratumumab with a hcAb that recognizes a non-overlapping epitope resulted in dramatically enhanced CDC. Further, introducing the E345R HexaBody mutation into the CH3 domain strongly enhanced the CDC potency of hcAbs to CD38-expressing cells. Exploiting their high solubility, we genetically fused two distinct nanobodies into heteromeric dimers via a flexible peptide linker and then fused these nanobody dimers to the hinge, CH2 and CH3 domains of human IgG1, yielding highly soluble, biparatopic hcAbs. These biparatopic hcAbs elicited CDC toward CD38-expressing myeloma cells more effectively than daratumumab. Our results underscore the advantage of nanobodies vs. pairs of VH and VL domains for constructing bispecific antibodies. Moreover, the CD38-specific biparatopic heavy chain antibodies described here represent potential new powerful therapeutics for treatment of multiple myeloma.
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PMID:CD38-Specific Biparatopic Heavy Chain Antibodies Display Potent Complement-Dependent Cytotoxicity Against Multiple Myeloma Cells. 3052 21

The purpose of this study was to evaluate changes in the proportion of lymphoid neoplasm subtypes in South Korea. A total of 8615 cases of lymphoid neoplasms diagnosed in 1997-2016 at Samsung Medical Center in South Korea were classified according to the 2008 World Health Organization system. The total number and proportion of lymphoid neoplasms were compared between these two decades, with data from nationwide studies, and with other countries. To evaluate changes in the proportion of subtypes, crude rate of each subtype per 100 lymphoma patients during each decade and age adjusted rate were calculated. There were 3024 patients with lymphoid neoplasm in 1997-2006, and 5591 in 2007-2016, which represents an average increase of 1.85 times over the 20-year study period. Crude rate and age adjusted rate were increased in Hodgkin's lymphoma and mature B cell lymphoma while precursor lymphoid neoplasms and mature T cell lymphoma were decreased. Among B cell neoplasms, age adjusted rate of plasma cell neoplasm, follicular lymphoma, mantle cell lymphoma increased while there was no significant change in extranodal marginal zone lymphoma and Burkitt lymphoma. The increase in follicular lymphoma was due to the increases in nodal follicular lymphoma of low grade and duodenal-type follicular lymphoma. These results are consistent with the dynamics of causative factors, including socioeconomic factors, in Korea.
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PMID:Changing trends in lymphoid neoplasm distribution in South Korea: analysis of 8615 cases from a single institute, 1997-2016: An observational study. 3170 15

Non coding RNAs (ncRNAs) have emerged as regulators of human carcinogenesis by affecting the expression of key tumor suppressor genes and oncogenes. They are divided into short and long ncRNAs, according to their length. Circular RNAs (circRNAs) are included in the second group and were recently discovered as being originated by back-splicing, joining either single or multiple exons, or exons with retained introns. The human Plasmacytoma Variant Translocation 1 (PVT1) gene maps on the long arm of chromosome 8 (8q24) and encodes for 52 ncRNAs variants, including 26 linear and 26 circular isoforms, and 6 microRNAs. PVT1 genomic locus is 54 Kb downstream to MYC and several interactions have been described among these two genes, including a feedback regulatory mechanism. MYC-independent functions of PVT1/circPVT1 have been also reported, especially in the regulation of immune responses. We here review and discuss the role of both PVT1 and circPVT1 in the hematopoietic system. No information is currently available concerning their transforming ability in hematopoietic cells. However, present literature supports their cooperation with a more aggressive and/or undifferentiated cell phenotype, thus contributing to cancer progression. PVT1/circPVT1 upregulation through genomic amplification or rearrangements and/or increased transcription, provides a proliferative advantage to malignant cells in acute myeloid leukemia, acute promyelocytic leukemia, Burkitt lymphoma, multiple myeloma (linear PVT1) and acute lymphoblastic leukemia (circPVT1). In addition, PVT1 and circPVT1 regulate immune responses: the overexpression of the linear form in myeloid derived suppressor cells induced immune tolerance in preclinical tumor models and circPVT1 showed immunosuppressive properties in myeloid and lymphoid cell subsets. Overall, these recent data on PVT1 and circPVT1 functions in hematological malignancies and immune responses reflect two faces of the same coin: involvement in cancer progression by promoting a more aggressive phenotype of malignant cells and negative regulation of the immune system as a novel potential therapy-resistance mechanism.
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PMID:Linear and circular PVT1 in hematological malignancies and immune response: two faces of the same coin. 3222 2

People living with HIV or AIDS are at increased risk of Hodgkin and non-Hodgkin lymphoma compared with HIV-negative individuals. Data on the risk of multiple myeloma or leukaemia are inconsistent and of low quality but the risk does not seem to be increased. Specific haematological malignancies occur in different contexts of age, CD4 cell count, HIV control, viral co-infections, or chronic inflammation, and the expansion of combination antiretroviral therapy has led to varied demographic and epidemiological shifts among people with HIV. Increased use of combination antiretroviral therapy has substantially reduced the risks of diffuse large B-cell lymphoma, Burkitt lymphoma, and primary CNS lymphoma, and to a lesser extent, Hodgkin lymphoma. There is no effect of combination antiretroviral therapy use on multiple myeloma or leukaemia. Although many cases of HIV are in low-income and middle-income countries, high-quality epidemiological data for haematological malignancies from these regions are scarce. Closing this gap is an essential first step in decreasing mortality from HIV-associated haematological malignancies worldwide. Finally, although multicentric Castleman disease is not a neoplastic condition, it is an emerging precursor to neoplastic high-grade B-cell lymphoproliferation among people with HIV, especially for individuals on long-term combination antiretroviral therapy with well controlled HIV.
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PMID:Epidemiology of haematological malignancies in people living with HIV. 3279 Oct 47


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