Efficacy of Antiviral Treatment in Hepatitis C Virus (HCV)-Driven Monoclonal Gammopathies Including Myeloma

Multiple myeloma (MM) remains an incurable plasma cell malignancy. While its origin is enigmatic, an association with infectious pathogens including hepatitis C virus (HCV) has been suggested. Here we report nine patients with monoclonal gammopathy of undetermined significance (MGUS) or MM with previous HCV infection, six of whom received antiviral treatment. We studied the evolution of the gammopathy disease, according to anti-HCV treatment and antigen specificity of purified monoclonal immunoglobulin, determined using the INNO-LIA™ HCV Score assay, dot-blot assays, and a multiplex infectious antigen microarray. The monoclonal immunoglobulin from 6/9 patients reacted against HCV. Four of these patients received antiviral treatment and had a better evolution than untreated patients. Following antiviral treatment, one patient with MM in third relapse achieved complete remission with minimal residual disease negativity. For two patients who did not receive antiviral treatment, disease progressed. For the two patients whose monoclonal immunoglobulin did not react against HCV, antiviral treatment was not effective for MGUS or MM disease. Our results suggest a causal relationship between HCV infection and MGUS and MM progression. When HCV was eliminated, chronic antigen-stimulation disappeared, allowing control of clonal plasma cells. This opens new possibilities of treatment for MGUS and myeloma.

Microglia-Derived Olfactomedin-like 3 Promotes Pro-Tumorigenic Microglial Function and Malignant Features of Glioma Cells

Under the influence of transforming growth factor-beta (TGFβ), glioma-associated microglia produce molecules that promote glioma growth and invasion. Olfactomedin-like 3 (Olfml3), a novel, secreted glycoprotein, is known to promote several non-CNS cancers. While it is a direct TGFβ1 target gene in microglia, the role of microglia-derived OLFML3 in glioma progression is unknown. Here, we tested the hypotheses that microglial Olfml3 is integral to the pro-tumorigenic glioma-associated microglia phenotype and promotes glioma cell malignancy. Using an Olfml3 knockout microglial cell line (N9), we demonstrated that Olfml3 is a direct target gene of all TGFβ isoforms in murine microglia. Moreover, loss of Olfml3 attenuated TGFβ-induced restraint on microglial immune function and production of cytokines that are critical in promoting glioma cell malignancy. Importantly, microglia-derived OLFML3 directly contributes to glioma cell malignancy through increased migration and invasion. While exposure to conditioned medium (CM) from isogenic control microglia pre-treated with TGFβ increased mouse glioma cell (GL261) migration and invasion, this effect was abolished with exposure to CM from TGFβ-treated Olfml3-/- microglia. Taken together, our data suggest that Olfml3 may serve as a gatekeeper for TGFβ-induced microglial gene expression, thereby promoting the pro-tumorigenic microglia phenotype and glioma cell malignancy.

PESV represses non-small cell lung cancer cell malignancy through circ_0016760 under hypoxia

Background Non-small cell lung cancer (NSCLC) accounts for more than 80% of lung cancers, which is the most common malignant tumor worldwide. Polypeptide extract from scorpion venom (PESV) has been reported to inhibit NSCLC process. The present study aims to reveal the roles of PESV in NSCLC progression under hypoxia and the inner mechanism. Methods The expression levels of circular RNA 0016760 (circ_0016760) and microRNA-29b (miR-29b) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was determined by western blot and immunohistochemistry assays. Cell migration, invasion, proliferation and tube formation were investigated by transwell, cell colony formation, 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide and tube formation assays. The impacts between PESV and circ_0016760 overexpression on tumor growth in vivo were investigated by in vivo tumor formation assay. Results Circ_0016760 expression was dramatically upregulated in NSCLC tissues and cells, compared with adjacent lung tissues and cells, respectively. PESV treatment downregulated circ_0016760 expression. Circ_0016760 silencing or PESV treatment repressed cell migration, invasion, proliferation and tube formation under hypoxia in NSCLC cells. Circ_0016760 overexpression restored the effects of PESV treatment on NSCLC process under hypoxia. Additionally, circ_0016760 acted as a sponge of miR-29b, and miR-29b bound to HIF1A. Meanwhile, miR-29b inhibitor impaired the influences of circ_0016760 knockdown on NSCLC process under hypoxia. Further, ectopic circ_0016760 expression restrained the effects of PESV exposure on tumor formation in vivo. Conclusion Circ_0016760 overexpression counteracted PESV-induced repression of NSCLC cell malignancy and angiogenesis under hypoxia through miR-29b/HIF1A axis.

Thrombotic Microangiopathy, an Unusual Form of Monoclonal Gammopathy of Renal Significance: Report of 3 Cases and Literature Review

Monoclonal gammopathies result from neoplastic clones of the B-cell lineage and may cause kidney disease by various mechanisms. When the underlying clone does not meet criteria for a malignancy requiring treatment, the paraprotein is called a monoclonal gammopathy of renal significance (MGRS). One rarely reported kidney lesion associated with benign paraproteins is thrombotic microangiopathy (TMA), provisionally considered as a combination signifying MGRS. Such cases may lack systemic features of TMA, such as a microangiopathic hemolytic anemia, and the disease may be kidney limited. There is no direct deposition of the paraprotein in the kidney, and the presumed mechanism is disordered complement regulation. We report three cases of kidney limited TMA associated with benign paraproteins that had no other detectable cause for the TMA, representing cases of MGRS. Two of the cases are receiving clone directed therapy, and none are receiving eculizumab. We discuss in detail the pathophysiological basis for this possible association. Our approach to therapy involves first ruling out other causes of TMA as well as an underlying B-cell malignancy that would necessitate direct treatment. Otherwise, clone directed therapy should be considered. If refractory to such therapy or the disease is severe and multisystemic, C5 inhibition (eculizumab or ravulizumab) may be indicated as well.

Survival Analysis of Patients with T-Cell Lymphoma or T-Cell Large Granular Leukemia and Concomitant Plasma Cell Dyscrasias

Introduction: Sporadic cases of patients with a combined T-cell malignancy and plasma cell dyscrasia (PCD) have been reported in the literature. While the most commonly observed association is with T-cell large granular lymphocytic leukemia (T-LGLL) and PCD, there are case reports of other T-cell malignancies and PCD, such as peripheral T-cell lymphoma (PTCL) and angioimmunoblastic T-cell lymphoma (AITL) with multiple myeloma (MM). Nearly one-third of MM patients develop clonal T-cell populations that share a similar immunophenotype to T-LGLL, suggesting likely under diagnosis of concomitant T-cell malignancies in patients with PCD. However, with the limited data available regarding the overlap between PCD and T-cell malignancy, the significance, associated pathogenesis, and impact on survival outcomes is unknown. The purpose of this study is to describe the outcomes of patients with overlapping T-cell malignancies and PCD in order to determine the survival outcomes and ultimately make management/diagnostic recommendations. Methods: In this IRB approved study, we retrospectively evaluated patients with concomitant T-cell malignancy and PCD at Ohio State University from 2010-2020. Patients were identified using a database search for T-cell malignancies as well as PCD. All patients that were included met the 2016 World Health Organization diagnostic criteria for their respective T-cell malignancy and PCD. Progression-free survival (PFS) was measured as time from the start of treatment until first progression, death, or last follow-up according to the Kaplan-Meier method with median survival times and 95% confidence intervals reported. Results: A total of 21 patients, with a median follow-up time of 22 months (range 1-153), were included in this analysis. Baseline demographics are in table 1. The most common T-cell malignancy was T-LGLL (11/21; 52%) and the most common PCD were MGUS (8/21; 38%) and MM (8/21; 38%). Ten (48%) patients presented with a T-cell malignancy as their primary malignancy, 9 (43%) presented with a PCD as their primary malignancy, 1 (5%) patient was diagnosed with both at the same time, and for 1 (5%) patient it is unknown. Within the cohort, 62% (13/21) of patients received primary treatment for their T-cell malignancy and 38% (8/21) of patients received primary treatment for their PCD. Of the 7 patients that had their PCD clone 4 were treated concomitantly and 3 were treated for only their T-cell malignancy. Overall, 9/21 (42.9%) of patients had progression of their T-cell malignancy. A summary of outcomes is provided in Table 2. 54.6% of patients with T-LGLL and 60% of patients with AITL/PTCL experienced progressive T-cell disease and no patients with CTCL had progressive T-cell disease. The median overall survival (OS) across all patients was 4.1 years. Median OS was not reached for patients with T-LGLL, 1.7 years for AITL/PTCL, and 12.4 years for CTCL. PFS was 11 months for patients with T-LGLL, 1 year for AITL/PTCL, and 12.37 years for CTCL. Survival probability is shown in Figure 1. The rates of progression, OS, and PFS were consistent with previously published data for patients with these T-cell malignancies. Conclusions: Herein, we characterize a cohort of patients with concomitant T-cell malignancies and PCD with an emphasis on survival outcomes. Our data suggests that there is no PFS or OS difference for patients with T-cell malignancies and concomitant PCD when treated with standard T-cell directed therapy. There is the potential that treating a patient's T-cell malignancy may lead to resolution of their PCD clone, even without therapy directed at the PCD. While our data is limited by small sample size, this report represents the largest data set available in this rarely described patient population. Larger retrospective cohort studies are needed to further characterize this population and validate these findings. For patients with T-cell malignancies as the primary diagnosis with concomitant PCD, treatment with standard T-cell directed therapies is recommended with continued follow-up and monitoring of the concomitant PCD. Figure 1 Figure 1. Disclosures Bumma: Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy.

Identification of candidate therapeutics and signaling pathways for multiple myeloma

Multiple myeloma (MM), a plasma cell malignancy, is related to critical morbidity due to end-organ destruction. A number of factors affect the MM cell proliferation and functions. Though MM is not curable, novel targets and inhibitors have shown great effects on MM patients. Here, we aim to identify significant genes and signaling pathways of MM with SI2 treatment using a bioinformatics method. The GSE156871 dataset was originally produced by using the high-throughput BGISEQ-500. The KEGG and GO results suggested that biological pathways such as "the complement and coagulation cascades" and "the transcription activator activity" are mostly affected in the SI2 treatment of MM cells. Moreover, we identified several genes including SRC, KNG1, and PI3KCG were involved in the treatment of MM cells. Therefore, our study provides further insights into the treatment of MM.

PMEPA1 Is a Prognostic Biomarker That Correlates With Cell Malignancy and the Tumor Microenvironment in Bladder Cancer

Prostate transmembrane protein androgen induced 1 (PMEPA1) has been reported to promote cancer progression, but the potential role of PMEPA1 in bladder cancer (BLCA) remains elusive. We assess the role of PMEPA1 in BLCA, via a publicly available database and in vitro study. PMEPA1 was identified from 107 differentially expressed genes (DEGs) to have prognostic value. GO, KEGG, and GSEA analysis indicated that PMEPA1 was involved in cancer progression and the tumor microenvironment (TME). Then bioinformatical analysis in TCGA, GEO, TIMER, and TISIDB show a positive correlation with the inflammation and infiltration levels of three tumor-infiltrating immune cells (TAMs, CAFs, and MDSCs) and immune/stromal scores in TME. Moreover, in vitro study revealed that PMEPA1 promotes bladder cancer cell malignancy. Immunohistochemistry and survival analysis shed light on PMEPA1 potential to be a novel biomarker in predicting tumor progression and prognosis. At last, we also analyzed the role of PMEPA1 in predicting the molecular subtype and the response to several treatment options in BLCA. We found that PMEPA1 may be a novel potential biomarker to predict the progression, prognosis, and molecular subtype of BLCA.

Apatinib inhibits glioma cell malignancy in patient-derived orthotopic xenograft mouse model by targeting thrombospondin 1/myosin heavy chain 9 axis

We determined the antitumor mechanism of apatinib in glioma using a patient-derived orthotopic xenograft (PDOX) glioma mouse model and glioblastoma (GBM) cell lines. The PDOX mouse model was established using tumor tissues from two glioma patients via single-cell injections. Sixteen mice were successfully modeled and randomly divided into two equal groups (n = 8/group): apatinib and normal control. Survival analysis and in vivo imaging was performed to determine the effect of apatinib on glioma proliferation in vivo. Candidate genes in GBM cells that may be affected by apatinib treatment were screened using RNA-sequencing coupled with quantitative mass spectrometry, data mining of The Cancer Genome Atlas, and Chinese Glioma Genome Atlas databases, and immunohistochemistry analysis of clinical high-grade glioma pathology samples. Quantitative reverse transcription-polymerase chain reaction (qPCR), western blotting, and co-immunoprecipitation (co-IP) were performed to assess gene expression and the apatinib-mediated effect on glioma cell malignancy. Apatinib inhibited the proliferation and malignancy of glioma cells in vivo and in vitro. Thrombospondin 1 (THBS1) was identified as a potential target of apatinib that lead to inhibited glioma cell proliferation. Apatinib-mediated THBS1 downregulation in glioma cells was confirmed by qPCR and western blotting. Co-IP and mass spectrometry analysis revealed that THBS1 could interact with myosin heavy chain 9 (MYH9) in glioma cells. Simultaneous THBS1 overexpression and MYH9 knockdown suppressed glioma cell invasion and migration. These data suggest that apatinib targets THBS1 in glioma cells, potentially via MYH9, to inhibit glioma cell malignancy and may provide novel targets for glioma therapy.

Concept of the influence of SARS -COV-2 viruses on cell malignancy

To date, in the context of the COVID 19 pandemic, there are rumors and speculations about the consequences of the infection, as well as a concern on growing cancer risk due to vaccines and vaccination. In this study we reviewed the concepts of the viral action on cancer development and analyzed the data on the possibility of the malignant effect of the SARS-CoV-2 virus on cells. Analysis of the literature data showed that SARS-CoV-2 damages cells, like other viruses, but does not lead to their mutations. There are no changes in DNA, there is only misregulation of repression and expression of the genome, a perversion of signaling intercellular interactions that disrupt the mechanisms of differentiation and specialization of cells. The need of viruses to multiply in cambial cells of tissues contributes to the induction of their proliferation and the lack of specialization. Thus, the available information on the cytopathic effects caused by viruses in cells infected with COVID-19 does not yet provide information on the malignant effect of SARS-CoV-2. Our study is aimed at collecting and analyzing data that are necessary for planning effective treatment of patients with COVID 19 and predicting outcomes in the long term after the disease.

Tissue-resident macrophages promote early dissemination of multiple myeloma via IL-6 and TNFα

Multiple myeloma (MM) is a plasma cell malignancy characterized by the presence of multiple foci in the skeleton. These distinct tumor foci represent cycles of tumor growth and dissemination that seed new clusters and drive disease progression. By using an intratibial Vk*MYC murine myeloma model, we found that CD169+ radiation-resistant tissue-resident macrophages (MPs) were critical for early dissemination of myeloma and disease progression. Depletion of these MPs had no effect on tumor proliferation, but it did reduce egress of myeloma from bone marrow (BM) and its spread to other bones. Depletion of MPs as a single therapy and in combination with BM transplantation improved overall survival. Dissemination of myeloma was correlated with an increased inflammatory signature in BM MPs. It was also correlated with the production of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) by tumor-associated MPs. Exogenous intravenous IL-6 and TNFα can trigger myeloma intravasation in the BM by increasing vascular permeability in the BM and by enhancing the motility of myeloma cells by reducing the adhesion of CD138. Moreover, mice that lacked IL-6 had defects in disseminating myeloma similar to those in MP-depleted recipients. Mice that were deficient in TNFα or TNFα receptor (TNFR) had defects in disseminating MM, and engraftment was also impaired. These effects on dissemination of myeloma required production of cytokines in the radiation-resistant compartment that contained these radiation-resistant BM MPs. Taken together, we propose that egress of myeloma cells from BM is regulated by localized inflammation in foci, driven in part by CD169+ MPs.