Smad4

Activin

Colon cancer

GST M1

GST T1

GST P1

Lysyl oxidase

BACKGROUND: Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. METHODS: The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18-49, 50-69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty. RESULTS: NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year. CONCLUSION: As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population.

Peri-operative SARS-CoV-2 infection increases postoperative mortality. The aim of this study was to determine the optimal duration of planned delay before surgery in patients who have had SARS-CoV-2 infection. This international, multicentre, prospective cohort study included patients undergoing elective or emergency surgery during October 2020. Surgical patients with pre-operative SARS-CoV-2 infection were compared with those without previous SARS-CoV-2 infection. The primary outcome measure was 30-day postoperative mortality. Logistic regression models were used to calculate adjusted 30-day mortality rates stratified by time from diagnosis of SARS-CoV-2 infection to surgery. Among 140,231 patients (116 countries), 3127 patients (2.2%) had a pre-operative SARS-CoV-2 diagnosis. Adjusted 30-day mortality in patients without SARS-CoV-2 infection was 1.5% (95%CI 1.4-1.5). In patients with a pre-operative SARS-CoV-2 diagnosis, mortality was increased in patients having surgery within 0-2 weeks, 3-4 weeks and 5-6 weeks of the diagnosis (odds ratio (95%CI) 4.1 (3.3-4.8), 3.9 (2.6-5.1) and 3.6 (2.0-5.2), respectively). Surgery performed >/= 7 weeks after SARS-CoV-2 diagnosis was associated with a similar mortality risk to baseline (odds ratio (95%CI) 1.5 (0.9-2.1)). After a >/= 7 week delay in undertaking surgery following SARS-CoV-2 infection, patients with ongoing symptoms had a higher mortality than patients whose symptoms had resolved or who had been asymptomatic (6.0% (95%CI 3.2-8.7) vs. 2.4% (95%CI 1.4-3.4) vs. 1.3% (95%CI 0.6-2.0), respectively). Where possible, surgery should be delayed for at least 7 weeks following SARS-CoV-2 infection. Patients with ongoing symptoms >/= 7 weeks from diagnosis may benefit from further delay.

Human myeloma cells from about 10% of cases with multiple myeloma expressed CD33 and had monocytoid morphology with convoluted nuclei, and all these patients had no increase in serum CRP values. In CD33(+) myeloma cells as well as myeloma cell lines, CD33 expression levels were correlated with the increased expression levels of CEBPA (C/EBPalpha). This correlation was confirmed by the finding that transfection with the CEBPA gene induced CD33 expression in a CD33(-) myeloma cell line. As suggested by the lack of an increase in serum CRP values in CD33(+) myelomas, IL-6 down-regulated the expression of CD33 in CD33(+) myeloma cell lines along with the down-regulation of CEBPA gene expression. Cucurbitacin I (STAT3 inhibitor), but not U0126 (MAPK inhibitor), could abolish the effect of IL-6. Furthermore, IL-6 up-regulated the expression of MYC via STAT3 phosphorylation and MYC bound to the promoter region of the CEBPA gene followed by the down-regulation of CEBPA expression. It was confirmed that introduction of shRNA for MYC into a CD33(+) myeloma cell line blocked the IL-6-induced down-regulation of CD33 and CEBPA expression. Therefore, these results indicate that IL-6 can reverse the expression level of CD33 by up-regulating MYC followed by the down-regulation of CEBPA expression.

Multiple myeloma (MM) is a proliferative disorder of monoclonal plasma cells which accumulate in human bone marrow (BM). CD19 is a hallmark differentiation antigen of the B cell lineage and positively regulates antigen receptor signal transduction in mature B cells. We have previously shown that malignant plasma cells (myeloma cells) isolated from the MM patients lack the CD19 expression, while non-malignant plasma cells isolated from the healthy donors do express the CD19 antigens. It is also intriguing that there exists both CD19- and CD19+ plasma cells in some cases in pre-myeloma states including monoclonal gammopathy of undetermined significance (MGUS). It indicates that MGUS is usually composed of phenotypically non-malignant (CD19+) and malignant (CD19-) plasma cells. Furthermore, we recently demonstrate that, expression of the CD19 gene markedly inhibits the proliferation of human myeloma cell lines in vitro, and exhibits the reduced tumorigenicity in vivo and no anchorage-independent growth in vitro of a tumorigenic myeloma cell line. This inhibitory effect might result from the CD19-mediated intracellular signals because it is not observed in cells expressing the mutant CD19, which lacks the cytoplasmic domain. In this review, we suggest that loss of CD19 in MM could contribute to the proliferative advantage of the malignant plasma cell clones in this disease. Furthermore, we propose the usefulness of the phenotypic analysis of plasma cells in human plasma cell dyscrasia as a new diagnostic tool, and the CD19 gene as a potential target for the gene therapy in MM.

In the peripheral blood (PB) we detected so-called early plasma cells that might already be committed to entering the bone marrow (BM). By two-colour staining with FITC-anti-CD38 antibody, their intensity (CD38++) of expression of CD38 antigen was between that of germinal center (GC) B cells (low expression (CD38+)) and that of BM plasma cells (high expression (CD38++), and their phenotype was CD38++ CD19+ CD10- CD20- CD21+ CD24- CD39+ CD5- VLA-4+ VLA-5- MPC-1- without expression of surface membrane IgM (SmIgM). Morphological and immunological examination of the sorted cells confirmed that they were plasmacytoid cells with expression of cytoplasmic IgG (cIgG). Variations of these early plasma cells were examined in various diseases. In active systemic lupus erythematosus, bacterial septicaemia and liver cirrhosis, early plasma cell levels were significantly increased in PB, and after subsidence of such inflammation (inactive states) these cells returned to normal levels. In contrast, normal early plasma cells were significantly suppressed in myelomas, whilst normal or slightly increased numbers of early plasma cells was found in benign monoclonal gammopathy (BMG). In addition, the number of normal early plasma cells returned to a normal level in myeloma cases with complete responses. Therefore, early plasma cells were identified phenotypically, and an increase and decrease in these cells in PB may reflect mobilization and suppression, respectively, of activated B cells into BM plasma cells.

To evaluate nuclear factor-κB (NF-κB) activity in primary myeloma cells from myeloma patients, we confirmed that the expression levels of CD54 showed a good correlation with the levels of DNA binding activity for NF-κB in human myeloma cell lines, and thus analyzed the expression levels of CD54 on CD38(++) plasma cell fractions as one of NF-κB activity. Primary myeloma cells unexpectedly showed constitutively lower expressions of CD54 than normal bone marrow (BM) plasma cells. Furthermore, the expression levels of CD54 on these plasma cells showed a significant correlation with the plasma levels of CXCL12 stromal cell-derived factor-1a (SDF-1a) in their BM aspirates, and the expressions of CXCR4, the receptor for CXCL12, decreased on primary myeloma cells compared with normal BM plasma cells. It was also confirmed that the addition of CXCL12 to the in vitro culture significantly induced the up-regulation of CD54 expression in primary myeloma cells. In addition, myeloma cells with lower expressions of CD54 were more unstable in the in vitro culture, resulting in a marked reduction of the viable cell number. In the immunohistochemical analysis of BM aspirates, myeloma cells with lower CD54 expression resided in the perivascular regions. Therefore, these data suggest that primary myeloma cells exhibit constitutively lower CD54 that might be partially regulated by CXCL12, and their localizations in the BM may be associated with the expression levels of CD54.