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Purpose: Immune-checkpoint inhibitors have shown therapeutic efficacy in various malignant diseases. However, antiprogrammed death (PD)-1 therapy has not shown clinical efficacy in multiple myeloma.Experimental Design: Bone marrow (BM) mononuclear cells were obtained from 77 newly diagnosed multiple myeloma patients. We examined the expression of immune-checkpoint receptors in BM CD8 þ T cells and their functional restoration by ex vivo treatment with anti-PD-1 and TGFb inhibitors.Results: We confirmed the upregulation of PD-1 and PD-L1 expression in CD8 þ T cells and myeloma cells, respectively, from the BM of multiple myeloma patients. PD-1-expressing CD8 þ T cells from the BM of multiple myeloma patients coexpressed other checkpoint inhibitory receptors and exhibited a terminally dif-ferentiated phenotype. These results were also observed in BM CD8 þ T cells specific to myeloma antigens NY-ESO-1 and HM1.24. BM CD8 þ T cells from multiple myeloma patients exhibited reduced proliferation and cytokine production upon T-cell receptor stimulation. However, anti-PD-1 did not increase the proliferation of BM CD8 þ T cells from multiple myeloma patients, indicating that T-cell exhaustion in multiple myeloma is hardly reversed by PD-1 blockade alone. Intriguingly, anti-PD-1 significantly increased the proliferation of BM CD8 þ T cells from multiple myeloma patients in the presence of inhibitors of TGFb, which was overexpressed by myeloma cells.Conclusions: Our findings indicate that combined blockade of PD-1 and TGFb may be useful for the treatment of multiple myeloma.

Highlights d IL-15 upregulates CCR5 in memory CD8 + T cells in the absence of TCR stimulation d CCR5 is upregulated in IL-15-induced bystander-activated CD8 + T cells d IL-15-treated CD8 + T cells migrate in a CCR5-dependent manner d CCR5 upregulation is associated with liver injury during acute hepatitis A

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BackgroundInflammation is an important underlying mechanism in the pathogenesis of atherosclerosis, and an elevated resting heart rate underlies the process of atherosclerotic plaque formation. We hypothesized an association between resting heart rate and subclinical inflammation.MethodsResting heart rate was recorded at baseline in the KoGES-ARIRANG (Korean Genome and Epidemiology Study on Atherosclerosis Risk of Rural Areas in the Korean General Population) cohort study, and was then divided into quartiles. Subclinical inflammation was measured by white blood cell count and high-sensitivity C-reactive protein. We used progressively adjusted regression models with terms for muscle mass, body fat proportion, and adiponectin in the fully adjusted models. We examined inflammatory markers as both continuous and categorical variables, using the clinical cut point of the highest quartile of white blood cell count (≥7,900/mm3) and ≥3 mg/dL for high-sensitivity C-reactive protein.ResultsParticipants had a mean age of 56.3±8.1 years and a mean resting heart rate of 71.4±10.7 beats/min; 39.1% were men. In a fully adjusted model, an increased resting heart rate was significantly associated with a higher white blood cell count and higher levels of high-sensitivity C-reactive protein in both continuous (P for trend <0.001) and categorical (P for trend <0.001) models.ConclusionAn increased resting heart rate is associated with a higher level of subclinical inflammation among healthy Korean people.

Complete blood count (CBC) is one of the most common blood tests requested by clinicians and evaluates the total numbers and characteristics of cell components in the blood. Recently, many investigations have suggested that the risk of cancer, cardiovascular disease (CVD), arteriosclerosis, type 2 diabetes (T2DM), and metabolic syndrome can be predicted using CBC components. This review introduces that white blood cell (WBC), neutrophil-to-lymphocyte ratio (NLR), hemoglobin (Hb), mean corpuscular volume (MCV), red cell distribution width (RDW), platelet count, mean platelet volume (MPV), and platelet-to-lymphocyte ratio (PLR) are useful markers to predict CVD and metabolic diseases. Furthermore, we would like to support various uses of CBC by organizing pathophysiology that can explain the relationship between CBC components and diseases.

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An adaptive feedback linearization technique combined with the neural network is addressed to control uncertain nonlinear systems. The neural network-based adaptive control theory has been widely studied. However, the stability analysis of the closed-loop system with the neural network is rather complicated and difficult to understand, and sometimes unnecessary assumptions are involved. As a result, unnecessary assumptions for stability analysis are avoided by using the neural network with input normalization technique. The ultimate boundedness of the tracking error is simply proved by the Lyapunov stability theory. A new simple update law as an adaptive nonlinear control is derived by the simplification of the input normalized neural network assuming the variation of the uncertain term is sufficiently small.