Fulminant type 1 diabetes mellitus with anti‐programmed cell death‐1 therapy

Anti‐programmed cell death‐1 (PD‐1) antibodies are regarded as a risk factor for insulin‐dependent diabetes mellitus as a side‐effect. While a small number of cases have been reported, evidence remains limited. This is the first report of an Asian patient developing insulin‐dependent diabetes during anti‐PD‐1 therapy. A 55‐year‐old euglycemic woman receiving nivolumab for malignant melanoma showed abrupt onset of ketonuria, and elevated levels of plasma glucose (580 mg/dL) and hemoglobin A1c (7.0%). Over the next 2 weeks, serum C‐peptide levels fell below the limit of detection. Islet autoantibodies were negative, and the patient showed a human leukocyte antigen haplotype associated with type 1 diabetes. Anti‐PD‐1 therapy can cause rapid onset of insulin‐dependent diabetes, possibly because of inappropriate activation of T cells. Human leukocyte antigen haplotypes might be related to the onset of this disease. Physicians should be aware of this serious adverse event and carry out routine blood glucose testing during anti‐PD‐1 therapy.     

Effect of ICAM‐1 and LFA‐1 in hyperleukocytic acute myeloid leukaemia

Acute hyperleukocytic leukemia [AHL; WBC count >100 × 10⁹/l] is associated with a life‐threatening complication. The mechanisms of hyperleukocytosis in acute myeloid leukaemia (AML) remain unclear. However, the interaction of intercellular adhesion molecule‐1 (ICAM‐1) and lymphocyte function‐associated antigen‐1 (LFA‐1) plays an important role in the adhesion and migration of normal leukocytes and AML cells. Therefore, effects of ICAM‐1 and LFA‐1 were studied in hyperleukocytic AML. The adhesion of hyperleukocytic AML blasts and human umbilical vein endothelial cells (HUVECs) was significantly increased compared with that of blasts from non‐hyperleukocytic AML (WBC < 100 × 10⁹/l). The adhesion of normal neutrophils and HUVECs treated with hyperleukocytic AML blast supernatant was increased significantly. Finally, we determined the ICAM‐1 on the surface of HUVECs treated with the supernatant of hyperleukocytic AML blasts and LFA‐1 on hyperleukocytic AML blasts by flow cytometry. It showed that the ICAM‐1 expression on the surface of the HUVECs treated with hyperleukocytic AML blast supernatant for 24 h could be increased, and the expression of LFA‐1 on hyperleukocytic AML was also increased significantly. Our data show that hyperleukocytic AML blasts stimulate the endothelium to secrete more ICAM‐1 and promote their own adhesion to vascular endothelium, suggesting that ICAM‐1 and LFA‐1 may have a role in hyperleukocytic AML.     

PD‐1/PD‐L1 pathway and T‐cell exhaustion in chronic hepatitis virus infection

Summary. Dysfunctional virus‐specific T cells are a hallmark of many chronic viral infections. Recent studies have implicated the inhibitory PD‐1/PD‐L1 pathway with the functional impairment of T cells. In this respect, we will review the latest research on PD‐1/PD‐L1 pathway and T‐cell exhaustion in the context of human chronic hepatitis B and C virus infections. We will also discuss the therapeutic potential of PD‐1 blockade and how it may be enhanced through the modulation of other co‐stimulatory/inhibitory pathways.     

Melatonin prevents Drp1‐mediated mitochondrial fission in diabetic hearts through SIRT1‐PGC1α pathway

Myocardial contractile dysfunction is associated with an increase in mitochondrial fission in patients with diabetes. However, whether mitochondrial fission directly promotes diabetes‐induced cardiac dysfunction is still unknown. Melatonin exerts a substantial influence on the regulation of mitochondrial fission/fusion. This study investigated whether melatonin protects against diabetes‐induced cardiac dysfunction via regulation of mitochondrial fission/fusion and explored its underlying mechanisms. Here, we show that melatonin prevented diabetes‐induced cardiac dysfunction by inhibiting dynamin‐related protein 1 (Drp1)‐mediated mitochondrial fission. Melatonin treatment decreased Drp1 expression, inhibited mitochondrial fragmentation, suppressed oxidative stress, reduced cardiomyocyte apoptosis, improved mitochondrial function and cardiac function in streptozotocin (STZ )‐induced diabetic mice, but not in SIRT 1^?/? diabetic mice. In high glucose‐exposed H9c2 cells, melatonin treatment increased the expression of SIRT 1 and PGC ‐1α and inhibited Drp1‐mediated mitochondrial fission and mitochondria‐derived superoxide production. In contrast, SIRT 1 or PGC ‐1α siRNA knockdown blunted the inhibitory effects of melatonin on Drp1 expression and mitochondrial fission. These data indicated that melatonin exerted its cardioprotective effects by reducing Drp1‐mediated mitochondrial fission in a SIRT 1/PGC ‐1α‐dependent manner. Moreover, chromatin immunoprecipitation analysis revealed that PGC ‐1α directly regulated the expression of Drp1 by binding to its promoter. Inhibition of mitochondrial fission with Drp1 inhibitor mdivi‐1 suppressed oxidative stress, alleviated mitochondrial dysfunction and cardiac dysfunction in diabetic mice. These findings show that melatonin attenuates the development of diabetes‐induced cardiac dysfunction by preventing mitochondrial fission through SIRT 1‐PGC 1α pathway, which negatively regulates the expression of Drp1 directly. Inhibition of mitochondrial fission may be a potential target for delaying cardiac complications in patients with diabetes.     

Analysis of N1‐acetyl‐N2‐formyl‐5‐methoxykynuramine/N1‐acetyl‐5‐methoxy‐kynuramine formation from melatonin in mice

Abstract: The interactions of melatonin, a potent endogenous antioxidant, with reactive oxygen species generate several products that include N¹‐acetyl‐N²‐formyl‐5‐methoxykynuramine (AFMK) and N¹‐acetyl‐5‐methoxy‐kynuramine (AMK). The physiological or pathological significance of AFMK/AMK formation during the process of melatonin metabolism in mammals has not been clarified. Using a metabolomic approach in the current study, the AFMK/AMK pathway was thoroughly investigated both in mice and humans. Unexpectedly, AFMK and AMK were not identified in the urine of humans nor in the urine, feces or tissues (including liver, brain, and eyes) in mice under the current experimental conditions. Metabolomic analysis did identify novel metabolites of AMK, i.e. hydroxy‐AMK and glucuronide‐conjugated hydroxy‐AMK. These two newly identified metabolites were, however, not found in the urine of humans. In addition, oxidative stress induced by acetaminophen in the mouse model did not boost AFMK/AMK formation. These data suggest that AFMK/AMK formation is not a significant pathway of melatonin disposition in mice, even under conditions of oxidative stress.     

Short‐acting glucagon‐like peptide‐1 receptor agonists as add‐on to insulin therapy in type 1 diabetes: A review

A large proportion of patients with type 1 diabetes do not reach their glycaemic target of glycated hemoglobin (HbA1c) <7.0% (53 mmol/mol) and, furthermore, an increasing number of patients with type 1 diabetes are overweight and obese. Treatment of type 1 diabetes is based on insulin therapy, which is associated with well‐described and unfortunate adverse effects such as hypoglycaemia and increased body weight. Glucagon‐like peptide‐1 (GLP‐1) receptor agonists (RAs) are the focus of increasing interest as a possible adjunctive treatment to insulin in type 1 diabetes because of their glucagonostatic and extrapancreatic effects. So far, the focus has mainly been on the long‐acting GLP‐1RAs, but the risk–benefit ratio emerging from studies evaluating the effect of long‐acting GLP‐1RAs as adjunctive therapy to insulin therapy in patients with type 1 diabetes has been disappointing. This might be attributable to a lack of glucagonostatic effect of these long‐acting GLP‐1RAs in type 1 diabetes, alongside development of tachyphylaxis to GLP‐1‐induced retardation of gastric emptying. In contrast, the short‐acting GLP‐1RAs seem to have a preserved and sustained effect on glucagon secretion and gastric emptying in patients with type 1 diabetes, which could translate into effective lowering of postprandial glucose excursions; however, these observations regarding short‐acting GLP‐1RAs are all derived from small open‐label trials and should thus be interpreted with caution. In the present paper we review the potential role of GLP‐1RAs, in particular short‐acting GLP‐1RAs, as add‐on to insulin in the treatment of type 1 diabetes.     

A novel multi‐epitope vaccine from MMSA‐1 and DKK1 for multiple myeloma immunotherapy

The identification of novel tumour‐associated antigens is urgently needed to improve the efficacy of immunotherapy for multiple myeloma (MM). In this study, we identified a membrane protein MMSA‐1 (multiple myeloma special antigen‐1) that was specifically expressed in MM and exhibited significantly positive correlation with MM. We then identified HLA‐A*0201‐restricted MMSA‐1 epitopes and tested their cytotoxic T lymphocyte (CTL) response. The MMSA‐1 epitope SLSLLTIYV vaccine was shown to induce an obvious CTL response in vitro. To improve the immunotherapy, we constructed a multi‐epitope peptide vaccine by combining epitopes derived from MMSA‐1 and Dickkopf‐1 (DKK1). The effector T cells induced by multi‐epitope peptide vaccine‐loaded dendritic cells lysed U266 cells more effectively than MMSA‐1/DKK1 single‐epitope vaccine. In myeloma‐bearing severe combined immunodeficient mice, the multi‐epitope vaccine improved the survival rate significantly compared with single‐epitope vaccine. Consistently, multi‐epitope vaccine decreased the tumour volume greatly and alleviated bone destruction. The frequencies of CD4⁺ and CD8⁺ T cells was significantly increased in mouse blood induced by the multi‐epitope vaccine, indicating that it inhibits myeloma growth by changing T cell subsets and alleviating immune paralysis. This study identified a novel peptide from MMSA‐1 and the multi‐epitope vaccine will be used to establish appropriate individualized therapy for MM.     

Estimation of monocyte‐chemoattractantprotein‐1 (Mcp‐1) level in patients with lupus nephritis

Aim: To evaluate the use of non‐invasive estimation of CP‐1 in urine as a good indicator for lupus nephritis activity. Methods: The study was conducted on 30 patients with systemic lupus erythematosus (SLE) (group I): 15 of these patients were selected without renal involvement (group I [A]), and the other 15 were selected with evidence of renal involvement (group I [B]). Further 10 age‐ and sex‐matched healthy subjects were taken as a control group (group II). The SLE disease activity index (SLEDAI) was applied. Laboratory investigations done for the studied group of patients included: renal function tests (antinuclear antibody) titer, (anti‐double‐stranded DNA) titer, and monocyte chemotactic protein 1 (MCP‐1) level in serum and urine samples. Results: Serum MCP‐1 was significantly higher in SLE patients with nephritis than in the control group, while no significant difference was found between SLE patients without nephritis and the control group. Urinary MCP‐1 in patients with active lupus nephritis (LN) were significantly higher than both patients with inactive LN and control the group. Urinary MCP‐1 in SLE patients with nephritis was significantly higher than both group I (A) and group II. Urinary MCP‐1 correlated positively with proteinuria, and negatively with creatinine clearance and hemoglobin; thus, urinary MCP‐1 correlates with the severity of nephritis. Conclusion: Urinary and not serum MCP‐1 is a useful invasive technique for the assessment of renal disease activity in patients with LN.