Development and medical application of unsaturated carbaglycosylamine glycosidase inhibitors

This article reviews synthesis and structures of carbaglycosylamines, a group of carbocyclic sugar analogues. Some unsaturated derivatives are known to be potent glycosidase inhibitors. Among them, N-octyl-4-epi-beta-valienamine as a lysosomal beta-galactosidase inhibitor is currently undergoing a new molecular therapeutic trial (chemical chaperone therapy) for control of the human beta-galactosidase deficiency disorder, G(M1)-gangliosidosis.     

Glucose controls cytosolic Ca2+ and insulin secretion in mouse islets lacking adenosine triphosphate-sensitive K+ channels owing to a knockout of the pore-forming subunit Kir6.2

Glucose-induced insulin secretion is classically attributed to the cooperation of an ATP-sensitive potassium (K ATP) channel-dependent Ca2+ influx with a subsequent increase of the cytosolic free Ca2+ concentration ([Ca2+]c) (triggering pathway) and a K ATP channel-independent augmentation of secretion without further increase of [Ca2+]c (amplifying pathway). Here, we characterized the effects of glucose in beta-cells lacking K ATP channels because of a knockout (KO) of the pore-forming subunit Kir6.2. Islets from 1-yr and 2-wk-old Kir6.2KO mice were used freshly after isolation and after 18 h culture to measure glucose effects on [Ca2+]c and insulin secretion. Kir6.2KO islets were insensitive to diazoxide and tolbutamide. In fresh adult Kir6.2KO islets, basal [Ca2+]c and insulin secretion were marginally elevated, and high glucose increased [Ca2+]c only transiently, so that the secretory response was minimal (10% of controls) despite a functioning amplifying pathway (evidenced in 30 mm KCl). Culture in 10 mm glucose increased basal secretion and considerably improved glucose-induced insulin secretion (200% of controls), unexpectedly because of an increase in [Ca2+]c with modulation of [Ca2+]c oscillations. Similar results were obtained in 2-wk-old Kir6.2KO islets. Under selected conditions, high glucose evoked biphasic increases in [Ca2+]c and insulin secretion, by inducing K ATP channel-independent depolarization and Ca2+ influx via voltage-dependent Ca2+ channels. In conclusion, Kir6.2KO beta-cells down-regulate insulin secretion by maintaining low [Ca2+]c, but culture reveals a glucose-responsive phenotype mainly by increasing [Ca2+]c. The results support models implicating a K ATP channel-independent amplifying pathway in glucose-induced insulin secretion, and show that K ATP channels are not the only possible transducers of metabolic effects on the triggering Ca2+ signal.     

Effects of structural variations of APOBEC3A and APOBEC3B genes in chronic hepatitis B virus infection

Aim: Human APOBEC3 deaminases induce G to A hypermutation in nascent DNA strand of hepatitis B virus (HBV) genomes and seem to operate as part of the innate antiviral immune system. We analyzed the importance of APOBEC3A (A3A) and APOBEC3B (A3B) proteins, which are potent inhibitors of adeno‐associated‐virus and long terminal repeat (LTR)‐retrotransposons, in chronic HBV infection. Methods: We focused on the common deletion polymorphism that spans from the 3′ part of A3A gene to the 3′ portion of A3B gene. An association study was carried out in 724 HBV carriers and 469 healthy control subjects. We also analyzed hypermutated genomes detected in deletion and insertion (non‐deletion) homozygous patients to determine the effect of APOBEC3 gene deletion. Further, we performed functional analysis of A3A gene by transient transfection experiments. Results: The association study showed no significant association between deletion polymorphism and chronic HBV carrier state. Context analysis also showed a negligible effect for the deletion. Rather, mild liver fibrosis was associated with APOBEC gene deletion homozygosity, suggesting that A3B deletion is not responsible for chronic HBV infection. Functional analysis of A3A showed that overexpression of A3A induced hypermutation in HBV genome, although the levels of hypermutants were less than those introduced by A3G. However, overexpression of A3A did not decrease replicative intermediates of HBV. Conclusion: These results suggest that A3A and A3B play little role in HBV elimination through anti‐viral defense mechanisms. The significance of hypermutation induced by A3A should be investigated further.     

Sj?gren’s syndrome patients presenting with hypergammaglobulinemia are relatively unresponsive to cevimeline treatment

Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by sicca symptoms, including dry eyes and dry mouth. Cevimeline is used for the treatment of dry mouth in patients with SS. Here we prospectively tested the clinical effectiveness of cevimeline at increasing saliva secretion in patients with SS, and the results were compared with the clinical parameters of the patients. Saliva secretion was increased >160% in 17 of 30 (56.7%) patients (P < 0.005). When the clinical parameters were compared between the patients who responded to cevimeline treatment and those who did not respond to the treatment, the frequency of patients presenting with hypergammaglobulinemia was significantly higher in the nonresponder group (P < 0.05). It thus appears that cevimeline is effective in SS patients with milder disease activity.     

Hemoperfusion With an Immobilized Polymyxin B Fiber Column Decreases Macrophage and Monocyte Activity

We investigated whether direct hemoperfusion with a polymyxin B column (DHP‐PMX) was able to decrease macrophage and monocyte activity in patients with sepsis. Nineteen patients with sepsis were enrolled in the study. They all had signs of systemic inflammatory response syndrome (SIRS) due to infection and a mean arterial blood pressure ≥65 mm Hg (irrespective of the use of catecholamines). A thermodilution catheter was inserted prior to DHP‐PMX for intravenous infusion, and DHP‐PMX was performed twice within 24 h for 3 h each time. Serum neopterin was measured four times: before DHP‐PMX, and 24, 48, 72 h after it had begun. The serum concentrations of neopterin were 654 ± 234 nmol/L prior to DHP‐PMX vs. 573 ± 196 nmol/L at 24 h, 452 ± 161 nmol/L at 48 h, and 372 ± 139 nmol/L at 72 h, showing a significant decrease from 48 h onwards compared with before treatment. These data suggest that DHP‐PMX decreases macrophage and monocyte activity.     

Cardiac resynchronization and cardioverter defibrillation therapy in a patient with isolated noncompaction of the ventricular myocardium

Isolated noncompaction of the ventricular myocardium (INVM) is an unclassified cardiomyopathy and is thought to be due to arrest of myocardial morphogenesis. Left ventricular failure and ventricular arrhythmias may occur in approximately half of the patients and account for half of the death in this disorder. In this report, we describe a patient with INVM in whom cardiac resynchronization and cardioverter defibrillation therapy was effective for the improvement of left ventricular function and for the prevention of ventricular arrhythmias.     

Successful treatment of young-onset adult T cell leukemia/lymphoma and preceding chronic refractory eczema and corneal injury by allogeneic hematopoietic stem cell transplantation

Only some carriers of human T cell lymphotropic virus type I (HTLV-1) develop adult T cell leukemia/lymphoma (ATLL) after a long latency period, and an association has been reported between chronic refractory eczema, known as infective dermatitis, and young-onset ATLL. A 25-year-old female developed ATLL and underwent allogeneic hematopoietic stem cell transplantation (HSCT) in non-remission. She had chronic refractory eczema and corneal injury at the onset of ATLL. Remission of ATLL was achieved, and the HTLV-1 proviral load decreased after HSCT. In addition, her pre-existing eczema and corneal injuries almost disappeared. More than a year has passed since the transplantation was performed, and she has had no recurrence of either ATLL or lesions in the skin and eye. Her clinical course suggests a possible association between skin and eye lesions and HTLV-1 infection. Changes in the immunological condition after HSCT might play a key role. Special attention is needed when HTLV-1 carriers develop eye or skin lesions.     

Marked improvement of platelet transfusion refractoriness after bortezomib therapy in multiple myeloma

We report a patient with refractory multiple myeloma (MM) who developed platelet transfusion refractoriness (PTR). A 61-year-old woman was diagnosed with MM in July 2003. She underwent high-dose chemotherapy followed by autologous stem cell transplantation, and achieved a very good partial response. However, she relapsed in June 2006, and was referred to our hospital in October of the same year. Laboratory examinations showed pancytopenia and increased plasma cells in the peripheral blood. Platelet transfusions from random donors became ineffective, and anti-HLA class I antibody (83.8% positive) was detected in the serum by flow cytometry assay (Flow PRA). Therefore, she was considered to have developed PTR due to anti-HLA class I antibody caused by the previous blood transfusions. She was transfused with HLA-matched platelets, and then treated with bortezomib plus dexamethasone (BD) for refractory MM. The serum IgG level decreased from 7,451 to 1,735 mg/dL, and HLA class I antibody was markedly decreased to 1.9%. In addition, platelet transfusion from random donors showed clinical effects after BD therapy. This case suggests that bortezomib might be effective in different types of immune disease by inhibiting allo-reactive antibody.     

Successful treatment with intravenous colistin for sinusitis, orbital cellulites, and pneumonia caused by multidrug-resistant metallo-beta-lactamase-producing Pseudomonas aeruginosa in a patient with acute myeloid leukemia

The incidence of multidrug-resistant Pseudomonas aeruginosa (MDRPA) and metallo-beta-lactamase (MBL)-producing P. aeruginosa has increased worldwide. The treatment options are limited for infectious diseases caused by these two organisms. The use of colistin has been of recent interest in cases involving both types. We report the case of a 74-year-old man with acute myeloid leukemia who was successfully treated with intravenous colistin for maxillary sinusitis and orbital cellulites due to MBL-producing MDRPA during neutropenia, and then for pneumonia caused by the bacteria after the recovery of neutrophil counts.     

EGFR Protein Expression Relates with Tumor Histology,Methylation Status of EGFR and HPV16 E6 Viral Load in Oropharyngeal Carcinoma

The epidermal growth factor receptor (EGFR) pathway is important in tumorigenesis of oropharyngeal carcinoma (OPC). However, the molecular mechanisms contributing to EGFR expression in OPC are not well-known. To detect relating factors and clinicopathological impact of EGFR protein expression in OPC, gene amplification/loss, point mutations including synonymous mutations, and promoter methylation of EGFR, and the viral genome load of human papillomavirus type 16 (HPV16)-E5, -E6, and -E7, after extracting HPV16-related OPCs with qPCR of HPV16-E6 and E7, were investigated in 74 OPC surgical cases, including 52 HPV-related (HPV-OPC) and 22 HPV-unrelated (nHPV-OPC). Immunohistochemical (IHC) data of EGFR expression (high, weak, and negative), validated by the qPCR of EGFR mRNA, were compared with molecular, viral, and clinicopathological data of patients. All nHPV-OPC cases were EGFR-IHC-high, whereas 21.2%, 65.4%, and 13.5% of HPV-OPC cases showed EGFR-IHC-high, -weak, -negative (p < 0.01), respectively. In HPV-OPC cases, EGFR-IHC-weak/negative status was related to promoter methylation of EGFR (p = 0.009), but not with gene amplification/loss or the point mutation of EGFR and was more often seen in HPV16-OPC cases (p = 0.049). Among HPV16-OPC cases, EGFR-IHC-weak/negative was related to high E6 expression. EGFR protein-loss was related to the tumor histology of non-keratinizing squamous cell carcinoma (SCC) (p = 0.035) but not with patient prognosis. In conclusion, decreased EGFR protein expression was more frequent in HPV-OPC than in nHPV-OPC and was related to EGFR methylation, infection of HPV16, and the viral genome load of HPV16-E6. Clinicopathologically, it was related to the tumor histology of non-keratinizing SCC.Supplementary informationThe online version of this article (10.1007/s12105-020-01261-w) contains supplementary material, which is available to authorized users.