We investigated the presence of beta-adrenoceptor subtypes in human urinary bladder urothelium and examined whether beta-adrenoceptors in the urothelium modulate the relaxation responses of isolated human detrusor strips to a beta-adrenoceptor agonist. Expression of beta1-, beta2-, and beta3-adrenoceptor mRNA in urothelium and detrusor smooth muscle was determined by reverse transcription-polymerase chain reaction, and the distribution of beta1-, beta2-, and beta3-adrenoceptors in human urinary bladder urothelium were examined by immunohistochemistry. Paired human longitudinal detrusor strips with and without an intact urothelium were suspended in organ baths to construct concentration-response curves to isoproterenol. The possible involvement of urothelium-derived nitric oxide (NO) in this response was examined in additional experiments with urothelium-intact strips in the presence of NG-nitro-L-arginine methylester (L-NAME). Results confirmed the expression of beta1-, beta2-, and beta3-adrenoceptors in the human urinary bladder urothelium. Further, the presence of the urothelium caused a parallel rightward shift of the concentration-response curve to isoproterenol with a significant reduction in potency (pEC50). L-NAME failed to exert any significant effect on the relaxation response to isoproterenol in the urothelium-intact strips. These results confirm the presence of beta1-, beta2-, and beta3-adrenoceptors in human urinary bladder urothelium. Further, they suggest that urothelial beta-adrenoceptors induce the release of a urothelium-derived factor which inhibits the beta-adrenoceptor agonist-induced relaxation of the human detrusor smooth muscle and that this inhibitory mechanism might not involve NO.
Background: Acral melanoma (AM) is an epidemiologically and molecularly distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma. We aimed to analyze the efficacy of anti-programmed cell death 1 (anti-PD-1) antibodies in advanced AM. Patients and methods: We retrospectively evaluated unresectable stage III or stage IV AM patients treated with an anti-PD-1 antibody in any line at 21 Japanese institutions between 2014 and 2018. The clinicobiologic characteristics, objective response rate (ORR, RECIST), survival estimated using KaplaneMeier analysis, and toxicity (Common Terminology Criteria for Adverse Events 4.0.) were analyzed to estimate the efficacy of the anti-PD-1 antibodies. Results: In total, 193 patients (nail apparatus, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 patients (74.1%). Baseline lactate dehydrogenase (LDH) was within the normal concentration in 102 patients (52.8%). The ORR of all patients was 16.6% (complete response, 3.1%; partial response, 13.5%), and the median overall survival (OS) was 18.1 months. Normal LDH concentrations showed a significantly stronger association with better OS than abnormal concentrations (median OS 24.9 versus 10.7 months; P < 0.001). Although baseline characteristics were similar between the nail apparatus and the palm and sole groups, ORR was significantly lower in the nail apparatus group [6/70 patients (8.6%) versus 26/123 patients (21.1%); P ¼ 0.026]. Moreover, the median OS in this group was significantly poorer (12.8 versus 22.3 months; P ¼ 0.03). Conclusions: Anti-PD-1 antibodies have limited efficacy in AM patients. Notably, patients with nail apparatus melanoma had poorer response and survival, making nail apparatus melanoma a strong candidate for further research on the efficacy of novel combination therapies with immune checkpoint inhibitors.
Atopic dermatitis (AD) is a common chronic skin inflammatory disorder characterized by recurrent eczema accompanied by an intractable itch that leads to an impaired quality of life. Extensive recent studies have shed light on the multifaceted pathogenesis of the disease. The complex interplay among skin barrier deficiency, immunological derangement, and pruritus contributes to the development, progression, and chronicity of the disease. Abnormalities in filaggrin, other stratum corneum constituents, and tight junctions induce and/or promote skin inflammation. This inflammation, in turn, can further deteriorate the barrier function by downregulating a myriad of essential barrier-maintaining molecules. Pruritus in AD, which may be due to hyperinnervation of the epidermis, increases pruritogens, and central sensitization compromises the skin integrity and promotes inflammation. There are unmet needs in the treatment of AD. Based on the detailed evidence available to date, certain disease mechanisms can be chosen as treatment targets. Numerous clinical trials of biological agents are currently being conducted and are expected to provide treatments for patients suffering from AD in the future. This review summarizes the etiopathogenesis of the disease and provides a rationale for choosing the novel targeted therapy that will be available in the future.
Trehalose dimycolate (TDM), also known as cord factor, is a major surface glycolipid of the cell wall of mycobacteria. Because of its potent biological functions in models of infection, adjuvancy, and immunotherapy, it is important to determine how its biosynthesis is regulated. Here we show that glucose, a host-derived product that is not readily available in the environment, causes Mycobacterium avium to down-regulate TDM expression while up-regulating production of another major glycolipid with immunological roles in T cell activation, glucose monomycolate (GMM). In vitro, the mechanism of reciprocal regulation of TDM and GMM involves competitive substrate selection by antigen 85A. The switch from TDM to GMM biosynthesis occurs near the physiological concentration of glucose present in mammalian hosts. We further demonstrate that GMM is produced in vivo by mycobacteria growing in mouse lung. These results establish an enzymatic pathway for GMM production. More generally, these observations provide a specific enzymatic mechanism for dynamic alterations of cell wall glycolipid remodeling in response to the transition from noncellular to cellular growth environments, including factors that are monitored by the host immune system. Mycobacterium avium complex (MAC)2 includes a group of acid-fast bacteria that distribute widely in natural environments, including soil, water, aerosols, and dust (1). Although less virulent than Mycobacterium tuberculosis, these environmental mycobacteria occasionally infect humans, especially patients infected with human immunodeficiency virus type 1, where they represent a major cause of morbidity. The incidence of clinically overt MAC infection has increased significantly in recent years, and because of the multidrug resistance evolved by the microbes, MAC infection is difficult to clear with chemotherapeutic agents. Thus, M. tuberculosis and MAC are now the two major groups of mycobacteria species that require further efforts for prevention and treatment. Unlike M. tuberculosis, which transmits primarily from individuals with active disease, epidemiologic evidence suggests that such transmission pathways are unlikely for MAC. Rather, MAC infection appears to occur when susceptible individuals are exposed to environmental MAC. These observations predict that, upon infection, environmental MAC should undergo significant adaptive changes to allow its survival and replication within the host.Mycobacteria possess highly lipid-rich cell walls that are critical not simply for their acid-fast properties but also for their survival and replication. The cell wall contains mycolic acids, an ␣-alkyl--hydroxy fatty acid with extremely long carbon chains (ϳC 80 ), which are densely aligned in covalent association with the 6-position of arabinose termini of the underlying arabinogalactan sugar layer or exist as free molecules complexed to sugars, either glucose or trehalose. Arabinogalactan-linked mycolates are proposed to extend outward and interact noncovalently with carbon chains of the so-c...
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