Exploring novel systemic therapies for pancreatic cancer: a review of emerging anti-PD-1/PD-L1 combination therapy.

Despite attempts to apply single therapy such as surgical treatment, chemotherapy, or radiotherapy, pancreatic cancer (PC) is still one of the most lethal solid tumors. Moreover, immune checkpoint inhibitors against PD-1/PD-L1, which have shown good efficacies against many other solid tumors, have not shown encouraging results in PC treatment. Therefore, some studies are evaluating the efficacies of combination therapies based on anti-PD-1/PD-L1 for PC. In this review, we summarized the emerging anti-PD-1/PD-L1 combination therapies for PC in these years. We realized that anti-PD-1/PD-L1-based combination therapies have the potential to be efficacious in PC treatment, and further relevant studies are needed. Moreover, we elucidated the reasons for the ineffectiveness of anti-PD-1/PD-L1 alone in PC treatment. We concluded that this was mainly because PC has an immunosuppressive tumor microenvironment and develops drug resistance during treatment. Anti-PD-1/PD-L1-based combination therapeutic regimens that alter the immunosuppressive tumor microenvironment and reduce the development of drug resistance in PC are summarized in this review, and we expect that these regimens will achieve good clinical application prospects.

Role of ion channels in chronic intermittent hypoxia-induced atrial remodeling in rats.

AIMS: Atrial remodeling, including structural and electrical remodeling, is considered as the substrate in the development of atrial fibrillation (AF). Structural remodeling mainly involves atrial fibrosis, and electrical remodeling is closely related to the changes of ion channels in atrial myocytes. In this study, we aimed to investigate the changes of ion channels in atrial remodeling induced by CIH in rats, which provide the explication for the mechanisms of AF. MATERIALS AND METHODS: 80 male Sprague-Dawley rats were randomized into two groups: Control and CIH group (n = 40). CIH rats were subjected to CIH 8 h/d for 30 days. Atrial epicardial conduction velocity, conduction inhomogeneity and AF inducibility were examined. Masson's trichrome staining was used to evaluate the extent of atrial fibrosis, and the expression levels of ion channel subunits were measured by RT-qPCR, Western blot, and IHC, respectively. The remaining 40 rats were used for whole-cell patch clamp experiments. Action potential, INa, ICa-L, Ito were recorded and compared between two groups. KEY FINDINGS: CIH rats showed increased AF inducibility, atrial interstitial collagen deposition, APD, expression levels of RyR2, p-RyR2, CaMKII, p-CaMKII, and decreased atrial epicardial conduction velocity, expression levels of Nav1.5, Cav1.2, Kv1.5, Kv4.2, Kv4.3 compared to the Control rats, and the current density of INa, ICa-L, Ito were significantly decreased in CIH group. SIGNIFICANCE: We observed significant atrial remodeling induced by CIH in our rat model, which was characterized by changes in ion channels. These changes may be the mechanisms of CIH promoting AF.

Improvement of butanol production by the development and co-culture of C. acetobutylicum TSH1 and B. cereus TSH2.

Butanol fermentation comprises two successive and distinct stages, namely acidogenesis and solventogenesis. The current lack of clarity regarding the underlying metabolic regulation of fermentation impedes improvements in biobutanol production. Here, a proteomics study was performed in the acidogenesis phase, the lowest pH point (transition point), and the solventogenesis phase in the butanol-producing symbiotic system TSH06. Forty-two Clostridium acetobutylicum proteins demonstrated differential expression levels at different stages. The protein level of butanol dehydrogenase increased in the solventogenesis phase, which was in accordance with the trend of butanol concentration. Stress proteins were upregulated either at the transition point or in the solventogenesis phase. The cell division-related protein Maf was upregulated at the transition point. We disrupted the maf gene in C. acetobutylicum TSH1, and Bacillus cereus TSH2 was added to form a new symbiotic system. TSH06△maf produced 13.9 ± 1.0 g/L butanol, which was higher than that of TSH06 (12.3 ± 0.9 g/L). Butanol was furtherly improved in fermentation at variable temperature with neutral red addition for both TSH06 and TSH06△maf. The butanol titer of the maf deletion strain was higher than that of the wild type, although the exact mechanism remains to be determined.

[Key enzymes in butanol fermentation by a facultative anaerobe Bacillus sp. TSH1].

Bacillus sp. TSH1 is a butanol-producing microorganism newly isolated in our laboratory; it can grow and ferment under facultative anaerobic conditions, while sharing similar fermentation pathways and products with Clostridium acetobutylicum. To illustrate the relationships between the products and the enzyme activities in Bacillus sp. TSH1, key butanol- and ethanol-forming enzymes were studied, including butyraldehyde dehydrogenase, butanol dehydrogenase and alcohol dehydrogenase. The activities of the three enzymes increased rapidly after the initiation of fermentation. Activities of three enzymes peaked before 21 h, and simultaneously, product concentrations also began to increase gradually. The maximum activity of alcohol dehydrogenase was 0.054 U/mg at 12 h, butyraldehyde dehydrogenase 0.035 U/mg at 21 h and butanol dehydrogenase 0.055 U/mg at 15 h. The enzyme activities then decreased, but remained constant at a low level after 24 h, while the concentrations of butanol, acetone, and ethanol continued increasing until the end of the fermentation. The results will attribute to the understanding of the butanol metabolic mechanism, and provide a reference for further study of a facultative Bacillus metabolic pathway.