Relationship between blood amyloid A and resting magnetic resonance functional brain connections in patients with obstructive sleep apnea-hypopnea syndrome.

OBJECTIVE: The aim of this study was to analyze the relationship between serum amyloid A (SAA) concentrations in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) and their magnetic resonance imaging (MRI) of resting brain function. METHODS: Male patients with OSAHS were enrolled from January to June 2019 in Suzhou Ninth People's Hospital Affiliated to Soochow University, and nineteen healthy male volunteers were selected as the normal control group. The patients with OSAHS were divided into mild, moderate, and severe groups according to their apnea-hypopnea index (AHI). Early in the morning after the polysomnography (PSG), blood samples were collected and serum levels of serum amyloid A (SAA) were measured by enzyme-linked immunosorbent assay. All subjects were scored by the Auditory Verbal Learning Test (AVLT) scale. Resting brain function images of healthy male volunteers and patients in the severe group were collected by 3.0 T magnetic resonance scanner. SPSS25.0 software was used for statistical analysis. RESULTS: The SAA of the OSAHS group (n = 43) were higher than those of control group (n = 19). The scores of AVLT-immediate and AVLT-delay in the severe OSAHS group were lower than those in the control group (P < 0.05), and it was negatively correlated with SAA. In the severe OSAHS group, the rest state Function Connection (rsFC) in temporal lobe, marginal lobe, and frontal lobe was lower than that in the control group (P < 0.05) and was significantly negatively correlated with SAA. The rsFC in bilateral parietal lobes was higher than that in the control group (P < 0.05), was significantly positively correlated with SAA, and was negatively correlated with AVLT-delay. CONCLUSIONS: The significant increase in SAA concentration in patients with OSAHS correlated with brain rsFC intensity, providing a reference role for the diagnosis, treatment, and prognosis of cognitive dysfunction in patients with OSAHS.

NAMPT Inhibitor and P73 Activator Represses P53 R175H Mutated HNSCC Cell Proliferation in a Synergistic Manner.

The p53 family has the following three members: p53, p63 and p73. p53 is a tumor suppressor gene that frequently exhibits mutation in head and neck cancer. Most p53 mutants are loss-of-function (LoF) mutants, but some acquire some oncogenic function, such as gain of function (GoF). It is known that the aggregation of mutant p53 can induce p53 GoF. The p73 activators RETRA and NSC59984 have an anti-cancer effect in p53 mutation cells, but we found that p73 activators were not effective in all head and neck squamous cell carcinoma (HNSCC) cell lines, with different p53 mutants. A comparison of the gene expression profiles of several regulator(s) in mutant HNSCC cells with or without aggregation of p53 revealed that nicotinamide phosphoribosyltransferase (NAMPT) is a key regulator of mutant p53 aggregation. An NAMPT inhibitor, to reduce abnormal aggregation of mutant p53, used in combination with a p73 activator, was able to effectively repress growth in HNSCC cells with p53 GoF mutants. This study, therefore, suggests a potential combination therapy approach for HNSCC with a p53 GoF mutation.

PTC124 Rescues Nonsense Mutation of Two Tumor Suppressor Genes NOTCH1 and FAT1 to Repress HNSCC Cell Proliferation.

(1) Background: PTC124 (Ataluren) is an investigational drug for the treatment of nonsense mutation-mediated genetic diseases. With the exception of the TP53 tumor suppressor gene, there has been little research on cancers with nonsense mutation. By conducting a database search, we found that another two tumor suppressor genes, NOTCH1 and FAT1, have a high nonsense mutation rate in head and neck squamous cell carcinoma (HNSCC). PTC124 may re-express the functional NOTCH1 or FAT1 in nonsense mutation NOTCH1 or FAT1 in HSNCC (2) Methods: DOK (with NOTCH1 Y550X) or HO-1-u-1 (with FAT1 E378X) HNSCC cells were treated with PTC124, and the NOTCH1 or FAT1 expression, cell viability, and NOTCH1- or FAT1-related downstream gene profiles were assayed. (3) Results: PTC124 was able to induce NOTCH1 or FAT1 expression in DOK and HO-1-u-1 cells. PTC124 was able to upregulate NOTCH downstream genes HES5, AJUBA, and ADAM10 in DOK cells. PTC124 enhanced DDIT4, which is under the control of the FAT1-YAP1 pathway, in HO-1-u-1 cells. FLI-06 (a NOTCH signaling inhibitor) reversed PTC124-mediated cell growth inhibition in DOK cells. PTC124 could reverse TT-10 (a YAP signaling activator)-mediated HO-1-u-1 cell proliferation. (4) Conclusions: PTC124 can rescue nonsense mutation of NOTCH1 and FAT1 to repress HNSCC cell proliferation.

P63 and P73 Activation in Cancers with p53 Mutation.

The members of the p53 family comprise p53, p63, and p73, and full-length isoforms of the p53 family have a tumor suppressor function. However, p53, but not p63 or p73, has a high mutation rate in cancers causing it to lose its tumor suppressor function. The top and second-most prevalent p53 mutations are missense and nonsense mutations, respectively. In this review, we discuss possible drug therapies for nonsense mutation and a missense mutation in p53. p63 and p73 activators may be able to replace mutant p53 and act as anti-cancer drugs. Herein, these p63 and p73 activators are summarized and how to improve these activator responses, particularly focusing on p53 gain-of-function mutants, is discussed.

Impact of Environmental Microbes on the Composition of the Gut Microbiota of Adult BALB/c Mice.

To investigate the impact of microbes within the living environment on the gut microbiota of adults, we raised three groups of BALB/c mice from 3-4 weeks age in the same specific-pathogen-free animal room for 8 weeks. The control group lived in cages with sterilized bedding (pelletized cardboard), the probiotics group had three probiotics added to the sterilized bedding, and the intestinal microbes (IM) group had the intestinal microbes of a healthy goat added to the bedding. All other variables such as diet, age, genetic background, physiological status, original gut microbiota, and living room were controlled. Using high-throughput sequencing of the 16S rRNA gene, we observed that the control and probiotics groups had similar diversity and richness of gut microbiota. The two groups had significantly lower diversity than the IM group. We also observed that the IM group had a specific structure of gut microbial community compared with the control and probiotics groups. However, the dominate bacteria changed slightly upon exposure to intestinal microbes, and the abundance of the non-dominate species changed significantly. In addition, exposure to intestinal microbes inhibited DNFB-induced elevation of serum IgE levels. Our results provide new evidence in support of the microflora and hygiene hypotheses.