Establishment of an in vitro model of monocyte-like THP-1 cells for trained immunity induced by bacillus Calmette-Guérin.

BACKGROUND: Mycobacteria bloodstream infections are common in immunocompromised people and usually have disastrous consequences. As the primary phagocytes in the bloodstream, monocytes and neutrophils play critical roles in the fight against bloodstream mycobacteria infections. In contrast to macrophages, the responses of monocytes infected with the mycobacteria have been less investigated. RESULTS: In this study, we first established a protocol for infection of non-adherent monocyte-like THP-1 cells (i.e. without the differentiation induced by phorbol 12-myristate 13-acetate (PMA) by bacillus Calmette-Guérin (BCG). Via the protocol, we were then capable of exploring the global transcriptomic profiles of non-adherent THP-1 cells infected with BCG, and found that NF-κB, MAPK and PI3K-Akt signaling pathways were enhanced, as well as some inflammatory chemokine/cytokine genes (e.g. CCL4, CXCL10, TNF and IL-1ß) were up-regulated. Surprisingly, the Akt-HIF-mTOR signaling pathway was also activated, which induces trained immunity. In this in vitro infection model, increased cytokine responses to lipopolysaccharides (LPS) restimulation, higher cell viability, and decreased Candida albicans loads were observed. CONCLUSIONS: We have first characterized the transcriptomic profiles of BCG-infected non-adherent THP-1 cells, and first developed a trained immunity in vitro model of the cells.

Whole-Exome Sequencing Identifies Mutation Profile and Mutation Signature-Based Clustering Associated with Prognosis in Appendiceal Pseudomyxoma Peritonei.

Pseudomyxoma peritonei (PMP) is a rare malignant clinical syndrome with little known about the global mutation profile. In this study, whole-exome sequencing (WES) was performed in 49 appendiceal PMP to investigate mutation profiles and mutation signatures. A total of 4,020 somatic mutations were detected, with a median mutation number of 56 (1-402). Tumor mutation burden (TMB) was generally low (median 1.55 mutations/Mb, 0.12-11.26 mutations/Mb). Mutations were mainly enriched in the function of cancer-related axonogenesis, extracellular matrix-related processes, calcium signaling pathway, and cAMP signaling pathway. Mutations in FCGBP, RBFOX1, SPEG, RTK-RAS, PI3K-AKT, and focal adhesion pathways were associated with high-grade mucinous carcinoma peritonei. These findings revealed distinct mutation profile in appendiceal PMP. Ten mutation signatures were identified, dividing patients into mutation signature cluster (MSC) 1 (N = 28, 57.1%) and MSC 2 (N = 21, 42.9%) groups. MSC (P = 0.007) was one of the four independent factors associated with 3-year survival. TMB (P = 0.003) and microsatellite instability (P = 0.002) were independent factors associated with MSC 2 grouping. Taken together, our findings provided a broader view in the understanding of molecular pathologic mechanism in appendiceal PMP and may be critical to developing an individualized approach to appendiceal PMP treatment. IMPLICATIONS: This work describes exhaustive mutation profile of PMP based on WES data and derives ten mutation signatures, which divides patients into two clusters and serve as an independent prognostic factor associated with 3-year survival.

Significance of laparoscopic cytoreductive surgery for appendiceal pseudomyxoma peritonei with limited disease and low tumor burden.

OBJECTIVE: To investigate the clinical value of laparoscopic cytoreductive surgery (CRS) in treating of appendiceal pseudomyxoma peritonei with limited disease and low tumor burden. METHODS: The clinical data of patients with appendiceal pseudomyxoma peritonei treated by surgery with CRS at the Aerospace Center Hospital from January 2018 to December 2021 were retrospectively analyzed. The patients were divided into laparoscopic or open CRS groups according to the operation method. A propensity score-matched (PSM) analysis (1:1) was performed, the related clinical variables were compared between the two groups, and the effect on progression-free survival (PFS) was also analyzed. RESULTS: One hundred and eight patients were included in this study. After PSM, 33 patients were selected from each group and the age and peritoneal cancer index were matched between the two groups. There were significant differences in operation time (P < 0.001), intraoperative bleeding (P < 0.001), intraoperative blood transfusion (P = 0.007), hospital stay (P < 0.001). The analysis of PFS showed that there was no significant difference between the two operation methods. After multivariate analysis, the pathologic subtype (P = 0.012) was identified as an independent prognostic factor for PFS. CONCLUSION: The curative effect of laparoscopic CRS is like that of open operation, which can significantly shorten the operation time and hospital stay and reduce intraoperative bleeding and blood transfusion event. The laparoscopic CRS is safe and feasible in strictly selected patients. The pathologic subtype is an independent factor affecting the prognosis for PFS.

Compound Cocktail Inhibits Influenza Viral Pneumonia via Phospholipase Cγ1 Phosphorylation-Related Necroptosis and Partial Autophagy in Natural Killer Cells.

Influenza viral infections are prone to global outbreaks and cause pneumonia in affected populations. High morbidity and mortality caused by pneumonia occur during an influenza pandemic. Antivirals or control of inflammation is the primary means of influenza treatment. A compound cocktail composed of arctiin, daidzein, glycyrrhizic acid, and liquiritin inhibited mouse pneumonia resulting from a PR8 viral infection and caused a weight gain after oral administration. Natural killer cell activating receptors, both Ly49D and Ly49H in the lungs, were increased in the treatment in mice. In H3N2 virus-infected natural killer-92MI cells, the cocktail treatment had different effects on phosphorylation sites of phospholipase Cγ1 (PLCγ1) and killed infected cells through necroptosis or late apoptosis, in which RIP3 was increased and both caspase-3 and phosphorylated-JNK in the cells were downregulated. Acid phosphatase activity in viral-infected natural killer-92MI cells was induced by the compound cocktail treatment, which could be related to the p62 decrease in natural killer-92MI cells. In addition, an autophagic flux induction was observed in alveolar basal epithelial cells (A549). Protein p65, but not phosphorylated-p65, was significantly decreased by the treatment. Our results indicate that the compound cocktail strengthened the phosphorylation of PLCγ1-related necroptosis and partial autophagy in natural killer cells, which could yield an inhibitory effect on viral pneumonia in influenza.

Arginine vasopressin improves the memory deficits in Han Chinese patients with first-episode schizophrenia.

The memory impairment is a core deficit in the first-episode schizophrenia patients. Arginine vasopressin (AVP) in the brain can improve learning and memory. We performed multicentre, randomized, double-blind, placebo-controlled, parallel-group clinical trial to study the cognitive functioning in Han Chinese first-episode schizophrenic patients in a 12-week treatment regime with the intranasal administration of AVP (128 cases) or placebo (131 cases) in addition to the conventional treatment. The methods of positive and negative syndrome scale (PANSS), Wechsler memory scale-4th edition (WMS-IV) and event-related potential (ERP) were used to study the effects of AVP on the cognitive function. The results showed that (1) AVP concentration decreased in cerebrospinal fluid (CSF) of the right-handed Han Chinese first-episode schizophrenic patients comparing with that of the health volunteers (7.1±1.5pg/ml vs 13.3±1.9pg/ml, p<0.01), and did not change in plasma; (2) AVP significantly improved PANSS scores including total scores, positive symptoms, negative symptoms and general psychopathology comparing with those of the placebo group; (3) AVP elevated WMS-IV scores including the long-term memory (accumulation), short-term memory (recognition, comprehension), immediate memory (number recitation) and memory quotient 4, 8 and 12 weeks after treatment; and (4) AVP did not influence the latency and wave amplitude of target stimulus of P300 of right-handed Han Chinese first-episode schizophrenic patients. The data suggested that AVP might improve cognitive process, such as memorizing and extraction of the information although there were many changes of cognitive functions in the right-handed Han Chinese first-episode schizophrenic patients.

Arginine vasopressin relates with spatial learning and memory in a mouse model of spinocerebellar ataxia type 3.

Spinocerebellar ataxia is an inherited neurodegenerative disorder that the most prevalent type is type 3 (SCA3). Arginine vasopressin (AVP) is released within the lateral septum for controlling the learning and memory. This communication studied the effect of AVP on the spatial learning and memory of SCA3 mice. The spatial learning and memory were analyzed by Morris water maze test (MWM), and AVP concentration was measured by radioimmunoassay. The results showed that (Alves et al., 2010) the swimming velocity, distance traveled and latency to the platform of MWM in SCA3 mice were reduced slower than those in WT mice over 4 training days (p<0.05, 0.01 or 0.001); (Antunes and Zimmerman, 1978) SCA3 mice showed a lower performance of spatial learning and memory of MWM during the fifth day (test day) compared to WT mice; (Bao et al., 2014) SCA3 mice had a decrease of AVP concentration in cerebral cortex (6.3±0.6pg/mg vs. 11.4±1.0pg/mg, p<0.01), hypothalamus (6.1±1.3ng/mg vs. 10.3±2.1ng/mg, p<0.05), hippocampus (3.2±0.5pg/mg vs. 5.2±1.0pg/mg, p<0.01) and cerebellum (4.7±0.9pg/mg vs. 8.3±1.1pg/mg, p<0.01), not in spinal cord, pituitary and serum; and (Barberies and Tribollet, 1996) intraventricular AVP could significantly quicken swimming velocity, cut down distance traveled and reduce latency to the platform of MWM in a dose-dependent manner, but intraventricular AVP receptor antagonist weakened the spatial learning and memory of MWM in SCA3 mice during the fifth day. The data suggested that AVP in the brain, not spinal cord and peripheral system of SCA3 mice related with the change of the spatial learning and memory of MWM.

Oxytocin in hypothalamic supraoptic nucleus is transferred to the caudate nucleus to influence pain modulation.

Oxytocin (OXT), which is synthesized and secreted in the hypothalamic supraoptic nucleus (SON), is the most important bioactive substance in SON regulating pain process. Our previous study has pointed that OXT in the caudate nucleus (CdN) plays a role in pain modulation. The communication was designed to investigate the source of OXT in the rat CdN during pain process using the methods of push-pull perfusion and radioimmunoassay. The results showed that (1) pain stimulation increased the OXT concentration in the CdN perfusion liquid; (2) SON cauterization inhibited the increase of OXT concentration in CdN perfusion liquid induced by the pain stimulation, which role in both sides of SON cauterization was stronger than that in one side of SON cauterization; and (3) SON microinjection of l-glutamate sodium, which excited the SON neurons, increased OXT concentration in the CdN perfusion liquid. The data suggested that OXT in the CdN was influenced by SON during pain process, i.e., OXT in the SON might be transferred to the CdN to influence pain modulation.

Stability of pre-tilt angle and polar anchoring strength and its impact on the performance of liquid crystal devices.

: In this paper, the optical performance degradation of a liquid crystal (LC) cell due to the instability of pre-tilt angle and polar anchoring strength of the alignment surface of liquid crystal devices is explored. Under accelerated thermal treatment, changes in both the pre-tilt angle and polar anchoring strength are observed. The impacts of these changes are modeled for both twist nematic (TN) and electrically controlled birefringence (ECB) cells. Through this modeling, we find that a stable surface is very important to the long term performance of liquid crystal devices for the telecommunication applications.