Interleukin-12 in multimodal tumor therapies for induction of anti-tumor immunity.

Interleukin-12 (IL-12) can be used as an immunomodulator in cancer immunotherapy. And it has demonstrated enormous potential in inhibiting tumor growth and improving the tumor microenvironment (TME) by several preclinical models. However, some disappointing results have showed in the early clinical trials when IL-12 used as a single agent for systemic cancer therapy. Combination therapy is an effective way to significantly fulfill the great potential of IL-12 as an immunomodulator. Here, we discuss the effects of IL-12 combined with traditional methods (chemotherapy, radiotherapy and surgery), targeted therapy or immunotherapy in the preclinical and clinical studies. Moreover, we summarized the potential mechanism underlying the anti-tumor effect of IL-12 in the combination strategies. And we also discussed the delivery methods and tumor-targeted modification of IL-12 and outlines future prospects for IL-12 as an immunomodulator.

Association of serum vitamin C with all-cause and cause-specific death: Data from National Health and Nutrition Examination Survey (NHANES 2003-2006).

OBJECTIVES: The association between levels of circulating vitamin C and mortality remains controversial. The aim of this study was to explore the non-linear association between serum vitamin C levels and all-cause or cause-specific mortality. METHODS: We included 9902 US adults with their serum vitamin C levels from the National Health and Nutrition Examination Survey (NHANES 2003-2006). Their survival information was retrieved from baseline until 2015 using the national death index. Multivariable Cox proportional hazards models were used to show the risk for all-cause or cause-specific death according to baseline serum vitamin C levels. Smooth curve fitting and threshold effect analyses were used to clarify potential nonlinearity. RESULTS: During a median follow-up of 10.6 y, there were 1558 all-cause deaths, including 320 from cancer, 374 from cardiovascular disease (CVD), and 120 from respiratory diseases. Serum vitamin C levels had a U-shaped relationship with all-cause or CVD-associated mortality. Interestingly, serum vitamin C levels lower than the threshold value (1.06 mg/dL) were negatively associated with all-cause (fully adjusted hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.59-0.86) and CVD (fully adjusted HR, 0.70; 95% CI, 0.47-1.03) mortality. In contrast, serum vitamin C levels higher than the threshold value (1.06 mg/dL) were positively associated with all-cause (fully adjusted HR, 1.33; 95% CI, 1.15-1.54) and CVD (fully adjusted HR, 1.60, 95% CI, 1.23-2.10) mortality, respectively. CONCLUSION: Serum vitamin C levels showed a U-shaped relationship with all-cause and CVD-associated deaths among US adults using the NHANES data.

Processed Multiparameter Electroencephalogram-Guided General Anesthesia Management Can Reduce Postoperative Delirium Following Carotid Endarterectomy: A Randomized Clinical Trial.

Background: Patients undergoing carotid endarterectomy (CEA) for severe carotid stenosis are vulnerable to postoperative delirium, a complication frequently associated with poor outcome. This study investigated the impact of processed electroencephalogram (EEG)-guided anesthesia management on the incidence of postoperative delirium in patients undergoing CEA. Methods: This single-center, prospective, randomized clinical trial on 255 patients receiving CEA under general anesthesia compared the outcomes of patient state index (PSI) monitoring [SEDLine Brain Function Monitor (Masimo, Inc, Irvine, CA)] (standard group, n = 128) with PSI combined with density spectral array(DSA) -guided monitoring (intervention group, n = 127) to reduce the risk of intraoperative EEG burst suppression. All patients were monitored by continuous transcranial Doppler ultrasound (TCD) and near-infrared spectroscopy (NIRS) to avoid perioperative cerebral hypoperfusion or hyperperfusion. According to the surgical process, EEG suppression time was calculated separately for three stages: S1 (from anesthesia induction to carotid artery clamping), S2 (from clamping to declamping), and S3 (from declamping to the end of surgery). The primary outcome was incidence of postoperative delirium according to the Confusion Assessment Method algorithm during the first 3 days post-surgery, and secondary outcomes were other neurologic complications and length of hospital stay. Results: There were no episodes of cerebral hypoperfusion or hyperperfusion according to TCD and NIRS monitoring in either group during surgery. The incidence of postoperative delirium within 3 days post-surgery was significantly lower in the intervention group than the standard group (7.87 vs. 28.91%, P < 0.01). In the intervention group, the total EEG suppression time and the EEG suppression time during S2 and S3 were shorter (Total, 0 "0" vs. 0 "1.17" min, P = 0.04; S2, 0 "0" vs. 0 "0.1" min, P < 0.01; S3, 0 "0" vs. 0 "0" min, P = 0.02). There were no group differences in incidence of neurologic complications and length of postoperative hospital stay. Conclusion: Processed electroencephalogram-guided general anesthesia management, consisting of PSI combined with DSA monitoring, can significantly reduce the risk of postoperative delirium in patients undergoing CEA. Patients, especially those exhibiting hemodynamic fluctuations or receiving surgical procedures that disrupt cerebral perfusion, may benefit from the monitoring of multiple EEG parameters during surgery. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03622515.

Clinical characteristics of familial schizophrenia.

INTRODUCTION: A family history of psychiatric disorders is one of the strongest risk factors for schizophrenia. The characteristics of patients with a family history of psychiatric disorders have not been systematically evaluated. METHODS: This multicenter study (26 centers, 2425 cases) was performed in a Chinese population to examine the sociodemographic and clinical characteristics of schizophrenia patients with a family history of psychotic disorders in comparison with those of patients with sporadic schizophrenia. RESULTS: Nineteen percent of patients had a family history of mental disease. Multiple logistic regression analysis revealed that ≥4 hospitalizations (OR = 1.78, P = .004), tobacco dependence (OR = 1.48, P = .006), alcohol dependence (OR = 1.74, P = .013), and physical illness (OR = 1.89, P = .001) were independently and significantly associated with a family history of mental disease. CONCLUSION: Patients with a family history of mental disorders present different demographics and clinical features than patients without a family history of psychiatric disorders.

Hybrid Hydrogels for Synergistic Periodontal Antibacterial Treatment with Sustained Drug Release and NIR-Responsive Photothermal Effect.

BACKGROUND: Periodontal pathogenic bacteria promote the destruction of periodontal tissues and cause loosening and loss of teeth in adults. However, complete removal of periodontal pathogenic bacteria, at both the bottom of the periodontal pocket and the root bifurcation area, remains challenging. In this work, we explored a synergistic antibiotic and photothermal treatment, which is considered an alternative strategy for highly efficient periodontal antibacterial therapy. METHODS: Mesoporous silica (MSNs) on the surface of Au nanobipyramids (Au NBPs) were designed to achieve the sustained release of the drug and photothermal antibacterials. The mesoporous silica-coated Au NBPs (Au NBPs@SiO2) were mixed with gelatin methacrylate (GelMA-Au NBPs@SiO2). Au NBPs@SiO2 and GelMA-Au NBPs@SiO2 hybrid hydrogels were characterized, and the drug content and photothermal properties in terms of the release profile, bacterial inhibition, and cell growth were investigated. RESULTS: The GelMA-Au NBPs@SiO2 hybrid hydrogels showed controllable minocycline delivery, and the drug release rates increased under 808 nm near-infrared (NIR) light irradiation. The hydrogels also exhibited excellent antibacterial properties, and the antibacterial efficacy of the antibiotic and photothermal treatment was as high as 90% and 66.7% against Porphyromonas gingivalis (P. gingivalis), respectively. Moreover, regardless of NIR irradiation, cell viability was over 80% and the concentration of Au NBPs@SiO2 in the hybrid hydrogels was as high as 100 µg/mL. CONCLUSION: We designed a new near-infrared light (NIR)-activated hybrid hydrogel that offers both sustained release of antibacterial drugs and photothermal treatment. Such sustained release pattern yields the potential to rapidly eliminate periodontal pathogens in the periodontal pocket, and the photothermal treatment maintains low bacterial retention after the drug treatment.

Comparisons between Psychiatric Symptoms of Patients with Anti-NMDAR Encephalitis and New-Onset Psychiatric Patients.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a potentially lethal autoimmune disease. Early diagnosis and immunotherapy can improve prognosis; however, early prominent psychiatric symptoms have led to misdiagnosis in numerous cases, delaying diagnosis and treatment. This study aimed to explore the clinical features and psychiatric symptoms of anti-NMDAR encephalitis and the association between antibody titers and psychiatric symptoms. METHODS: In this retrospective study, 43 patients with anti-NMDAR encephalitis and 70 new-onset psychiatric patients were enrolled. Psychiatric symptoms were assessed by trained psychiatrists using the Positive and Negative Syndrome Scale. RESULTS: There were significant differences in psychiatric symptoms between the antibody-positive and antibody-negative groups. The item scores for poor rapport (p < 0.01), difficulty in abstract thinking (p < 0.01), lack of spontaneity and flow of conversation (p < 0.01), unusual thought content (p < 0.01), and disorientation (p < 0.01) were significantly higher in the antibody-positive group, while the item scores for delusions (p < 0.01) were significantly higher in the antibody-negative group. These differences all remained significant after Holm-Bonferroni correction. In the antibody-positive group, scores for each item, subscale, and factor increased with increases in antibody titer, particularly for delusions (p < 0.05) and hallucinatory behavior (p < 0.01). Thereafter, only hallucinatory behavior remained significant. CONCLUSIONS: Patients with anti-NMDAR encephalitis with initial psychiatric symptoms may have the following characteristics: poor rapport, difficulty in abstract thinking, lack of spontaneity and flow of conversation, unusual thought content, and disorientation. Furthermore, antibody titer may be associated with psychiatric symptom severity, especially in hallucinatory behavior.

piRNA-3878 targets P450 (CpCYP307B1) to regulate pyrethroid resistance in Culex pipiens pallens.

Piwi-interacting RNAs (piRNAs) are a novel class of noncoding single-strand RNAs. They play an important role in the germ cell maintenance, brain development, epigenetic regulation of cancer, and antiviral function. However, little is known about the relationship between the piRNAs and insecticide resistance in mosquitoes. In this study, we reported that piRNA-3878 was related with pyrethroid resistance in Culex pipiens pallens. The expression level of piRNA-3878 was lower in both laboratory and field-collected deltamethrin-resistant (DR) strains. Overexpression of piRNA-3878 increased the susceptibility of the DR strain, while inhibiting the expression of piRNA-3878 in DS strain made the mosquitoes more resistant to deltamethrin. Furthermore, we identified that CpCYP307B1 was the target of piRNA-3878. The mosquito mortality rate was increased after downregulating the expression of CpCYP307B1. These findings revealed that piRNA-3878 could target CpCYP307B1 to regulate pyrethroid resistance.

Investigation of mental health and its influence on Chinese cancer patients using a multidisciplinary screening flow: an epidemiological survey in the west of China.

BACKGROUND: Despite psycho-oncological concerns and studies having thrived these past decades, sparse reports illustrate to what extent Chinese cancer patients are involved and influenced by comorbid mental health problems. To investigate the mental health condition of cancer patient, as well as its possible impacts on prognosis, the first large-scale survey was performed in the west of China. METHODS: For standardizing and facilitating the assessment of mental illness in inpatients with cancer, a multidisciplinary rating flow was designed and established. On the basis of this system, between May 1st and 31st 2009, 2279 cancer inpatients from nine medical centers received preliminarily screening executed by oncologists using screening scales Mental Health Screening Questionnaire (MHSQ), Zung self-rating depression scales (SDS), Zung self-rating anxiety scale (SAS), and posttraumatic stress disorder checklist-civilian version (PCL-C). Further analyses of the ones screened positively were conducted by psychiatrists applying corresponding symptom-rating scales (HAMA/HAMD/BPRS). We summarized the overall proportion of patients with impaired mental health based on the data acquired from preliminary screening, and then calculated occurrence rates of each clinical syndrome of mental disorder according to symptom conclusions. The impact of comorbid mental illness was evaluated through the follow-up scheduled 1 year later, by comparing the survival rate, progression of disease, and quality of life (QoL) between subgroup patients with or without clinical syndrome of mental disorder. RESULTS: In preliminary screenings, 26.1% (595/2279) yielded positive results. Further symptom conclusions confirmed 15.8% (359/2279) with clinical syndrome of mental disorder. Regarding specific type of syndrome, the occurrence rates of depression, anxiety, psychotic symptoms, and stress-related disorders were 13.3%, 10.2%, 2.8%, and 1.4%, respectively. Follow-up assessments were successfully performed in 1918 subjects (84.2%). Further analyses indicated that although insignificant influence was observed in terms of 1-year survival rate and disease progression, cancer patients with a clinical syndrome of mental disorder obtained significantly lower levels (P < 0.05) in five domains of QoL (scored by QLQ-C30). CONCLUSION: In China, at least 26% of cancer patients experienced impaired mental health, of which 60% already had a detectable clinical syndrome of mental disorder, which could significantly undermine their QoL.

Dnt1 acts as a mitotic inhibitor of the spindle checkpoint protein dma1 in fission yeast.

The Schizosaccharomyces pombe checkpoint protein Dma1 couples mitotic progression with cytokinesis and is important in delaying mitotic exit and cytokinesis when kinetochores are not properly attached to the mitotic spindle. Dma1 is a ubiquitin ligase and potential functional relative of the human tumor suppressor Chfr. Dma1 delays mitotic exit and cytokinesis by ubiquitinating a scaffold protein (Sid4) of the septation initiation network, which, in turn, antagonizes the ability of the Polo-like kinase Plo1 to promote cell division. Here we identify Dnt1 as a Dma1-binding protein. Several lines of evidence indicate that Dnt1 inhibits Dma1 function during metaphase. First, Dnt1 interacts preferentially with Dma1 during metaphase. Second, Dma1 ubiquitin ligase activity and Sid4 ubiquitination are elevated in dnt1 cells. Third, the enhanced mitotic defects in dnt1Δ plo1 double mutants are partially rescued by deletion of dma1(+), suggesting that the defects in dnt1 plo1 double mutants are attributable to excess Dma1 activity. Taken together, these data show that Dnt1 acts to restrain Dma1 activity in early mitosis to allow normal mitotic progression.

Exposure to organochlorine pesticides is an independent risk factor of hepatocellular carcinoma: a case-control study.

Primary hepatocellular carcinoma (HCC) is highly prevalent in China. Although hepatitis B virus (HBV) and aflatoxin B1 (AFB1) are considered the major risk factors, among the high-risk cohorts only a small fraction develops liver cancer. Therefore, we investigated whether organochlorine pesticide exposure contributed to HCC risk in the Xiamen population. The questionnaire database was built from 346 HCC cases and 961 healthy controls during 2007-2009. The serum levels of α-, ß-, γ-, δ-HCH, 1,1,1-trichloro-2,2-bis (p-chlorophenyl) ethane (p,p'-DDT), (1,1-dichloro-2,2-bis (p-chlorophenyl) ethylene (p,p'-DDE), 1,1,1-trichloro-2,2-bis (o-chlorophenyl) ethane and 1,1-dichloro-2,2-bis (p-chlorophenyl) ethane were measured by gas chromatography-tandem mass spectrometer, and statistical analysis was done using SPSS16. Significantly, we observed p,p'-DDT and p,p'-DDE, and at the first time ß-HCH displayed quartile dose-dependent HCC risk trends; p,p'-DDT showed positive (i.e., synergistic) interactions with HBV, diabetes mellitus, AFB1 and polyaromatic hydrocarbon (PAH) exposure, but negative (i.e., antagonistic) interaction with heavy drinking; p,p'-DDE had positive interaction with PAH but negative interaction with HBV and p,p'-DDT; and ß-HCH positively interacted with p,p'-DDT but negatively interacted with heavy drinking and diabetes. p,p'-DDT, p,p'-DDE and ß-HCH were independent HCC risk factors. Because of their synergistic interactions with other factors, the high-level exposure combined with common AFB1 and HBV exposure in the investigated area may greatly enhance the risk of HCC.

Exposure to organochlorine pesticides is independent risk factor of hepatocellular carcinoma: a case--control study.

Primary hepatocellular carcinoma (HCC) is highly prevalent in China. Although hepatitis B virus (HBV) and aflatoxin B1 (AFB1) are considered the major risk factors, among the high-risk cohorts only a small fraction develops liver cancer. Therefore, we investigated if organochlorine pesticides (OCPs) exposure contributed to HCC risk in the Xiamen population. The questionnaire database was built from 346 HCC cases and 961 healthy controls during 2007-2009. The serum levels of α-, ß-, γ-, δ-HCH, p, p'-DDT, p, p'-DDE, o, p'-DDT and p, p'-DDD were measured by gas chromatography-tandem mass spectrometer and statistical analysis was done using SPSS16. Significantly, we observed p, p'-DDT, p, p'-DDE, and at first time ß-HCH displayed quartile dose-dependent HCC risk trends; p, p'-DDT showed positive (i.e., synergistic) interactions with HBV, diabetes mellitus, AFB1 and polycyclic aromatic hydrocarbon (PAH) exposure, but negative (i.e., antagonistic) interaction with heavy drinking; p, p'-DDE had positive interaction with PAH but negative interaction with HBV and p, p'-DDT; and ß-HCH was positively interacted with p, p'-DDT but negatively interacted with heavy drinking and diabetes. p, p'-DDT, p, p'-DDE and ß-HCH were independent HCC risk factors. Because of their synergistic interactions with other factors, the high level exposure combined with common AFB1 and HBV exposure in the investigated area may greatly enhance the risk of HCC.

Cognitive and neural correlates of depression-like behaviour in socially defeated mice: an animal model of depression with cognitive dysfunction.

Human depression is associated with cognitive deficits. It is critical to have valid animal models in order to investigate mechanisms and treatment strategies for these associated conditions. The goal of this study was to determine the association of cognitive dysfunction with depression-like behaviour in an animal model of depression and investigate the neural circuits underlying the behaviour. Mice that were exposed to social defeat for 14 d developed depression-like behaviour, i.e. anhedonia and social avoidance as indicated by reduced sucrose preference and decreased social interaction. The assessment of cognitive performance of defeated mice demonstrated impaired working memory in the T-maze continuous alternation task and enhanced fear memory in the contextual and cued fear-conditioning tests. In contrast, reference learning and memory in the Morris water maze test were intact in defeated mice. Neuronal activation following chronic social defeat was investigated by c-fosin-situ hybridization. Defeated mice exhibited preferential neural activity in the prefrontal cortex, cingulate cortex, hippocampal formation, septum, amygdala, and hypothalamic nuclei. Taken together, our results suggest that the chronic social defeat mouse model could serve as a valid animal model to study depression with cognitive impairments. The patterns of neuronal activation provide a neural basis for social defeat-induced changes in behaviour.

[Synergistic effects of different types of smoking and other risk factors on risk of hepatocellular carcinoma in Xiamen, China].

OBJECTIVE: To evaluated the independent effects of different types of smoking exposure along with multiple risk factors for hepatocellular carcinoma (HCC) and determined whether the magnitude of smoking was modified by other risk factors, both in men and women. METHODS: We conducted a case-control study in Xiamen China. 345 HCC patients and 961 healthy control subjects were personally interviewed for several HCC risk factors. Multivariate logistic regression analysis was performed to estimate the adjusted odds ratio (AOR) and 95% confidence interval (CI) for each potential risk factor. RESULTS: Cigars and pipes were not related to HCC among non-cigarette smokers. However, passive smoking exposure was associated with HCC in women: AOR, 2.35 (95%CI: 1.19 - 4.07). Regular cigarette smoking was associated with HCC in men: AOR, 2.27 (95%CI: 1.14 - 3.31). Cigarette smoking and chronic infection of hepatitis B virus showed positive additive model interactions in men: RERI (relative excess risk due to interaction) was 98.70 and AP (attributable proportion due to interactions) was 81.0%. Data on cigarette smoking with high AFB1-albumin adducts in women showed that the RERI was 2.69 and AP was 50.0%. CONCLUSION: We concluded that sex differences were seen in HCC relationship with cigarette smoking. Controlling of exposure to smoking might be a prudent approach to the prevention of HCC, especially in patients with chronic viral hepatitis infections.

The androgen receptor gene polyglycine repeat polymorphism is associated with memory performance in healthy Chinese individuals.

Cognitive functions such as memory are quantitative traits in human, and have both genetic and environmental influences. Testosterone has been implicated in the modulation of memory function. Therefore, genetic variation which influences testosterone signaling may modulate memory function. The principal receptor for testosterone is the androgen receptor, the gene for which maps to the X chromosome. In the present study, we hypothesized that common variation in two functional polymorphisms in the androgen receptor gene, the polyglutamine (CAG) and/or polyglycine (GGN) repeats, would influence memory function in healthy subjects. Variation in length of either repeat modulates the function of the AR gene, either by changing the amount of protein produced, by altering transactivation of the receptor or by producing toxic polyglycine or polyglutamine fragments. In order to test this hypothesis, we analyzed 449 healthy Chinese individuals. CAG repeats were not associated with memory performance. However we observed a significant association between GGN repeats and Immediate Logical Memory (chi(2)=23.6, d.f.=7, p=0.001) and Delayed Logical Memory (chi(2)=16.3, d.f.=7, p=0.022). The association of GGN repeats with Immediate Logical Memory remained significant after 6000 permutation corrections (p=0.013). There was also a sex difference, as association between GGN repeats and memory was observed only in females (p=0.002 for Immediate and p=0.014 for Delayed Logical Memory), but not in males (p=0.31 and 0.83, respectively). We conclude that functional variation of the androgen receptor gene is able to modulate memory function in women.

[Impact of anxiety-depression symptoms on clinical recovery and serum TNF-alpha and IL-6 of patients with burns].

OBJECTIVE: To investigate the impact of anxiety-depression symptoms on the healing of burn wounds and the serum tumor necrosis factor a (TNF-alpha) and interleukin-6 (IL-6) in the patients with moderate and severe burns. METHODS: The patients with moderate and severe burns were divided into anxiety-depression group (24 patients) and non-anxiety-depression group (27 patients)according to the scores of anxiety-depression scores three days after burn measured by Hamilton Rating Scale for Depression (HAMD) and Hamilton Rating Scale for Anxiety (HAMA). The routine therapy was applied for both groups for 30 days. Then the scores of anxiety and depression and the degrees of wound healing were examined. The serum TNF-alpha IL-6 were measured with enzyme linked immunosorbent assay (ELISA). RESULTS: No significant decrease of the scores of depression was found before and after treatments in the anxiety-depression group (P > 0.05). The days that were needed for healing the wounds and the serum TNF-alpha and IL-6 increased in the patients with depression compared with the control group (P < 0.05). CONCLUSION: There are anxious and depressive reactions to burns by the patients. The continuous negative emotion can induce the increase of serum TNF-alpha and IL-6 and lead to delay of the healing of the burn wounds.