A comprehensive comparison of molecular and phenotypic profiles between hepatitis B virus (HBV)-infected and non-HBV-infected hepatocellular carcinoma by multi-omics analysis.

Hepatitis B virus (HBV) infection is a major etiology of hepatocellular carcinoma (HCC). An interesting question is how different are the molecular and phenotypic profiles between HBV-infected (HBV+) and non-HBV-infected (HBV-) HCCs? Based on the publicly available multi-omics data for HCC, including bulk and single-cell data, and the data we collected and sequenced, we performed a comprehensive comparison of molecular and phenotypic features between HBV+ and HBV- HCCs. Our analysis showed that compared to HBV- HCCs, HBV+ HCCs had significantly better clinical outcomes, higher degree of genomic instability, higher enrichment of DNA repair and immune-related pathways, lower enrichment of stromal and oncogenic signaling pathways, and better response to immunotherapy. Furthermore, in vitro experiments confirmed that HBV+ HCCs had higher immunity, PD-L1 expression and activation of DNA damage response pathways. This study may provide insights into the profiles of HBV+ and HBV- HCCs, and guide rational therapeutic interventions for HCC patients.

TMPRSS2 is a tumor suppressor and its downregulation promotes antitumor immunity and immunotherapy response in lung adenocarcinoma.

BACKGROUND: TMPRSS2, a key molecule for SARS-CoV-2 invading human host cells, has an association with cancer. However, its association with lung cancer remains insufficiently unexplored. METHODS: In five bulk transcriptomics datasets, one single-cell RNA sequencing (scRNA-seq) dataset and one proteomics dataset for lung adenocarcinoma (LUAD), we explored associations between TMPRSS2 expression and immune signatures, tumor progression phenotypes, genomic features, and clinical prognosis in LUAD by the bioinformatics approach. Furthermore, we performed experimental validation of the bioinformatics findings. RESULTS: TMPRSS2 expression levels correlated negatively with the enrichment levels of both immune-stimulatory and immune-inhibitory signatures, while they correlated positively with the ratios of immune-stimulatory/immune-inhibitory signatures. It indicated that TMPRSS2 levels had a stronger negative correlation with immune-inhibitory than with immune-stimulatory signatures. TMPRSS2 downregulation correlated with increased proliferation, stemness, genomic instability, tumor progression, and worse survival in LUAD. We further validated that TMPRSS2 was downregulated with tumor progression in the LUAD cohort we collected from Jiangsu Cancer Hospital, China. In vitro and in vivo experiments verified the association of TMPRSS2 deficiency with increased tumor cell proliferation and invasion and antitumor immunity in LUAD. Moreover, in vivo experiments demonstrated that TMPRSS2-knockdown tumors were more sensitive to BMS-1, an inhibitor of PD-1/PD-L1. CONCLUSIONS: TMPRSS2 is a tumor suppressor, while its downregulation is a positive biomarker of immunotherapy in LUAD. Our data provide a potential link between lung cancer and pneumonia caused by SARS-CoV-2 infection.

DITHER: an algorithm for Defining IntraTumor Heterogeneity based on EntRopy.

Intratumor heterogeneity (ITH) is associated with tumor development, prognosis, immune evasion and therapeutic effects. We proposed the Defining ITH based on EntRopy (DITHER) algorithm for evaluating ITH. We first evaluated the entropies of somatic mutation profiles and copy number alteration (CNA) profiles in a tumor, respectively, and defined their average as the ITH level for the tumor. Using DITHER, we analyzed 33 cancer types from The Cancer Genome Atlas (TCGA) program. We demonstrated that the ITH defined by DITHER had the typical properties of ITH, namely its strong correlations with tumor progression, unfavorable phenotype, genomic instability and immune evasion. Compared with two other ITH evaluation methods: MATH and PhyloWGS, the DITHER ITH had more prominent characteristics of ITH. Moreover, different from MATH and PhyloWGS, DITHER scores were positively correlated with tumor purity, suggesting that DITHER tends to capture the ITH between tumor cells. Interestingly, microsatellite instability (MSI)-high tumors had significantly lower DITHER scores than microsatellite stability (MSS)/MSI-low tumors, although the former had significantly higher tumor mutation loads than the latter. It suggests that the hypermutability of MSI is homogeneous between different cellular populations in bulk tumors. The DITHER ITH may provide novel insights into tumor biology and potential clinical applications.

Mendelian randomization and transcriptomic analysis reveal an inverse causal relationship between Alzheimer's disease and cancer.

BACKGROUND: Alzheimer's disease (AD) and cancer are common age-related diseases, and epidemiological evidence suggests an inverse relationship between them. However, investigating the potential mechanism underlying their relationship remains insufficient. METHODS: Based on genome-wide association summary statistics for 42,034 AD patients and 609,951 cancer patients from the GWAS Catalog using the two-sample Mendelian randomization (MR) method. Moreover, we utilized two-step MR to identify metabolites mediating between AD and cancer. Furthermore, we employed colocalization analysis to identify genes whose upregulation is a risk factor for AD and demonstrated the genes' upregulation to be a favorable prognostic factor for cancer by analyzing transcriptomic data for 33 TCGA cancer types. RESULTS: Two-sample MR analysis revealed a significant causal influence for increased AD risk on reduced cancer risk. Two-step MR analysis identified very low-density lipoprotein (VLDL) as a key mediator of the negative cause-effect relationship between AD and cancer. Colocalization analysis uncovered PVRIG upregulation to be a risk factor for AD. Transcriptomic analysis showed that PVRIG expression had significant negative correlations with stemness scores, and positive correlations with antitumor immune responses and overall survival in pan-cancer and multiple cancer types. CONCLUSION: AD may result in lower cancer risk. VLDL is a significant intermediate variable linking AD with cancer. PVRIG abundance is a risk factor for AD but a protective factor for cancer. This study demonstrates a causal influence for AD on cancer and provides potential molecular connections between both diseases.

DEPTH2: an mRNA-based algorithm to evaluate intratumor heterogeneity without reference to normal controls.

BACKGROUND: Intratumor heterogeneity (ITH) is associated with tumor progression, unfavorable prognosis, immunosuppression, genomic instability, and therapeutic resistance. Thus, evaluation of ITH levels is valuable in cancer diagnosis and treatment. METHODS: We proposed a new mRNA-based ITH evaluation algorithm (DEPTH2) without reference to normal controls. DEPTH2 evaluates ITH levels based on the standard deviations of absolute z-scored transcriptome levels in tumors, reflecting the asynchronous level of transcriptome alterations relative to the central tendency in a tumor. RESULTS: By analyzing 33 TCGA cancer types, we demonstrated that DEPTH2 ITH was effective in measuring ITH for its significant associations with tumor progression, unfavorable prognosis, genomic instability, reduced antitumor immunity and immunotherapy response, and altered drug response in diverse cancers. Compared to other five ITH evaluation algorithms (MATH, PhyloWGS, ABSOLUTE, DEPTH, and tITH), DEPTH2 ITH showed a stronger association with unfavorable clinical outcomes, and in characterizing other properties of ITH, such as its associations with genomic instability and antitumor immunosuppression, DEPTH2 also displayed competitive performance. CONCLUSIONS: DEPTH2 is expected to have a wider spectrum of applications in evaluating ITH in comparison to other algorithms.

Evaluation of the effects of meteorological factors on COVID-19 prevalence by the distributed lag nonlinear model.

BACKGROUND: Although numerous studies have explored the impact of meteorological factors on the epidemic of COVID-19, their relationship remains controversial and needs to be clarified. METHODS: We assessed the risk effect of various meteorological factors on COVID-19 infection using the distributed lag nonlinear model, based on related data from July 1, 2020, to June 30, 2021, in eight countries, including Portugal, Greece, Egypt, South Africa, Paraguay, Uruguay, South Korea, and Japan, which are in Europe, Africa, South America, and Asia, respectively. We also explored associations between COVID-19 prevalence and individual meteorological factors by the Spearman's rank correlation test. RESULTS: There were significant non-linear relationships between both temperature and relative humidity and COVID-19 prevalence. In the countries located in the Northern Hemisphere with similar latitudes, the risk of COVID-19 infection was the highest at temperature below 5 â„ƒ. In the countries located in the Southern Hemisphere with similar latitudes, their highest infection risk occurred at around 15 â„ƒ. Nevertheless, in most countries, high temperature showed no significant association with reduced risk of COVID-19 infection. The effect pattern of relative humidity on COVID-19 depended on the range of its variation in countries. Overall, low relative humidity was correlated with increased risk of COVID-19 infection, while the high risk of infection at extremely high relative humidity could occur in some countries. In addition, relative humidity had a longer lag effect on COVID-19 than temperature. CONCLUSIONS: The effects of meteorological factors on COVID-19 prevalence are nonlinear and hysteretic. Although low temperature and relative humidity may lower the risk of COVID-19, high temperature or relative humidity could also be associated with a high prevalence of COVID-19 in some regions.

Subtyping of sarcomas based on pathway enrichment scores in bulk and single cell transcriptomes.

BACKGROUND: Sarcomas are highly heterogeneous in molecular, pathologic, and clinical features. However, a classification of sarcomas by integrating different types of pathways remains mostly unexplored. METHODS: We performed hierarchical clustering analysis of sarcomas based on the enrichment scores of 14 pathways involved in immune, stromal, DNA damage repair (DDR), and oncogenic signatures in three bulk tumor transcriptome datasets. RESULTS: Consistently in the three datasets, sarcomas were classified into three subtypes: Immune Class (Imm-C), Stromal Class (Str-C), and DDR Class (DDR-C). Imm-C had the strongest anti-tumor immune signatures and the lowest intratumor heterogeneity (ITH); Str-C showed the strongest stromal signatures, the highest genomic stability and global methylation levels, and the lowest proliferation potential; DDR-C had the highest DDR activity, expression of the cell cycle pathway, tumor purity, stemness scores, proliferation potential, and ITH, the most frequent TP53 mutations, and the worst survival. We further validated the stability and reliability of our classification method by analyzing a single cell RNA-Seq (scRNA-seq) dataset. Based on the expression levels of five genes in the pathways of T cell receptor signaling, cell cycle, mismatch repair, focal adhesion, and calcium signaling, we built a linear risk scoring model (ICMScore) for sarcomas. We demonstrated that ICMScore was an adverse prognostic factor for sarcomas and many other cancers. CONCLUSIONS: Our classification method provides novel insights into tumor biology and clinical implications for sarcomas.

Retrospective prediction of the epidemic trend of COVID-19 in Wuhan at four phases.

The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in December 2019 and was basically under control in April 2020 in Wuhan. To explore the impact of intervention measures on the COVID-19 epidemic, we established susceptible-exposed-infectious-recovered (SEIR) models to predict the epidemic characteristics of COVID-19 at four different phases (beginning, outbreak, recession, and plateau) from January 1st to March 30th, 2020. We found that the infection rate rapidly grew up to 0.3647 at Phase II from 0.1100 at Phase I and went down to 0.0600 and 0.0006 at Phase III and IV, respectively. The reproduction numbers of COVID-19 were 10.7843, 13.8144, 1.4815, and 0.0137 at Phase I, II, III, and IV, respectively. These results suggest that intensive interventions, including compulsory home isolation and rapid improvement of medical resources, can effectively reduce the COVID-19 transmission. Furthermore, the predicted COVID-19 epidemic trend by our models was close to the actual epidemic trend in Wuhan. Our phase-based SEIR models demonstrate that intensive intervention measures can effectively control COVID-19 spread even without specific medicines and vaccines against this disease.

Predicting the development trend of the second wave of COVID-19 in five European countries.

The second wave of COVID-19 has caused a dramatic increase in COVID-19 cases and deaths globally. An accurate prediction of its development trend is significant. We predicted the development trend of the second wave of COVID-19 in five European countries, including France, Germany, Italy, Spain, and the UK. We first built models to predict daily numbers of COVID-19 cases and deaths based on the data of the first wave of COVID-19 in these countries. Based on these models, we built new models to predict the development trend of the second wave of COVID-19. We predicted that the second wave of COVID-19 would have peaked around on November 16, 2020, January 10, 2021, December 1, 2020, March 1, 2021, and January 10, 2021, in France, Germany, Italy, Spain, and the UK, respectively. It will be basically under control on April 26, 2021, September 20, 2021, August 1, 2021, September 15, 2021, and August 10, 2021, in these countries, respectively. Their total number of COVID-19 cases will reach around 4,745,000, 7,890,000, 6,852,000, 8,071,000, and 10,198,000, respectively, and total number of COVID-19 deaths will be around 262,000, 262,000, 231,000, 253,000, and 350,000 during the second wave of COVID-19. The COVID-19 mortality rate in the second wave of COVID-19 is predicted to be about 3.4%, 3.5%, 3.4%, 3.4%, and 3.1% in France, Spain, Germany, France, and the UK. The second wave of COVID-19 is expected to cause many more cases and deaths, last for a much longer time, and have a lower COVID-19 mortality rate than the first wave.

Factor structure and sex invariance of the temporal experience of pleasure scale (TEPS) in Chinese university students and clinical population.

BACKGROUND: A motivation dimension of the core psychiatric symptom anhedonia additional has been suggested. The Temporal Experience of Pleasure Scale (TEPS) has been reported to assess anticipatory and consummatory pleasure separately in multiple factor-structure models. This study explored the factor structure of a Chinese version of the 18-item TEPS and further explored the measurement invariance of the TEPS across sex and clinical status (non-clinical, psychiatric). METHODS: Best-fit factor structure of the TEPS was examined in a non-clinical cohort of 7410 undergraduates, randomized into sample 1 (N = 3755) for exploratory factor analysis (EFA) and sample 2 (N = 3663) for confirmatory factor analysis (CFA). Additionally, serial CFA was conducted to evaluate measurement invariance across sex and between clinical (N = 313) and non-clinical (N = 341) samples. RESULTS: EFA supported a new four-factor structure with a motivation component, based on the original two-factor model (consummatory pleasure with/without motivation drive, anticipatory pleasure with/without motivation drive). CFA confirmed the four-factor model as the best-fit structure and revealed a second-order hierarchy in non-clinical and clinical samples. Full scalar invariance was observed across clinical and non-clinical samples and across sex in the clinical sample; only partial scalar invariance was observed across sex in the non-clinical sample. CONCLUSIONS: A four-factor structured TEPS can assess motivation-driving dimensions of anticipatory and consummatory pleasure, consistent with the recently advanced multidimensional structure of anhedonia. CFA and measurement invariance results support application of the TEPS for assessing motivation aspects of anhedonia.

Personality inventory for DSM-5 brief form(PID-5-BF) in Chinese students and patients: evaluating the five-factor model and a culturally informed six-factor model.

BACKGROUND: The Personality Inventory for DSM-5 Brief Form (PID-5-BF) is a 25-item measuring tool evaluating maladaptive personality traits for the diagnosis of personality disorders(PDs). As a promising scale, its impressive psychometric properties have been verified in some countries, however, there have been no studies about the utility of the PID-5-BF in Chinese settings. The current study aimed to explore the maladaptive personality factor model which was culturally adapted to China and to examine psychometric properties of the PID-5-BF among Chinese undergraduate students and clinical patients. METHODS: Seven thousand one hundred fifty-five undergraduate students and 451 clinical patients completed the Chinese version of the PID-5-BF. Two hundered twenty-eight students were chosen randomly for test-retest reliability at a 4-week interval. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were conducted to discover the most suitable factor structure in China, measurement invariance(MI), internal consistency, and external validity were also calculated. RESULTS: The theoretical five-factor model was acceptable, but the exploratory six-factor model was more applicable in both samples (Undergraduate sample: CFI = 0.905, TLI = 0.888, RMSEA = 0.044, SRMR = 0.039; Clinical sample: CFI = 0.904, TLI = 0.886, RMSEA = 0.047, SRMR = 0.060). In the Chinese six-factor model, the Negative Affect domain was divided into two factors and the new factor was named "Interpersonal Relationships", which was in line with the Big-Six Personality model in Chinese. Measurement invariance across non-clinical and clinical sample was established (configural, weak, strong MI, and partial strict MI). Aside from acceptable internal consistency (Undergraduate sample: alpha = 0.84, MIC = 0.21; Clinical sample: alpha = 0.86, MIC = 0.19) and test-retest reliability(0.73), the correlation between the 25-item PID-5-BF and the 220-item PID-5 was significant(p < 0.01). The six PDs measured by Personality diagnostic questionnaire-4+ (PDQ-4+) were associated with and predicted by expected domains of PID-5-BF. CONCLUSIONS: Both the theoretical five-factor model and the exploratory six-factor model of the PID-5-BF were acceptable to the Chinese population. The five-factor model could allow for comparison and integration with other work on the original theoretical model. However, the Chinese six-factor structure may be more culturally informed in East Asian settings. In sum, the PID-5-BF is a convenient and useful screening tool for personality disorders.

Immunological classification of gliomas based on immunogenomic profiling.

BACKGROUND: Gliomas are heterogeneous in the tumor immune microenvironment (TIM). However, a classification of gliomas based on immunogenomic profiling remains lacking. METHODS: We hierarchically clustered gliomas based on the enrichment levels of 28 immune cells in the TIM in five datasets and obtained three clusters: immunity-high, immunity-medium, and immunity-low. RESULTS: Glioblastomas were mainly distributed in immunity-high and immunity-medium, while lower-grade gliomas were distributed in all the three subtypes and predominated in immunity-low. Immunity-low displayed a better survival than other subtypes, indicating a negative correlation between immune infiltration and survival prognosis in gliomas. IDH mutations had a negative correlation with glioma immunity. Immunity-high had higher tumor stemness and epithelial-mesenchymal transition scores and included more high-grade tumors than immunity-low, suggesting that elevated immunity is associated with tumor progression in gliomas. Immunity-high had higher tumor mutation burden and more frequent somatic copy number alterations, suggesting a positive association between tumor immunity and genomic instability in gliomas. CONCLUSIONS: The identification of immune-specific glioma subtypes has potential clinical implications for the immunotherapy of gliomas.

Recent advances targeting C-C chemokine receptor type 2 for liver diseases in monocyte/macrophage.

Liver plays a critical role in metabolism, nutrient storage and detoxification. Emergency signals or appropriate immune response leads to pathological inflammation and breaks the steady state when liver dysfunction appears, which makes body more susceptible to chronic liver infection, autoimmune diseases and tumour. Compelling proof has illustrated the non-redundant importance of C-C chemokine receptor type 2 (CCR2), one of G-protein-coupled receptors, in different diseases. Selectively expressed on the surface of cells, CCR2 is involved in various signalling pathways and regulates the migration of cells. Especially, a peculiar role of CCR2 has been identified within decades in the onset and progression of hepatic diseases, which led to particular focusing on CCR2 as a new therapeutic and diagnostic target for non-alcoholic fatty liver disease and hepatocellular carcinoma. In this review, we discuss the effect of CCR2 in monocytes/macrophages on liver diseases. The application and translation of the decades of discoveries into therapies promise novel approaches in the treatment of liver disease.

A novel construct of anhedonia revealed in a Chinese sample via the Revised Physical and Social Anhedonia Scales.

BACKGROUND: Anhedonia is a core clinical symptom of mental disorders. The Revised Physical Anhedonia Scale (RPAS) and the Revised Social Anhedonia Scale (RSAS) have been applied in clinical and non-clinical samples since 1980s. However, the construct of a unified RPAS&RSAS for comprehensive measurement of anhedonia has never been explored. Therefore, the purpose of our study was to examine the factor structure of the unified RPAS&RSAS among undergraduates and clinical patients. METHODS: A total of 3435 undergraduates from two universities and 294 clinical patients with mental disorders had completed the Chinese version of the RPAS and the RSAS. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were each conducted to reveal the constructs of the RPAS and the RSAS. CFA was used to evaluate first- and second-order models for the unified RPAS&RSAS in undergraduates and clinical patients. The internal consistency and test-retest reliability of the RPAS and the RSAS were also evaluated. RESULTS: EFA and CFA indicated 2-factor structures for RPAS and RSAS, with the factors being defined as anticipatory anhedonia and consummatory anhedonia. The second-order model of the unified RPAS&RSAS in the undergraduates and clinical patients both had satisfactory fit index values (Undergraduate sample: CFI = 0.901, TLI = 0.899, RMSEA = 0.055, SRMR = 0.086; Clinical sample: CFI = 0.922, TLI = 0.911, RMSEA = 0.052, SRMR = 0.078). The psychometric robustness of the RPAS&RSAS were confirmed by high internal consistency and test-retest reliability values. CONCLUSIONS: The unified RPAS&RSAS with a second-order structure was confirmed in both undergraduates and clinical samples in Chinese. The construct of anhedonia was refreshed as covering physical and social domains, and each of them includes both anticipatory and consummatory components.

Correlate tumor mutation burden with immune signatures in human cancers.

BACKGROUND: Tumor mutation burden (TMB) has been associated with cancer immunotherapeutic response and cancer prognosis. Although many explorations have revealed that high TMB may yield many neoantigens to incite antitumor immune response, a systematic exploration of the correlation between TMB and immune signatures in different cancer types is lacking. RESULTS: We classified cancer into the lower-TMB subtype and the higher-TMB subtype for each of 32 cancer types based on their somatic mutation data from the Cancer Genome Atlas (TCGA), and compared the expression levels of immune-related genes and gene-sets between both subtypes of cancers in each cancer type. In some cancer types most of the immune signatures analyzed were upregulated in the lower-TMB subtype, while in some other cancer types the immune signatures were prone to be upregulated in the higher-TMB subtype. However, the regulatory T cells, immune cell infiltrate, tumor-infiltrating lymphocytes, and cytokine signatures tended to be upregulated in the lower-TMB subtype, and the cancer-testis antigen (CTA) and pro-inflammatory signatures were inclined to be upregulated in the higher-TMB subtype. Importantly, high TMB was associated with elevated expression of PD-L1 in diverse prevailing cancers. Furthermore, we found that higher TMB was associated with better survival prognosis in numerous cancer types while was associated with worse prognosis in a few cancer types. CONCLUSIONS: High TMB may inhibit immune cell infiltrations while promote CTAs expression and inflammatory response in cancer. In many common cancer types, higher TMB may respond favorably to anti-PD-1/PD-L1 immunotherapy. Our data implicate that higher-TMB patients could gain a more favorable prognosis in diverse cancer types if treated with immunotherapy, otherwise would have a poorer prognosis compared to lower-TMB patients.

Functional dysconnectivity of the limbic loop of frontostriatal circuits in first-episode, treatment-naive schizophrenia.

Frontostriatal circuits dysfunction has been implicated in the etiology and psychopathology of patients with schizophrenia (SZ). However, few studies have investigated SZ-related functional connectivity (FC) alterations in discrete frontostriatal circuits and their relationship with pathopsychology in first-episode schizophrenia (FESZ). The goal of this study was to identify dysfunctions in discrete frontostriatal circuits that are associated with key features of FESZ. To this end, a case-control, cross-sectional study was conducted, wherein resting-state (RS) functional magnetic resonance (fMRI) data were collected from 37 treatment-naïve FESZ patients and 29 healthy control (HC) subjects. Seed-based FC analyses were performed by placing six bilateral pairs of seeds within a priori defined subdivisions of the striatum. We observed significantly decreased FC for the FESZ group relative to the HC group [p < .05, family-wise error (FWE)-corrected] in the limbic loop, but not in the sensorimotor or associative loops, of frontostriatal circuitry. Moreover, bilaterally decreased inferior ventral striatum/nucleus accumbens (VSi)-dorsal anterior cingulate cortex (dACC) FC within the limbic loop correlated inversely with overall FESZ symptom severity and the disorganization factor score of PANSS. These findings provide new insight into the role of frontostriatal limbic loop hypoconnectivity in early-stage schizophrenia pathology and suggest potential novel therapeutic targets.

KLF2 attenuates bleomycin-induced pulmonary fibrosis and inflammation with regulation of AP-1.

Pulmonary fibrosis (PF) is a chronic, fibrosing interstitial pneumonia and devastating disease. Here we investigated the potential roles of Kruppel-like factor 2 (KLF2) on pulmonary fibrosis and inflammation response. A mouse model of pulmonary fibrosis was established by intratracheal injection of bleomycin (BLM). The mRNA and protein levels of KLF2 were assayed by RT-PCR and Western blotting respectively. The extent of lung fibrosis was determined using hematoxylin and eosin (HE) staining and Masson's trichrome staining, and the hydroxyproline content was quantified. RT-PCR was used to evaluate the mRNA expression of collagen type 1a1 (col1a1), col3a1, α-SMA, TNF-α, IL-1ß and IL-6. The concentrations of TNF-α, IL-1ß, and IL-6 in bronchoalveolar lavage fluid (BALF) and lung tissue were examined by ELISA. Also, the effects of KLF2 on activator protein-1 (AP-1) were evaluated by measuring the c-Jun and c-Fos protein levels. We found that KLF2 was remarkably downregulated in BLM-treated rats, both in mRNA and protein levels. Additionally, overexpression of KLF2 attenuated the destruction of the alveolar space and pulmonary interstitial collagen hyperplasia, and deposition reduced the expression of col1a1, col3a1, and α-SMA, and blocked the production of TNF-α, IL-1ß, and IL-6 in BALF and lung tissue in vivo. Moreover, adenoviral transduction of KLF2 inhibited TGF-ß1-induced expression of col1a1, col3a1, and α-SMA in vitro. Mechanically, BLM up-regulated c-Jun and c-Fos expression, which was impeded by KLF2 overexpression. Taken together, our data indicate that KLF2 attenuates pulmonary fibrosis and inflammation, possibly through the regulation of AP-1.

ß-Catenin is important for cancer stem cell generation and tumorigenic activity in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors with poor prognosis and recurrence in South China. The hard eradication of NPC in clinic is predominantly due to cancer stem cells (CSCs). Increasing evidence revealed that the aberrant activation of Wnt/ß-catenin was positively correlated with the produce of CSCs. To further investigate the effect of ß-catenin on CSCs and tumorigenesis in NPC, a CNE2 cell line (pLKO.1-sh-ß-catenin-CNE2) with stably suppressed expression of ß-catenin was used in this study. The expressions of biomarkers in CSCs including c-myc, Nanog, Oct3/4, Sox2, EpCAM as well as adhesion-related proteins like E-cadherin and vimentin were analyzed by western blot analysis and immunofluorescent staining. The proliferation and migration abilities were investigated by MTT assay and Transwell assay, respectively. Cell cycle was analyzed by flow cytometry. Finally, xenograft was performed to determine the effect of ß-catenin on oncogenesis in vivo. Results showed that the expressions of c-myc, Nanog, Oct3/4, Sox2, and EpCAM were all decreased in pLKO.1-sh-ß-catenin-CNE2 cells. It was also found that vimentin was downregulated, while E-cadherin was upregulated. Results of MTT and Transwell assays suggested that the proliferation and migration abilities were impaired by silencing of ß-catenin, and more cells were arrested in G1 phase when compared with the control. In vivo study indicated that the tumor growth was markedly suppressed in experimental group. Based on current findings, ß-catenin may function as an essential protein for the maintenance of migration and proliferation abilities of NPC cells, and a complicated network consisting of c-myc, Nanog, Oct3/4, Sox2, EpCAM, E-cadherin, vimentin, and ß-catenin may be involved in the inherent regulation mechanisms.

[Characteristics of subgroups classified by pulmonary function test in chronic obstructive pulmonary disease patients].

OBJECTIVE: To compare the clinical characteristics and the therapeutic responses in chronic obstructive pulmonary disease (COPD) subgroups, classified by diffusing capacity of the lung for carbon monoxide (D(L)CO) and inspiratary capacity (IC). METHODS: A total of 105 mild-severe patients (70 males, 35 females, 44 to 85 years of age), with stable COPD were recruited in Cangzhou Central Hospital from June 2012 to June 2014. According to baseline D(L)CO and IC, the patients were divided into normal D(L)CO/IC group (group A, n=10), low D(L)CO/normal IC group (group B, n=18), normal D(L)CO/low IC group (group C, n=22) and low D(L)CO/IC group (group D, n=55). We compared the clinical characteristics, induced sputum cells and the therapeutic responses to 3-month treatment of budesonide/formoterol(320 µg/9 µg, inhale, bid)among the 4 groups. RESULTS: Group D showed the highest CAT scores(27.6 ± 6.4). Group C showed a higher prevalence of patients with wheezing(81.8)% and the highest percentage of sputum eosinophils (7.6 ± 3.2)%. Group C showed the greatest FEV(1) increase(0.214 ± 0.053)L. Group D showed a greater FEV(1) increase than Group B [(0.137 ± 0.063) vs (0.092 ± 0.048)L]. Group C showed a greater FVC[(0.342 ± 0.073), (0.190 ± 0.081), (0.223 ± 0.094)L] increase and CAT[(4.4 ± 2.0), (2.3 ± 1.3), (3.9 ± 1.9)] decrease than Group B and Group D(P<0.05). CONCLUSION: These findings suggest that COPD subgroups classified by D(L)CO and IC show several clinical characteristics and may be helpful to predict responses to treatment.

Activity-dependent regulation of release probability at excitatory hippocampal synapses: a crucial role of fragile X mental retardation protein in neurotransmission.

Transcriptional silencing of the Fmr1 gene encoding fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS), the most common form of inherited intellectual disability and the leading genetic cause of autism. FMRP has been suggested to play important roles in regulating neurotransmission and short-term synaptic plasticity at excitatory hippocampal and cortical synapses. However, the origins and mechanisms of these FMRP actions remain incompletely understood, and the role of FMRP in regulating synaptic release probability and presynaptic function remains debated. Here we used variance-mean analysis and peak-scaled nonstationary variance analysis to examine changes in both presynaptic and postsynaptic parameters during repetitive activity at excitatory CA3-CA1 hippocampal synapses in a mouse model of FXS. Our analyses revealed that loss of FMRP did not affect the basal release probability or basal synaptic transmission, but caused an abnormally elevated release probability specifically during repetitive activity. These abnormalities were not accompanied by changes in excitatory postsynaptic current kinetics, quantal size or postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor conductance. Our results thus indicate that FMRP regulates neurotransmission at excitatory hippocampal synapses specifically during repetitive activity via modulation of release probability in a presynaptic manner. Our study suggests that FMRP function in regulating neurotransmitter release is an activity-dependent phenomenon that may contribute to the pathophysiology of FXS.