SERPINB5 promotes colorectal cancer invasion and migration by promoting EMT and angiogenesis via the TNF-α/NF-κB pathway.

This study aimed to investigate the role of SERPINB5 in colorectal cancer (CRC). We established knockdown and overexpression models of SERPINB5 in CRC cells and conducted bioinformatics analysis to assess the clinicopathological significance of SERPINB5 expression in CRC patients. Human CRC cells were transfected with LV-SERPINB5 and sh-SERPINB5 lentivirus for subsequent functional and mechanistic studies. Results showed that high SERPINB5 expression correlated positively with CEA levels, N stage and lymphatic infiltration, while displaying a negative correlation with progression-free survival. Overexpression of SERPINB5 in CRC cells upregulated the expression of TNF-α, p-NF-κB/p65, N-cadherin, MMP2 and MMP9, accompanied by decreased E-cadherin expression. In addition, SERPINB5 overexpression enhanced the migration, invasion, and proliferation of CRC cells. Furthermore, overexpression of SERPINB5 in CRC cells increased VEGFA expression, and the conditioned medium from SERPINB5-overexpressing CRC cells promoted tube formation of HUVECs. Conversely, overexpression of SERPINB5 in HUVECs decreased VEGFA expression and inhibited tube formation. Notably, these changes in CRC cells were reversed by QNZ, a specific inhibitor of the TNF-α/NF-κB pathway. In summary, our findings revealed that high SERPINB5 expression correlated with poor progression-free survival in CRC patients. Moreover, SERPINB5 could induce EMT and angiogenesis by activating the TNF-α/NF-κB pathway, thereby promoting the invasion and migration of CRC cells.

MACC1 Correlates with Tumor Progression and Immune Cell Infiltration of Colon Adenocarcinoma and is Regulated by the lncRNA ZFAS1/miR-642a-5p Axis.

Colon adenocarcinoma (COAD) is the most common pathologic type of colon cancer. Metastasis is responsible for the high mortality rate of patients with COAD. The gene, metastasis-associated in colon cancer 1 (MACC1), is a biomarker predictive of both metastatic and metastasis-free survival in patients with colon cancer and other solid tumors. However, the underlying mechanism by which MACC1 affect COAD progression and metastasis remains unknown. In this study, we analyzed the expression level and prognostic value of MACC1, as well as their correlation, in patients with various types of cancer included in The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. High MACC1 expression was found to be significantly associated with poor prognosis in patients with COAD. Analysis of the potential upstream miRNA of MACC1 showed that miR-642a-5p was downregulated in COAD and was negatively correlated with MACC1 expression. Analysis of the upstream regulators of miR-642a-5p showed that the long non-coding RNA (lncRNA) ZFAS1was the most likely upstream regulator of miR-642a-5p. In addition, the expression of MACC1 correlated positively with tumor immune cell infiltration, as well as with the levels of biomarkers of five kinds of immune cells. In summary, these findings suggest that MACC1 contributes to COAD progression and immune cell infiltration via the ZFAS1/miR-642a-5p/MACC1 axis.

Risk of inflammatory bowel disease appears to vary across different frequency, amount, and subtype of alcoholic beverages.

Objective: Inflammatory bowel disease (IBD) and alcohol use has become a significant and growing public health concern. Alcohol use has been reported to be the most-avoided diet item among IBD patients. However, knowledge regarding the impact of different classes of alcoholic beverages on the management of IBD is limited. Our study aims to evaluate the association of different frequencies, amounts, and subtypes of alcoholic beverages with IBD risk. Methods: The UK Biobank comprised 7,095 subjects with IBD and 4,95,410 subjects without IBD. Multivariate Logistic regression, stratifying analysis, and interaction terms were used to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) of IBD. A generalized additive model was used to evaluate the linearity associations of the total amount of all alcoholic beverages or that of each of five alcoholic beverages with IBD risk. Results: Compared with non-drinkers, the IBD risk was 12 to 16% lower in red wine consumers (1-2 glasses/week, OR [95%CI], 0.88 [0.80, 0.97]; 3-4 glasses/week, 0.84 [0.76, 0.93]; ≥5 glasses/week, 0.86 [0.78, 0.95]), whereas 12% higher in white wine and champagne consumers (1-2 glasses/week, 1.12 [1.03, 1.22]). Stratifying analysis showed low-frequency red wine consumers were associated with a lower IBD risk (0.85 [0.74, 0.97]), whereas spirits consumers were associated with a higher risk (1.28 [1.03, 1.59]). High doge of red wine consumers were associated with a lower IBD risk (above guidelines, 0.80 [0.67, 0.97]; double above, 0.83 [0.71, 0.97]), whereas high doge white wine and champagne (1.32 [1.09, 1.61]) and beer and cider (1.26 [1.02, 1.54]) consumers were associated with a higher IBD risk. White wine and champagne showed a significant interaction effect with high doge alcohol consumption (1.27 [1.03-1.58], p = 0.029). The dose-response association showed an increased IBD risk with more number of alcohol consumption of white wine and champagne, beer and cider, or the total amount of all alcoholic beverages. However, red wine is at low risk across the whole dose cycle. Conclusions: The IBD risk appears to vary across different frequencies, amounts, and subtypes of alcoholic beverages. Overall, alcohol intake is not recommended.

Prognostic Value of S100P Expression in Patients With Digestive System Cancers: A Meta-Analysis.

BACKGROUND: Digestive system cancers (DSCs) are associated with high morbidity and mortality. S100P has been reported as a prognostic biomarker in DSCs, but its prognostic value remains controversial. Accordingly, we conducted a meta-analysis to investigate whether S100P is correlated with overall survival (OS) of patients with DSCs. The relationship between S100P and clinicopathological features was also evaluated. METHODS: We systematically searched PubMed, Embase, Web of Science and Cochrane Library for eligible studies up to January 2020. In total, 16 publications with 1,925 patients were included. RESULTS: S100P overexpression was associated with poor OS of patient with DSCs (HR=1.54, 95% CI: 1.14-2.08, P=0.005). When stratified by anatomic structure, S100P overexpression was associated with poor prognosis in non-gastrointestinal tract cancers (HR=1.98, 95% CI: 1.44-2.72, P<0.001) but not in gastrointestinal tract cancers (HR=1.09, 95% CI: 0.66-1.81, P=0.727). When stratified by tumor type, S100P overexpression predicted poor OS in cholangiocarcinoma (HR=2.14, 95% CI: 1.30-3.50, P=0.003) and hepatocellular carcinoma (HR=1.91, 95% CI: 1.22-2.99, P =0.005) but not in gastric cancer (HR=0.97, 95% CI: 0.65-1.45, P=0.872), colorectal cancer (HR=1.18, 95% CI: 0.32-4.41, P=0.807), gallbladder cancer (HR=1.40, 95% CI: 0.84-2.34, P=0.198), and pancreatic cancer (HR=1.92, 95% CI: 0.99-3.72, P=0.053). Furthermore, high S100P expression was significantly associated with distant metastasis (OR=3.58, P=0.044), advanced clinical stage (OR=2.03, P=0.041) and recurrence (OR=1.66, P=0.007). CONCLUSION: S100P might act as a prognostic indicator of non-gastrointestinal tract cancers.

Analyzing and predicting the LNM rate and prognosis of patients with intraductal papillary mucinous neoplasm of the pancreas.

BACKGROUND: Current the surveillance and management are controversial for patients with IPMN. We aimed to develop an alternative nomogram to individualize IPMN prognosis and LNM. METHODS: Based on the data from SEER database of patients diagnosed with IPMN between 2004 and 2015, a nomogram predicting the survival and LNM of IPMN based on univariate and multivariate and Lasso regression analysis was performed, internally and externally validated, and measured by C-index, and decision curve analysis (DCA), and compared to the 7th TNM stage. RESULTS: A total of 941 patients were included. Age, T stage examined nodes, tumor size, and pathology grade were identified as an independent factor for predicting LNM. The nomogram we established to predict LNM had a high predicting value with a C-index value of 0.735 and an AUC value of 0.753. Interestingly, including T1 stage, we found an inverse correlation was between age and LNM. In addition, nomogram for predicting CSS also performed better than TNM stage both in the internal validation group (1-year AUC:0.753 vs. 0.693, 3-year AUC: 0.801 vs. 0.731, 5-year AUC: 0.803 vs. 0.733) and external validation group (1-year AUC: 0.761 vs. 0.701, 3-year AUC: 0.772 vs. 0.713, 5-year AUC:0.811 vs. 0.735). DCA analysis showed the nomogram showed a greater benefit across the period of follow-up compared to 7th TNM stage. CONCLUSION: A nomogram based on multivariate and Lasso regression analysis showed great clinical usability compared with current criteria. Also, for LNM of IPMN, younger age patients with IPMN should be attached more importance.

Altered inter-hemispheric communication of default-mode and visual networks underlie etiology of primary insomnia : Altered inter-hemispheric communication underlie etiology of insomnia.

To identify altered inter-hemispheric communication between patients with primary insomnia (PIs) and good sleepers (GSs), and their relationships with sleep and emotion-related parameters. Forty-eight PIs and 48 status-matched GSs were asked to complete a number of sleep and emotion-related questionnaires. Voxel-mirrored homotopic connectivity(VMHC) and seed-based functional connectivity were used to characterize the inter-hemispheric coordination. Seven PIs were examined twice to evaluate the test-retest reliability. Support vector machine and ROC curve were applied to discriminate the two groups. Pearson correlation and mediating causality analysis were used to describe the relationships between insomnia-related brain networks and sleep/emotion-related parameters. High test-retest stability (intraclass correlation coefficient ≥ 0.8) of the VMHC maps was observed. Intra-, and inter-hemispheric coordination dysfunctions of the default mode network, visual pathways and executive control network were found. These differences received good discriminatory power to distinguish the two groups (AUC, 0.887; sensitivity, 81.3%; specificity, 87.5%). Intra-, and inter-hemispheric communication within the default mode network and visual pathways correlated with and partially mediated the insomnia-related parameters, while the executive control network correlated with post-insomnia negative emotions. Altered inter-hemispheric coordination within the default mode network and visual pathway may be identified as core predisposing or perpetuating factors in the etiology of PIs, while the executive control network may underlie the post-insomnia negative emotional symptoms. These findings may suggest that the inter-hemispheric communication might be potential neuroimaging markers to discribe underlie neurobiological mechanism of PIs and expand our understanding of the etiology of PIs.

Ventral Visual Pathway-Cerebellar Circuit Deficits in Alcohol Dependence: Long- and Short-Range Functional Connectivity Density Study.

Objective: To identify the underlying intrinsic functional connectome changes in patients with alcohol dependence. Methods: A functional connectivity density (FCD) analysis was used to report on the functional connectivity changes in 24 male patients with alcohol dependence (age, 47.83 ± 6.93 years) and 24 healthy male subjects (age, 47.67 ± 6.99 years). We defined the voxels with a correlated threshold of r > 0.25 inside their neighborhood (radius sphere ≤ 6 mm) as shortFCD, and radius sphere > 6 mm as longFCD. We repeated the network analysis using a range of correlation r thresholds (r = 0.30, 0.35, 0.40, 0.45, 0.50, 0.6, and 0.75) to determine whether between-group differences were substantially affected by the selection of the different R-value thresholds used. A ROC curve was used to test the ability of the FCD in discriminating between the two groups. Pearson's correlation was used to evaluate the relationships between the FCD differences in brain areas and demographic characteristics. Results: The covered differences in brain areas in binarized shortFCD were larger than binarized longFCD in both groups. The intra-group FCD differences did not depend on the selection of different thresholds used. Patients with alcohol dependence were associated with the longFCD deficit in the cerebellum posterior lobe, and shortFCD deficit in the ventral system of the visual pathway and increased shortFCD in the left precentral gyrus, right salience network and right cingulate gyrus. A ROC curve demonstrated that these specific brain areas alone discriminated between the two groups with a high degree of sensitivity and specificity. In the alcohol dependence group, the cerebellum posterior lobe, visual association cortex and the salience network displayed significant correlations with demographic characteristics. Conclusions: The shortFCD analysis was more sensitive than the longFCD analysis in finding differences in the brain areas. The ventral visual pathway-cerebellar circuit deficit appeared to be altered in patients with alcohol dependence.

Aberrant prefrontal-parietal-cerebellar circuits in alcohol dependence.

OBJECTIVE: To identify whether the amplitude of low-frequency fluctuations (ALFF) analysis has the potential to serve as a biological marker to detect alcohol-induced spontaneous brain activities and distinguish the patients with alcohol dependence from the healthy subjects. METHODS: We utilized the ALFF analysis to report on the alcohol-induced spontaneous brain activities in 29 patients with alcohol dependence (9 female, 20 male) relative to 29 status-matched healthy subjects (11 female, 18 male). Receiver operating characteristic curve was used to test the ability of the ALFF analysis in discriminating the patients with alcohol dependence from the healthy subjects. Pearson correlation was used to evaluate the relationships between the signal value of those ALFF differences in brain areas and behavioral characteristics. RESULTS: Alcohol-induced brain differences located in the right inferior parietal lobule and right supplementary motor area with significant higher ALFF values, and in the left precuneus and bilateral cerebellum posterior lobe with lower ALFF values. The movement-related areas were significantly correlated with each other (P<0.05). Receiver operating characteristic curve revealed good area under the curve values (mean, 0.86±0.079; 0.774-0.951) of the ALFF differences in those specific brain areas, as well as high degree of sensitivities (mean, 80.84%±14.01% or 80%±14.56%; 62.5%-100%) and specificities (mean, 83.32%±9.31%; 70.8%-95.8% or 84.16%±8%; 75%-95.8%). CONCLUSION: The ALFF analysis may serve as a biological indicator to detect the spontaneous brain activities in patients with alcohol dependence. The prefrontal-parietal-cerebellar circuit appears to be disturbed by long-term alcoholism in patients with alcohol dependence.

Plasticity and Susceptibility of Brain Morphometry Alterations to Insufficient Sleep.

Background: Insufficient sleep is common in daily life and can lead to cognitive impairment. Sleep disturbance also exists in neuropsychiatric diseases. However, whether and how acute and chronic sleep loss affect brain morphology remain largely unknown. Methods: We used voxel-based morphology method to study the brain structural changes during sleep deprivation (SD) at six time points of rested wakefulness, 20, 24, 32, 36 h SD, and after one night sleep in 22 healthy subjects, and in 39 patients with chronic primary insomnia relative to 39 status-matched good sleepers. Attention network and spatial memory tests were performed at each SD time point in the SD Procedure. The longitudinal data were analyzed using one-way repeated measures ANOVA, and post-hoc analysis was used to determine the between-group differences. Results: Acute SD is associated with widespread gray matter volume (GMV) changes in the thalamus, cerebellum, insula and parietal cortex. Insomnia is associated with increased GMV in temporal cortex, insula and cerebellum. Acute SD is associated with brain atrophy and as SD hours prolong more areas show reduced GMV, and after one night sleep the brain atrophy is restored and replaced by increased GMV in brain areas. SD has accumulative negative effects on attention and working memory. Conclusions: Acute SD and insomnia exhibit distinct morphological changes of GMV. SD has accumulative negative effects on brain morphology and advanced cognitive function. The altered GMV may provide neurobiological basis for attention and memory impairments following sleep loss. STATEMENT OF SIGNIFICANCE: Sleep is less frequently studied using imaging techniques than neurological and psychiatric disorders. Whether and how acute and chronic sleep loss affect brain morphology remain largely unknown. We used voxel-based morphology method to study brain structural changes in healthy subjects over multiple time points during sleep deprivation (SD) status and in patients with chronic insomnia. We found that prolonged acute SD together with one night sleep recovery exhibits accumulative atrophic effect and recovering plasticity on brain morphology, in line with behavioral changes on attentional tasks. Furthermore, acute SD and chronic insomnia exhibit distinct morphological changes of gray matter volume (GMV) but they also share overlapping GMV changes. The altered GMV may provide structural basis for attention and memory impairments following sleep loss.

Altered connection properties of important network hubs may be neural risk factors for individuals with primary insomnia.

Primary insomnia (PIs) is highly prevalent and can lead to adverse socioeconomic impacts, but the underlying mechanism of its complex brain network impairment remains largely unknown. Functional studies are too few and diverse in methodology, which makes it difficult to glean general conclusions. To answer this question, we first used graph theory-based network analyse, together with seed-based functional connectivity approach, to characterize the topology architecture of whole-brain functional networks associated with PIs. Forty-eight subjects with PIs and 48 age/sex/education-matched good sleepers were recruited. We found PIs is associated with altered connection properties of intra-networks within the executive control network, default mode network and salience network, and inter-network between auditory language comprehension center and executive control network. These complex networks were correlated with negative emotions and insomnia severity in the PIs group. Altered connection properties of these network hubs appeared to be neural risk factors for neuropsychological changes of PIs, and might be used as potential neuroimaging markers to distinguish the PIs from the good sleepers. These findings highlight the role of functional connectivity in the pathophysiology of PIs, and may underlie the neural mechanisms of etiology of PIs.

Cerebellar cryptococcosis characterized by a space-occupying lesion in an immunocompetent non-HIV patient.

Central nervous system (CNS) cryptococcosis is an opportunistic fungal infection that typically occurs in patients with reduced immunological function, such as patients with AIDS, patients receiving organ transplants, or patients receiving corticosteroid and immunosuppressive therapy. CNS cryptococcosis rarely occurs in immunocompetent patients. CNS cryptococcosis is characterized by meningitis and encephalitis and occasionally forms isolated granulomas. Isolated cerebellar cryptococcoma is a rare condition, especially in immunocompetent patients, and the misdiagnosis rate is high. A definite diagnosis must be based on pathology. To raise awareness of this disease, the clinical data of a patient with cryptococcomas in the right side of the cerebellum are reported.

Efficacy and safety of bevacizumab in Chinese patients with metastatic colorectal cancer.

OBJECTIVE: To evaluate the efficacy and safety of bevacizumab in the treatment of patients with metastatic colorectal cancer (mCRC). METHODS: In a single-center, observational study of 91 Chinese patients with mCRC who received bevacizumab in combination with chemotherapy was conducted. OBJECTIVE response rates (ORRs), progression-free survival (PFS), overall survival (OS) and adverse events were recorded, and the relationships between various clinical factors and PFS or OS were evaluated by Cox proportional hazards models. RESULTS: Treatment with bevacizumab and chemotherapy was effective and tolerable. Univariate analysis showed that PFS and OS were significantly associated with the Eastern Cooperative Oncology Group performance status (ECOG- PS) score, duration of bevacizumab exposure, and whether chemotherapy was continued after discontinuation of bevacizumab treatment. A multivariate analysis showed that the duration of bevacizumab exposure and whether chemotherapy was continued after discontinuation of bevacizumab were independent prognostic factors for PFS and OS. CONCLUSION: In Chinese mCRC population, the shorter the duration of exposure to bevacizumab and chemotherapy, the worse the prognosis is.

Gender differences in brain regional homogeneity of healthy subjects after normal sleep and after sleep deprivation: a resting-state fMRI study.

OBJECTIVE: To explore the gender differences of brain regional homogeneity (ReHo) in healthy subjects during the resting-state, after normal sleep, and after sleep deprivation (SD) using functional magnetic resonance imaging (fMRI) and the ReHo method. METHODS: Sixteen healthy subjects (eight males and eight females) each underwent the resting-state fMRI exams twice, i.e., once after normal sleep and again after 24h's SD. According to the gender and sleep, 16 subjects were all measured twice and divided into four groups: the male control group (MC), female control group (FC), male SD group (MSD), and female SD group (FSD). The ReHo method was used to calculate and analyze the data, SPM5 software was used to perform a two-sample T-test and a two-pair T-test with a P value <0.001, and cluster volume ≥ 270 mm(3) was used to determine statistical significance. RESULTS: Compared with the MC, the MSD showed significantly higher ReHo in the right paracentral lobule (BA3/6), but in no obviously lower regions. Compared with the FC, the FSD showed significantly higher ReHo in bilateral parietal lobes (BA2/3), bilateral vision-related regions of occipital lobes (BA17/18/19), right frontal lobe (BA4/6), and lower ReHo in the right frontal lobe. Compared with the FC, the MC showed significantly higher ReHo in the left occipital lobe (BA18/19), and left temporal lobe (BA21), left frontal lobe, and lower ReHo in the right insula and in the left parietal lobe. Compared with the FSD, the MSD showed significantly higher ReHo in the left cerebellum posterior lobe (uvula/declive of vermis), left parietal lobe, and bilateral frontal lobes, and lower ReHo in the right occipital lobe (BA17) and right frontal lobe (BA4). CONCLUSIONS: The differences of brain activity in the resting state can be widely found not only between the control and SD group in a same gender group, but also between the male group and female group. Thus, we should take the gender differences into consideration in future fMRI studies, especially the treatment of brain-related diseases (e.g., depression).

[Evaluation of the post-effect of acupuncture at Sanyinjiao (SP 6) under sleep deprivation by resting-state amplitude of low-frequency fluctuation: a fMRI study].

OBJECTIVE: To discuss the central modulating mechanism of Sanyinjiao (SP 6) and the amplitude of low-frequency fluctuation (ALFF) differences of the functional brain regions between SP 6 and sham acupoint. METHODS: Sixteen volunteers accepted right Sanyinjiao (SP 6) (SP 6 group) or right sham (sham group) acupuncture for two times after 24 h sleep deprivation (SD), there was two weeks between two acupunctures. The needle was retained for 4 minutes and the brain fMRI scanning was performed by 3.0 TMR every time. The ALFF consequent data was processed by REST. One-sample t-test and two-pair t-test were performed by SPM5. RESULTS: SP 6 group mainly caused ALFF change in inferior parietal lobule, posterior cingulated while sham group in precuneus, posterior cingulated. SP 6 group increased ALFF in left fusiform temporal gyrus, medial frontal gyrus with no decreased regions compared with sham group. CONCLUSIONS: Retaining needle dose influence the activity of the brain region during resting-state in both group, especially the mood-related regions. And its mechanism is probably that the relevant effect is carried out by regulating function to target organs of complex brain network comprised of relevant functional center and related brain region. There are differences between SP 6 and Sham acupoint.

Developments in metastatic pancreatic cancer: is gemcitabine still the standard?

In the past 15 years, we have seen few therapeutic advances for patients with pancreatic cancer, which is the fourth leading cause of cancer-related death in the United States. Currently, only about 6% of patients with advanced disease respond to standard gemcitabine therapy, and median survival is only about 6 mo. Moreover, phase III trials have shown that adding various cytotoxic and targeted chemotherapeutic agents to gemcitabine has failed to improve overall survival, except in cases in which gemcitabine combined with erlotinib show minimal survival benefit. Several meta-analyses have shown that the combination of gemcitabine with either a platinum analog or capecitabine may lead to clinically relevant survival prolongation, especially for patients with good performance status. Meanwhile, many studies have focused on the pharmacokinetic modulation of gemcitabine by fixed-dose administration, and metabolic or transport enzymes related to the response and toxicity of gemcitabine. Strikingly, a phase III trial in 2010 showed that, in comparison to gemcitabine alone, the FOLFIRINOX regimen in patients with advanced disease and good performance status, produced better median overall survival, median progression-free survival, and objective response rates. This regimen also resulted in greater, albeit manageable toxicity.