ISL1 and POU4F1 Directly Interact to Regulate the Differentiation and Survival of Inner Ear Sensory Neurons.

The inner ear sensory neurons play a pivotal role in auditory processing and balance control. Though significant progresses have been made, the underlying mechanisms controlling the differentiation and survival of the inner ear sensory neurons remain largely unknown. During development, ISL1 and POU4F transcription factors are co-expressed and are required for terminal differentiation, pathfinding, axon outgrowth and the survival of neurons in the central and peripheral nervous systems. However, little is understood about their functional relationship and regulatory mechanism in neural development. Here, we have knocked out Isl1 or Pou4f1 or both in mice of both sexes. In the absence of Isl1, the differentiation of cochleovestibular ganglion (CVG) neurons is disturbed and with that Isl1-deficient CVG neurons display defects in migration and axon pathfinding. Compound deletion of Isl1 and Pou4f1 causes a delay in CVG differentiation and results in a more severe CVG defect with a loss of nearly all of spiral ganglion neurons (SGNs). Moreover, ISL1 and POU4F1 interact directly in developing CVG neurons and act cooperatively as well as independently in regulating the expression of unique sets of CVG-specific genes crucial for CVG development and survival by binding to the cis-regulatory elements including the promoters of Fgf10, Pou4f2, and Epha5 and enhancers of Eya1 and Ntng2 These findings demonstrate that Isl1 and Pou4f1 are indispensable for CVG development and maintenance by acting epistatically to regulate genes essential for CVG development.

Comprehensive multi-omics analysis and experimental verification reveal PFDN5 is a novel prognostic and therapeutic biomarker for gastric cancer.

Prefoldin Subunit 5 (PFDN5) plays a critical role as a member of the prefoldins (PFDNs) in maintaining a finely tuned equilibrium between protein production and degradation. However, there has been no comprehensive analysis specifically focused on PFDN5 thus far. Here, a comprehensive multi-omics (transcriptomics, genomics, and proteomics) analysis, systematic molecular biology experiments (in vitro and in vivo), transcriptome sequencing and PCR Array were performed for identifying the value of PFDN5 in pan-cancer, especially in Gastric Cancer (GC). We found PFDN5 had the potential to serve as a prognostic and therapeutic biomarker in GC. And PFDN5 could promote the proliferation of GC cells, primarily by affecting the cell cycle, cell death and immune process etc. These findings provide novel insights into the molecular mechanisms and precise treatments of in GC.

Stereocontrolled Synthesis of α-3-Deoxy-d-manno-oct-2-ulosonic Acid (α-Kdo) Glycosides Using C3-p-Tolylthio-Substituted Kdo Donors: Access to Highly Branched Kdo Oligosaccharides.

3-Deoxy-d-manno-oct-2-ulosonic acid (Kdo) is an eight-carbon monosaccharide found widely in bacterial lipopolysaccharides (LPSs) and capsule polysaccharides (CPSs). We developed an indirect method for the stereoselective synthesis of α-Kdo glycosides with a C3-p-tolylthio-substituted Kdo phosphite donor. The presence of the p-tolylthio group enhanced the reactivity, suppressed the formation of elimination by-products (2,3-enes), and provided complete α-stereocontrol. A variety of Kdo α-glycosides were synthesized by our method in excellent yields (up to 98 %). After glycosylation, the p-tolylthio group can be efficiently removed by free-radical reduction. Subsequently, the orthogonality of the phosphite donor and thioglycoside donor was demonstrated by the one-pot synthesis of a trisaccharide in Helicobacter pylori and Neisseria meningitidis LPS. Moreover, an efficient total synthesis route to the challenging 4,5-branched Kdo trisaccharide in LPSs from several A. baumannii strains was highlighted. To demonstrate the high reactivity of our approach further, the highly crowded 4,5,7,8-branched Kdo pentasaccharide was synthesized as a model molecule for the first time. Additionally, the reaction mechanism was investigated by DFT calculations.

Polyamine metabolism patterns characterized tumor microenvironment, prognosis, and response to immunotherapy in colorectal cancer.

BACKGROUND: Changes in Polyamine metabolism (PAM) have been shown to establish a suppressive tumor microenvironment (TME) and substantially influence the progression of cancer in the recent studies. However, newly emerging data have still been unable to fully illuminate the specific effects of PAM in human cancers. Here, we analyzed the expression profiles and clinical relevance of PAM genes in colorectal cancer (CRC). METHODS: Based on unsupervised consensus clustering and principal component analysis (PCA) algorithm, we designed a scoring model to evaluate the prognosis of CRC patients and characterize the TME immune profiles, with related independent immunohistochemical validation cohort. Through comparative profiling of cell communities defined by single cell sequencing data, we identified the distinct characteristics of polyamine metabolism in the TME of CRC. RESULTS: Three PAM patterns with distinct prognosis and TME features were recognized from 1224 CRC samples. Moreover, CRC patients could be divided into high- and low-PAMscore subgroups by PCA-based scoring system. High PAMscore subgroup were associated to more advanced stage, higher infiltration level of immunosuppressive cells, and unfavorable prognosis. These results were also validated in CRC samples from other public CRC datasets and our own cohort, which suggested PAM genes were ideal biomarkers for predicting CRC prognosis. Notably, PAMscore also corelated with microsatellite instability-high (MSI-H) status, higher tumor mutational burden (TMB), and increased immune checkpoint gene expression, implying a potential role of PAM genes in regulating response to immunotherapy. To further confirm above results, we demonstrated a high-resolution landscape of TME and cell-cell communication network in different PAM patterns using single cell sequencing data and found that polyamine metabolism affected the communication between cancer cells and several immune cells such as T cells, B cells and myeloid cells. CONCLUSION: In total, our findings highlighted the significance of polyamine metabolism in shaping the TME and predicting the prognosis of CRC patients, providing novel strategies for immunotherapy and the targeting polyamine metabolites.

Exploring the role of pyroptosis in shaping the tumor microenvironment of colorectal cancer by bulk and single-cell RNA sequencing.

BACKGROUND: Emerging studies have shown that pyroptosis plays a non-negligible role in the development and treatment of tumors. However, the mechanism of pyroptosis in colorectal cancer (CRC) remains still unclear. Therefore, this study investigated the role of pyroptosis in CRC. METHODS: A pyroptosis-related risk model was developed using univariate Cox regression and LASSO Cox regression analyses. Based on this model, pyroptosis-related risk scores (PRS) of CRC samples with OS time > 0 from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database were calculated. The abundance of immune cells in CRC tumor microenvironment (TME) was predicted by single-sample gene-set enrichment analysis (ssGSEA). Then, the responses to chemotherapy and immunotherapy were predicted by pRRophetic algorithm, the tumor immune dysfunction and exclusion (TIDE) and SubMap algorithms, respectively. Moreover, the Cancer Therapeutics Response Portal (CTRP) and PRISM Repurposing dataset (PRISM) were used to explore novel drug treatment strategies of CRC. Finally, we investigated pyroptosis-related genes in the level of single-cell and validated the expression levels of these genes between normal and CRC cell lines by RT-qPCR. RESULTS: Survival analysis showed that CRC samples with low PRS had better overall survival (OS) and progression-free survival (PFS). CRC samples with low PRS had higher immune-related gene expression and immune cell infiltration than those with high PRS. Besides, CRC samples with low PRS were more likely to benefit from 5-fluorouracil based chemotherapy and anti-PD-1 immunotherapy. In novel drug prediction, some compounds such as C6-ceramide and noretynodrel, were inferred as potential drugs for CRC with different PRS. Single-cell analysis revealed pyroptosis-related genes were highly expressed in tumor cells. RT-qPCR also demonstrated different expression levels of these genes between normal and CRC cell lines. CONCLUSIONS: Taken together, this study provides a comprehensive investigation of the role of pyroptosis in CRC at the bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) levels, advances our understanding of CRC characteristics, and guides more effective treatment regimens.

Biodegradable FePS3 nanoplatform for efficient treatment of osteosarcoma by combination of gene and NIR-II photothermal therapy.

As a common tumor with high incidence, osteosarcoma possesses extremely poor prognosis and high mortality. Improving the survival of osteosarcoma patients is still a great challenge due to the precipice of advancement in treatment. In this study, a combination strategy of gene therapy and photothermal therapy (PTT) is developed for efficient treatment of osteosarcoma. Two-dimensional (2D) FePS3 nanosheets are synthesized and functionalized by poly-L-lysine-PEG-folic acid (PPF) to fabricate a multifunctional nanoplatform (FePS@PPF) for further loading microRNAs inhibitor, miR-19a inhibitor (anti-miR-19a). The photothermal conversion efficiency of FePS@PPF is up to 47.1% under irradiation by 1064 nm laser. In vitro study shows that anti-miR-19a can be efficiently internalized into osteosarcoma cells through the protection and delivery of FePS@PPF nanaocarrier, which induces up-regulation of PTEN protein and down-regulation p-AKT protein. After intravenous injection, the FePS@PPF nanoplatform specifically accumulates to tumor site of osteosarcoma-bearing mice. The in vitro and in vivo investigations reveal that the combined PTT-gene therapy displays most significant tumor ablation compared with monotherapy. More importantly, the good biodegradability promotes FePS@PPF to be cleared from body avoiding potential toxicity of long-term retention. Our work not only develops a combined strategy of NIR-II PTT and gene therapy mediated by anti-miR-19a/FePS@PPF but also provides insights into the design and applications of other nanotherapeutic platforms.

LncRNA LENGA acts as a tumor suppressor in gastric cancer through BRD7/TP53 signaling.

It has been established that long noncoding RNAs (lncRNAs) play a crucial role in various cancer types, and there are vast numbers of long noncoding RNA transcripts that have been identified by high-throughput methods. However, the biological function of many novel aberrantly expressed lncRNAs remains poorly elucidated, especially in gastric cancer (GC). Here, we first identified a novel lncRNA termed LENGA (Low Expression Noncoding RNA in Gastric Adenocarcinoma), which was significantly downregulated in GC tissues compared to adjacent normal tissues. Next, we found that reduced expression of LENGA in GC was also associated with a shorter life expectancy. The proliferation, migration, and invasion of GC cells were increased after LENGA knockdown but restrained after LENGA overexpression in vitro and in vivo. It was further demonstrated that LENGA physically binds to BRD7 (bromodomain-containing 7) in the bromodomain domain and acts as a scaffold that enhances the interaction between BRD7 and TP53 (tumor protein p53), regulating the expression of a subset of genes in the p53 pathway, including CDKN1A (cyclin-dependent kinase inhibitor 1A) and PCDH7 (protocadherin 7), at the transcriptional level. Consistently, the expression of CDKN1A has a positive correlation with LENGA in GC patients. Taken together, this study uncovers a novel tumor suppressor lncRNA, LENGA, and describes its biological function, molecular mechanism, and clinical significance. This highlights the potential importance of targeting the LENGA/BRD7/TP53 axis in GC treatment.

"Drum Tower Hospital" strategy for acute type A aortic dissection with coma.

OVERVIEW: Acute type A aortic dissection (ATAAD) with persistent coma is a life-threatening condition associated with high mortality and poor neurological outcomes. The optimal timing for surgical intervention in these patients remains uncertain, and many patients are not eligible for surgery due to their poor prognosis. DESCRIPTION: In this case, a 53-year-old man with hypertension presented to the emergency department in a coma that had lasted for 9 hours. The patient was diagnosed with ATAAD and underwent the "Drum Tower Hospital" strategy, which involved preoperative assessments, including computed tomography angiography (CTA) and quantitative electroencephalogram (qEEG) monitoring. Surgical interventions, such as emergency stenting and aortic replacement, were performed to restore blood flow and repair the aorta. Postoperative monitoring, including qEEG, showed improvements in brain function. Despite the patient experiencing hemiplegia and a neurological deficit, the "Drum Tower Hospital" strategy, guided by comprehensive brain assessments, showed promise in managing ATAAD with coma. However, further research is needed to establish effective treatment strategies for these patients. Overall, ATAAD with persistent coma is a critical condition with limited treatment options. The "Drum Tower Hospital" strategy, supported by multimodal brain assessment, offers a potential approach to improve outcomes in these patients.

Assessing the accuracy of fabricated implant surgical guides by reconstructing the implant position based on cone beam computed tomography images: A dental technique.

A protocol for qualitatively reviewing the accuracy of fabricated implant surgical guides is presented. Once these guides have been inserted and fixed intraorally, cone beam computed tomography (CBCT) scans are made. Implant positions can be recalculated by processing the series of sleeve images on the CBCT scans. This protocol offers an opportunity for double-checking the accuracy of a fabricated guide before surgery in certain circumstances.

A Modified Billroth-II with Braun Anastomosis in Totally Laparoscopic Distal Gastrectomy: Initial Experience Compared with Roux-en-Y Anastomosis.

BACKGROUND: This retrospective study aimed to compare the feasibility and effectiveness of a modified Billroth-II with Braun (B-II Braun) reconstruction and those of a Roux-en-Y (R-Y) reconstruction after laparoscopic distal gastrectomy. METHODS: From January 2016 to December 2019, 247 patients underwent total laparoscopic distal gastrectomy (TLDG), with B-II Braun reconstruction for 145 patients and R-Y reconstruction for 102 patients. The patients' data were collected prospectively and reviewed retrospectively. RESULTS: In this study, the median times of the operation were statistically shorter for B-II Braun than for R-Y (167 min [range, 110-331 min] vs 191 min [range, 123-384 min]; p = 0.001), including anastomotic times (33 min [range, 30-42 min] vs 42 min [range, 40-48 min]; p = 0.001). After a short-term follow-up period, endoscopy showed 31 cases of bile reflux (21.4%), 15 cases of grade 2 gastritis (10.3%), and 6 cases of grade 2 food residue (4.1%) in the B-II Braun group after 6 months. After 1 year, 10 patients (6.9%) had grade 2 gastritis and 2 patients (1.4%) had grade 3 gastritis. However, the remnant stomach of the two groups did not differ significantly in the rate of gastric residue (p = 0.112 after 6 months; p = 0.579 after 1 year, respectively), gastritis (p = 0.726 after 6 months; p = 0.261 after 1 year, respectively), or bile reflux (p = 0.262 after 6 months; p = 0.349 after 1 year, respectively). CONCLUSIONS: For gastric cancer patients, TLDG with modified B-II Braun reconstruction could be technically feasible. It has an acceptable range of postoperative complications and is effective in preventing bile reflux into the gastric remnant.

ACACB is a novel metabolism-related biomarker in the prediction of response to cetuximab therapy inmetastatic colorectal cancer.

Cetuximab is one of the most valuable targeted therapy monoclonal antibodies in the treatment of metastatic colorectal cancer (CRC). However, the mechanisms affecting cetuximab resistance in CRC treatment remain unclear. Metabolism, especially fatty acid metabolism, has been reported to play an important role in tumor treatment. The correlation between cetuximab resistance and metabolism and whether it can be a new biomarker to evaluate the sensitivity of cetuximab in CRC treatment still need to be further explored. In this study, we perform a comprehensive analysis to confirm the relationship between fatty acid metabolism and cetuximab resistance, and the differentially expressed genes (DEGs) related to cetuximab drug resistance in CRC are screened by bioinformatics technology. We find that acetyl-CoA carboxylase beta (ACACB), ADH1C, CES1, MGLL, FMO5, and GPT are the hub DEGs, and ACACB is the most important biomarker among them. In addition, we systematically analyze the role of ACACB in the tumorigenesis of CRC, including tissue expression, CRC cell growth, cetuximab sensitivity, and potential downstream pathways, by using bioinformatics techniques, in vitro experiments and clinical cohort validation. Our results confirm that cetuximab resistance is correlated with metabolism. ACACB can lead to decreased sensitivity to cetuximab in CRC, and its mechanism may be related to EGFR phosphorylation, which could affect the activation of the mTOR/Akt signaling pathway and regulation of CDT1-, cyclin D1-, and p21-related cell cycle modulation.

Synergistic Therapy for Cervical Cancer by Codelivery of Cisplatin and JQ1 Inhibiting Plk1-Mutant Trp53 Axis.

JQ1, a specific inhibitor of bromodomain-containing protein 4 (BRD4), could have great potential in the treatment of cervical cancer. However, its clinical application is limited by its short plasma half-life and limited antitumor efficacy. In this work, cisplatin (CDDP) was first utilized as the stabilizer and cooperator in the nanosystem (mPEG113-b-P(Glu10-co-Phe10)-CDDP/JQ1, called PGP-CDDP/JQ1) to break through the efficiency limitation of JQ1. The PGP-CDDP/JQ1 had a combination index (CI) of 0.21, exerting a strong cytotoxic synergistic effect. In vivo experiments revealed that PGP-CDDP/JQ1 had a significantly higher tumor inhibition effect (tumor inhibition rate: 85% vs 14%) and plasma stability of JQ1 (area under the curve (AUC0-∞): 335.97 vs 16.88 µg × h/mL) than free JQ1. The mechanism underling the synergism of JQ1 with CDDP in PGP-CDDP/JQ1 was uncovered to be inhibiting Plk1-mutant Trp53 axis. Thus, this study provides an optional method for improving the clinical application of JQ1 in cervical cancer.

A greater lymph node yield is required during pathological examination in microsatellite instability-high gastric cancer.

BACKGROUND: The impact of microsatellite status on lymph node (LN) yield during lymphadenectomy and pathological examination has never been assessed in gastric cancer (GC). In this study, we aimed to appraise the association between microsatellite instability-high (MSI-H) and LN yield after curative gastrectomy. METHODS: We retrospectively analyzed 1757 patients with GC undergoing curative gastrectomy and divided them into two groups: MSI-H (n = 185(10.5%)) and microsatellite stability (MSS) (n = 1572(89.5%)), using a five-Bethesda-marker (NR-24, BAT-25, BAT-26, CAT-25, MONO-27) panel. The median LN count and the percentage of specimens with a minimum of 16 LNs (adequate LN ratio) were compared between the two groups. The log odds (LODDS) of positive LN count (PLNC) to negative LN count (NLNC) and the target LN examined threshold (TLNT(x%)) were calculated in both groups. RESULTS: Statistically significant differences were found in the median LN count between MSI-H and MSS groups for the complete cohort (30 vs. 28, p = 0.031), for patients undergoing distal gastrectomy (DG) (30 vs. 27, p = 0.002), for stage II patients undergoing DG (34 vs. 28, p = 0.005), and for LN-negative patients undergoing DG (28 vs. 24, p = 0.002). MSI-H was an independent factor for higher total LN count in patients undergoing DG (p = 0.011), but it was not statistically correlated to the adequate LN ratio. Statistically significant differences in PLNC, NLNC and LODDS were found between MSI-H GC and MSS GC (all p < 0.001). The TLNT(90%) for MSI-H and MSS groups were 31 and 25, respectively. TLNT(X%) of MSI-H GC was always higher than that of MSS GC regardless of the given value of X%. CONCLUSIONS: MSI-H was associated with higher LN yield in patients undergoing gastrectomy for GC. Although MSI-H did not affect the adequacy of LN harvest, we speculate that a greater lymph node yield is required during pathological examination in MSI-H GC.

Impact of microsatellite status on negative lymph node count and prognostic relevance after curative gastrectomy.

BACKGROUND AND OBJECTIVES: The impact of microsatellite instability-high (MSI-H) phenotype on lymph node yield after lymphadenectomy has never been discussed in gastric cancer (GC). In this study, we aimed to assess the association of microsatellite status with negative lymph node count (NLNC) as well as its prognostic value. METHODS: We retrospectively analyzed 1491 GC patients and divided them into two groups: MSI-HGC (n = 141 [9.5%]) and microsatellite stability (MSSGC ) (n = 1350 [90.5%]). The NLNC and survival data were compared between the two groups. The log odds of positive lymph nodes (LNs) to negative LNs and the target lymph node examined threshold (TLNT) were calculated in both groups. RESULTS: A statistically significant difference was found in median NLNC (26 vs. 23, p < .001) between MSI-HGC and MSSGC patients. MSI status was an independent factor for NLNC (p < .001). NLNC showed positive prognostic value for cases with metastatic lymph node (LN+ ) in both MSI-HGC and MSSGC groups. The TLNT(90%) for MSI-HGC and MSSGC were 33 and 26, respectively. CONCLUSIONS: MSI-HGC was associated with higher NLNC in GC patients and this was independent of the presence of LN+ . However, more LNs are needed during pathological examination to capture LN+ cases in MSI-HGC.

[Mechanism of Potentilla discolor in treating UC by regulating mitochondrial autophagy].

To evaluate the therapeutic effect of Potentilla discolor on 2,4,6-trinitrobenzensulfonic acid(TNBS)-induced experimental ulcerative colitis(UC) in rats and to determine its therapeutic mechanism through mitochondrial autophagy, immune cells, and cytokines. A rat model of UC was established by TNBS-ethanol enema. Rats were divided into six groups: control, UC model, sulfasalazine(positive drug), and high-dose, moderate-dose, and low-dose ethanol extract groups. After 14-day continuous administration of the corresponding drugs, the disease activity index(DAI) and hematoxylin and eosin(HE) were evaluated. The morphological structure of mitochondria was observed by using transmission electron microscope(TEM), mitophagy-related mRNA expression was detected by using Real-time quantitative polymerase chain reaction(qRT-PCR), immune cell differentiation in rat serum was detected by using flow cytometry(FCM), and cytokine expression in colon tissues of rats was detected by protein microarray. The results showed that compared with the model group, each dose group of P. discolor could significantly reduce the DAI of UC model rats, and decrease the degree of inflammatory cells infiltration in the colon tissue of UC model rats. Meanwhile the expressions of T cells and Th cells in the serum increased significantly, the expression of Tc cells in the serum decreased significantly. Transmission electron microscope found that there was fusion of mitochondria and lysosomes in the colon tissue of the administration group. The expressions of mitochondrial autophagy related genes NF-κB, p62 and parkin were significantly increased in colon tissues. The results of protein chip showed that compared with the model group, the high dose group of P. discolor could significantly regulate the expression of cytokines. In conclusion, these results suggested that P. discolor improved TNBS-induced acute ulcerative colitis in rats by regulating the mitochondrial autophagy and the inflammatory factor expression.

Role of colonic microbiota in the pathogenesis of ulcerative colitis.

BACKGROUND: Recent studies have found gut microbiota to be closely associated with onset and perpetuation of UC. Currently, studies about gut microbiota have mainly covered samples collected from the intestinal lumen. However, the luminal flora is only part of the gut microbiota. Studies of the changes in mucosal flora under pathological conditions have been lacking. In this study, we investigated the correlation between the onset of UC and flora changes in different intestinal layers. METHODS: The dextran sulfate sodium(DSS)-induced UC model was established by exposing mice to cycles of DSS. The luminal contents, an inner mucus layer, and outer mucus layer were harvested under sterile conditions. The samples were then analyzed using high-throughput sequencing of 16S rRNA V3 + V4 amplicons. The colonic microbiota composition and diversity were analyzed and compared using MetaStat, LefSe, multivariate analysis of variance, and spatial statistics. RESULTS: The DSS-induced UC mouse model was successfully established. The diversity of the microbiota from luminal content, the outer mucus layer, and inner mucus layer were significantly different in both control and UC model groups. The statistically different OTUs belonged to Lachnospiraceae and Ruminococcaceae families within the order Clostridiales were mainly localized to the outer mucus layer. CONCLUSIONS: The alterations in flora composition and diversity mainly occurred in the colonic outer mucus layer. The change of flora in the colonic mucus layers is of great significance in the understanding of common features of gut flora in IBD and the understanding of the relationship between gut flora and disease progression.

Regulatory effect of Garidisan on dysbiosis of the gut microbiota in the mouse model of ulcerative colitis induced by dextran sulfate sodium.

BACKGROUND: Ulcerative colitis (UC) is a modern refractory disease, and its etiology has been difficult to discern. Studies have shown that UC is closely associated with the gut microbiota. Garidisan is composed of wild poppy and Artemisia frigida Willd and is commonly used for the treatment of UC in Inner Mongolia, China. In clinical settings, Garidisan has been found to treat UC effectively, with low recurrence. Previous studies have shown that Garidisan has a good therapeutic effect on mice with UC, but the therapeutic mechanism is still unclear. In this study, we investigated the regulatory effect of Garidisan on dysbiosis of the gut microbiota in a UC mouse model and explored the possible mechanism of the therapeutic effect of Garidisan on UC. METHODS: The UC mouse model was established by the dextran sulfate sodium (DSS) circulating free water drinking method, and the luminal contents were sampled under sterile conditions. High-throughput sequencing of the 16S rRNA gene V3 + V4 region of the luminal contents of the control group, model group, and Garidisan group was conducted, and clustering of operational taxonomic units (OTUs) and species annotation were performed. The differences in species composition and microbial community structure between individual groups of samples were analyzed using MetaStat, LefSe, rank sum test, and Bayesian causal network analysis. RESULTS: The UC mouse model was successfully established and the sequencing results were of adequate quality. There were significant differences in the diversity of luminal contents between the control group, model group, and Garidisan group, and the differences between groups were greater than those within any group. The therapeutic effect of Garidisan on UC is attributed to the direct effect on the Lachnospiraceae family of bacteria. CONCLUSION: Garidisan has a good regulatory effect on the gut microbiota, and Lachnospiraceae could be an important direct target of Garidisan for the treatment of UC.

Epigenetic silencing of sonic hedgehog elicits antitumor immune response and suppresses tumor growth by inhibiting the hedgehog signaling pathway in metastatic spine tumors in Sprague-Dawley rats.

BACKGROUND: Patients with metastatic spine tumors may suffer from pain or neurologic deficit, and the disease may be detected in patients with a known malignancy. Sonic hedgehog (SHH) has received special attention due to its role in cancers. Therefore, this study investigated the effects of epigenetic silencing of SHH on antitumor immune response and tumor growth by regulating the hedgehog (Hh) signaling pathway in metastatic spine tumors. METHODS: Rat models of metastatic spine tumors were successfully established. We first calculated the tumor volume and the inhibition rate of tumor growth to investigate the effect of SHH on tumor growth. Afterwards, immunohistochemistry was used to determine whether proliferation was delayed by SHH depletion, and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was conducted to test the changes in the lymphocyte transformation rate in the spleen triggered by SHH silencing. Then, the influence of SHH depletion on immune function was investigated. Later, quantitative reverse transcription polymerase chain reaction and Western blot assay were performed to explore the Hh signaling pathway-related factors. Finally, we added the Hh signaling pathway inhibitor, GDC-0449, to confirm the role of the pathway in tumor progression. RESULTS: Initially, we observed that SHH depletion was a negative factor for tumor growth. Afterwards, it was revealed that epigenetic silencing of SHH served as an inhibitor factor for the function of spleen lymphocyte transformation and inflammation while promoting antitumor immune function. CONCLUSION: Our preliminary results indicate that epigenetic silencing of SHH elicits an antitumor immune response and suppresses tumor growth by inhibiting the Hh signaling pathway in metastatic spine tumors.

The identification of induction chemo-sensitivity genes of laryngeal squamous cell carcinoma and their clinical utilization.

PURPOSE: To identify potential molecular markers for induction chemotherapy of Laryngeal squamous cell carcinoma (LSCC). METHODS: Differently expressed genes between chemo-sensitive group (seven cases) and chemo-insensitive (five cases) group after induction chemotherapy by TPF were identified by microarrays. Bayes network and Random forest analyses were employed to identify core genes for induction chemotherapy. The diagnostic value of these core genes was also evaluated by ROC analysis. RESULTS: Six genes (SPP1, FOLR3, KYNU, LOC653219, ADH7 and XAGE1A) are highly expressed, while seven gene (CADM1, NDUFA4L2, CCND2, RARRES3, ERAP2, LYD6 and CNTNAP2) present significantly low expression. Among these genes, genes CADM1, FOLR3, KYNU, and CNTNAP2 are core candidates for LSCC chemo-sensitivity. And that the low expression of CADM1 may result in chemo-sensitivity, which leads to high expression of gene FOLR3 and KYNU, and low expression of gene CNTNAP2. Besides, ROC analysis shows that these four genes exhibit effective diagnostic value for induction chemo-sensitivity. CONCLUSIONS: CADM1 may be a potential molecular marker for LSCC induction chemotherapy, while CADM1, FOLR3, KYNU, and CNTNAP2 may provide essential guidance for LSCC diagnosis and follow-up treatment strategies.

A meta-analysis of the effect of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of metoprolol
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OBJECTIVE: To conduct a meta-analysis on the effect of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of metoprolol. METHODS: A systematic review and meta-analysis of studies on the effect of CYP2D6 polymorphism on metoprolol pharmacokinetics and pharmacodynamics was performed by using the China national knowledge infrastructure (CNKI), database for Chinese technical periodicals (VIP), Wanfang, and PubMed databases up to the end of January 2015. Review Manager 5.3 (the coherence collaboration, www.gradepro.org) and comprehensive Meta-Analysis Software v2 (CMA) Biostat, Englewood, NJ, USA) were used for meta-analysis. RESULTS: A total of 567 cases from 7 studies were included in the present study. Meta-analysis results showed that the area under the curve (AUC)0-∞ (RR = -6.75, 95% CI (-9.18, -4.31), p < 0.00001); Cmax (RR = -2.40, 95% CI (-3.25, -1.54), p < 0.00001); T1/2 (RR = -4.81, 95% CI (-6.86, -2.76), p < 0.00001); CL/F (RR = 1.60, 95% CI (1.03,2.17), p < 0.00001); heart rate (RR = 1.48, 95% CI (0.03, 2.92), p = 0.05), systolic blood pressure (RR = -0.69, 95% CI (-1.85,0.47), p = 0.24); and diastolic blood pressure (RR = -1.95, 95% CI (-3.14, -0.76), p = 0.001). Begg's funnel plot test showed that the pharmacokinetic parameters (AUC0-∞, Cmax, T1/2, and CL/F) and pharmacodynamic parameters (HR, DBP, and SBP) were symmetric. Egger's test showed that the pharmacokinetic parameters were asymmetrical, and its intercept was statistically significant (p < 0.05), which was indicative of publication bias. The pharmacodynamic parameter intercept was not statistically significant (p > 0.05), indicating that no publication bias existed. CONCLUSION: CYP2D6 polymorphism significantly influenced the pharmacokinetic parameters of metoprolol. It also affected heart rate and diastolic blood pressure, whereas systolic pressure was not affected.
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