Oncogenic KRAS induces arginine auxotrophy and confers a therapeutic vulnerability to SLC7A1 inhibition in non-small cell lung cancer.

The urea cycle is frequently rewired in cancer cells to meet the metabolic demands of cancer. Elucidation of the underlying mechanism by which oncogenic signaling mediates urea cycle reprogramming could help identify targetable metabolic vulnerabilities. In this study, we discovered that oncogenic activation of KRAS in non-small cell lung cancer (NSCLC) silenced the expression of argininosuccinate synthase 1 (ASS1), a urea cycle enzyme that catalyzes the production of arginine from aspartate and citrulline, and thereby diverted the utilization of aspartate to pyrimidine synthesis to meet the high demand for DNA replication. Specifically, KRAS signaling facilitated a hypo-acetylated state in the promoter region of the ASS1 gene in a histone deacetylase 3 (HDAC3)-dependent manner, which in turn impeded the recruitment of c-MYC for ASS1 transcription. ASS1 suppression in KRAS-mutant NSCLC cells impaired the biosynthesis of arginine and rendered a dependency on the arginine transmembrane transporter SLC7A1 to import extracellular arginine. Depletion of SLC7A1 in both patient-derived organoid and xenograft models inhibited KRAS-driven NSCLC growth. Together, these findings uncover the role of oncogenic KRAS in rewiring urea cycle metabolism and identify SLC7A1-mediated arginine uptake as a therapeutic vulnerability for treating KRAS-mutant NSCLC.

Two-Dimensional Biodegradable Black Phosphorus Nanosheets Promote Large Full-Thickness Wound Healing through In Situ Regeneration Therapy.

Large full-thickness skin lesions have been one of the most challenging clinical problems in plastic surgery repair and reconstruction. To achieve in situ skin regeneration and perfect clinical outcomes, we must address two significant obstacles: angiogenesis deficiency and inflammatory dysfunction. Recently, black phosphorus has shown great promise in wound healing. However, few studies have explored the bio-effects of BP to promote in situ skin regeneration based on its nanoproperties. Here, to investigate whether black phosphorus nanosheets have positive bio-effects on in situ skin repair, we verified black phosphorus nanosheets' positive effects on angiogenic and anti-inflammatory abilities in vitro. Next, the in vivo evaluation performed on the rat large full-thickness excisional wound splinting model more comprehensively showed that the positive bio-effects of black phosphorus nanosheets are multilevel in wound healing, which can effectively enhance anti-inflammatory ability, angiogenesis, collagen deposition, and skin re-epithelialization. Then, multiomics analysis was performed to explore further the mechanism of black phosphorus nanosheets' regulation of endothelial cells in depth. Molecular mechanistically, black phosphorus nanosheets activated the JAK-STAT-OAS signaling pathway to promote cellular function and mitochondrial energy metabolism in endothelial cells. This study can provide a theoretical basis for applying two-dimensional black phosphorus nanosheets as nanomedicine to achieve in situ tissue regeneration in complex human pathological microenvironments, guiding the subsequent optimization of black phosphorus.

Potential therapeutic drug targets and pathways prediction for premature ovarian insufficiency -Based on network pharmacologic method.

ETHNOPHARMACOLOGICAL RELEVANCE: The incidence of premature ovarian insufficiency (POI) is gradually increasing, the proportion is rising especially in female infertility patients. The risk of death of POI patients with cardiovascular disease also increases significantly. The cause of POI is complex and unclear, and clinical treatment is still in the exploratory stage, are two major constraints of treating POI. Traditional Chinese medicine (TCM) is widely used in the treatment of POI, and it is a good way to combine the development of modern new drugs with the help of TCM to predict the therapeutic targets. AIM OF THE STUDY: In this study, four herbs commonly used in clinical treatment of POI, namely Radix Paeoniae, Polygonatum sibiricum, Rehmannia glutinosa and Eucommia ulmoides were selected to predict their mechanism in the treatment of POI, using network pharmacology methods. Then verify the predicted targets by animal test. Aim to find more effective POI potential core treatment targets and main pathways. MATERIALS AND METHODS: We screened the active ingredients of drugs from the TCM System Pharmacology Analysis Platform (TCMSP), Performed target prediction of active ingredients from databases such as SwissTargetPrediction and compare and analyze the POI-related targets retrieved from them to obtain potential targets for drug treatment of POI. Used STRING database to construct a protein interaction network, Cytoscape 3.7.2 software to construct an active ingredient-target-pathway network, and DAVID database to conduct the Kyoto Encyclopedia of Genes and Genomes (KEGG) on the intersection targets and gene ontology (GO) enrichment analysis. RESULTS: The result is: there were 25 key targets for the treatment of POI with Radix Paeoniae Alba, 31 for the treatment of POI by Eucommia ulmoides, 28 for the treatment of POI by Polygonatum sibiricum, and 8 key targets for the treatment of Rehmannia glutinosa. The intersection targets of four herbs were defined as the core targets, which are CYP19A1, EGF, ESR1, ESR2, MDM2, AR, PCYP17A1, PPARG. Four Chinese herbs treat POI mainly through HIF-1 signaling pathway, PI3K-Akt signaling pathway, FoxO signaling pathway, Estrogen signaling pathway etc. A mouse model of POI was constructed based on the results of network pharmacology to verify the predicted targets. The results showed that the protein expression of the core target changed, and the estrogen level was increased by reducing the expression of peroxisome proliferator-activated receptor gamma (PPARG). CONCLUSIONS: This study predicts the mechanism of multiple herbs in the treatment of POI, screens out more potential therapeutic drug targets and main pathways of POI treatment and provides new ideas for the subsequent development of POI therapeutic drugs.

Intermittent Fasting Alleviates Risk Markers in a Murine Model of Ulcerative Colitis by Modulating the Gut Microbiome and Metabolome.

Clinical trials have demonstrated the health benefits of intermittent fasting (IF). However, the potential mechanism of IF in alleviating dextran sulfate sodium (DSS)-induced colitis is not fully understood. The present study was mainly designed to explore the dynamic changes in the gut microbiota and metabolome after short-term (2 weeks) or long-term (20 weeks) IF and therefore clarify the potential mechanisms by which IF ameliorates DSS-induced colitis in a murine model. Thirty-two C57BL/6 male mice were equally divided into four groups and underwent IF intervention for 2 weeks (SIF group, n = 8), 20 weeks (LIF group, n = 8), or were allowed free access to food for 2 weeks (SAL group, n = 8) or 20 weeks (LAL group, n = 8). The thirty-two C57BL/6 male mice were accepted for the diet intervention of 2 weeks of IF or fed ad libitum. Colitis was induced by drinking 2% DSS for 7 days. Our findings showed that short-term IF prominently elevates the abundance of Bacteroides, Muibaculum and Akkermansia (p < 0.001, p < 0.001, p < 0.001, respectively), and decreased the abundance of Ruminiclostridium (p < 0.05). Long-term IF, however, decreased the abundance of Akkermansia and obviously increased the abundance of Lactobacillus (p < 0.05, p < 0.001, respectively). Metabolites mainly associated with nucleoside, carbohydrate, amino acid, bile acid, fatty acid, polyol, steroid and amine metabolism were identified in the faeces using untargeted GC/MS. In particular, inosine was extremely enriched after short-term IF and long-term IF (p < 0.01, p < 0.01, respectively); butyrate, 2-methyl butyric acid and valeric acid were significantly decreased after short-term IF (p < 0.001, p < 0.001, p < 0.01, respectively); and 2-methyl butyric acid was significantly increased after long-term IF (p < 0.001). The abundance of lithocholic acid (LCA), one of the secondary bile acids, increased significantly after short-term and long-term IF based on UPLC−MS/MS (p < 0.001, p < 0.5, respectively). Of note, IF markedly mitigated DSS-induced acute colitis symptoms and down-regulated pro-inflammatory cytokines IL-1α, IL-6, keratinocyte-derived chemokine (KC) and G-CSF levels in the serum (p < 0.01, p < 0.001, p < 0.05, p < 0.001, respectively). Furthermore, a correlation analysis indicated that the disease activity index (DAI) score and serum levels of IL-1α, IL-6, KC, and G-CSF were negatively correlated with the relative abundance of Akkermansia and the faecal metabolites LCA and inosine. This study confirmed that IF altered microbiota and reprogramed metabolism, which was a promising development in the attempt to prevent DSS-induced colitis. Moreover, our findings provide new insights regarding the correlations among the mucosal barrier dysfunction, metabolome, and microbiome.

The negative effect of Akkermansia muciniphila-mediated post-antibiotic reconstitution of the gut microbiota on the development of colitis-associated colorectal cancer in mice.

The bidirectional relationship between colorectal cancer (CRC) and the gut microbiome has been well-documented. Here, we investigated the impact of Akkermansia muciniphila-mediated post-antibiotic gut microbial reconstitution on the development of colitis-associated CRC (CAC). The results showed that post-antibiotic replenishment of A. muciniphila worsened the tumorigenesis of CAC as indicated by increased number of large (>2 mm in diameter) tumors and both average and total tumor diameters. Measures of intestinal barrier function showed that post-antibiotic A. muciniphila gavage damaged the intestinal barrier as reflected by lower transcriptional levels of Tjp1, Ocln, Cdh1, and MUC2. Impaired gut barrier was followed by lipopolysaccharides (LPS) translocation as indicated by higher level of serum LPS-binding protein (LBP). The increased colonic mRNA levels of Il1b, Il6, and Tnfa and serum levels of IL-1ß, IL-6, and TNF-α indicated that post-antibiotic A. muciniphila replenishment resulted in overactivated inflammatory environment in CAC. The analysis of the evolution of the microbial community during the progression of CAC showed that post-antibiotic supplementation of A. muciniphila led to a distinct microbial configuration when compared with other treatments characterized by enriched Firmicutes, Lachnospiraceae, and Ruminococcaceae, and depleted Bacteroidetes, which was accompanied by higher Firmicutes/Bacteroidetes (F/B) ratio. Furthermore, post-antibiotic A. muciniphila administration changed the bile acid (BA) metabolic profile as indicated by decreased concentrations of secondary BA (SBA), ω-murocholic acid (ωMCA), and murocholic acid (muroCA). In addition, the A. muciniphila supplementation after antibiotic pretreatment also impacted the metabolism of short-chain fatty acids (SCFAs) as evidenced by increased concentrations of acetic acid, propionic acid, butyric acid, and valeric acid. Our study surprisingly observed that A. muciniphila-mediated post-antibiotic reconstitution of the gut microbiota aggravated the CAC in mice. It might exert its effect by damaging the gut barrier, exacerbating inflammatory responses, disrupting the post-antibiotic recovery of the microbial community, and further influencing the metabolism of BA and SCFAs. These findings indicated that maintaining the homeostasis of intestinal microorganisms is more crucial to health than replenishing a single beneficial microbe, and probiotics should be used with caution after antibiotic treatment.

Interleukin-10-Modified Adipose-Derived Mesenchymal Stem Cells Prevent Hypertrophic Scar Formation via Regulating the Biological Characteristics of Fibroblasts and Inflammation.

Hypertrophic scar causes serious functional and cosmetic problem, but no treatment method is known to achieve a satisfactory therapeutic effect. However, mesenchymal stem cells show a possible cure prospect. Here, we investigated the effect of interleukin-10-modified adipose-derived mesenchymal stem cells (IL-10-ADMSC) on the formation of hypertrophic scar. In vitro, IL-10-ADMSC could highly express IL-10 and exhibited stronger inhibition of hypertrophic scar fibroblasts (HSFs) proliferation, migration, and extracellular matrix synthesis (the expression of collagen I, collagen III, FN, and α-SMA protein) than ADMSC. In vivo, we found that IL-10-ADMSC speeded up wound healing time and reduced scar area and scar outstanding height. Same as in vitro, IL-10-ADMSC also exhibited stronger inhibition of extracellular matrix synthesis (the expression of collagen I, collagen III protein) in wound than ADMSC. In addition, we also found that IL-10-ADMSC is also a stronger inhibitory effect on inflammation in wound than ADMSC, and IL-10-ADMSC inhibited TGF-ß/Smads and NF-κB pathway. In conclusion, IL-10-ADMSC demonstrated the ability to prevent hypertrophic scar formation. And its possible molecular mechanism might be related to IL-10-ADMSC inhibiting the proliferation and migration of the synthesis of extracellular matrix of HSFs, and IL-10-ADMSC inhibited the inflammation during the wound healing.

Akkermansia muciniphila Ameliorates Acetaminophen-Induced Liver Injury by Regulating Gut Microbial Composition and Metabolism.

The gut microbiota drives individual sensitivity to excess acetaminophen (APAP)-mediated hepatotoxicity. It has been reported that the bacterium Akkermansia muciniphila protects hosts against liver disease via the liver-gut axis, but its therapeutic potential for drug-induced liver injury remains unclear. In this study, we aimed to investigate the effect of A. muciniphila on APAP-induced liver injury and the underlying mechanism. Administration of A. muciniphila efficiently alleviated APAP-induced hepatotoxicity and reduced the levels of serum alanine aminotransferase (ALT) and aspartate transaminase (AST). A. muciniphila significantly attenuated APAP-induced oxidative stress and the inflammatory response, as evidenced by restoration of the reduced glutathione/oxidized glutathione (GSH/GSSG) balance, enhanced superoxide dismutase (SOD) activity, reduced proinflammatory cytokine production, and alleviation of macrophage and neutrophil infiltration. Moreover, A. muciniphila maintained gut barrier function, reshaped the perturbed microbial community and promoted short-chain fatty acid (SCFA) secretion. The beneficial effects of A. muciniphila were accompanied by alterations in hepatic gene expression at the transcriptional level and activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Our results suggested that A. muciniphila could be a potential pretreatment for APAP-induced liver injury. IMPORTANCE Our work revealed that A. muciniphila attenuated APAP-induced liver injury by alleviating oxidative stress and inflammation in the liver, and its hepatoprotective effect was accompanied by activation of the PI3K/Akt pathway and mediated by regulation of the composition and metabolic function of the intestinal microbiota. This finding suggested that the microbial community is a non-negligible impact on drug metabolism and probiotic administration could be a potential therapy for drug-induced liver injury.

Relationship Between Masticatory Muscle Size and Bone Regeneration After Mandibular Angle Osteotomy.

ABSTRACT: Mandibular angle osteotomy with outer cortex grinding has become the preferred cosmetic procedure for correcting square faces. After surgery, bone hyperplasia at the mandibular angle affects the operation result. This study evaluated the effect of the masticatory muscles on bone repair. From January 2016 to January 2019, patients who underwent mandibular angle osteotomy with outer cortex grinding were retrospectively reviewed. Computed tomography data of these patients were collected, and the bone volume of the mandibular angle changes and its correlation with masticatory muscle morphology were analyzed. Computed tomography data measurement results showed that a large amount of bone in the mandibular angle area was removed by the operation; however, the long-term follow-up results showed that there was bone hyperplasia in the mandibular angle areas. Compared with the immediate postoperative bone volume, the difference was statistically significant (P < 0.01). The thickness and cross-sectional area of the masseter muscle were significantly related to bone regeneration (P < 0.01). This study suggests that mandibular angle osteotomy with outer cortex grinding could ablate the symptoms of a prominent mandibular angle; however, muscle-related bone hyperplasia in the mandibular angle area after surgery was a non-negligible event, which may significantly compromise surgical outcomes.

Craniofacial and Upper Airway Development in Patients With Treacher Collins Syndrome.

ABSTRACT: This study evaluated age-associated morphology changes in the cranial base, facial development, and upper airway of patients with Treacher Collins syndrome (TCS). A total of 33 preoperative computed tomographic images (TCS, n = 14; control, n = 19) were included in the study and divided into three age-related subgroups (2-6 years, 7-18 years, and older than 18 years). Linear, angular cephalometric measurements and upper airway volumes were collected. All measurements were analyzed using ProPlan CMF software (version 3.0; Materialize, Leuven, Belgium). The association between aging and upper airway morphology was analyzed. Compared to control subjects, TCS patients had a smaller cranial base, maxilla, and nose; they also had reduced upper airway volume compared to control subjects. The observed differences were most significant in patients between the ages of 7 and 18 years. This study used computed tomography-based three-dimensional analyses to provide a detailed description of age-related changes that occur in craniofacial measurements and upper airway volumes in children, adolescents, and young adult patients with TCS in China. These data can be used to evaluate individual patients with TCS and to select treatment to improve the growth of the craniofacial region.

The Salivary Microbiota of Patients With Primary Biliary Cholangitis Is Distinctive and Pathogenic.

The role of host-microbiota interactions in primary biliary cholangitis (PBC) has received increased attention. However, the impact of PBC on the oral microbiota and contribution of the oral microbiota to PBC are unclear. In this study, thirty-nine PBC patients without other diseases and 37 healthy controls (HCs) were enrolled and tested for liver functions and haematological variables. Saliva specimens were collected before and after brushing, microbiota was determined using 16S rDNA sequencing, metabolomics was profiled using Gas Chromatography-Mass Spectrometer (GC-MS), 80 cytokines were assayed using biochips, and inflammation inducibility was evaluated using OKF6 keratinocytes and THP-1 macrophages. Finally, the effect of ultrasonic scaling on PBC was estimated. Compared with HCs, PBC saliva had enriched taxa such as Bacteroidetes, Campylobacter, Prevotella and Veillonella and depleted taxa such as Enterococcaceae, Granulicatella, Rothia and Streptococcus. PBC saliva also had enriched sCD163, enriched metabolites such as 2-aminomalonic acid and 1-dodecanol, and depleted metabolites such as dodecanoic acid and propylene glycol. sCD163, 4-hydroxybenzeneacetic acid and 2-aminomalonic acid were significantly correlated with salivary cytokines, bacteria and metabolites. Salivary Veillonellaceae members, 2-aminomalonic acid, and sCD163 were positively correlated with liver function indicators such as serum alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). PBC salivary microbes induced more soluble interleukin (IL)-6 receptor α (sIL-6Rα), sIL-6Rß and tumour necrosis factor ligand superfamily (TNFSF)13B from OKF6 keratinocytes, and PBC salivary supernatant induced more IL-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), chemokine (C-C motif) ligand (CCL)13, C-X-C motif chemokine (CXC)L1 and CXCL16 from THP-1 macrophages. Toothbrushing significantly reduced the expression of inflammatory cytokines such as IL-1ß, IL-8 and TNF-α and harmful metabolites such as cadaverine and putrescine in PBC but not HC saliva after P-value correction. The levels of ALP and bilirubin in PBC serum were decreased after ultrasonic scaling. Together, PBC patients show significant alterations in their salivary microbiota, likely representing one cause and treatment target of oral inflammation and worsening liver functions.

[Three-dimensional measurement analysis of midface morphology in Treacher Collins syndromes].

OBJECTIVE: To three-dimensionally calculate the craniofacial parameters of midface of patients with Treacher Collins syndrome (TCS) in China, in order to understand the changes in the spatial position relationship between the various anatomical structures of the midface. METHODS: CT imaging data of TCS patients and age- and gender-matched normal populations between January 2013 and July 2020 was retrospectively analyzed. A total of 33 cases met the selection criteria for inclusion in the study, including 14 cases in the TCS group and 19 cases in the control group. ProPlan CMF 3.0 software was used to perform three-dimensional digital reconstruction of the craniofacial bone, measure the anatomical parameters of the midface, and analyze its morphological structure; at the same time perform three-dimensional digital reconstruction of the upper airway for morphological analysis (measure upper airway volume). RESULTS: CT images analysis revealed that all 14 patients with TCS presented the typical features with downward slanting of the palpebral fissures and different degrees of zygomatico-orbital complex dysplasia. Cephalometric and morphological analysis of the midface revealed that, multiple transverse diameters of the midface of TCS patients were significantly decreased when compared with the control group ( P<0.05), such as the width of the maxillary base, the length of the maxillary complex, and some distances related to the nasal morphology; but the distance between bilateral orbitales increased in TCS group ( P<0.05). Several anteroposterior distances in TCS group were decreased significantly when compared to control group and the distance between the skull base point and the posterior nasal spine was the most shortened ( P<0.05). But there was no significant difference of the distance between nasion and anterior nasal spine, which represented anterior midface height, between groups ( P>0.05). The skull base angle and SNB angle (the angle between the sella point-nose root point-inferior alveolar seat point) of the TCS group both decreased when compared with the control group ( P<0.05), but there was no significant difference in SNA angle (the angle between the sella point-nose root point-upper alveolar seat point) between the two groups ( P>0.05). The total volume of the upper airway was (24 621.07±8 476.63) mm 3 in the TCS group, which was significantly lower than that of the control group [(32 864.21±13 148.74) mm 3] ( t=2.185, P=0.037). CONCLUSION: The transverse distances, anteroposterior distances, and multiple craniofacial angles measurement of TCS patients were significantly decreased when compared to the control group, presented with different degrees of zygomatico-orbital complex dysplasia, nasal and maxillary dysplasia, but there was no obvious restriction in face height development. Reduced internal diameters of the upper airway maybe responsible for the decreased upper airway volume of patients with TCS.

Modulation of the immune response and metabolism in germ-free rats colonized by the probiotic Lactobacillus salivarius LI01.

The gut microbiota plays an important role in multifaceted physiological functions in the host. Previous studies have assessed the probiotic effects of Lactobacillus salivarius LI01. In this study, we aimed to investigate the potential effects and putative mechanism of L. salivarius LI01 in immune modulation and metabolic regulation through the monocolonization of germ-free (GF) Sprague-Dawley (SD) rats with L. salivarius LI01. The GF rats were separated into two groups and administered a gavage of L. salivarius LI01 or an equal amount of phosphate-buffered saline. The levels of serum biomarkers, such as interleukin (IL)-1α, IL-5, and IL-10, were restored by L. salivarius LI01, which indicated the activation of Th0 cell differentiation toward immune homeostasis. L. salivarius LI01 also stimulated the immune response and metabolic process by altering transcriptional expression in the ileum and liver. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed significant enrichment of the 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, which indicated that L. salivarius LI01 exerts an effect on energy accumulation. The LI01 group showed alterations in fecal carbohydrates accompanied by an increased body weight gain. In addition, L. salivarius LI01 produced indole-3-lactic acid (ILA) and enhanced arginine metabolism by rebalancing the interconversion between arginine and proline. These findings provide evidence showing that L. salivarius LI01 can directly impact the host by modulating immunity and metabolism. KEY POINTS : • Lactobacillus salivarius LI01 conventionalizes the cytokine profile and activates the immune response. • LI01 modulates carbohydrate metabolism and arginine transaction. • LI01 generates tryptophan-derived indole-3-lactic acid. • The cytochrome P450 family contributes to the response to altered metabolites.

The impact of a prior malignancy on outcomes in gastric cancer patients.

BACKGROUND: The number of cancer survivors has increased rapidly, and there is a higher risk of developing a second cancer. Whether a prior malignancy could affect survival outcomes is unknown. We aimed to investigate the clinical characteristics and prognostic outcomes of prior malignancies in patients with gastric cancer. METHODS: Patient data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. We used the Kaplan-Meier method, competing risk models, and Cox regression models to evaluate the impact of prior malignancy on survival outcomes. RESULTS: Among 71,809 patients with primary gastric cancer, 6667 (9.3%) patients had a pre-existing cancer. Prostate (31.86%), breast (14.34%), and colon and rectum (10.32%) cancer were the most common types. A significant difference was observed in the overall survival rates between patients with and without prior cancer (log-rank=139.73, p < 0.001). In the subgroup analysis, patients with prostate, uterine corpus, lung and bronchus, colon and rectum, esophagus, urinary bladder, leukemia, brain and other nervous system, oral cavity and pharynx, and breast cancer faced inferior survival than those without prior cancer. CONCLUSIONS: A history of prior cancer was associated with worse overall survival in patients with gastric cancer, and the effects varied by different initial cancer types. The exclusion and inclusion of patients who had previous malignancies should be reconsidered according to the specific malignancy types.

Epicanthoplasty With Rotated-advanced-back Cut Flap.

BACKGROUND: Epicanthoplasty is one of the most popular cosmetic surgeries in Asia. The aim of this study was to present a rotated, advanced, back cut flap (R-A-B flap) that leads to correct the congenital epicanthus effectively with satisfactory results. METHODS: From January of 2017 to December of 2018, we performed the modified cut back flap epicanthoplasty to correct epicanthus. The esthetic results were evaluated with patients' feedback: perfect, good, dissatisfied, or failed. RESULTS: A total of 118 patients were involved. Postoperative evaluation using a grading scale indicated "perfect" results for 86 patients (73%) and "good" results for 32 patients (27%). No patients rated the results as "dissatisfied" or "failed." There were no significant postoperative complications. CONCLUSION: The R-A-B flap for epicanthoplasty is a reliable and simple method, resulting in good cosmetic outcome with minimal scar formation.

Gene signatures of m5C regulators may predict prognoses of patients with head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the fifth most common malignancy in the world. The 5-methylcytosine (m5C) plays vital roles in pathological conditions, such as cancer. METHODS: This study investigated The Cancer Genome Atlas (TCGA) database for patients with HNSCC. We characterized the mutations and copy number variations (CNVs) in m5C-regulatory genes, in addition to analyzing their mRNA expressions. Gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) analyses were used to explore relevant functional annotations of m5C-regulatory genes. RESULTS: Alterations in m5C-regulatory genes were closely associated with patient clinicopathological characteristics. The expression of ten m5C-regulatory genes was significantly correlated with CNV patterns, indicating that m5C-regulatory genes have important regulatory effects. There was increased expression of m5C-regulatory genes, particularly ALYREF and NSUN5, during the tumor, node, and metastasis stages. Cox regression analysis revealed that the expression of DNMT1, TET2, and NSUN6 correlated with HNSCC prognoses. Furthermore, the expression of DNMT1 and ALYREF could effectively predict HNSCC risk in patients. In addition, the high expression levels of ALYREF correlated with mitochondrial function, and the elevated DNMT1 expression was associated with peptide cross-linking and humoral immunity. These results provide promising insight into the roles of m5C genes in tumor energy-metabolism and protein synthesis. CONCLUSIONS: Collectively, the results indicate that m5C plays critical roles in HNSCC progression, and is also a potential HNSCC prognostic marker.

Interleukin-10 modified bone marrow mesenchymal stem cells prevent hypertrophic scar formation by inhibiting inflammation.

This study was performed to examine the effect of Interleukin-10 (IL-10) modified bone marrow mesenchymal stem cells (BMSCs) on hypertrophic scar formation on the rabbit ear hypertrophic scar model. Rabbit BMSCs were obtained by whole bone marrow adherence method and IL-10-modified BMSCs (IL-10BMSCs) were established by transfecting BMSCs with an adenovirus. We treated the rabbit ear hypertrophic scar with BMSCs and IL-10-BMSCs, then evaluated the area and measured the height of the hypertrophic scar, and detected expression using real-time PCR and western blot. Compared with wild type BMSCs, the proliferative capability of IL-10 modified BMSCs was significantly reduced, but the expression of IL-10 in IL-10-BMSCs was significantly increased. After treating with a local injection of BMSCs or IL-10-BMSCs in the rabbit ear hypertrophic scar, we found that the time of wound healing, the area and height of scar were all significantly reduced in the IL-10-BMSCs group when compared to those in the BMSCs group. Moreover, the expression of Collagen-I, α-SMA, TNF-α, IL-6 and IL-1ß mRNA, the number of CD45-positive cells, CD3-positive cells and ED-1-positive cells, and the expression of p-IKBα / IKBα, p-p65 / p65, p-JNK / JNK and p-c-JUN / c-JUN in the scar of the IL-10-BMSCs group were significantly lower than those in BMSCs group. IL-10 modified BMSCs prevented hypertrophic scar formation in the rabbit ear hypertrophic scar model, and the results suggest this could be due to the inhibition of inflammation by IL-10 modified BMSCs through the JNK / NF-κB pathway.

New strain of Pediococcus pentosaceus alleviates ethanol-induced liver injury by modulating the gut microbiota and short-chain fatty acid metabolism.

BACKGROUND: Intestinal dysbiosis has been shown to be associated with the pathogenesis of alcoholic liver disease (ALD), which includes changes in the microbiota composition and bacterial overgrowth, but an effective microbe-based therapy is lacking. Pediococcus pentosaceus (P. pentosaceus) CGMCC 7049 is a newly isolated strain of probiotic that has been shown to be resistant to ethanol and bile salts. However, further studies are needed to determine whether P. pentosaceus exerts a protective effect on ALD and to elucidate the potential mechanism. AIM: To evaluate the protective effect of the probiotic P. pentosaceus on ethanol-induced liver injury in mice. METHODS: A new ethanol-resistant strain of P. pentosaceus CGMCC 7049 was isolated from healthy adults in our laboratory. The chronic plus binge model of experimental ALD was established to evaluate the protective effects. Twenty-eight C57BL/6 mice were randomly divided into three groups: The control group received a pair-fed control diet and oral gavage with sterile phosphate buffered saline, the EtOH group received a ten-day Lieber-DeCarli diet containing 5% ethanol and oral gavage with phosphate buffered saline, and the P. pentosaceus group received a 5% ethanol Lieber-DeCarli diet but was treated with P. pentosaceus. One dose of isocaloric maltose dextrin or ethanol was administered by oral gavage on day 11, and the mice were sacrificed nine hours later. Blood and tissue samples (liver and gut) were harvested to evaluate gut barrier function and liver injury-related parameters. Fresh cecal contents were collected, gas chromatography-mass spectrometry was used to measure short-chain fatty acid (SCFA) concentrations, and the microbiota composition was analyzed using 16S rRNA gene sequencing. RESULTS: The P. pentosaceus treatment improved ethanol-induced liver injury, with lower alanine aminotransferase, aspartate transaminase and triglyceride levels and decreased neutrophil infiltration. These changes were accompanied by decreased levels of endotoxin and inflammatory cytokines, including interleukin-5, tumor necrosis factor-α, granulocyte colony-stimulating factor, keratinocyte-derived protein chemokine, macrophage inflammatory protein-1α and monocyte chemoattractant protein-1. Ethanol feeding resulted in intestinal dysbiosis and gut barrier disruption, increased relative abundance of potentially pathogenic Escherichia and Staphylococcus, and the depletion of SCFA-producing bacteria, such as Prevotella, Faecalibacterium, and Clostridium. In contrast, P. pentosaceus administration increased the microbial diversity, restored the relative abundance of Lactobacillus, Pediococcus, Prevotella, Clostridium and Akkermansia and increased propionic acid and butyric acid production by modifying SCFA-producing bacteria. Furthermore, the levels of the tight junction protein ZO-1, mucin proteins (mucin [MUC]-1, MUC-2 and MUC-4) and the antimicrobial peptide Reg3ß were increased after probiotic supplementation. CONCLUSION: Based on these results, the new strain of P. pentosaceus alleviated ethanol-induced liver injury by reversing gut microbiota dysbiosis, regulating intestinal SCFA metabolism, improving intestinal barrier function, and reducing circulating levels of endotoxin and proinflammatory cytokines and chemokines. Thus, this strain is a potential probiotic treatment for ALD.

The effects of a prior malignancy on the survival of patients with ovarian cancer: a population-based study.

Background: With the improvement in the prognostic outcomes of multiple malignancies, the population of cancer survivors is growing rapidly and is at higher risk of developing secondary ovarian cancer. However, the prevalence and clinical outcomes of prior cancer among newly diagnosed ovarian cancer patients remain unknown. Methods: Patients diagnosed with ovarian cancer between 2004 and 2015 were identified using the Surveillance, Epidemiology, and End Results database. Patients were divided into two groups based on whether there was a prior malignancy. A multivariate Cox regression analysis was used to calculate all-cause and ovarian-specific survival. Furthermore, we conducted subgroup survival analyses of patients stratified by previous cancer site to explore the associations between prior cancer site and survival outcomes. Results: A total of 52,182 patients with primary ovarian cancer were identified, and 3.6% (n=1,860) had a documented prior malignancy. In multivariate analyses, patients with prior malignancies had a worse all-cause and ovarian cancer-specific prognosis than those without. In subset analyses, patients with a history of thyroid cancer had a better all-cause and ovarian cancer-specific prognosis, and patients with prior colorectal, urinary system, skin, lung, haematologic and stomach cancers were at risk of decreased survival compared to that of patients without a prior cancer. Conclusions: Prior malignancy has an adverse impact on the survival of patients with ovarian cancer, and the impact on prognostic outcomes varies by different prior cancer sites. The inconsistent survival effects of previous malignancies should be considered in clinical trial design and recruitment.

The fiber metabolite butyrate reduces gp130 by targeting TRAF5 in colorectal cancer cells.

BACKGROUND: Dietary fiber is effective for colorectal cancer (CRC) treatment. Interleukin-6 (IL-6) and its adaptors are potential targets for CRC therapy. Butyrate, a metabolite of dietary fiber, is a new, highly safe type of targeted drug. METHODS: In this study, Cell Counting Kit-8 cell viability and wound healing assays, western blot analysis, immunofluorescence staining, and xenograft tumor mouse models were used to evaluate the anticancer effect of butyrate and its possible mechanism in vivo and in vitro. RESULTS: Dietary fiber and sodium butyrate (NaB) decreased CRC burden by decreasing IL-6 receptor gp130 and blocking IL-6/JAK2/STAT3 axis activation in vitro and in vivo. Furthermore, NaB reduced the gp130 protein level by regulating its degradation rate via targeting TRAF5. CONCLUSIONS: The fiber metabolite butyrate inhibits CRC development by reducing gp130 via TRAF5.

Administration of Bifidobacterium bifidum CGMCC 15068 modulates gut microbiota and metabolome in azoxymethane (AOM)/dextran sulphate sodium (DSS)-induced colitis-associated colon cancer (CAC) in mice.

The gut microbiota plays an important role in colorectal cancer (CRC), and the use of probiotics might be a promising intervention method. The aim of our study was to investigate the beneficial effect of Bifidobacterium bifidum CGMCC 15068 on an azoxymethane (AOM)/dextran sulphate sodium (DSS)-induced colitis-associated CRC (CAC) mouse model. CAC was induced by an intra-peritoneal injection of AOM (10 mg/kg) and three 7-day cycles of 2% DSS in drinking water with a 14-day recovery period between two consecutive DSS administrations. B. bifidum CGMCC 15068 (3 × 109 CFU/mL) was gavaged once daily during the recovery period. Then, the faecal microbial composition and metabolome were profiled using the 16S rRNA sequencing technology and gas chromatography-mass spectrometry (GC-MS), respectively. The administration of B. bifidum CGMCC 15068 attenuated tumourigenesis in the CAC mouse model. In addition, B. bifidum CGMCC 15068 pre-treatment increased the relative abundance of Akkermansia, Desulfovibrionaceae, Romboutsia, Turicibacter, Verrucomicrobiaceae, Ruminococcaceae_UCG_013, Lachnospiraceae_UCG_004, and Lactobacillus. Meanwhile, B. bifidum CGMCC 15068 altered metabolites involved in the citrate cycle (TCA cycle), glycolysis, butyrate metabolism, fatty acid biosynthesis, and galactose metabolism. Several significant correlations were identified between the differentially abundant microbes and metabolites. These findings supported the beneficial role of B. bifidum CGMCC 15068 in intestinal health by modulating dysbiosis and the gut metabolic profile. The manipulation of the gut microbial composition using probiotics might be a promising prevention strategy for CRC. Long-term and large-scale clinical trials are warranted for the potential clinical applications of this strategy in the future.