The Systemic Risk Factors for the Development of Infectious Keratitis after Penetrating Keratoplasty: A Population-Based Cohort Study.

Penetrating keratoplasty (PK) is a corneal surgery that is employed to repair the full-thickness corneal lesion. This study aimed to survey the possible systemic risk factors of infectious keratitis after penetrating keratoplasty (PK) via the Taiwan National Health Insurance Research Database (NHIRD). A retrospective case-control study was conducted, and 327 patients who received the PK were enrolled after exclusion. The main outcome was the development of infectious keratitis, and people were divided into those with infectious keratitis and those without the outcome. Cox proportional hazard regression was conducted to produce adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of specific demographic indexes and systemic diseases on infectious keratitis. There were 68 patients who developed infectious keratitis after the whole follow-up period. The diabetes mellitus (DM) (aHR: 1.440, 95% CI: 1.122-2.874, p = 0.0310) and chronic ischemic heart disease (aHR: 1.534, 95% CI: 1.259-3.464, p = 0.0273) groups demonstrated a significant association with infectious keratitis. The DM group also revealed significant influence on infectious keratitis development in all the subgroups (all p < 0.05). Nevertheless, the effect of chronic ischemic heart disease on infectious keratitis was only significant on those aged older than 60 years (p = 0.0094) and both sexes (both p < 0.05). In conclusion, the presence of DM and chronic ischemic heart disease are associated with infectious keratitis after PK. However, local risk factors for infectious keratitis developed in those receiving PK had not been evaluated.

Prognostic impact of caspase-8 mutation in oral cavity squamous cell carcinoma.

OBJECTIVE: Identifying the drive genes and inhibiting their significant signals were persistently the main concepts in cancer treatment. However, for oral cavity squamous cell carcinoma (OCSCC), the most influential genes for overall survival (OS) remain unclear. METHODS: A total of 120 OCSCC patients with corresponding pathologic specimens were collected in Taiwan. Whole-exome sequencing was done and the prognostic impact of each gene was analyzed. TCGA database was used to validate. RESULTS: The incidences of caspase-8 mutation were 22.1% and 10.9% in the Taiwan and TCGA cohort, respectively. In the Taiwan cohort, caspase-8 mutation was the most significant independent for OS with an adjusted hazard ratio (HR) ([95% CI]: 3.83 [1.84-7.99]). It was validated by the TCGA database (HR [95% CI]: 1.51 [1.00-2.29]). The 5-year OSs of the patients with or without caspase-8 mutation were 38.1% vs. 75.3% (p < 0.001) (HR [95% CI]: 3.264 [1.645-6.438]) in the Taiwan cohort, and 26.1% vs. 49.0% (p = 0.048) (1.513 [1.001-2.288]) in the TCGA cohorts, respectively. Caspase-8 mutation was also individually associated with poor prognosis for TNM stage I/II/III/IV, respectively. CASP8 R127* and R494*, defined as pathogenic mutations in ClinVar, were presented in both cohorts. CONCLUSIONS: Caspase-8 mutation was the most significant genetic alteration impacting prognosis.

L48H37, a curcumin analog, suppresses matrix metalloproteinase-9 expression and activity to hamper nasopharyngeal cancer cell migration.

OBJECTIVE: Metastatic disease is a major issue of treatment failure in nasopharyngeal carcinoma (NPC) patients and often linked to high mortality. L48H37, a synthetic analog of curcumin with augmented bioavailability over its parent compound, has demonstrated several oncostatic characteristics. This study was aimed to explore the anti-metastatic effect of L48H37 on NPC cancer cells and its underlying mechanism. METHODS: Cell viability was evaluated using MTT assay. Regulation of signaling pathways was elucidated by immunoblotting, and specific kinase inhibitors. RESULTS: In this study, we showed that L48H37 suppressed TPA-stimulated invasive and migratory capacities of NPC cell lines and gave rise to very little cytotoxic responses. Such anti-cancer effect of L48H37 was accompanied with attenuated expression levels and enzymatic activities of matrix metalloproteinase-9 (MMP-9), a pivotal mediator of metastatic processes. In addition, L48H37 interfered with TPA-induced JNK activation, and the treatment of L48H37 combined with a JNK antagonist demonstrated a synergistic effect on restraining TPA-stimulated MMP-9 activity and migration events in NPC cells. CONCLUSIONS: Our results revealed that L48H37 impeded the invasive potential of NPC cells via impairment of MMP-9 function and abundance, highlighting possible complementary therapies using curcumin or its effective analogs to manage NPC dissemination.

Association of long noncoding RNA GAS5 gene polymorphism with progression of diabetic kidney disease.

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes, whose complex etiology involves a genetic component. Growth arrest-specific 5 (GAS5), a long noncoding RNA (lncRNA) gene, has been recently shown to regulate renal fibrosis. Here, we aimed to explore the potential role of GAS5 gene polymorphisms in the predisposition to DKD. One single-nucleotide (rs55829688) and one insertion/deletion polymorphism (rs145204276) of GAS5 gene were surveyed in 778 DKD cases and 788 DKD-free diabetic controls. We demonstrated that diabetic subjects who are heterozygous at rs55829688 (TC; AOR, 1.737; 95% CI, 1.028-2.937; p=0.039) are more susceptible to advanced DKD but not early-staged DKD, as compared to diabetic subjects who are homozygous for the major allele of rs55829688 (TT). Carriers of at least one minor allele (C) of rs55829688 (TC and CC; AOR, 1.317; 95% CI, 1.023-1.696; p=0.033) more frequently suffer from advanced DKD than do those homozygotes for the major allele (TT). Furthermore, in comparison to those who do not carry the minor allele of rs55829688 (TT), advanced DKD patients possessing at least one minor allele of rs55829688 (TC and CC) exhibited a lower glomerular filtration rate, revealing an impact of rs55829688 on renal co-morbidities of diabetes. In conclusion, our data indicate an association of GAS5 gene polymorphisms with the progression of DKD.

Functional variants of the pentraxin 3 gene are associated with the metastasis and progression of prostate cancer.

Age, ethnic background and genetic components have been identified as the established risks for prostate cancer (PCa). Pentraxin 3 (PTX3), originally identified as a pattern-recognition molecule for defence against infectious agents, has multiple functions in tissue repair and in the regulation of cancer-associated inflammation. In this study, we sought to investigate the impact of PTX3 gene variants on the development of PCa. Genotypes of four common single-nucleotide polymorphisms (SNPs) of PTX3 gene, including rs1840680, rs2305619, rs3816527 and rs2120243, were profiled among 705 PCa patients and 705 ethnicity-matched controls. In this study, we found that patients who carry at least one minor allele (C) of rs3816527 (AC and CC) tended to develop advanced forms of diseases (clinical large T stage, OR, 1.593, p = 0.032; pathologically-confirmed nodal spread, OR, 1.987, p = 0.011; metastatic tumour, OR, 3.896, p = 0.032) as compared with those homologous for the major allele (AA). Further stratification analysis showed that such association of rs3816527 with lymphatic and distal metastasis of PCa was accentuated in the younger age group (≤65 at diagnosis) but not seen in the older age group (>65 at diagnosis), suggesting an age-specific effect of PTX3 variants. Prediction of PTX3 protein structure implied that polymorphism may alter the quaternary organization and oligomerization of PTX3 protein. Moreover, our gene silencing experiments and survey of public datasets revealed that elevation of PTX3 levels in PCa was required for cell migration and associated with tumour metastasis. Our results highlight an association of PTX3 rs3816527 with the progression of PCa.

Genetic association of diabetic retinopathy with long noncoding RNA CDKN2B-AS1 gene polymorphism.

AIM: We attempted to test the influences of cyclin dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) gene polymorphisms on the susceptibility to Diabetic retinopathy (DR). METHODS: Five single-nucleotide polymorphisms (SNPs) of the CDKN2B-AS1 gene, rs564398, rs1333048, rs1537373, rs2151280, and rs8181047 were examined in 280 DR cases and 455 DR-free diabetic controls. RESULTS: Among these loci tested, we demonstrated that diabetic carriers of at least one polymorphic allele (G) of rs2151280 (AG and GG; AOR, 1.613; 95% CI, 1.040-2.501; p = 0.033) are more susceptible to proliferative DR but not non-proliferative DR. This genetic association with the risk of developing proliferative DR was further strengthened in homozygotes for the polymorphic allele (G) of rs2151280 (GG; AOR, 2.194; 95% CI, 1.117-4.308; p = 0.023). We detected a significant association of the polymorphic allele (G) of rs2151280 with proliferative DR patients (OR, 1.503; 95% CI, 1.112-2.033; p = 0.008) but not with the entire DR or non-proliferative DR group. Moreover, as compared to those who do not possess the polymorphic allele of rs2151280 (AA), DR patients carrying at least one polymorphic allele of rs2151280 (AG + GG) exhibited a lower glomerular filtration rate and HDL cholesterol level, revealing a promotive role of rs2151280 in renal and cardiovascular complications of diabetes. CONCLUSION: Taken together, our findings implicate an impact of CDKN2B-AS1 gene polymorphisms on the progression of DR.

Impact of LINC00312 gene polymorphism coupled with habitual risks on buccal mucosa cancer.

Oral squamous cell carcinoma (OSCC) is a prevalent and lethal malignancy with a diverse etiology. LINC00312 is a long intergenic non-coding RNA that functions as a signal hub to regulate the progression and treatment of head and neck cancer. The aim of this study was to evaluate the effect of LINC00312 single nucleotide polymorphisms (SNPs) on the development of oral cancer. Two LINC00312 SNPs, namely rs12497104 and rs164966, were investigated among 469 male patients with cancer of buccal mucosa and 1194 gender- and age-matched controls. No significant correlation was observed between these two SNPs and the occurrence of OSCC in the case and control groups. While assessing the clinicopathological features, carriers of at least one minor allele of rs164966 (GA and GG) were less prone to develop lymph node metastasis (adjusted odds ratio [AOR], 0.666; 95% confidence interval [CI], 0.447-0.991; p=0.045) in comparison with homozygous carriers of the major allele (AA). Subsequent stratifying surveys revealed that this genetic association with nodal spread was seen only in cases who habitually chewed betel quid (AOR, 0.616; 95% CI, 0.386-0.985; p=0.042) or smoked cigarettes (AOR, 0.612; 95% CI, 0.393-0.953; p=0.029), but undetected in cases free of these main behavioral risks. Our results indicate an interactivity of LINC00312 rs164966 with lifestyle-related risks on modulating OSCC progression.

Gut flora metagenomic analysis coupled with metabolic and deep immune profiling in chronic kidney disease.

BACKGROUND: Perturbation of gut microbiota has been linked to chronic kidney disease (CKD), which was correlated with a sophisticated milieu of metabolic and immune dysregulation. METHODS: To clarify the underlying host-microbe interaction in CKD, we performed multi-omics measurements, including systems-level gut microbiome, targeted serum metabolome and deep immunotyping, in a cohort of patients and non-CKD controls. RESULTS: Our analyses on functional profiles of the gut microbiome showed a decrease in the diversity and abundance of carbohydrate-active enzyme (CAZyme) genes but an increase in the abundance of antibiotic resistance, nitrogen cycling enzyme and virulence factor genes in CKD. Moreover, models generated using measurements of serum metabolites (amino acids, bile acids and short-chain fatty acids) or immunotypes were predictive of renal impairment but less so than many of the functional profiles derived from gut microbiota, with the CAZyme genes being the top-performing model to accurately predict the early stage of diseases. In addition, co-occurrence analyses revealed coordinated host-microbe relationships in CKD. Specifically, the highest fractions of significant correlations were identified with circulating metabolites by several taxonomic and functional profiles of gut microbiome, while immunotype features were moderately associated with the abundance of microbiome-encoded metabolic pathways and serum levels of amino acids (e.g. B cell cluster tryptophan and B cell cluster tryptophan metabolism). CONCLUSION: Overall, our multi-omics integration revealed several signatures of systems-level gut microbiome in robust associations with host-microbe co-metabolites and renal function, which may have aetiological and diagnostic implications in CKD.

IGF2BP2 promotes cell invasion and epithelial-mesenchymal transition through Src-mediated upregulation of EREG in oral cancer.

Insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), with high affinity to a myriad of RNA transcripts, has been shown to elicit promotive effects on tumorigenesis and metastasis. Yet, the functional involvement of IGF2BP2 in the progression of oral squamous cell carcinoma (OSCC) remains poorly understood. In this study, we showed that IGF2BP2 was upregulated in head and neck cancer, and high levels of IGF2BP2 were associated with poor survival. In in vitro experiments, IGF2BP2 promoted migration and invasion responses of OSCC cells. Moreover, we identified an IGF2BP2-regulated gene, EREG, which functioned as a modulator of OSCC invasion downstream of IGF2BP2. In addition, EREG expression triggered the epithelia-mesenchymal transition (EMT) in OSCC, as evidenced by the observation that knockdown of EREG weakened the induction of EMT mediated by IFG2BP2, and replenishment of EREG favored the EMT in IGF2BP2-depleted cells. Such IGF2BP2-regulated EREG expression, EMT, and cell invasion were dependent on the activation of FAK/Src signaling pathway. Collectively, these findings suggest that EREG, serving as a functional mediator of IGF2BP2-regulated EMT and cell invasion in oral cancer, may be implicated as a potential target for antimetastatic therapies.

HO-3867, a curcumin analog, elicits cell apoptosis and p38-mediated caspase activation in hepatocellular carcinoma.

HO-3867, a synthetic curcumin analog, has displayed various tumor-suppressive characteristics and improved bioabsorption over its parent compound. However, its influences on the development of hepatocellular carcinoma (HCC) are poorly defined. To address this, we tested the anticarcinogenic impact of HO-3867 and investigated the underlying mechanisms in fighting liver cancer. Our result demonstrated that HO-3867 reduced the viability of HCC cells, accompanied by promotion of cell cycle arrest at the sub-G1 stage and apoptotic responses. Furthermore, a distinctive profile of apoptosis associated proteins, encompassing elevated heme oxygenase-1 (HO-1) level and caspase activation, was detected in HO-3867-stimulated HCC cells. In addition, such HO-3867-mediated elevation in caspase activation was dampened by pharmacological suppression of p38 activities. Taken together, our findings unveiled that HO-3867 triggered cell cycle arrest and apoptotic events in liver cancer, involving a p38-mediated activation of caspase cascades. These data highlighted a usefulness of curcumin or its analogs on the management of hepatocarcinogenesis.

Interactive effects of CDKN2B-AS1 gene polymorphism and habitual risk factors on oral cancer.

Oral squamous cell carcinoma (OSCC) is a common malignant disease associated with a high mortality rate and heterogeneous disease aetiology. Cyclin dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1), is a long noncoding RNA that has been shown to act as a scaffold, sponge, or signal hub to promote carcinogenesis. Here, we attempted to assess the effect of CDKN2B-AS1 single-nucleotide polymorphisms (SNPs) on the susceptibility to OSCC. Five CDKN2B-AS1 SNPs, including rs564398, rs1333048, rs1537373, rs2151280 and rs8181047, were analysed in 1060 OSCC cases and 1183 cancer-free controls. No significant association of these five SNPs with the risk of developing OSCC was detected between the case and control group. However, while examining the clinical characteristics, patients bearing at least one minor allele of rs1333048 (CA and CC) were more inclined to develop late-stage (stage III/IV, adjusted OR, 1.480; 95% CI, 1.129-1.940; p = 0.005) and large-size (greater than 2 cm in the greatest dimension, adjusted OR, 1.347; 95% CI, 1.028-1.765; p = 0.031) tumours, as compared with those homologous for the major allele (AA). Further stratification analyses demonstrated that this genetic correlation with the advanced stage of disease was observed only in habitual betel quid chewers (adjusted OR, 1.480; 95% CI, 1.076-2.035; p = 0.016) or cigarette smokers (adjusted OR, 1.531; 95% CI, 1.136-2.063; p = 0.005) but not in patients who were not exposed to these major habitual risks. These data reveal an interactive effect of CDKN2B-AS1 rs1333048 with habitual exposure to behavioural risks on the progression of oral cancer.

Compositional Alteration of Gut Microbiota in Psoriasis Treated with IL-23 and IL-17 Inhibitors.

Alterations in the gut microbiota composition and their associated metabolic dysfunction exist in psoriasis. However, the impact of biologics on shaping gut microbiota is not well known. This study aimed to determine the association of gut microorganisms and microbiome-encoded metabolic pathways with the treatment in patients with psoriasis. A total of 48 patients with psoriasis, including 30 cases who received an IL-23 inhibitor (guselkumab) and 18 cases who received an IL-17 inhibitor (secukinumab or ixekizumab) were recruited. Longitudinal profiles of the gut microbiome were conducted by using 16S rRNA gene sequencing. The gut microbial compositions dynamically changed in psoriatic patients during a 24-week treatment. The relative abundance of individual taxa altered differently between patients receiving the IL-23 inhibitor and those receiving the IL-17 inhibitor. Functional prediction of the gut microbiome revealed microbial genes related to metabolism involving the biosynthesis of antibiotics and amino acids were differentially enriched between responders and non-responders receiving IL-17 inhibitors, as the abundance of the taurine and hypotaurine pathway was found to be augmented in responders treated with the IL-23 inhibitor. Our analyses showed a longitudinal shift in the gut microbiota in psoriatic patients after treatment. These taxonomic signatures and functional alterations of the gut microbiome could serve as potential biomarkers for the response to biologics treatment in psoriasis.

EF-24, a Curcumin Analog, Inhibits Cancer Cell Invasion in Human Nasopharyngeal Carcinoma through Transcriptional Suppression of Matrix Metalloproteinase-9 Gene Expression.

Cancer metastasis is a main cause of failure in treating subjects with nasopharyngeal carcinoma (NPC) and is frequently linked to high death rates. EF-24, an analog of curcumin, has exhibited many anti-cancer properties and enhanced bioavailability over curcumin. Nevertheless, the effects of EF-24 on the invasiveness of NPC are poorly understood. In this study, we demonstrated that EF-24 effectively inhibited TPA-induced motility and invasion responses of human NPC cells but elicited very limited cytotoxicity. In addition, the TPA-induced activity and expression of matrix metalloproteinase-9 (MMP-9), a crucial mediator of cancer dissemination, were found to be reduced in EF-24-treated cells. Our reporter assays revealed that such a reduction in MMP-9 expression by EF-24 was transcriptionally mediated by NF-κB via impeding its nuclear translocation. Further chromatin immunoprecipitation assays displayed that the EF-24 treatment decreased the TPA-induced interaction of NF-κB with the MMP-9 promoter in NPC cells. Moreover, EF-24 inhibited the activation of JNK in TPA-treated NPC cells, and the treatment of EF-24 together with a JNK inhibitor showed a synergistic effect on suppressing TPA-induced invasion responses and MMP-9 activities in NPC cells. Taken together, our data demonstrated that EF-24 restrained the invasiveness of NPC cells through the transcriptional suppression of MMP-9 gene expression, implicating the usefulness of curcumin or its analogs in controlling the spread of NPC.

Potential impact of ADAM-10 genetic variants with the clinical features of oral squamous cell carcinoma.

A disintegrin and metalloproteinase domain-containing protein 10 (ADAM-10) involves in the tumour progression, but the impacts of single-nucleotide polymorphism (SNP) of ADAM-10 on oral squamous cell carcinoma (OSCC) remain unclear. The aim of this study was to investigate the influence of SNP of ADAM-10 on the clinical features of OSCC in male Taiwanese. Five loci of ADAM-10 SNPs including rs653765 (C/T), rs2305421 (A/G), rs514049 (A/C), rs383902 (T/C) and rs2054096 (A/T) were genotyped by TaqMan allelic discrimination in 1138 OSCC patients and 1199 non-OSCC individuals. The ADAM-10 SNP rs2305421 GG (AOR: 1.399, 95% CI: 1.045-1.874, p = 0.024) and G allele (AOR: 1.170, 95% CI: 1.012-1.351, p = 0.034) illustrated a significantly higher genotypic frequencies in the OSCC group compared to the distribution of the ADAM-10 SNP rs2305421 AA wild type. In the subgroup analysis, the ADAM-10 SNP rs383902 TC+CC was significantly correlated to tumour size larger than T2 in betel quid chewer (AOR: 1.375, 95% CI: 1.010-1.872, p = 0.043), while the ADAM-10 SNP rs653765 CT+TT was significantly associated with tumour size larger than T2 in cigarette smoker (AOR: 1.346, 95% CI: 1.023-1.772, p = 0.034). The results from The Cancer Genome Atlas revealed highest ADAM-10 mRNA level in T2 stage of current smokers with head and neck squamous cell carcinoma (HNSCC). In conclusions, the ADAM-10 SNP rs2305421 G allele is associated with the presence of OSCC, and the ADAM-10 SNP rs383902 TC+CC and ADAM-10 SNP rs653765 CT+TT correlates to large tumour size in specific conditions.

Deep immune profiling of patients with renal impairment unveils distinct immunotypes associated with disease severity.

Background: Chronic kidney disease (CKD) is pathologically correlated with a sophisticated milieu of innate and adaptive immune dysregulation, but the underlying immunological disturbances remain poorly understood. Methods: To address this, we comprehensively interrogated cellular and soluble elements of the immune system by using high-dimensional flow cytometry to analyze peripheral blood mononuclear cells and performing cytokine/chemokine profiling of serum samples, respectively, in a cohort of 69 patients and 19 non-CKD controls. Results: Altered serum levels of several cytokines/chemokines were identified, among which concentrations of stem cell factor (SCF) were found to be elevated with the progression of CKD and inversely correlated with estimated glomerular filtration rate (eGFR). Deep immunophenotyping analyses reveal a global change in immune modulation associated with CKD severity. Specifically, a decrease in the subsets of CD56dim natural killer (NK) cells (KLRG-1+CD38+CD64+CD15+CD197+) and monocytes (KLRG-1+CD38+PD-1+) was detected in severe CKD compared with controls and mild CKD. In addition, comparisons between mild and severe CKD demonstrated a loss of a mature B cell population (PD-1+CD197+IgD+HLA-DR+) in the advanced stages of disease. Further, we identified immunophenotypic markers to discriminate mild CKD from the controls, among which the portion of CD38+ monocytes was of particular value in early diagnosis. Conclusions: Our data unveil severity-specific immunological signatures perturbed in CKD patients.

Histone deacetylation-regulated cell surface Siglec-7 expression promoted megakaryocytic maturation and enhanced platelet-like particle release.

BACKGROUND: Functioning as important hematologic cells for hemostasis, wound healing and immune defense platelets are produced before being released into the blood by cytoplasmic fragmentation at the end of the megakaryocyte (MK) differentiation, during which the involvement of both apoptosis and autophagy has been reported. Inhibitory sialic acid-binding immunoglobulin-like lectin-7 gene (Siglec-7) can be expressed on platelets and induce apoptosis on activation for uncharacterized function. OBJECTIVE: We aimed to investigate the regulatory mechanism for Siglec-7 activation along MK differentiation and its physiologic role during the MK maturation and platelet formation. METHODS: By using 2 well-established MK differentiation models (HEL and K562) and human primary CD34+ cell, we examined the upregulations of transcript and protein levels of Siglec-7 during MK differentiation, and the effect of Siglec-7 surface presence on MK differentiation and platelet-like particles (PLPs) release. RESULTS: We show that both transcripts and surface Siglec-7 were elevated during MK differentiation, and the histone deacetylase 1 (HDAC1) acted as a negative regulator for Siglec-7 activation. By increasing Siglec-7 surface expression, we found that increased presence of Siglec-7 not only enhanced MK maturation but also the release of PLPs by activating caspase 3-dependent signaling, as evidenced in the observation of more CD41, polyploidy, and platelet factor 4 transcript formations. CONCLUSION: In this study, we demonstrated that Siglec-7 activation was subjected to epigenetic regulation, and the resulting induced expression of surface Siglec-7 played an important regulatory role in promoting MK differentiation, maturation, and PLP formation.

Phenotype-specific signatures of systems-level gut microbiome associated with childhood airway allergies.

BACKGROUND: Perturbation of gut symbiosis has been linked to childhood allergic diseases. However, the underlying host-microbe interaction connected with specific phenotypes is poorly understood. METHODS: To address this, integrative analyses of stool metagenomic and metabolomic profiles associated with IgE reactions in 56 children with mite-sensitized airway allergies (25 with rhinitis and 31 with asthma) and 28 nonallergic healthy controls were conducted. RESULTS: We noted a decrease in the number and abundance of gut microbiome-encoded carbohydrate-active enzyme (CAZyme) genes, accompanied with a reduction in species richness, in the asthmatic gut microflora but not in that from allergic rhinitis. Such loss of CAZymes was consistent with the observation that a CAZyme-linked decrease in fecal butyrate was found in asthmatics and negatively correlated with mite-specific IgE responses. Different from the CAZymes, we demonstrated an increase in α diversity at the virulome levels in asthmatic gut microbiota and identified phenotype-specific variations of gut virulome. Moreover, use of fecal metagenomic and metabolomic signatures resulted in distinct effects on differentiating rhinitis and asthma from nonallergic healthy controls. CONCLUSION: Overall, our integrative analyses reveal several signatures of systems-level gut microbiome in robust associations with fecal metabolites and disease phenotypes, which may be of etiological and diagnostic implications in childhood airway allergies.

Oral Absorbent AST-120 Is Associated with Compositional and Functional Adaptations of Gut Microbiota and Modification of Serum Short and Medium-Chain Fatty Acids in Advanced CKD Patients.

Background: Animal studies have demonstrated that an oral absorbent AST-120 modulates gut environment. However, this phenomenon remains unclear in humans. This study aimed to assess the effects of AST-120 on the gut microbiota, related functional capability and metabolomic profiling in advanced chronic kidney diseases (CKD) patients. Methods: Eight advanced CKD patients with AST-120 (CKD+AST), 24 CKD patients (CKD), and 24 non-CKD controls were enrolled. We analyzed 16S rRNA pyrosequencing of feces and serum metabolomics profiling. Results: The CKD+AST group exhibited dispersed microbial community structure (ß-diversity, p < 0.001) compared to other groups. The relative abundances of at least 16 genera were significantly different amongst the three groups. Increases of fatty acids-producing bacteria (Clostridium_sensu_stricto_1, Ruminococcus_2, Eubacterium_nodatum and Phascolarctobacterium) associated with elevated serum acetic acid and octanoic acid levels were found in CKD+AST group. Analysis of microbial gene function indicated that pathway modules relevant to metabolisms of lipids, amino acids and carbohydrates were differentially enriched between CKD+AST and CKD groups. Specifically, enrichments of gene markers of the biosynthesis of fatty acids were noted in the CKD+AST group. Conclusion: Advanced CKD patients exhibited significant gut dysbiosis. AST-120 can partially restore the gut microbiota and intervenes in a possible signature of short- and medium-chain fatty acids metabolism.

Impact of carbonic anhydrase 9 gene polymorphism on the progression of colorectal cancer.

Colorectal cancer (CRC) is a commonly occurring tumor type worldwide, and its development is governed by a connection between genetic variations and acquired factors. Carbonic anhydrase 9 (CA9) is a cell-surface pH modulator that has been demonstrated to contribute to key steps of cancer progression. Here, we attempted to interrogate the effect of CA9 gene polymorphisms on the development of CRC in 470 cases and 470 gender- and age-matched non-cancer controls. We found that none of three CA9 single-nucleotide polymorphisms (SNPs) tested, including rs2071676, rs3829078, and rs1048638, was significantly associated with the occurrence of CRC. Yet, while evaluating the clinicopathological variables, cases carrying at least one reference allele (G allele) of rs2071676 tended to develop poorly differentiated tumors less frequently than those who are homozygous for the alternative allele (A allele) of rs2071676 (GA+GG vs AA; OR, 0.483; 95% CI, 0.242-0.963; p=0.036). Further stratification revealed that as compared to homozygous carriers of the alternative allele (AA), cases of colon cancer bearing at least one reference allele of rs2071676 (GA+GG) less frequently developed poorly differentiated tumors (OR, 0.449; 95% CI, 0.221-0.911; p=0.024) and lymphovascular invasion (OR, 0.570; 95% CI, 0.361-0.900; p=0.015). Such genetic effect was exclusively observed in colon cancer but not in rectal cancer. Our results indicate an anatomical site-specific impact of CA9 gene polymorphisms on modulating the progression of colorectal malignancies.

Gambogic Acid Induces HO-1 Expression and Cell Apoptosis through p38 Signaling in Oral Squamous Cell Carcinoma.

Gambogic acid (GA), a natural and bioactive compound from the gamboge resin, has been reported to exhibit many oncostatic activities against several types of malignancies. However, its effects on the progression of oral squamous cell carcinoma (OSCC) remain largely unexplored. To fill this gap, we investigated the anticancer role of GA and molecular mechanisms underlying GA's actions in combating oral cancer. We found that GA negatively regulated the viability of OSCC cells, involving induction of the sub-G1 phase and cell apoptosis. In addition, a specific signature of apoptotic proteome, such as upregulation of heme oxygenase-1 (HO-1) and activation of caspase cascades, was identified in GA-treated OSCC. Moreover, such induction of HO-1 expression and caspase cleavage by GA was significantly diminished through the pharmacological inhibition of p38 kinase. In conclusion, these results demonstrate that GA promotes cell apoptosis in OSCC, accompanied with the activation of a p38-dependent apoptotic pathway. Our findings provide potential avenues for the use of GA with high safety and therapeutic implications in restraining oral cancer.