Most cases of oral squamous cell carcinoma (OSCC) develop from visible oral potentially malignant disorders (OPMDs). The latter exhibit heterogeneous subtypes with different transformation ...potentials, complicating the early detection of OSCC during routine visual oral cancer screenings. To develop clinically applicable biomarkers, we collected saliva samples from 96 healthy controls, 103 low-risk OPMDs, 130 high-risk OPMDs, and 131 OSCC subjects. These individuals were enrolled in Taiwan’s Oral Cancer Screening Program. We identified 302 protein biomarkers reported in the literature and/or through in-house studies and prioritized 49 proteins for quantification in the saliva samples using multiple reaction monitoring-MS. Twenty-eight proteins were successfully quantified with high confidence. The quantification data from non-OSCC subjects (healthy controls + low-risk OPMDs) and OSCC subjects in the training set were subjected to classification and regression tree analyses, through which we generated a four-protein panel consisting of MMP1, KNG1, ANXA2, and HSPA5. A risk-score scheme was established, and the panel showed high sensitivity (87.5%) and specificity (80.5%) in the test set to distinguish OSCC samples from non-OSCC samples. The risk score >0.4 detected 84% (42/50) of the stage I OSCCs and a significant portion (42%) of the high-risk OPMDs. Moreover, among 88 high-risk OPMD patients with available follow-up results, 18 developed OSCC within 5 y; of them, 77.8% (14/18) had risk scores >0.4. Our four-protein panel may therefore offer a clinically effective tool for detecting OSCC and monitoring high-risk OPMDs through a readily available biofluid.
Objectives
This study aimed to investigate the association between salivary matrix metalloproteinase‐1 (MMP‐1) and clinicopathological parameters of oral cavity squamous cell carcinoma (OSCC) and ...compare the prognostic efficacy of salivary MMP‐1 and other established circulating markers for OSCC.
Methods
Saliva specimens from 479 OSCC subjects were examined using an enzyme‐linked immunosorbent assay. The area under the curve (AUC) values of salivary MMP‐1 and other markers were calculated, and survival analyses were conducted using Kaplan–Meier and multivariate regression methods.
Results
Salivary MMP‐1 showed good discrimination in predicting overall survival, with an AUC of 0.638, which was significantly higher than that of albumin (0.530, p = .021) and Charlson comorbidity index (0.568, p = .048) and comparable with neutrophil‐to‐lymphocyte ratio (0.620, p = .987), platelet‐to‐lymphocyte ratio (0.575, p = .125), and squamous cell carcinoma antigen (0.609, p = .605). Elevated levels of salivary MMP‐1 were significantly associated with higher pT classification, pN classification, overall pathological stage, positive extranodal extension, tumor differentiation, positive lymphovascular invasion, positive perineural invasion, and tumor depth (p all <.05). Multivariate analyses indicated that a higher level of salivary MMP‐1 (≥2060.0 pg/mL) was an independent predictive factor of poorer overall survival (adjusted hazard ratio: 1.421 95% confidential interval: 1.014–1.989, p = .041).
Conclusion
The study found that the salivary MMP‐1 level was significantly associated with many adverse clinicopathological parameters of OSCC. In OSCC, it was found to have superior efficacy in predicting prognosis and was an independent prognostic factor of post‐treatment outcome.
Level of evidence
3.
Salivary MMP‐1 showed a significantly higher AUC than albumin and CCI and a higher or comparable AUC to the NLR, the PLR, and SCCA in predicting overall survival in OSCC patients. The study also indicates that patients with high levels of salivary MMP‐1 have poorer prognosis in terms of OS and DSS. Overall, these findings may facilitate development of a noninvasive and user‐friendly salivary detection tool for OSCC treatment.
The hidden structure of human enamel Beniash, Elia; Stifler, Cayla A; Sun, Chang-Yu ...
Nature communications,
09/2019, Volume:
10, Issue:
1
Journal Article
Peer reviewed
Open access
Enamel is the hardest and most resilient tissue in the human body. Enamel includes morphologically aligned, parallel, ∼50 nm wide, microns-long nanocrystals, bundled either into 5-μm-wide rods or ...their space-filling interrod. The orientation of enamel crystals, however, is poorly understood. Here we show that the crystalline c-axes are homogenously oriented in interrod crystals across most of the enamel layer thickness. Within each rod crystals are not co-oriented with one another or with the long axis of the rod, as previously assumed: the c-axes of adjacent nanocrystals are most frequently mis-oriented by 1°-30°, and this orientation within each rod gradually changes, with an overall angle spread that is never zero, but varies between 30°-90° within one rod. Molecular dynamics simulations demonstrate that the observed mis-orientations of adjacent crystals induce crack deflection. This toughening mechanism contributes to the unique resilience of enamel, which lasts a lifetime under extreme physical and chemical challenges.
Conjugated polymers (CPs) have recently gained increasing attention as photocatalysts for sunlight-driven hydrogen evolution. However, they suffer from insufficient electron output sites and poor ...solubility in organic solvents, severely limiting their photocatalytic performance and applicability. Herein, solution-processable all-acceptor (A
-A
)-type CPs based on sulfide-oxidized ladder-type heteroarene are synthesized. A
-A
-type CPs showed upsurging efficiency improvements by two to three orders of magnitude, compared to their donor-acceptor -type CP counterparts. Furthermore, by seawater splitting, PBDTTTSOS exhibited an apparent quantum yield of 18.9% to 14.8% at 500 to 550 nm. More importantly, PBDTTTSOS achieved an excellent hydrogen evolution rate of 35.7 mmol h
g
and 150.7 mmol h
m
in the thin-film state, which is among the highest efficiencies in thin film polymer photocatalysts to date. This work provides a novel strategy for designing polymer photocatalysts with high efficiency and broad applicability.
Acute kidney injury (AKI) is a common complication of acute myocardial infarction (AMI), and is associated with adverse outcomes. The study aimed to identify a miRNA signature for the early diagnosis ...of post-AMI AKI.
A total of 108 patients admitted to a coronary care unit (CCU) were divided into four subgroups: AMI
AKI
, AMI
AKI
, AMI
AKI
, and AMI
AKI
. Thirty-six miRNA candidates were selected based on an extensive literature review. Real-time quantitative RT-PCR analysis was used to determine the expression levels of these miRNAs in the serum collected on the day of CCU admittance. TargetScan 7.1 and miRDB databases were used for target prediction and Metacore 6.13 was used for pathway analysis.
Through a stepwise selection based on abundance, hemolytic effect and differential expression between four groups, 9 miRNAs were found to have significantly differential expression levels as potential biomarkers for post-AMI AKI specifically. Noticeably, the expression levels of miR-24, miR-23a and miR-145 were significantly down-regulated in AMI
AKI
patients compared to those in AMI
AKI
patients. Combination of the three miRNAs as a panel showed the best performance in the early detection of AKI following AMI (AUC = 0.853, sensitivity 95.65%), compared to the analysis of serum neutrophil gelatinase-associated lipocalin (AUC = 0.735, sensitivity 63.16%). Furthermore, bioinformatic analysis indicated that these three miRNAs regulate the transforming growth factor beta signaling pathway and involve in apoptosis and fibrosis in AKI.
For the first time, this study identify a unique circulating miRNA signature (miR-24-3p, miR-23a-3p, miR-145-5p) that can potentially early detect AKI following AMI and may be involved in renal injury and fibrosis in post-AMI AKI pathogenesis.
Mice are widely used as experimental models for gut microbiome (GM) studies, yet the majority of mouse GM members remain uncharacterized. Here, we report the construction of a mouse gut microbial ...biobank (mGMB) that contains 126 species, represented by 244 strains that have been deposited in the China General Microorganism Culture Collection. We sequence and phenotypically characterize 77 potential new species and propose their nomenclatures. The mGMB includes 22 and 17 species that are significantly enriched in ob/ob and wild-type C57BL/6J mouse cecal samples, respectively. The genomes of the 126 species in the mGMB cover 52% of the metagenomic nonredundant gene catalog (sequence identity ≥ 60%) and represent 93-95% of the KEGG-Orthology-annotated functions of the sampled mouse GMs. The microbial and genome data assembled in the mGMB enlarges the taxonomic characterization of mouse GMs and represents a useful resource for studies of host-microbe interactions and of GM functions associated with host health and diseases.
Virus-encoded microRNAs (miRNAs) have been shown to regulate a variety of biological processes involved in viral infection and viral-associated pathogenesis. Epstein-Barr virus (EBV) is a herpesvirus ...implicated in nasopharyngeal carcinoma (NPC) and other human malignancies. EBV-encoded miRNAs were among the first group of viral miRNAs identified. To understand the roles of EBV miRNAs in the pathogenesis of NPC, we utilized deep sequencing technology to characterize the EBV miRNA transcriptome in clinical NPC tissues. We obtained more than 110,000 sequence reads in NPC samples and identified 44 EBV BART miRNAs, including four new mature miRNAs derived from previously identified BART miRNA precursor hairpins. Further analysis revealed extensive sequence variations (isomiRs) of EBV miRNAs, including terminal isomiRs at both the 5' and 3' ends and nucleotide variants. Analysis of EBV genomic sequences indicated that the majority of EBV miRNA nucleotide variants resulted from post-transcriptional modifications. Read counts of individual EBV miRNA in NPC tissue spanned from a few reads to approximately 18,000 reads, confirming the wide expression range of EBV miRNAs. Several EBV miRNAs were expressed at levels similar to highly abundant human miRNAs. Sequence analysis revealed that most of the highly abundant EBV miRNAs share their seed sequences (nucleotides 2-7) with human miRNAs, suggesting that seed sequence content may be an important factor underlying the differential accumulation of BART miRNAs. Interestingly, many of these human miRNAs have been found to be dysregulated in human malignancies, including NPC. These observations not only provide a potential linkage between EBV miRNAs and human malignancy but also suggest a highly coordinated mechanism through which EBV miRNAs may mimic or compete with human miRNAs to affect cellular functions.
This study evaluated the effects of pretransplantation minimal residual disease (pre‐MRD) on outcomes of patients with acute lymphoblastic leukemia (ALL) who underwent unmanipulated haploidentical ...stem cell transplantation (haplo‐SCT). A retrospective study including 543 patients with ALL was performed. MRD was determined using multiparametric flow cytometry. Both in the entire cohort of patients and in subgroup cases with T‐ALL or B‐ALL, patients with positive pre‐MRD had a higher incidence of relapse (CIR) than those with negative pre‐MRD in MSDT settings (P < 0.01 for all). Landmark analysis at 6 months showed that MRD positivity was significantly and independently associated with inferior rates of relapse (HR, 1.908; P = 0.007), leukemia‐free survival (LFS) (HR, 1.559; P = 0.038), and OS (HR, 1.545; P = 0.049). The levels of pre‐MRD according to a logarithmic scale were also associated with leukemia relapse, LFS, and OS, except that cases with MRD <0.01% experienced comparable CIR and LFS to those with negative pre‐MRD. A risk score for CIR was developed using the variables pre‐MRD, disease status, and immunophenotype of ALL. The CIR was 14%, 26%, and 59% for subjects with scores of 0, 1, and 2‐3, respectively (P < 0.001). Three‐year LFS was 75%, 64%, and 42%, respectively (P < 0.001). Multivariate analysis confirmed the association of the risk score with CIR and LFS. The results indicate that positive pre‐MRD, except for low level one (MRD < 0.01%), is associated with poor outcomes in patients with ALL who underwent unmanipulated haplo‐SCT.
Colorectal cancer (CRC) is one of the most common malignancies worldwide. Inflammation contributes to cancer development and inflammatory bowel disease is an important risk factor for CRC. The aim of ...this study is to assess whether a widely used probiotic
can modulate the NLRP3 inflammasome and protect against colitis and colitis-associated CRC. We studied the effect of heat-killed cells of
on NLRP3 inflammasome activation in THP-1-derived macrophages. Pretreatment of
or NLRP3 siRNA can inhibit NLRP3 inflammasome activation in macrophages in response to fecal content or commensal microbes,
or
, according to the reduction of caspase-1 activation and IL-1β maturation. Mechanistically,
attenuates the phagocytosis that is required for the full activation of the NLRP3 inflammasome. In in vivo mouse experiments,
can ameliorate the severity of intestinal inflammation and thereby protect mice from dextran sodium sulfate (DSS)-induced colitis and the formation of CRC in wild type mice. On the other hand,
cannot prevent DSS-induced colitis in NLRP3 knockout mice. Our findings indicate that application of the inactivated probiotic,
, may be a useful and safe strategy for attenuation of NLRP3-mediated colitis and inflammation-associated colon carcinogenesis.
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•A method was established for simultaneously determining 68 glucocorticoids.•Sixteen natural and synthetic glucocorticoids were first reported in river samples.•Concentrations of ...natural metabolites were up to 36 times those of cortisol itself.•Halogenated GCs are the main contributors to GC activities in the studied waters.•GCs could be used as potential indicators of sewage input.
Glucocorticoids (GCs) have been increasingly reported to have adverse effects on aquatic organisms, but the lack of comprehensive analytical methods for a broad number of GCs has limited the effective management of pollution by these molecules in surface and coastal waters. In this study, we developed an original analytical method for simultaneously monitoring 25 natural GCs, and 43 synthetic GCs (4 hydrocortisone types, 6 acetonide types, 8 betamethasone types, 14 halogenated esters, and 11 labile prodrug esters) in water samples. Of the river samples investigated, 15 natural and 25 synthetic compounds were detected with the concentrations ranging from 0.13 ng/L (11-epitetrahydrocortisol) to 433 ng/L (cortisone) and from 0.05 (clobetasol) to 94 ng/L (prednisolone), respectively. Thirteen natural metabolites of cortisol (CRL) were first detected, and their concentrations were up to 36 times higher than that of CRL. Hydrocortisone-type GCs were the dominant synthetic compounds (≤154 ng/L), followed by halogenated esters (≤81 ng/L), acetonide type GCs (≤57 ng/L), betamethasone type GCs (≤32 ng/L), and labile prodrug esters (≤22 ng/L). Considering the relative potencies for detected GCs compared to dexamethasone, halogenated esters predominantly contributed to the GC activities in the samples. Notably, this is the first report of the halogenated esters 11-oxo fluticasone propionate (OFP) and cloticasone propionate (CTP) in environmental waters. Untreated wastewater is the main source of GCs in the studied waters, and the concentration ratios between natural and synthetic GCs can be used as potential indicators of sewage input. Because of the high detected concentrations and bioactivity potency of halogenated GCs, they are the main contributors to GC activities in the studied waters, and deserved more study in the future.
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