Intracellular reactive oxygen species is involved in a wide variety of physiological and pathological processes. In this work, we have developed a new mitochondria-targeting probe (DPP-S) for ...superoxide anion detection with ratiometric fluorescence response. DPP-S exhibited an obvious color change from violet to orange along with a distinct fluorescence change with maximum emission peak from 652 to 545 nm in response to superoxide anion. The limit of detection of DPP-S for superoxide anion was calculated to be 20.5 nM. Imaging studies taken in MCF-7 and RAW264.7 cells showed that DPP-S could be employed as a ratiometric fluorescent probe for endogenous superoxide anion detection and imaging in living cells with a large emission shift. Furthermore, the colocalization study indicated that DPP-S can localize in mitochondria specifically. Finally, the fluorescent probe was successfully applied for superoxide anion imaging in mice.
A new diketopyrrolopyrrole-based fluorescent probe (DPP-AM) was designed and synthesized for ratiometric detection of esterase and for imaging of live and dead cells in different modes. DPP-AM showed ...red fluorescence because of the intramolecular charge transfer (ICT) process from the DPP moiety to the pyridinium cation and gave remarkable ratio changes (about 70 folds), with the fluorescence changing from red to yellow, after treating with esterase because of the broken ICT process. Besides, the detection limit of DPP-AM toward esterase in vitro was 9.51 × 10–5 U/mL. After pretreating with H2O2 and ultraviolet light radiation, the health status of TPC1 cells was successfully imaged. More importantly, DPP-AM showed yellow fluorescence in live cells and a red fluorescent signal in dead cells, indicating that DPP-AM has great potential applications for assessing esterase activity as well as for discriminating live and dead cells.
tRNA-derived small noncoding RNAs (sncRNAs) are mainly categorized into tRNA halves (tiRNAs) and fragments (tRFs). Biological functions of tiRNAs in human solid tumor are attracting more and more ...attention, but researches concerning the mechanisms in tiRNAs-mediated tumorigenesis are rarely. The direct regulatory relationship between tiRNAs and splicing-related proteins remain elusive.
Papillary thyroid carcinoma (PTC) associated tRNA fragments were screened by tRNA fragments deep sequencing and validated by qRT-PCR and Northern Blot in PTC tissues. The biological function of tRNA fragments were assessed by cell counting kit, transwells and subcutaneous transplantation tumor of nude mice. For mechanistic study, tRNA fragments pull-down, RNA immunoprecipitation, Western Blot, Immunofluorescence, Immunohistochemical staining were performed.
Herein, we have identified a 33 nt tiRNA-Gly significantly increases in papillary thyroid cancer (PTC) based on tRFs & tiRNAs sequencing. The ectopic expression of tiRNA-Gly promotes cell proliferation and migration, whereas down-regulation of tiRNA-Gly exhibits reverse effects. Mechanistic investigations reveal tiRNA-Gly directly bind the UHM domain of a splicing-related RNA-binding protein RBM17. The interaction with tiRNA-Gly could translocate RBM17 from cytoplasm into nucleus. In addition, tiRNA-Gly increases RBM17 protein expression via inhibiting its degradation in a ubiquitin/proteasome-dependent way. Moreover, RBM17 level in tiRNA-Gly high-expressing human PTC tissues is upregulated. In vivo mouse model shows that suppression of tiRNA-Gly decreases RBM17 expression. Importantly, tiRNA-Gly can induce exon 16 splicing of MAP4K4 mRNA leading to phosphorylation of downstream signaling pathway, which is RBM17 dependent.
Our study firstly illustrates tiRNA-Gly can directly bind to RBM17 and display oncogenic effect via RBM17-mediated alternative splicing. This fully novel model broadens our understanding of molecular mechanism in which tRNA fragment in tumor cells directly bind RNA binding protein and play a role in alternative splicing.
Background:
Recently, radioiodine refractory differentiated thyroid cancer (RR-DTC) has received increasing attention due to its poor prognosis. The roles of clinical, pathological, and molecular ...features in the development of RR-DTC remain controversial and require additional investigation. This study aimed to evaluate the association between these risk factors and the occurrence of RR-DTC.
Methods:
We performed a systematic search for relevant literature following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) in PubMed, EMBASE, Medline, SCOPUS, and Web of Science up to the July 15, 2020. Observational studies that investigated the risk factors for RR-DTC were included. Fixed- or random-effects models were used to calculate pooled odds ratios (ORs) or mean differences (MD) with corresponding 95% confidence intervals.
Results:
We included 13 eligible studies incorporating 1,431 cases, of which 603 were patients with RR-DTC. The pooled analysis indicated that four parameters significantly increased the risk of RR-DTC: extrathyroidal extension (ETE) (OR: 2.28, 95% CI: 1.43–3.64,
I
2
= 14%),
BRAF
V
600
E
mutation (OR: 3.60, 95% CI: 1.74–7.46,
I
2
= 69%),
TERT
promoter mutation (OR: 9.84, 95% CI: 3.60–26.89,
I
2
= 61%) and high-risk histological subtype (OR: 1.94, 95% CI: 1.15–3.27,
I
2
= 15%), including tall cell variant papillary thyroid carcinoma (PTC), sclerosing diffuse PTC, hobnail variant PTC, follicular thyroid carcinoma (FTC) (including Hürthle cell), and poorly differentiated thyroid carcinoma (PDTC). However, there was no statistical significance regarding sex, age, tumor size, multifocality, or lateral lymph node metastasis. Subgroup and sensitivity analyses were conducted to further confirm the robustness of the results.
Conclusions:
Histological subtype, ETE,
BRAF
V
600
E
mutation, and
TERT
promoter mutation could be considered clinicopathological factors and biomarkers. They could assist in risk stratification, prognostic prediction, and individual therapy options for RR-DTC.
Objects
To evaluate prognostic factors and treatment outcomes of primary squamous cell carcinoma in thyroid (PSCCTh) over the past decades using a large national database.
Methods
All patients ...diagnosed with PSCCTh between 1973 and 2015 were identified with the Surveillance, Epidemiology, and End Results Program (SEER) 18-registry database. Relevant clinical data were collected, and prognostic factors of overall survival (OS) and disease-specific survival (DSS) were analyzed.
Results
This cohort study included 242 patients, accounting for 0.12% of all primary thyroid carcinomas from 1973 to 2015 nationwide. Of the patients with PSCCTh, 75% were older than 60 years at diagnosis. Patient age older than 60 years (HR 2.242, 95% CI 1.367–3.676,
P
= 0.001) and a tumor size larger than or equal to 50 mm (HR 1.479, 95% CI 1.011–2.165,
P
= 0.044) were independent negative prognostic factors. The univariate analysis suggested that the morphological subtype (OS,
P
= 0.033; DSS,
P
= 0.048), clinical treatment modality (OS,
P
< 0.0001; DSS,
P
< 0.0001), and T stage (OS,
P
= 0.004; DSS,
P
= 0.001) were important predictive factors for OS and DSS. In contrast, gender, race, year of diagnosis, geographic location, N stage, and M stage were not prognostic factors.
Conclusions
PSCCTh is a rare malignancy with an aggressive nature and poor prognosis. Survival is predicted by the treatment modality, patient age, T stage, tumor size, and morphological subtypes. This study showed that early diagnosis and complete surgical resection plus adjuvant radiation therapy were associated with a better outcome.
Fluorescent biosensors with aggregation-induced emission (AIE) have received much attention in the field of bioimaging and therapeutic applications. Although the side chains of AIE sensors have ...important impacts on the optical performance, imaging and therapy, only a few studies were emphasized on side chain effects compared to the well-established fluorescent backbone systems. In this work, a series of turn-on near-infrared (NIR) pyridinium-functionalized dibenzo
a
,
c
phenazine salt fluorescent probes (
BD2C
/
BD8C
/
BD16C
) possessing ethyl, octyl and hexadecyl chains were designed and facilely synthesized, and the influence of the alkyl chain length on their optical properties, lipopolysaccharide (LPS) detection and singlet-oxygen quantum yield were systematically investigated. The homologs can exhibit both promising AIE properties and desirable large Stokes shift (
ca.
190 nm). Owing to the electrostatic interactions between the two oppositely charged species, the probe with pyridine salt of positive charge could efficiently aggregate with the negatively charged LPS. By reducing the alkyl chain length,
BD2C
toward LPS showed significant fluorescence enhancement with a relatively low detection limit (2.6 × 10
−8
M). Additionally, the singlet oxygen yield of
BD2C
also showed a significant improvement (70.6%) compared to
BD8C
and
BD16C
(30.7% and 30.2%, respectively). The amphiphilic
BD2C
bearing ethyl chain and positively charged pyridinium salt can embed into the bacterial membrane, thus increasing the membrane permeability and causing dark toxicity. Furthermore,
BD2C
can also serve as an effective antibacterial photosensitizer under 530 nm light irradiation by inducing reactive oxygen species (ROS) generation which is a rarely reported example to date.
A series of NIR fluorescent probes of dibenzophenazine pyridine salt with different alkyl chain were developed for the detection of LPS.
BD2C
with ethyl chain exhibited a significant improvement of the singlet oxygen yield and antibacterial property.
Abstract Fork-head box R2 (FOXR2), a member of FOX protein family, was reported to play important roles in the development and progression of cancers. However, the expression and function of FOXR2 in ...prostate cancer remain unclear. In this study, we investigated the role of FOXR2 in prostate cancer and cancer progression including the molecular mechanism that drives FOXR2-mediated oncogenesis. Our results showed that FOXR2 was overexpressed in prostate cancer cell lines. The in vitro experiments demonstrated that knockdown of FOXR2 significantly repressed the proliferation, migration and invasiveness of prostate cancer cells. Furthermore, the in vivo experiments indicated that knockdown of FOXR2 significantly attenuated prostate cancer growth. Finally, knockdown of FOXR2 significantly down-regulated the protein expression levels of β-catenin, cyclinD1 and c-Myc in DU-145 cells. Taken together, our results demonstrated for the first time that FOXR2 plays a critical role in cell proliferation and invasion, at least in part, through inhibiting the Wnt/β-catenin signaling pathway during prostate cancer progression. Thus, FOXR2 may be an attractive therapeutic target for the treatment of prostate cancer.
Long non-coding RNAs (lncRNAs) in immune cells play critical roles in tumor cell-immune cell interactions. This study aimed to characterize the landscape of tumor-infiltrating immune-related lncRNAs ...(Ti-lncRNAs) and reveal their correlations with prognoses and immunotherapy response in head and neck squamous cell carcinoma (HNSCC). We developed a computational model to identify Ti-lncRNAs in HNSCC and analyzed their associations with clinicopathological features, molecular alterations, and immunotherapy response. A signature of nine Ti-lncRNAs demonstrated an independent prognostic factor for both overall survival and disease-free survival among the cohorts from Fudan University Shanghai Cancer Center, The Cancer Genome Atlas, GSE41613, and GSE42743. The Ti-lncRNA signature scores in immune cells showed significant associations with
mutation,
mutation, and hypoxia. Inferior signature scores were enriched in patients with high levels of PDCD1 and CTLA4 and high expanded immune gene signature (IGS) scores, who displayed good response to PD-1 blockade in HNSCC. Consistently, superior clinical response emerged in melanoma patients with low signature scores undergoing anti-PD-1 therapy. Moreover, the Ti-lncRNA signature was a prognostic factor independent of PDCD1, CTLA4, and the expanded IGS score. In conclusion, tumor-infiltrating immune profiling identified a prognostic Ti-lncRNA signature indicative of clinical response to PD-1 blockade in HNSCC.
To identify a prognosis-related subtype of cancer-associated fibroblasts (CAFs) in head and neck squamous cell carcinoma (HNSCC) and comprehend its contributions to molecular characteristics, immune ...characteristics, and their potential benefits in immunotherapy and chemotherapy for HNSCC.
We performed single-cell RNA sequencing (scRNA-seq) analysis of CAFs from the samples of HNSCC patients derived from Gene Expression Omnibus (GEO), to identify the prognosis-related subtype of CAFs. CAFs were clustered into five subtypes, and a prognosis-related subtype was identified. Univariate and multivariate cox regression analyses were performed on the cohort selected from The Cancer Genome Atlas (TCGA) to determine signature construction, which was validated in GSE65858 and GSE42743. A prognostic signature based on 4 genes was constructed, which were derived from prognosis-related CAFs. The molecular characteristics, immune characteristics as well as the predicted chemosensitivity and immunotherapeutic response in the signature-defined subgroups were analyzed subsequently.
The patients with higher CAF scores correlated with poor survival outcomes. Additionally, a high CAF score correlated with lower infiltration levels of many immune cells including M1 macrophages, CD8
T cells, follicular T helper cells, monocytes, and naïve B cells. High CAF score also demonstrated different enrichment pathways, mutation genes and copy number variated genes. Furthermore, patients with high CAF scores showed lower sensitivity for chemotherapy and immunotherapy than those with low CAF scores.
The results of our study indicate the potential of the CAF signature as a biomarker for the prognosis of HNSCC patients. Furthermore, the signature could be a prospective therapeutic target in HNSCC.
Tumor protein D52 (TPD52) is a member of the TPD52-like protein family and plays different roles in various types of malignancies. However, its role in renal cell carcinoma (RCC) is still unclear. In ...this study, we investigated the role of TPD52 in RCC. The mechanism of TPD52 in RCC
was also investigated. Our data demonstrated that the expression levels of TPD52 in both mRNA and protein were significantly decreased in RCC cells. Overexpression of TPD52 inhibited proliferation, migration, and invasion with decreased epithelial-mesenchymal transition (EMT) phenotype
in RCC cells, as well as attenuated tumor growth in renal cancer xenografts. Mechanistically, overexpression of TPD52 significantly inhibited downregulated phosphorylation levels of PI3K and Akt in RCC cells. In conclusion, the present study demonstrated that TPD52 inhibited growth and metastasis
of RCC, at least in part, by suppressing the PI3K/Akt signaling pathway. Therefore, these findings suggest that TPD52 may be a promising therapeutic target for the treatment of human RCC.
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