Carbon dots as a promising therapeutic approach for combating cancer.

With advances in nanotechnology and the development of emerging therapeutic modalities, a surge in research on the use of nanomedicines for biomedical applications has occurred over the past three decades. Carbon dots (CDs) are new members of carbon-based nanomaterials that can be used in cancer treatment to reduce side effects of drugs and improve treatment efficiency, offering new medical opportunities for further research. Urged as such, we are encouraged to classify CDs-based cancer treatments, including photodynamic therapy (PDT), photothermal therapy (PTT), sonodynamic therapy (SDT), chemodynamic therapy (CDT), chemotherapy (CT), and synergistic therapy. The advantages of these approaches are summarized, as well as ways to improve certain shortcomings. Meanwhile, this review highlights the feasible practice of CDs in cancer treatment, which is further developed and widely used in the biomedical field.

Sensing performance and mechanism of carbon dots encapsulated into metal-organic frameworks.

Metal-organic frameworks (MOFs) can be combined with nanomaterials and the combined composites have excellent optical properties. Carbon dots (CDs) with tiny particle size, non-toxic and rich surface functional groups are novel fluorescent materials. Carbon dots@metal-organic frameworks (CDs@MOFs) are synthesized by encapsulating CDs into MOFs. CDs@MOFs are promising composites for the preparation of a new generation of fluorescence sensors, which combine the hybrid properties of MOFs and the special optical properties of CDs. Urged as such, we are encouraged to categorize according to the sensing mechanisms. These include fluorescence resonance energy transfer (FRET), aggregation-caused quenching (ACQ), static quenching, dynamic quenching, photo-induced electron transfer (PET), inner filter effect (IFE) and so on. Based on the above mechanisms, CDs@MOFs can specifically interact with target analytes to generate fluorescence quenching. This review covers the research progress of CDs@MOFs in recent five years (with 103 refs), synthetic design of CDs@MOFs and introduces the sensing mechanism. The current challenges and future research directions are discussed briefly. The sensing mechanism and applications of CDs@MOFs.

Self-quenching-resistant solid-state carbon dots for mechanism and applications.

Solid-state carbon dots (SCDs) have been widely investigated by scholars owing to their stability, environmental friendliness, and their good optical properties. The current studies on carbon dots (CDs) are mainly focused on the solutions of CDs, while the researches on SCDs are relatively few in comparison. Nowadays, the fabrication and design of high-performance SCDs have attracted much interest. However, due to resonance energy transfer and π-π interactions, CDs undergo aggregation-induced quenching (ACQ) phenomena. This poses an obstacle to the acquisition of SCDs and affects their luminescence performance. Publications of the past 5 years are reviewed on how to suppress the ACQ phenomenon and improve the fluorescence and phosphorescence emission of CDs (Ref. 87) and about the mechanism of achieving the luminescence of SCDs. Then, the applications of SCDs in the fields of luminescent devices, anti-counterfeiting, and detection are outlined. The concluding section analyzes the current challenges faced by SCDs and provides an outlook. Mechanism of photoluminescence from solid state carbon dots.

Carbon dots modified/prepared by supramolecular host molecules and their potential applications: A review.

Supramolecular host molecules are used as tools in the design of multifunctional nanoparticles for sensors, catalysts, biometric elements, etc. Combining with carbon dots (CDs) has excellent host-guest recognition properties and fluorescence characteristics, which can precisely capture and identify target analytes. Consequently, supramolecular host molecules-based CDs can significantly improve the detection performance of ions and molecules with different structures or intrinsic chemical properties. This currently responds to a wide range of analytes including metal cations, anions, organic compounds and other biomolecules, yielding fascinating achievements in the field of chemistry. Therefore, the present review summarizes outstanding supramolecular host molecules-based CDs reported in the past ten years. The focus is on elucidating the mechanisms, methodologies, advantages and disadvantages of modifying or preparing CDs with supramolecular host molecules. Current challenges encountered and outlooks are also be discussed.

The circadian gene NPAS2 is a novel prognostic biomarker for breast cancer.

Mounting evidence suggests that neuronal PAS domain protein 2 (NPAS2) and other circadian genes are involved in tumorigenesis and tumor growth, possibly through their control of cancer-related biologic pathways. A missense polymorphism in NPAS2 (Ala394Thr) has been shown to be associated with risk of human tumors including breast cancer. The current study further examined the prognostic significance of NPAS2 in breast cancer by genotyping the Ala394Thr polymorphism and measuring NPAS2 expression. DNA extracted from 348 breast cancer tissue samples was analyzed for NPAS2 genotype using the TaqMan allelic discrimination assay. Of these, 287 also had total RNA available for use in real-time PCR assays to determine NPAS2 expression. NPAS2 genotypes and expression levels were analyzed for associations with prognostic outcomes, as well as correlations with clinical characteristics. A high level of NPAS2 expression was strongly associated with improved disease free survival (AHR = 0.43, 95% CI: 0.21-0.86, P trend = 0.022) and overall survival (AHR = 0.42, 95% CI: 0.19-0.96, P trend = 0.036). In addition, there was a borderline, but nonsignificant association between the NPAS2 genotype corresponding to Thr394Thr and disease free survival (AHR = 1.82, 95% CI: 0.96-3.46). The Ala/Ala, Ala/Thr, and Thr/Thr genotypes were also differentially distributed by tumor severity, as measured by TNM classification (chi (2) (6df, N = 344) = 14.96, P = 0.020). These findings provide the first evidence suggesting prognostic significance of the circadian gene NPAS2 in breast cancer.

Phenotypic effects of the circadian gene Cryptochrome 2 on cancer-related pathways.

BACKGROUND: Circadian genes continue to gain attention as important transcriptional regulators with the potential to influence a variety of biological pathways, including many cancer-related processes. The core circadian gene cryptochrome 2 (CRY2) is essential for proper circadian timing, and is a key component of the negative arm of the circadian feedback loop. As such, aberrant expression of CRY2 may influence carcinogenic processes and thereby impact cancer susceptibility. METHODS: We silenced CRY2 in breast cancer cell lines (MCF-7) using small-interfering oligos (siRNA) and measured the impact of CRY2 knockdown on a number of cancer-relevant parameters. Cell cycle distribution, cell viability, and apoptotic response were measured in CRY2 knockdown (CRY2-) and normal (CRY2+) cell populations using flow cytometry in cells with and without exposure to a mutagen challenge. DNA damage accumulation was measured using the single cell gel electrophoresis (comet) assay, and damage was quantified using the Olive tail moment, which considers the amount and distance of DNA migration away from the nucleus, indicative of DNA strand breaks. Expression changes in cancer-relevant transcripts were measured by whole genome microarray. The Student's t-test was used for statistical comparisons, and P-values obtained from the microarray were adjusted for multiple comparisons using the false discovery rate correction, in order to obtain an adjusted Q-value for each observation. RESULTS: The comet assay results indicated that upon exposure to the same dose of chemical mutagen, CRY2- cells accumulate significantly more unrepaired DNA damage than CRY2+ cells (P = 0.040), suggesting that CRY2 may be important for DNA repair. In addition, a number of transcripts with relevance for DNA damage repair displayed altered expression following CRY2 silencing. These included BCCIP (Q = 0.002), BCL2 (Q = 0.049), CCND1 (Q = 0.009), CDKN1A (Q < 0.001), GADD45A (Q = 0.002), HERC5 (Q < 0.001), MCM5 (Q = 0.042), PPP1R15A (Q < 0.001), SUMO1 (Q < 0.001), and UBA1 (Q = 0.023). However, no significant influence of CRY2 knockdown on cell cycle distributions, cell cycle checkpoints in response to mutagen challenge, or apoptotic response was detected. CONCLUSIONS: In total, these data suggest a limited, but potentially important role for CRY2 in the regulation of DNA damage repair and the maintenance of genomic stability. Future investigations may focus on identifying the mechanisms by which CRY2 may regulate the expression of transcripts with known relevance for carcinogenesis.

Updates on Immunohistochemical and Molecular Markers in Selected Head and Neck Diagnostic Problems.

CONTEXT: - The head and neck regions have complex anatomic structures. They are not exempted from the rare occurrences of highly unusual, diagnostically challenging malignant neoplasms and mimickers. OBJECTIVE: - To review and update the utility of immunohistochemistry and molecular biomarkers and to pursue diagnostic accuracy on selected rare neoplasms, especially some poorly differentiated malignancies. DATA SOURCES: - Personal experience and information from the literature. CONCLUSIONS: - Head and neck tumors include neoplasms originating from heterogeneous tissue. Using the selected clinical cases, this review illustrates a continuous development of emerging molecular-genetic techniques to assist in the interpretation of uncommon, often poorly differentiated, highly malignant neoplasms. The diagnostic results are appropriately transmitted to the oncologists, radiation oncologists, and surgeons to create a coordinated plan of care for patients with these unusual disorders affecting the head and neck.

The Association between Ambient Air Pollution and Allergic Rhinitis: Further Epidemiological Evidence from Changchun, Northeastern China.

With the continuous rapid urbanization process over the last three decades, outdoors air pollution has become a progressively more serious public health hazard in China. To investigate the possible associations, lag effects and seasonal differences of urban air quality on respiratory health (allergic rhinitis) in Changchun, a city in Northeastern China, we carried out a time-series analysis of the incidents of allergic rhinitis (AR) from 2013 to 2015. Environmental monitoring showed that PM2.5 and PM10 were the major air pollutants in Changchun, followed by SO2, NO2 and O3. The results also demonstrated that the daily concentrations of air pollutants had obvious seasonal differences. PM10 had higher daily mean concentrations in spring (May, dust storms), autumn (October, straw burning) and winter (November to April, coal burning). The mean daily number of outpatient AR visits in the warm season was higher than in the cold season. The prevalence of allergic rhinitis was significantly associated with PM2.5, PM10, SO2 and NO2, and the increased mobility was 10.2% (95% CI, 5.5%-15.1%), 4.9% (95% CI, 0.8%-9.2%), 8.5% (95% CI, -1.8%-19.8%) and 11.1% (95% CI, 5.8%-16.5%) for exposure to each 1-Standard Deviation (1-SD) increase of pollutant, respectively. Weakly or no significant associations were observed for CO and O3. As for lag effects, the highest Relative Risks (RRs) of AR from SO2, NO2, PM10 and PM2.5 were on the same day, and the highest RR from CO was on day 4 (L4). The results also indicated that the concentration of air pollutants might contribute to the development of AR. To summarize, this study provides further evidence of the significant association between ambient particulate pollutants (PM2.5 and PM10, which are usually present in high concentrations) and the prevalence of respiratory effects (allergic rhinitis) in the city of Changchun, located in Northeastern China. Environmental control and public health strategies should be enforced to address this increasingly challenging problem.

20(s)-Protopanaxadiol (PPD) increases the radiotherapy sensitivity of laryngeal carcinoma.

Laryngeal carcinoma (LC) is one of the most prevalent malignant tumors in the head and neck area. Due to its high morbidity and mortality, LC poses a serious threat to human life and health. Even with surgical removal, some patients were not sensitive to radiotherapy or experienced transfer or recurrence. 20(s)-Protopanaxadiol (PPD), a natural product from Panax ginseng, has been reported to have cytotoxic effects against several cancer cell lines. However, whether it can improve the radiation sensitivity and the underlying mechanism of PPD's sensitization effect is still unknown. Herein, from in vitro and in vivo experiments, we found that the combination of PPD and radiation not only significantly inhibited proliferation and induced apoptosis, but also suppressed the tumor growth in mouse models. These findings confirmed the role of PPD in enhancing the sensitivity of radiotherapy. Moreover, our work showed that the expression levels of mTOR and its downstream effectors decreased remarkably after PPD addition when compared to radiation only. This result suggested that PPD's excellent synergistic effects with radiation might be associated with the down-regulation of the mTOR signaling pathway in Hep-2 cells.

Granulomatous Interstitial Nephritis Presenting as Hypercalcemia and Nephrolithiasis.

We report a case of acute kidney injury as the initial manifestation of sarcoidosis. A 55-year-old male was sent from his primary care physician's office with incidental lab findings significant for hypercalcemia and acute kidney injury with past medical history significant for nephrolithiasis. Initial treatment with intravenous hydration did not improve his condition. The renal biopsy subsequently revealed granulomatous interstitial nephritis (GIN). Treatment with the appropriate dose of glucocorticoids improved both the hypercalcemia and renal function. Our case demonstrates that renal limited GIN due to sarcoidosis, although a rare entity, can cause severe acute kidney injury and progressive renal failure unless promptly diagnosed and treated.

Interactions between MUC1 and p120 catenin regulate dynamic features of cell adhesion, motility, and metastasis.

The mechanisms by which MUC1 and p120 catenin contribute to progression of cancers from early transformation to metastasis are poorly understood. Here we show that p120 catenin ARM domains 1, 3-5, and 8 mediate interactions between p120 catenin and MUC1, and that these interactions modulate dynamic properties of cell adhesion, motility, and metastasis of pancreatic cancer cells. We also show that different isoforms of p120 catenin, when coexpressed with MUC1, create cells that exhibit distinct patterns of motility in culture (motility independent of cell adhesion, motility within a monolayer while exchanging contacts with other cells, and unified motility while maintaining static epithelial contacts) and patterns of metastasis. The results provide new insight into the dynamic interplay between cell adhesion and motility and the relationship of these to the metastatic process.

CLOCK in breast tumorigenesis: genetic, epigenetic, and transcriptional profiling analyses.

The transcription factors responsible for maintaining circadian rhythm influence a variety of biological processes. Recently, it has been suggested that the core circadian genes may play a role in breast tumorigenesis, possibly by influencing hormone regulation or other pathways relevant to cancer. To evaluate this hypothesis, we conducted a genetic and epigenetic association study, as well as a transcriptional profiling array and a pathway-based network analysis. We report significant correlations between single nucleotide polymorphisms associated with the central circadian regulator CLOCK and breast cancer risk, with apparent effect modification by estrogen receptor/progesterone receptor status. We also found that hypermethylation in the CLOCK promoter reduced the risk of breast cancer, and lower levels of CLOCK expression were documented in healthy controls relative to normal or tumor tissue from patients with breast cancer. Finally, we silenced CLOCK in vitro and performed a whole-genome expression microarray and pathway analysis, which identified a cancer-relevant network of transcripts with altered expression following CLOCK gene knockdown. Our findings support the hypothesis that circadian genes influence tumorigenesis, and identify a set of circadian gene variants as candidate breast cancer susceptibility biomarkers.

The core circadian gene Cryptochrome 2 influences breast cancer risk, possibly by mediating hormone signaling.

As transcriptional regulators, circadian genes have the potential to influence a variety of biological pathways, including many cancer-related processes. Cryptochrome 2 (CRY2) is essential for proper circadian timing and is a key component of the circadian regulatory feedback loop. Here, we report findings from genetic, epigenetic, loss-of-function, and transcriptional profiling analyses of CRY2 in breast cancer. Six single-nucleotide polymorphisms in CRY2 were identified for genotyping in a case-control population (n = 441 cases and n = 479 controls), and three single-nucleotide polymorphisms (rs11038689, rs7123390, and rs1401417) were significantly associated with postmenopausal breast cancer risk, with significant effect modification by menopausal status [dominant model for rs11038689: odds ratio (OR), 0.71; 95% confidence interval (95% CI), 0.51-0.99; P for trend = 0.028; homozygous variants for rs7123390: OR, 0.44; 95% CI, 0.22-0.86; P for trend = 0.028; and rs1401417: OR, 0.44; 95% CI, 0.21-0.92; P for trend = 0.017]. Interestingly, this association was only evident in women with estrogen and progesterone receptor (ER/PR)-negative breast tumors but not with ER/PR-positive tumors. Breast cancer patients also had significantly higher levels of CRY2 promoter methylation relative to controls, which is consistent with tissue array data showing lower levels of CRY2 expression in tumor tissue relative to adjacent normal tissue. Furthermore, in vitro analyses identified several breast cancer-relevant genes that displayed altered expression following CRY2 knockdown. These findings suggest a role for CRY2 in breast tumorigenesis and provide further evidence that the circadian system may be an important modulator of hormone-related cancer susceptibility.

Cancer-related transcriptional targets of the circadian gene NPAS2 identified by genome-wide ChIP-on-chip analysis.

The transcription factor NPAS2 is one of nine human core circadian genes that influence a variety of biological processes by regulating the 24-h circadian rhythm. Recently, it has been shown that NPAS2 is a risk biomarker in human cancers and plays a role in tumorigenesis by affecting cancer-related gene expression, and relevant biological pathways. However, it is difficult to study the biological involvement of NPAS2 in cancer development, as little is known about its direct transcriptional targets. The aim of the current study is to create a transcriptional profile of genes regulated by NPAS2, using a human binding ChIP-on-chip analysis of NPAS2 in MCF-7 cells. This genome-wide mapping approach identified 26 genes that contain potential NPAS2 binding regions. Subsequent real-time PCR assays confirmed 16 of these targets, and 9 of these genes (ARHGAP29, CDC25A, CDKN2AIP, CX3CL1, ELF4, GNAL, KDELR1, POU4F2, and THRA) have a known role in tumorigenesis. In addition, a networking analysis of these validated NPAS2 targets revealed that all nine genes, together with REN, are involved in a "Cancer, Cell cycle, Neurological Disease" network. These results report the first list of direct transcriptional targets of NPAS2 and will shed light on the role of circadian genes in tumorigenesis.

microRNA miR-196a-2 and breast cancer: a genetic and epigenetic association study and functional analysis.

Increasing evidence has suggested that microRNAs (miRNA) play an important role in tumorigenesis. As transcriptional regulators, altered miRNA expression may affect many cancer-related biological pathways, indicating that miRNAs can function as tumor suppressors and/or oncogenes. We first performed a genetic association analysis by screening genetic variants in 15 miRNA genes and detected that a common sequence variant in hsa-miR-196a-2 (rs11614913, C-->T) was significantly associated with decreased breast cancer risk (for homozygous variant: odds ratio, 0.44; 95% confidence interval, 0.28-0.70). Hypermethylation of a CpG island upstream (-700 bp) of the miR-196a-2 precursor was also associated with reduced breast cancer risk (odds ratio, 0.35; 95% confidence interval, 0.15-0.81). By delivering expression vectors containing either wild-type or mutant precursors of miR-196a-2 into breast cancer cells, we showed that this variant led to less efficient processing of the miRNA precursor to its mature form as well as diminished capacity to regulate target genes. A whole-genome expression microarray was done and a pathway-based analysis identified a cancer-relevant network formed by genes significantly altered following enforced expression of miR-196a-2. Mutagenesis analysis further showed that cell cycle response to mutagen challenge was significantly enhanced in cells treated with variant miR-196a-2 compared with cells treated with the wild-type. Taken together, our findings suggest that miR-196a-2 might have a potentially oncogenic role in breast tumorigenesis, and the functional genetic variant in its mature region could serve as a novel biomarker for breast cancer susceptibility.

Clock-cancer connection in non-Hodgkin's lymphoma: a genetic association study and pathway analysis of the circadian gene cryptochrome 2.

Circadian genes have the potential to influence a variety of cancer-related biological pathways, including immunoregulation, which may influence susceptibility to non-Hodgkin's lymphoma (NHL). However, few studies have examined the role of circadian genes in lymphomagenesis. The current study examined Cryptochrome 2 (CRY2), a core circadian gene and transcriptional repressor, as a potential circadian biomarker for NHL. We first performed genetic association analyses of tagging single nucleotide polymorphisms (SNP) in CRY2 and NHL risk using DNA samples from a population-based case-control study (n = 455 cases and 527 controls). Three SNPs were found to be significantly associated with risk of NHL when combining all subtypes [dbSNP IDs, odds ratios (ORs), and 95% confidence intervals: rs11038689, OR, 2.34 (1.28-4.27), P = 0.006; rs7123390, OR, 2.40 (1.39-4.13), P = 0.002; and rs1401417, OR, 2.97 (1.57-5.63, P = 0.001)]. Each of these associations remained significant when restricting the analysis to B-cell cases and when further restricting to follicular lymphomas. An analysis of CRY2 diplotypes confirmed these significant findings. To further determine the functional effect of CRY2, we silenced the gene in vitro and performed a whole genome expression microarray. A pathway-based analysis showed that genes significantly altered by CRY2 knockdown formed networks associated with immune response and hematologic system development. In addition, these genes were predicted to have significant effects on several disease processes, including cancer (B-H P = 3.75E(-9)) and hematologic disease (B-H P = 8.01E(-8)). In conclusion, both genetic association and functional analyses suggest that the circadian gene CRY2 may play an important role in NHL development.

Loss of fibulin-2 expression is associated with breast cancer progression.

Fibulin-2, an extracellular matrix protein expressed by normal epithelia, was found to be down-regulated in several breast cancer cell lines. Fibulin-2 protein expression was also decreased in breast cancer tissue samples as evaluated by immunohistochemistry. Reintroduction of Fibulin-2 into breast cancer cell lines that do not express Fibulin-2 reduced cancer cell motility and invasion in vitro but had no effect on cell growth and adhesion properties. Together with evidence that Fibulin-2 contributes to wound healing and inhibits smooth muscle cell migration, our findings suggest that loss of Fibulin-2 expression may facilitate migration and invasion in breast cancer.