miR-141-3p Enhanced Radiosensitivity of CRC Cells.

BACKGROUND: Colorectal cancer (CRC) is recognized as one of the frequently diagnosed malignancies, and numerous microRNAs (miRs) are identified to be active in CRC. OBJECTIVE: This work aimed to clarify the effect of miR-141-3p on the radiosensitivity of CRC cells. METHODS: Firstly, CRC cell lines were cultured and applied to construct radiation-resistant CRC cells via X-ray treatment. The expression levels of miR-141-3p and long non-coding RNA DLX6 antisense RNA 1 (lncRNA DLX6-AS1) in CRC cells were measured using real-time quantitative polymerase chain reaction. After transfection with miR-141-3p mimics and 24 h treatment with 6- MV X-ray (0, 2, 4, 6 Gy), the survival fraction (SF) and the colony formation ability of CRC cells were determined using the cell counting kit-8 and colony formation methods. The interactions between miR-141-3p and DLX6-AS1 were analyzed using the dual-luciferase assay. The impact of miR-141-3p on DLX6-AS1 stability was detected after adding actinomycin-D. The role of DLX6- AS1 in the radiosensitivity of CRC cells was explored by transfecting oe-DLX6-AS1 into radiation- resistant CRC cells overexpressing miR-141-3p. RESULTS: The relative expression levels of miR-141-3p were downregulated in CRC cells and further declined in radiation-resistant cells. Upregulation of miR-141-3p relative expression reduced SF and the colony formation ability while amplifying the radiosensitivity of radiation-resistant CRC cells. miR-141-3p directly bound to DLX6-AS1 to reduce DLX6-AS1 stability, and therefore downregulated DLX6-AS1 expression. DLX6-AS1 overexpression counteracted the role of miR- 141-3p overexpression in amplifying the radiosensitivity of radiation-resistant CRC cells. CONCLUSION: miR-141-3p binding to DLX6-AS1 significantly decreased DLX6-AS1 stability and expression, promoting the radiosensitivity of CRC cells.

TRAF inhibition drives cancer cell apoptosis and improves retinoic acid sensitivity in multiple cancers models.

TNF receptor-associated factors (TRAFs) are signaling adaptor proteins that play a crucial role in regulating cellular receptors' signaling transduction to downstream pathways and exert multifaceted roles in regulating signaling pathways, cell survival, and carcinogenesis. The 13-cis-retinoic acid (RA), an active metabolite of vitamin A, exhibits anti-cancer properties, but the development of retinoic acid resistance poses a challenge in clinical application. This study aimed to investigate the relationship between TRAFs and retinoic acid sensitivity in various cancers. Here, we revealed that TRAFs' expression varied significantly across The Cancer Genome Atlas (TCGA) cancer cohorts and human cancer cell lines. Additionally, inhibiting TRAF4, TRAF5, or TRAF6 improved retinoic acid sensitivity and reduced colony formation in ovarian cancer and melanoma cells. Mechanistically, knocking down TRAF4, TRAF5, or TRAF6 in retinoic acid-treated cancer cell lines increased the levels of procaspase 9 and induced cell apoptosis. Further in vivo studies using the SK-OV-3 and MeWo xenograft models confirmed the anti-tumor effects of TRAF knockdown combined with retinoic acid treatment. These findings support that combination therapy with retinoic acid and TRAF silencing may offer significant therapeutic advantages in treating melanoma and ovarian cancers.

High expression of KMT2D is a promising biomarker for poor gastric cancer prognosis.

OBJECTIVE: To investigate the expression of histone lysine N-methyltransferase 2D (KMT2D) in gastric cancer patients and its relationship with the prognosis. METHODS: A total of 126 gastric cancer patients admitted to Hubei Provincial Hospital of TCM from January 2014 to June 2017 were selected as the research subjects, and patients' clinical data were analyzed retrospectively. First, the KMT2D mRNA or protein expression in the patient's tissue was detected using quantitative real-time PCR or immunohistochemistry. Afterwards, the relationship between the KMT2D protein expression and the prognosis of patients was analyzed using a Kaplan-Meier curve. Also, the predictive value of the KMT2D mRNA and protein expression for the prognosis and death rate of gastric cancer patients was evaluated using a receiver operating characteristic curve. Finally, the risk factors for poor prognosis and death of the gastric cancer patients were analyzed using a Cox regression analysis. RESULTS: Overall, the KMT2D mRNA expression level and positive rate of protein expression in the gastric cancer tissues were significantly higher than that in paracancerous tissues (P<0.05). A positive expression of the KMT2D protein in gastric cancer tissues was correlated with the following factors in patients: age ≥60 years, tumor differentiation degree, TNM stage III-IV, lymph node metastasis, depth of invasion T3-T4, distant metastasis and high serum carbohydrate antigen 19-9 (CA19-9) levels (P<0.05). Also, the 5-year overall survival and progression-free survival of gastric cancer patients with a positive KMT2D expression were lower than those with negative KMT2D expressions (P<0.05). The resulting areas under the curve for predicting the prognosis and death of gastric cancer patients with the KMT2D mRNA and protein expression were 0.823 and 0.645, respectively. In addition, tumor maximum diameter >5 cm, poor differentiation, TNM stage III-IV, lymph node metastasis, high serum CA19-9 level, KMT2D mRNA expression ≥1.48 and KMT2D protein positive expression were risk factors affecting the prognosis and death of gastric cancer patients (P<0.05). CONCLUSION: KMT2D is highly expressed in gastric cancer tissue and it is expected to be a potential biomarker for predicting the poor prognosis of gastric cancer patients.

TRAF4 Silencing Induces Cell Apoptosis and Improves Retinoic Acid Sensitivity in Human Neuroblastoma.

Neuroblastoma (NB) is a pediatric malignancy that arises in the peripheral nervous system, and the prognosis in the high-risk group remains dismal, despite the breakthroughs in multidisciplinary treatments. The oral treatment with 13-cis-retinoic acid (RA) after high-dose chemotherapy and stem cell transplant has been proven to reduce the incidence of tumor relapse in children with high-risk neuroblastoma. However, many patients still have tumors relapsed following retinoid therapy, highlighting the need for the identification of resistant factors and the development of more effective treatments. Herein, we sought to investigate the potential oncogenic roles of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) family in neuroblastoma and explore the correlation between TRAFs and retinoic acid sensitivity. We discovered that all TRAFs were efficiently expressed in neuroblastoma, but TRAF4, in particular, was found to be strongly expressed. The high expression of TRAF4 was associated with a poor prognosis in human neuroblastoma. The inhibition of TRAF4, rather than other TRAFs, improved retinoic acid sensitivity in two human neuroblastoma cell lines, SH-SY5Y and SK-N-AS cells. Further in vitro studies indicated that TRAF4 suppression induced retinoic acid-induced cell apoptosis in neuroblastoma cells, probably by upregulating the expression of Caspase 9 and AP1 while downregulating Bcl-2, Survivin, and IRF-1. Notably, the improved anti-tumor effects from the combination of TRAF4 knockdown and retinoic acid were confirmed in vivo using the SK-N-AS human neuroblastoma xenograft model. In conclusion, the highly expressed TRAF4 might be implicated in developing resistance to retinoic acid treatment in neuroblastoma, and the combination therapy with retinoic acid and TRAF4 inhibition may offer significant therapeutic advantages in the treatment of relapsed neuroblastoma.

An ultrasensitive FRET-based fluorescent low molecular weight heparin nanoprobe for quantifying heparanase activity.

Heparanase (HPA) is a multifaceted endo-ß-glucuronidase, and its dysregulation facilitates cancer metastasis. Developing techniques for fast and sensitively monitoring HPA enzymatic activity is crucial for searching for molecular therapies targeting HPA. Herein, we developed a novel fluorescence resonance energy transfer (FRET)-based nanoprobe AuNCs-LMWH-AuNRs, with AuNCs@GSH-cys and AuNRs/end-NH2/side-SiO2 attached to the non-reducing terminus and reducing terminus of low molecular weight heparin (LMWH), respectively. AuNCs@GSH-cys exhibited an absolute quantum yield of 1.1%. The absorption spectra of AuNRs/end-NH2/side-SiO2 (825 nm for maximum longitudinal absorption) and the emission spectra of AuNCs@GSH-cys (824 nm for maximum emission) were precisely overlapping, further enhancing the efficiency of FRET. In the presence of HPA, the LMWH nanoprobe exhibited an ultrasensitive response with excitation/emission wavelength (lambda (ex) = 560 nm, lambda (em) = 824 nm). The probe presented a wide linear dynamic detection range (LDR) of 0.125 ng/µL - 0.01 µg/µL in vitro with a limit of detection (LODs) of 82.15 pM (0.43 pg/µL). The excellent selectivity and good fluorescence turn-on efficiency of the probe made it possible for one-step detection of cellular heparanase activity. High throughput screening of HPA inhibitors also can be accomplished using the highly efficient LMWH nanoprobe.

Macroeconomic conditions and health-related outcomes in the United States: A metropolitan and micropolitan statistical area-level analysis between 2004 and 2017.

We study the relationship between macroeconomic conditions and health in the United States using data from the Behavioral Risk Factor Surveillance System between 2004 and 2017. Unlike many existing studies that use state or county as the level of aggregation, our analysis uses a sample of metropolitan and micropolitan statistical areas. Our results suggest strong associations between worsening macroeconomic conditions and reduced access to care and health insurance coverage. While we do not detect any robust relationships between business cycles and health outcomes in the general population, we do find consistent evidence of worse self-reported health during economic downturns among minorities and less-educated individuals. In addition, there is some suggestive evidence of countercyclicality of healthier lifestyle choices. However, the findings for health behavior outcomes are not robust to adjusting for multiple hypothesis testing.

Pentachlorophenol inhibits CatSper function to compromise progesterone's action on human sperm.

Pentachlorophenol (PCP), a highly toxic contaminant of chlorophenols, is common in a variety of environments and presents serious risks to animal and human health. However, the reproductive toxicity and potential actions of PCP have not been investigated thoroughly, especially in humans. Here, human spermatozoa were used to evaluate the effect of PCP on cell function and to explore the underlying mechanisms. PCP had no substantive effects on sperm viability or motility, nor on the ability to penetrate viscous medium, sperm hyperactivation or spontaneous acrosome reactions. However, PCP significantly inhibited these properties induced by progesterone (P4). Consistent with the functional observations, although PCP itself did not affect the basal intracellular Ca2+ concentrations and CatSper current, PCP dose-dependently inhibited increases of intracellular Ca2+ concentrations caused by P4. In addition, the activation of CatSper induced by P4 was largely suppressed by PCP. This is the first report showing that PCP may serves as an antagonist of the P4 membrane receptor to interfere with Ca2+ signaling by compromising the action of P4 on regulating sperm function. These findings suggest that the reproductive toxicity of PCP should also be a matter of concern as a mammalian health risk.

The effects of paid sick leave on worker absenteeism and health care utilization.

We estimate the short-term effects of paid sick leave on worker absenteeism and health care utilization in the United States using data from the 2000-2013 Medical Expenditure Panel Survey. We use both parametric and matching-based difference-in-differences methods to account for nonrandom selection into jobs that offer paid sick leave and estimate the treatment effect separately for workers who gained and lost sick leave benefits. We find consistent evidence of increased absenteeism among female workers who gained paid sick leave but not for other groups. Estimates for office-based visits are mostly statistically insignificant and may not have a causal interpretation due to preexisting trends.

Aluminum-Enhanced Fluorescence of Cu8 Nanoclusters: An Effective Method for Sensitive Detection of Fluoride in Aqueous and Bioimaging.

Here, we report glutathione-protected water-soluble copper nanoclusters (Cu8 NCs) with excellent properties of high stability, large Stokes shift, and low toxicity. The molecular formula and structure of the Cu8 NCs were confirmed through good agreement between spectroscopic results and theoretical calculations. The origin of optical properties and chemical stability of the Cu8 NCs was determined through natural bond orbital analysis combined with time-dependent density functional theory calculations. It was found that the fluorescence emission and quantum yields of Cu8 NCs could be effectively enhanced by aluminum(III) ions (Al3+) through the aggregation-induced enhanced emission mechanism. On the basis of the strong reaction of Al3+ with F-, the enhanced fluorescence of the obtained Cu8 NC-Al3+ ensemble could be selectively turned off by fluoride ions (F-), achieving highly sensitive detection of F- in aqueous with a detection limit of 0.16 µM. Also, the fluorescence of Cu8 NC-Al3+ ensemble quenched by F- could be enhanced again upon binding additional Al3+. In addition, the proposed Cu8 NC-Al3+ ensemble with enhanced fluorescence was used for bioimaging in vitro and in vivo. These results indicated that Cu8 NCs are promising materials for sequential sensing and bioimaging in the future.

The effects of Medicaid expansion on labor market outcomes: Evidence from border counties.

This paper provides new empirical evidence on the employment and earning effects of the recent Medicaid expansion. Unlike most existing studies that use a conventional state and year fixed effects approach, our main identification strategy is based on the comparison of employment and wages in contiguous county-pairs in neighboring states (i.e., border counties) with different Medicaid expansion status. Using the 2008-2016 Quarterly Census of Employment and Wages, we estimate a set of distributed lag models in order to examine the dynamic effects of Medicaid expansion. Results from our preferred specification suggest a statistically significant decrease in total employment of 1.2% 1 year after the expansion of Medicaid. This translates into a 37% decrease in employment among newly eligible Medicaid enrollees under the strong assumption that Medicaid coverage did not crowd out private insurance coverage. We also find that this disemployment effect is transitory: 2 years after the Medicaid expansion employment returns to preexpansion levels. We do not find any statistically significant effect of the Medicaid expansion on wages at any point.

The health implications of unconventional natural gas development in Pennsylvania.

We investigate the health impacts of unconventional natural gas development of Marcellus shale in Pennsylvania between 2001 and 2013 by merging well permit data from the Pennsylvania Department of Environmental Protection with a database of all inpatient hospital admissions. After comparing changes in hospitalization rates over time for air pollution-sensitive diseases in counties with unconventional gas wells to changes in hospitalization rates in nonwell counties, we find a significant association between shale gas development and hospitalizations for pneumonia among the elderly, which is consistent with higher levels of air pollution resulting from unconventional natural gas development. We note that the lack of any detectable impact of shale gas development on younger populations may be due to unobserved factors contemporaneous with drilling, such as migration.

A mixed methods study of clinical information availability in obstetric triage and prenatal offices.

OBJECTIVE: To determine the effect of availability of clinical information from an integrated electronic health record system on pregnancy outcomes at the point of care. MATERIALS AND METHODS: We used provider interviews and surveys to evaluate the availability of pregnancy-related clinical information in ambulatory practices and the hospital, and applied multiple regression to determine whether greater clinical information availability is associated with improvements in pregnancy outcomes and changes in care processes. Our regression models are risk adjusted and include physician fixed effects to control for unobservable characteristics of physicians that are constant across patients and time. RESULTS: Making nonstress test results, blood pressure data, antenatal problem lists, and tubal sterilization requests from office records available to hospital-based providers is significantly associated with reductions in the likelihood of obstetric trauma and other adverse pregnancy outcomes. Better access to prenatal records also increases the probability of labor induction and decreases the probability of Cesarean section (C-section). Availability of lab test results and new diagnoses generated in the hospital at ambulatory offices is associated with fewer preterm births and low-birth-weight babies. DISCUSSION AND CONCLUSIONS: Increased availability of specific clinical information enables providers to deliver better care and improve outcomes, but some types of clinical data are more important than others. More available information does not always result from automated integration of electronic records, but rather from the availability of the source records. Providers depend upon information that they trust to be reliable, complete, consistent, and easily retrievable, even if this requires multiple interfaces.

Balanced multifilter banks for multiple description coding.

The parametrization for one kind of multifilter banks generating balanced multiwavelets is presented in this paper, in which two lowpass filters are flipping filters, and two highpass filters have linear phase. Based on these parametric expressions, some balanced multiwavelets and analysis-ready multiwavelets are constructed, which are symmetric, or antisymmetric. Moreover, on the basis of balanced multiwavelet transform, a new method of multiple description coding is given, and experiments show that this method works well. Compared with the traditional multiple description coding method, this method has low redundancy.

Balanced multiwavelets with interpolatory property.

Balanced multiwavelets with interpolatory property are discussed in this paper. This kind of multiwavelets can have a sampling property like Shannon's sampling theorem. It has been shown that the corresponding matrix-valued refinable mask has special structure, and an orthogonal multifilter bank {H(z),G(z)} can be reduced to a scalar valued conjugate quadrature filter (CQF) a(z) . But it does not mean that any scalar CQF can form a "good" multifilter bank which can generate a vector-valued refinable function with some degree of smoothness. In the context of balanced multiwavelets, we give the definition of transferring balance order, which a scalar CQF a(z) satisfies, to guarantee that the multiwavelet Ψ generated is balanced. On the basis of the parametrization of a scalar CQF with any length and conditions of transferring balance order, parametrization of multifilter banks which can generate interpolatory multiwavelet and interpolatory scaling function, is gotten. Moreover, some balanced interpolatory multiwavelets have been constructed. Interpolatory analysis-ready multiwavelets (armlets) are also discussed in this paper. It is known that conditions of armlets are easy to validate, compared with balanced multiwavelets. But it will be present that if the corresponding scaling function Φ is interpolatory, the multiwavelet Ψ is balanced of order n if and only if it is an armlet of order n. Finally, the application of balanced multiwavelets with interpolatory property in image processing is also discussed.