Enzalutamide and olaparib synergistically suppress castration-resistant prostate cancer progression by promoting apoptosis through inhibiting nonhomologous end joining pathway.

Recent studies revealed the relationship among homologous recombination repair (HRR), androgen receptor (AR), and poly(adenosine diphosphate-ribose) polymerase (PARP); however, the synergy between anti-androgen enzalutamide (ENZ) and PARP inhibitor olaparib (OLA) remains unclear. Here, we showed that the synergistic effect of ENZ and OLA significantly reduced proliferation and induced apoptosis in AR-positive prostate cancer cell lines. Next-generation sequencing followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed the significant effects of ENZ plus OLA on nonhomologous end joining (NHEJ) and apoptosis pathways. ENZ combined with OLA synergistically inhibited the NHEJ pathway by repressing DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and X-ray repair cross complementing 4 (XRCC4). Moreover, our data showed that ENZ could enhance the response of prostate cancer cells to the combination therapy by reversing the anti-apoptotic effect of OLA through the downregulation of anti-apoptotic gene insulin-like growth factor 1 receptor ( IGF1R ) and the upregulation of pro-apoptotic gene death-associated protein kinase 1 ( DAPK1 ). Collectively, our results suggested that ENZ combined with OLA can promote prostate cancer cell apoptosis by multiple pathways other than inducing HRR defects, providing evidence for the combined use of ENZ and OLA in prostate cancer regardless of HRR gene mutation status.

[Occurrence and Health Risk Assessment of Multiple Pesticides in Drinking Water Sources of Southeast China].

To elucidate the pollution characteristics and ecological risks of pesticide micro-pollutants in typical drinking water sources in Southeast China, the detection frequency, detection concentration, and risk quotient of each pesticide for three different trophic levels of organisms (green algae, daphnia, and fish) were analyzed for a total of 55 commonly used pesticides in 19 categories, including benzimidazoles, amides, triazoles, and organophosphates, in seven reservoirs in Southeast China. Among the 55 pesticides analyzed, two pesticides (carbendazim and acetochlor) had a detection frequency of 100%, and 12 pesticides had a detection frequency of 80% or more. The highest detection concentration was found for carbendazim (77.7 ng·L-1), followed by that of acetochlor (51.6 ng·L-1). The results of the risk assessment showed that most of the pesticides were at low risk in the target areas. For the three organisms, acetochlor was the risk-dominant pesticide for green algae, whereas carbendazim was the risk-dominant pesticide for fish and daphnia.

FOXA1 in prostate cancer.

Most prostate cancers initially respond to androgen deprivation therapy (ADT). With the long-term application of ADT, localized prostate cancer will progress to castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), and neuroendocrine prostate cancer (NEPC), and the transcriptional network shifted. Forkhead box protein A1 (FOXA1) may play a key role in this process through multiple mechanisms. To better understand the role of FOXA1 in prostate cancer, we review the interplay among FOXA1-targeted genes, modulators of FOXA1, and FOXA1 with a particular emphasis on androgen receptor (AR) function. Furthermore, we discuss the distinct role of FOXA1 mutations in prostate cancer and clinical significance of FOXA1. We summarize possible regulation pathways of FOXA1 in different stages of prostate cancer. We focus on links between FOXA1 and AR, which may play different roles in various types of prostate cancer. Finally, we discuss FOXA1 mutation and its clinical significance in prostate cancer. FOXA1 regulates the development of prostate cancer through various pathways, and it could be a biomarker for mCRPC and NEPC. Future efforts need to focus on mechanisms underlying mutation of FOXA1 in advanced prostate cancer. We believe that FOXA1 would be a prognostic marker and therapeutic target in prostate cancer.

PD-1/PD-L1 inhibitors-based treatment for advanced renal cell carcinoma: Mechanisms affecting efficacy and combination therapies.

With the widespread use of PD-1/PD-L1 monoclonal antibodies (mAbs) in the treatment of multiple malignant tumors, they were also gradually applied to advanced renal cell carcinoma (aRCC). Nowadays, multiple PD-1/PD-L1 mAbs, such as nivolumab, avelumab, and pembrolizumab, have achieved considerable efficacy in clinical trials. However, due to the primary, adaptive, and acquired resistance to these mAbs, the efficacy of this immunotherapy is not satisfactory. Theories also vary as to why the difference in efficacy occurs. The alterations of PD-L1 expression and the interference of cellular immunity may affect the efficacy. These mechanisms demand to be revealed to achieve a sustained and complete objective response in patients with aRCC. Tyrosine kinase inhibitors have been proven to have synergistic mechanisms with PD-1/PD-L1 mAb in the treatment of aRCC, and CTLA-4 mAb has been shown to have a non-redundant effect with PD-1/PD-L1 mAb to enhance efficacy. Although combinations with targeted agents or other checkpoint mAbs have yielded enhanced clinical outcomes in multiple clinical trials nowadays, the potential of PD-1/PD-L1 mAbs still has a large development space. More potential mechanisms that affect the efficacy demand to be developed and transformed into the clinical treatment of aRCC to search for possible combination regimens. We elucidate these mechanisms in RCC and present existing combination therapies applied in clinical trials. This may help physicians' select treatment options for patients with refractory kidney cancer.

[Accelerated Degradation of Aqueous Recalcitrant Iodinated Contrasting Media Using a UV/SO32- Advanced Reduction Process].

Based on the formation of free radical-hydrated electrons by the activation of sulfite (SO32-), the UV/SO32- process is an advanced reduction process that can reduce pollutants. This study investigated the degradation kinetics, mechanism, influencing factors, and degradation pathways of sodium diatrizoate (DTZ), an iodinated contrasting media, during the UV/SO32- process. The degradation kinetics of DTZ were well fitted by the pseudo-first-order model, the degradation rate of which was higher than that of UV only and UV/H2 O2. The degradation rate of DTZ during the UV/SO32- process was positively correlated with the initial SO32- concentration. Weakly alkaline and alkaline conditions promoted the degradation of DTZ, while organic matter inhibited degradation during the UV/SO32- process. The degradation mechanism included direct photolysis and free radical attack, whereby free radical attack played a more important role than direct photolysis. Sulfite radicals dominated DTZ degradation efficiency, and hydrated electrons controlled the deiodination efficiency. The degradation pathways of DTZ during the UV/SO32- process included substitution, decarboxylation-hydroxylation, and amide bond cleavage.

[Evaluation of Performance of an Aminated Rosin-based Resin for Adsorption of Norfloxacin from Aqueous Solutions].

An aminated rosin-based resin (ARBR) was synthesized as a novel environmentally-friendly adsorbent for removal of Norfloxacin (NOR) from aqueous solutions. Its features were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and surface area measurements (BET). The effects of resin dosage, pH, and ionic strength on the ARBR adsorption properties of NOR were investigated by batch experiments. Results showed that the NOR adsorption amounts increased with pH in the range from 2.0 to 6.0, but decreased at higher pH (8-10). The adsorption process of NOR followed a pseudo-second rate model and could be fitted to the Langmuir isotherm, with calculated maximum monolayer adsorption capacity of 30.29 mg·g-1 at pH 6.0 and 20℃. Thermodynamic calculations showed that the adsorption of NOR was a spontaneous and endothermic process and could be attributed to a combination of electrostatic interactions and hydrogen bonding. Furthermore, the adsorbed NOR on ARBR could be efficiently desorbed by 0.1 mol·L-1 HCl to regenerate the resin. After five adsorption-desorption recycles, ARBR had a stable adsorption performance and could be recycled. The adsorption performance is better than that of various commercial resins, and these research results contribute to the development of applications of rosin derivatives and their utilization in the environmental control of micro pollutants.

Bilateral blindness with secondary retinitis pigmentosa following postoperative docetaxel and platinum combination chemotherapy in primary small-cell carcinoma of the endometrium: An unusual case report and review of the literature.

Ocular toxicity is an uncommon complication of cytotoxic chemotherapy. Bilateral blindness with secondary retinitis pigmentosa (RP) following docetaxel and platinum combination chemotherapy at the recommended dose is extremely rare. The present study reports a case of advanced small-cell carcinoma (SCC) of the endometrium in a patient with diabetes mellitus type 2. The patient suffered from RP with a sharp decline in vision after the fourth course of postoperative docetaxel and platinum combination chemotherapy. Unfortunately, the patient developed bilateral blindness after another course of chemotherapy at a reduced dose. No tumor recurrence was observed during the 33 months of follow-up. A total of 35 cases of docetaxel- and/or platinum-induced retinal toxicity were found in the English literature and reviewed. The ischemic and electrophysiological hypotheses may have been implicated in the pathogenesis of ocular toxicity in the present case, particularly with the history of diabetes. Understanding the ocular side effects of this combination chemotherapy may assist gynecological oncologists and ophthalmologists with early recognition and timely intervention before blindness is established.

An in vitro and in vivo study on the synergistic effect and mechanism of itraconazole or voriconazole alone and in combination with tetrandrine against Aspergillus fumigatus.

In this study, we investigated the in vitro antifungal effects of itraconazole/voriconazole (ITR/VRC) alone and in combination with tetrandrine (TET) against 23 clinical isolates of A. fumigatus using a chequerboard microdilution method. The dynamic antifungal effects of TET with ITR/VRC against A. fumigatus were assessed in vivo using time-kill curves following systemic infection of mice with A. fumigatus. After treatment, efflux pump activity was determined by the efflux of rhodamine 6G (R6G). When ITR was combined with TET, ITR MICs were reduced from 0.125-32 to 0.0625-2 µg ml(-1), and TET MICs were reduced from 256-512 to 8-64 µg ml(-1). When VRC was combined with TET, VRC MICs were reduced from 0.125-2 to 0.03125-0.5 µg ml(-1), and TET MICs were reduced from 256-512 to 8-256 µg ml(-1). Time-kill curves revealed that A. fumigatus viability was reduced after treatment with ITR/VRC combined with TET versus ITR/VRC alone. ITR/VRC combined with TET significantly prolonged mouse survival and reduced kidney and brain tissue burdens versus ITR/VRC alone (P < 0.05). Moreover, TET inhibited R6G efflux of A. fumigatus. Thus, in vitro and in vivo, TET acted synergistically with ITR/VRC against A. fumigatus, and the synergistic mechanism was related to inhibition of the drug efflux pump.

[Comparative study on biological methane potential and methanogen biodiversity in the anaerobic digestion of excess sludge].

AP and DH excess sludge, sampled from AP and DH wastewater treatment plants respectively, were inoculated with their anaerobic sludge respectively and tested with biological methane potential (BMP) method. After the regression analysis with modified Gompertz and Michaelis-Menten model, it was found that although the maximum specific CH4 production rates of AP and DH anaerobic sludge were similar [74.21 and 51.99 mL x (g x d)(-1)], the half-saturation constants K(m) differed obviously (54098 and 19005 mg x L(-)), indicating DH anaerobic sludge exhibited a higher affinity for its excess sludge. At the end of both BMP tests, the concentrations of TSS and COD(T) decreased while the concentration of NH4(+)-N increased obviously, which were more significant at higher ratios of F/M. The T-RFLP analysis results were in accordance with BMP tests. After both BMP tests, the relative amount of diverse bacteria decreased while the relative amounts of Methanosaeta spp. (280 bps), Methanomicrobiaceae (80 bps) and RC-I (389 bps) increased obviously, which were more significant in DH-BMP test compared with AP-BMP.

Evaluation of rural wastewater treatment processes in a county of eastern China.

With the rapid urbanization and industrialization in China, wastewater treatment in rural areas has become an increasing national concern. The selection of appropriate treatment processes closely based on the actual local status is crucial for the prevention of water quality deterioration in rural areas of China. This study presents a full year survey on the performances of various rural wastewater treatment processes at a county level in eastern China including seven three-chamber septic tanks (ST), five micro-power biological facilities (MP), seven constructed wetlands (CW), three stabilization ponds (SP) and five centralized activated sludge treatment plants (AS). It was found that although ST could remove a notable portion of total suspended solids (TSS) and chemical oxygen demand (COD(Cr)), it was ineffective in reducing nutrients and pathogens. Reliability and stability analyses showed that the centralized AS and decentralized CW processes outperformed the SP and MP processes. There were obvious discrepancies between the mean design concentrations, which ensure that 95% of the effluents meet the discharge standards, and the actual effluent concentrations determined for each process. The expected compliance with the tentatively adopted second-grade discharge standards (GB 18918-2002) was unsatisfactory for most of the water quality parameters examined, indicating an urgent need to design more practical discharge standards for decentralized treatment processes. Based on an overall assessment of reliability, stability and cost-effectiveness, the centralized AS was suitable for densely populated towns while the decentralized CW was suitable for sparsely populated villages.

Analysis of vWF gene A1381T polymorphism in patients with coronary heart disease / 中国实验血液学杂志

This study was purposed to investigate the vWF gene A1381T polymorphism in patients with coronary heart disease (CHD). A case-control study was designed, including 104 continuously hospitalized patients with CHD, aging from 40 to 75 years (average 59) and 96 persons underwent physical examination in outpatient department as controls, aging from 39 to 70 years (average 56). The plasma vWF: Ag level of CHD patients and control persons was detected by ILISA. vWF gene A1381T polymorphism was analyzed by the polymerase chain reaction-restriction fragment length polymorphism and sequencing when it is necessary. The data were grouped by gender, blood group and/or genotype in CHD group and control groups. The difference of plasma vWF level between male and female was analyzed by independent sample t test; one way ANOVA was used to analyze the difference of vWF level between different blood group genotypes, while the factorial design ANOVA was used to test the difference of vWF level in plasma between A1381T genotype and/or ABO blood groups. χ(2) Crosstabs were used to test the CHD susceptibility. The results showed that the frequencies of GG genotype (wild type) of vWF gene A1381T polymorphism were 62.5% in CHD group and 67.7% in control group, and the frequencies of AG genotype (heterozygous variant) were 37.5% in CHD group and 32.3% in control group. χ(2) Crosstabs showed no significant correlation between vWF gene A1381T polymorphism (AG) and CHD (OR = 1.258, 95% CI = 0.702 - 2.255, χ(2) = 0.595, p = 0.440). The plasma vWF level in CHD group was statistically very higher than that in control group (p < 0.001), even though the relationship of vWF A1381T polymorphism (rs216311) and susceptibility of CHD in CHD group was not found. The plasma vWF level of AG or GG genotype was higher in CHD group than in control group (p < 0.001). The plasma vWF level of AG genotype was higher than that of GG in CHD group (p < 0.05), but not in control group. The plasma vWF of O blood group was lower than that of A, B and AB blood groups (p < 0.05), while among A, B, AB blood groups, the vWF level was not different (p > 0.05). Among O, A, B, AB blood groups in CHD group, vWF level was not different (p > 0.05). Although the two-way analysis of variance ANOVA showed no interaction of A1381T genotype and ABO blood groups on plasma vWF level, the plasma vWF level in AG mutant of vWF A1381T gene polymorphism with O blood group was higher than that of GG mutant (p = 0.023) in CHD group, not different in other blood groups. It is concluded that there is no association between vWF gene A1381T polymorphism and CHD susceptibility. The plasma vWF level in CHD group interrelated with ABO blood group and A1381T polymorphism, in which the plasma vWF level in AG genotype increase mostly. Plasma vWF level in vWF gene A1381T polymorphism with AG mutant was significantly much higher than GG mutant in CHD. This change may be beneficial to further study the effect of A1381T polymorphism on vWF gene expression and activity.

The expressional alterations of CSF-1R after ischemic injury of cerebral cortex / 中国应用生理学杂志

<p><b>AIM</b>To observe the expressional alterations of colony stimulating factor-1 receptor (CSF-1R) after ischemic injury of cerebral cortex, and study the function of colony stimulating factor-1 (CSF-1)/CSF-1R signal during the process of ischemic injury and repair of central nervous system (CNS).</p><p><b>METHODS</b>We examined the distribution and expression of CSF-1R in normal brain tissues and ischemic brain tissues by immunohistology and Western blot analysis.</p><p><b>RESULTS</b>The expression of CSF-1R in neurons could be up-regulated by ischemic injury in CNS.</p><p><b>CONCLUSION</b>CSF-1/CSF-1R might take part in the process of ischemic injury and repair.</p>