Particular internal recirculation frequency scope for enhancing denitrifying phosphorus removal in an oxidation ditch.

This study investigated the influence of the unique internal recirculation characteristics of an oxidation ditch (OD) system, namely, the internal recirculation frequency (IRF) on denitrifying phosphorus removal (DNPR). The ratios of denitrifying polyphosphate-accumulating organisms (DPAOs) to polyphosphate-accumulating organisms (PAOs) under different IRF conditions were measured using a batch experiment. On this basis, the variation of nutrient transformations was studied using the IRF changes by the mass balance method. The results showed that, for the OD system that had an anaerobic zone upstream from the circular corridor and set anoxic and aerobic zones along the circular corridor, when the IRF was between 3.4 h-1 and 7.5 h-1, the DPAOs/PAOs ratio reached about 50%. Approximately 20% of the total phosphorus (TP) was removed and over 11% of the total nitrogen (TN) was transformed into nitrogen gas by the DNPR process, and meanwhile the total removal efficiencies of the TP and TN were over 93% and 80%. When the IRF was greater than 11.5 h-1, the TN removal efficiency decreased significantly, and this was not conducive to simultaneous nitrogen and phosphorus removal. The results indicated that the OD process would possess a better DNPR potential if the IRF were controlled within the proper scope.

Chronic Supplementation of Curcumin Enhances the Efficacy of Antidepressants in Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Pilot Study.

Major depressive disorder is a devastating mental illness leading to a lifetime prevalence of higher than 16% on individuals. The treatment delay and inevitable adverse effects are major limitations of current depression interventions. Emerging evidence indicates that curcumin produced significant antidepressant properties in depression in both rodents and humans without adverse effects. Therefore, it is necessary to further clarify the antidepressant actions of curcumin and the underlying mechanism in depressed patients. A total of 108 male adults aged between 31 and 59 years were systematically recruited in Tianjin Anding Hospital. Subjects were administered the Chinese version of 17-item Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale that measures different scores of depressive symptoms. The subjects were asked to take 2 capsules containing either 1000 mg of curcumin or placebo soybean powder daily for 6 weeks on the basis of their current antidepressant medications. The plasma levels of interleukin 1ß, tumor necrosis factor α, brain-derived neurotrophic factor, and salivary cortisol were measured by enzyme-linked immunosorbent assay before and after curcumin or placebo treatment during the 6-week procedure. Chronic supplementation with curcumin produced significant antidepressant behavioral response in depressed patients by reduction of 17-item Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale scores. Furthermore, curcumin decreases inflammatory cytokines interleukin 1ß and tumor necrosis factor α level, increases plasma brain-derived neurotrophic factor levels, and decreases salivary cortisol concentrations compared with placebo group. These findings indicate the potential benefits of further implications of supplementary administration of curcumin to reverse the development of depression and enhance the outcome of antidepressants treatment in major depressive disorder.

Detecting the prevalence of bacterial colonization on tunneled cuffed hemodialysis catheters using quantitative PCR targeting 16S rRNA and scanning electron microscopy.

BACKGROUND AND OBJECTIVES: Tunneled cuffed hemodialysis catheters (TCC) get colonized by microorganisms, increasing risk for catheter related bacteremia (CRB). Our objective was to detect the prevalence of bacterial colonization of TCC by using quantitative PCR (qPCR) targeting 16S rRNA and by determining the intraluminal adherent biological material (ABM) coverage. METHODS: A total of 45 TCC were investigated. The 16S rRNA qPCR technique was used to detect bacterial colonization after scraping the intraluminal ABM. Proximal, middle, and distal TCC were evaluated by scanning electron microscopy (SEM) to determine the percentage (%) of intraluminal ABM coverage. All catheters were cultured following sonication. RESULTS: A total of 45 TCC were removed: 7 due to CRB, 3 for suspected CRB and 35 were removed for non-infectious etiologies. Bacterial colonization was detected in 27 TCC by documenting 16S rRNA qPCR (+) results (60%). Seven of these 16S rRNA qPCR (+) catheters were removed due to CRB. There was no difference in demographic, clinical, or laboratory values between the 16S rRNA (+) versus (-) TCC. The 16S rRNA qPCR (-) outcome was highly associated with CRB-free status with negative predictive value of 100%. Bacterial colonization was documented in 10 TCC using catheter cultures (22%), which was significantly less compared to qPCR method (p = 0.0002). ABM were detected in all catheter pieces, with mean intraluminal surface coverage (ABMC) of 68.4 ± 26.1%. ABM was unlikely to be microbial biofilm in at least 36% of removed TCC as their 16S rRNA qPCR and catheter culture results were both negative. CONCLUSIONS: Detecting bacterial colonization of TCC was significantly higher with 16S rRNA qPCR compared to catheter cultures. The 16S rRNA qPCR (-) cannot be predicted and was strongly associated with absence of CRB. Intraluminal ABM was not associated with microbial presence in about 1/3 of the TCC. These pieces of evidence may help to improve prophylactic strategies against CRB.

First American Cancer Patient to Receive Dicycloplatin (DCP) Chemotherapy Achieves Remission After Seven Weeks of DCP Capsules - A Case Report.

BACKGROUND: The majority of bladder cancer patients experience recurrence. Cisplatin is the standard chemotherapy for muscle-invasive bladder cancer though adverse effects are often severe. CASE REPORT: Intravenous (IV) dicycloplatin (DCP) sustained remission in an American bladder cancer patient for five years. A recurrent mass was observed in July 2021. The patient received DCP capsules for seven weeks with no significant side-effects. Complete blood count with differential and a basic metabolic panel showed no adverse effects of DCP capsules on the bone marrow, liver or renal parameters. Cystoscopy after oral DCP found no evident bladder tumors; cytology was negative for high-grade urothelial carcinoma. CONCLUSION: In this patient, DCP-capsules appeared to be as effective as DCP-IV for achieving bladder cancer remission. Both forms of DCP chemotherapy are convenient, active against several cancer types, with decreased adverse effects compared to cisplatin. Both have been available for treating cancer patients in China. A USA clinical trial of DCP in bladder and other cancers appears warranted.

Determination of textile dyeing wastewater COD components by comparison with respirometry and full-scale data.

A Modified Activated Sludge Model No. 1 (M-ASM1), including six COD components (S1, S(S), X1, X(S), X(H), and S(O)) and three biochemical processes (aerobic growth of heterotrophs, aerobic decay of heterotrophs and hydrolysis of entrapped organics) was used to simulate the anaerobic hydrolysis-aeration-sedimentation treatment series in a full-scale textile dyeing wastewater treatment plant (WWTP) with an influent flow rate of 200,000 m3/d. Using a respirometry method, the influent COD components of the WWTP activated sludge system were estimated. Then, calibration equations were set up depending on the full-scale treatment plant running data in order to calibrate the measurement results. This paper indicates that the influent COD components of a low biodegradability wastewater can be estimated using a respirometry method coupled with a calibration procedure based on full-scale plant running data.

[Effects of Long-term Poly-P Deficiency on the Metabolic Properties of Accumulibacter in AO-SBR System].

To investigate the changes in microbial community structure and metabolic properties of Accumulibacter under long-term Poly-P deficiency, an activated sludge enriched with Accumulibacter was inoculated into two SBR reactors, where sodium acetate and sodium propionate were used separately as organic carbon sources. The two reactors were operated for 60 days with an influent PO43--P concentration of 2.5 mg·L-1. The phosphorus removal performance, sludge production, and changes in the microbial community structure of the systems were analyzed. The results indicated that both SBR systems showed good performance of phosphorus and organic matter removal. However, microorganisms in both systems showed glycogen-accumulating metabolism properties under long-term Poly-P deficiency. In the unfavorable environment of long-term Poly-P deficiency, Accumulibacter Ⅰ maintained a high abundance (40%±7%) in the propionate SBR system, indicating that Accumulibacter Ⅰ had higher metabolic activity and its metabolic properties could be independent of Poly-P for survival under Poly-P deficiency for a long period. In comparison, propionate is more conducive to Accumulibacter adaptation to lower phosphorus loads, and Accumulibacter Ⅰ is more competitive than Accumulibacter Ⅱ under lower phosphorus loads.

Adverse Effects Profile of Dicycloplatin (DCP) Offers Chemotherapeutic Advantage Over Cisplatin and Carboplatin.

BACKGROUND/AIM: Platinum-based chemotherapy often fails due to its severe adverse effects. The aim of this study was to examine the adverse effects profile and efficacy of dicycloplatin and compare them to those of cisplatin and carboplatin. MATERIALS AND METHODS: Cystoscopy surveillance of the first American cancer patient treated with dicycloplatin was performed quarterly. In vitro and in vivo studies were conducted using immunoblotting and flow cytometry to assess immune status of spleen and bone marrow of mice treated with dicycloplatin, cisplatin and carboplatin. RESULTS: The American patient did not suffer clinically significant myelosuppression; dicycloplatin has sustained remission in this patient to date. Experimental studies showed that dicycloplatin is less toxic to bone marrow and spleen of mice than cisplatin and carboplatin. CONCLUSION: Dicycloplatin is a promising drug in cancer chemotherapy with less aggressive side-effects than those typically associated with cisplatin and carboplatin. This is an important therapeutic advantage in cancer chemotherapy. Clinical investigation of dicycloplatin as an alternative to cisplatin or carboplatin is warranted.

MZF1 possesses a repressively regulatory function in ERCC1 expression.

ERCC1 is a critical gene within the nucleotide excision repair pathway. Overexpression of ERCC1 through promoter-mediating transcriptional regulation is associated with repair of cisplatin-induced DNA damage and clinical resistance to platinum-chemotherapy. Several transcriptional repressors and activators within the 5'-flanking region of the ERCC1 gene may be involved in the up-regulation of this gene. Minimal sequence within the promoter region required for ERCC1 transcription was analyzed by CAT assay and demonstrated that the region of -220 to -110 is essential to constitutive expression of ERCC1 gene in ovarian cancer cell line A2780/CP70. A more forward upstream region seems to be responsible for cisplatin-induced expression. Study of the functional cis-element in this region by electrophoretic mobility shift assay indicates that a MZF1-like site as well as an AP1-like site responded in a time-dependent manner to cisplatin stimulation with altered binding activities. EMSA with MZF1 ZN1-4 consensus oligonucleotides suggests that the MZF1 N-terminal domain of zinc finger cluster may bind to the MZF1-like site of the ERCC1 promoter region. MZF1 mRNA in A2780/CP70 cells decreased upon cisplatin exposure as analyzed by quantitative PCR, suggesting that MZF1 may mediate cisplatin-invoked gene expression in these cells. Overexpression of MZF1 repressed the ERCC1 promoter activity as determined in co-transfection assay, suggesting that MZF1 might be a repressor of ERCC1 transcription upon cisplatin exposure. In summary, our studies revealed a core promoter region and adjacent drug-responsible region within the ERCC1 promoter. The drug-responsible region contains cis-elements of activator, AP1 and repressor, MZF1. In response to cisplatin treatment, decreased MZF1 and increased AP1 binding activities appear to be the leading mechanism of up-regulation of ERCC1 expression. Our findings imply potential therapeutic strategies to antagonize drug resistant mechanisms in treatment of human ovarian cancer.

Antisense telomerase RNA inhibits the growth of human glioma cells in vitro and in vivo.

Telomerase is implicated in the development of cellular immortality and oncogenesis. It has been shown that telomerase activity is considerably higher in the tissue of many different cancers than in normal tissue, and that the inhibition or downregulation of telomerase activity can prevent the malignant proliferation of tumor cells. Antisense oligonucleotides have been widely used in suppressing the expression of genes and, therefore, in the present research, we evaluated the effect of antisense human telomerase RNA (hTR) on glioma cell growth in vitro and in vivo. We showed that antisense hTR cDNA significantly inhibited TJ905 human glioma cell proliferation in vitro and tumor growth in vivo, as determined by MTT assay and by measuring the volume of glioma in nude mice. Consistent with these results, we found that telomerase activity and the mRNA levels of hTR and hTERT (human telomerase reverse transcriptase) expression were markedly decreased in tumor cells treated with antisense hTR cDNA, as assessed by TRAP (telomeric repeat amplification protocol) assay and RT-PCR (reverse transcription-polymerase chain reaction) analysis. Our study conclusively demonstrates that antisense hTR effectively inhibits the growth of human glioma cells in vitro and in vivo and, thus, may be potentially used for gene therapy of malignant gliomas and other cancers.

Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells.

High-fidelity maintenance of genomic integrity in eukaryotes is ensured by cell cycle checkpoints and DNA repair. The checkpoint kinase, Chk2, has been implicated in both of these responses. In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation. The fully activated Chk2 then phosphorylates downstream substrates of cell cycle control. However, the mechanism of inactivation of Chk2 is still unknown. Protein phosphatase type 2A (PP2A) plays an essential role in cell cycle regulation and induction of G2 arrest by a mechanism of phosphorylation/dephosphorylation with a variety of protein kinases. Data from our investigation provide evidence that, in response to cisplatin exposure, PP2A associates with Chk2 as a complex in cells and functions as a negative regulator of Chk2 activation by dephosphorylating p-Chk2. Results from immunostaining and coimmunoprecipitation demonstrate that Chk2 and PP2A can colocalize in cells, and the holoenzyme of PP2A (subunits A, B and C) coimmunoprecipitates with p-Chk2. Further, inhibition of PP2A by okadaic acid, an inhibitor of PP2A, and by small interfering RNA (siRNA) to PP2A results in enhanced Chk2 phosphorylation, implicating a direct enzyme-substrate relationship. An in vitro PP2A dephosphorylation assay shows that PP2A dephosphorylates p-Chk2 in a cell-free system. These findings suggest that the protein serine/threonine kinase, Chk2, is activated after cisplatin exposure and negatively regulated by a tightly associated protein serine/threonine phosphatase, PP2A.

Clear cell tumors have higher mRNA levels of ERCC1 and XPB than other histological types of epithelial ovarian cancer.

PURPOSE: The purpose of the present work was to investigate the relationship between mRNA expression of ERCC1 and XPB, two key genes in the nucleotide excision repair pathway, and clinical resistance of platinum-chemotherapy in histological subtypes of epithelial ovarian cancer. EXPERIMENTAL DESIGN: mRNA levels of ERCC1 and XPB in epithelial ovarian cancer specimens from 126 different individuals were assessed using reverse transcription-PCR and followed by Southern hybridization methodology. Data were analyzed by linear regression analyses and by exhaustive regression analyses. RESULTS: Five different histological types of tumors were examined; serous (n = 76), mucinous (n = 11), clear cell (n = 9), poorly differentiated (n = 9), and endometroid (n = 21). Numerical values for mRNA expression levels were based on internal controls for a stable comparative cell line and for beta-actin. Median values for ERCC1 and XPB mRNAs within clear cell tumors were, on average, >2-fold higher than the other histological tumor types. Linear regression analyses suggest a continuum of nucleotide excision repair gene expression among these cell types, and exhaustive regression analyses demonstrate that the higher mRNA levels seen in clear cell tumors are highly statistically significant. CONCLUSIONS: We conclude that mRNA levels of ERCC1 and XPB tend to be higher in clear cell tumors as opposed to other types of epithelial ovarian cancer. This is consistent with the long-standing observation that clear cell tumors are more likely to show de novo drug resistance against DNA damaging agents in the clinic.

Downregulation of ATG14 by EGR1-MIR152 sensitizes ovarian cancer cells to cisplatin-induced apoptosis by inhibiting cyto-protective autophagy.

Cisplatin is commonly used in ovarian cancer treatment by inducing apoptosis in cancer cells as a result of lethal DNA damage. However, the intrinsic and acquired resistance to cisplatin in cancer cells remains a big challenge for improving overall survival. The cyto-protective functions of autophagy in cancer cells have been suggested as a potential mechanism for chemoresistance. Here, we reported MIR152 as a new autophagy-regulating miRNA that plays a role in cisplatin-resistance. We showed that MIR152 expression was dramatically downregulated in the cisplatin-resistant cell lines A2780/CP70, SKOV3/DDP compared with their respective parental cells, and in ovarian cancer tissues associated with cisplatin-resistance. Overexpression of MIR152 sensitized cisplatin-resistant ovarian cancer cells by reducing cisplatin-induced autophagy, enhancing cisplatin-induced apoptosis and inhibition of cell proliferation. A mouse subcutaneous xenograft tumor model using A2780/CP70 cells with overexpressing MIR152 was established and displayed decreased tumor growth in response to cisplatin. We also identified that ATG14 is a functional target of MIR152 in regulating autophagy inhibition. Furthermore, we found that EGR1 (early growth response 1) regulated the MIR152 gene at the transcriptional level. Ectopic expression of EGR1 enhanced efficacy of chemotherapy in A2780/CP70 cells. More importantly, these findings were relevant to clinical cases. Both EGR1 and MIR152 expression levels were significantly lower in ovarian cancer tissues with high levels of ERCC1 (excision repair cross-complementation group 1), a marker for cisplatin-resistance. Collectively, these data provide insights into novel mechanisms for acquired cisplatin-resistance. Activation of EGR1 and MIR152 may be a useful therapeutic strategy to overcome cisplatin-resistance by preventing cyto-protective autophagy in ovarian cancer.

Confirmation of 42-bp deletion within the ERCC1 5' UTR.

Our previous studies revealed a splicing variant (lacking a 42 base pair segment) within the 5'-UTR of the ERCC1 gene, a critical component of the nucleotide excision repair (NER) pathway that plays an important role in the development of chemoresistance in platinum-based anticancer therapy. This 42-bp segment seems to possess a regulatory function in ERCC1 expression and representing the level of clinical response to platinum-treatment in ovarian cancer patients. To confirm the existence of the 42-bp deletion and to investigate the 42-bp function, we performed several experiments and assays. Northern blot analysis and RNase protection assay provide evidence that the 42-bp deletion occurs at RNA level of ERCC1 5'-UTR in both ovarian cancer cell lines and ovarian cancer tissues. Luciferase assay suggests that this gene fragment possesses a regulatory function as an enhancer of ERCC1 gene expression in ovarian cancer cells. In Electrophoretic Mobility Shift Assay (EMSA), a shift band present in the ovarian cancer cell line extracts is consistent with the presence of an intracellular protein that recognizes this specific 42-bp sequence. Further, specific EMSA results with 42-bp probe mutated at the site of RFX-1 indicate different putative-DNA binding proteins, rather than RFX-1. We conclude that the 42-bp sequence within the 5'-UTR influences the expression of ERCC1 and hence can influence response to cisplatin in ovarian cancer therapy.

Combinatorial treatment of ovarian cancer cells with harringtonine and cisplatin results in increased cisplatin-DNA adducts.

The current studies represent the first step in assessing the utility of harringtonine in combination with cisplatin as an improved approach for treating ovarian cancer. Three ovarian cancer cell lines, platinum-sensitive A2780, and platinum-resistant A2780/CP70 and OvCar-3, were exposed to their respective IC(50) dose of cisplatin for 1 h with or without a 24-h pretreatment with harringtonine. The level of platinum-DNA adducts was determined by atomic absorption spectrometry (AAS). These studies show for the first time that harringtonine pretreatment significantly increased the amount of platinum-DNA adducts in all ovarian cancer cell lines by 2-4 fold, immediately following 1-h exposure to cisplatin. Moreover, the level of cisplatin-DNA adducts in harringtonine-pretreated cells remained elevated by 3-4.7-fold for at least 6 h after cisplatin was removed, relative to cells only exposed to cisplatin. In all three cell lines the removal (repair) of platinum-DNA adducts was not significantly altered by harringtonine. In addition, the extent to which harringtonine altered the expression of select DNA damage response genes (p53, P16, ERCC1 and XPB) was determined using RT-PCR and Southern hybridization in A2780 and A2780/CP70 cells. The expression of ERCC1 and XPB RNAs were only modestly altered by harringtonine, consistent with a lack of effect of harringtonine on repair of cisplatin-DNA damage. However, harringtonine altered expression of p53 and P16 RNAs in both cell lines, although the down-regulation of p53 and P16 RNAs by harringtonine were more pronounced in A2780 cells. The novel observation that harringtonine augments platinum-DNA adducts in both platinum-sensitive and -resistant ovarian cancer cells indicates this combination of drugs may have utility in treating ovarian cancer and may be especially useful in managing platinum-resistant cancers. Additional studies are required to determine which sequence of these drugs is most beneficial, as well as the mechanism by which harringtonine increases cisplatin-DNA damage in ovarian cancer cells.

Excision repair cross complementing-group 1: gene expression and platinum resistance.

Platinum compounds induce their cytotoxic effect by binding to a DNA molecule in the form of a platinum-DNA-adduct. Many previous studies have shown that the level of platinum-DNA-adduct correlats with response to platinum-based chemotherapy. Although the mechanism of platinum resistance in vivo is not clearly understood, laboratory studies on cancer cell lines suggest that nucleotide excision repair (NER) is the main mechanism responsible for this resistance by increased platinum-DNA-adduct removal. NER pathway is a network of many proteins gathered in a DNA-repair system. The excision repair cross complementing-group 1 (ERCC1) gene has the leading role in NER-pathway because of its damage recognition and excision ability. In this report we reviewed the pathway leading to ERCC1 gene transcription and translation in cancer cells when exposed to cisplatin. We summarized data from different cancer cell lines and human cancers showing that the high level of ERCC1-mRNA and/or ERCC1 protein is associated with resistance to platinum compounds with direct impact on cancer patient survival and finally we analyzed drugs interfering with ERCC1 gene expression and causing the reversal of the platinum resistance when given to cancer cells prior to platinum-based chemotherapy.

Dicycloplatin, a novel platinum analog in chemotherapy: synthesis of chinese pre-clinical and clinical profile and emerging mechanistic studies.

Dicycloplatin (DCP) has better solubility and stability than both cisplatin and carboplatin. Pre-clinical and phase I studies demonstrated significant antitumor activity and fewer adverse events than carboplatin. Phase II clinical trials in advanced non-small cell lung cancer found efficacy and safety of DCP-plus-paclitaxel comparable to carboplatin-plus-paclitaxel but better tolerability. This article summarizes and reviews pre-clinical and clinical data for dicycloplatin from the Chinese medical literature. We also report on new mechanistic findings in our laboratory in West Virginia, USA. Patient blood samples were collected for DCP-prototype determination by liquid chromatography mass spectrometry (LC-MS/MS). Molecular studies of ovarian cancer cells treated with DCP or cisplatin were carried out for gene-signature profiling using immunoblotting. Pharmacokinetic mass-spectrometry showed different spectrum profiles of DCP and carboplatin in plasma. Plasma concentration of DCP prototype was 17.1 µg/ml 2h after administration, with a peak concentration of 26.9 µg/ml at 0.5 h. Immunoblotting showed DCP-induced activation of DNA damage pathways, including double-phosphorylated checkpoint kinase 2 (CHK2) and breast cancer 1 (BRCA1) and triple-phosphorylated p53, compared to controls. Cisplatin produced a similar profile, with increased p53 protein. DCP and cisplatin activate DNA-damage response through similar pathways. DCP may be more soluble and stable, and better-tolerated.

Clinical pharmacology of an atrasentan and docetaxel regimen in men with hormone-refractory prostate cancer.

PURPOSE: This study was conducted to evaluate potential pharmacokinetic interactions between docetaxel and atrasentan as part of a phase I/II clinical trial. METHODS: Patients with prostate cancer were treated with intravenous docetaxel (60-75 mg/m(2)) every 3 weeks and oral atrasentan (10 mg) daily starting on day 3 of cycle 1 and then given continuously. The pharmacokinetics of both drugs were evaluated individually (cycle 1, day 1 for docetaxel; day 21 for atrasentan) and in combination (cycle 2, day 1 for both drugs). Pharmacogenomics of alpha-1-acid glycoprotein (AAG) were also explored. RESULTS: Paired pharmacokinetic data sets for both drugs were evaluable in 21 patients. Atrasentan was rapidly absorbed and plasma concentrations varied over a fourfold range at steady state within a typical patient. The median apparent oral clearance of atrasentan was 17.4 L/h in cycle 1 and was not affected by docetaxel administration (p = 0.9). Median systemic clearance of docetaxel was 51.1 L/h on the first cycle and significantly slower (p = 0.01) compared with that obtained during co-administration of atrasentan, 61.6 L/h. Docetaxel systemic clearance in cycle 1 was 70.0 L/h in patients homozygous for a variant allele in AAG compared with 44.5 L/h in those with at least one wild-type allele (p = 0.03). CONCLUSION: Genetic polymorphism in AAG may explain some inter-patient variability in docetaxel pharmacokinetics. The systemic clearance of docetaxel is increased by approximately 21 % when given concomitantly with atrasentan; however, atrasentan pharmacokinetics does not appear to be influenced by docetaxel administration.

Inhibition of calcineurin in the prefrontal cortex induced depressive-like behavior through mTOR signaling pathway.

RATIONAL: Although it has been recognized that inhibition of calcineurin induced depressive-like behavior, the underlying neural mediators have not yet been identified. Mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that regulates protein synthesis in synapses, has been demonstrated to be involved in the rapid antidepressant effects of ketamine. OBJECTIVE: To investigate a potential role of mTOR signaling pathway which interferes with depressive-like behavior induced by calcineurin blockade and to determine the neurobiological mechanisms underlying mood-related disorders. METHODS: Calcineurin inhibitor cyclosporine A (CsA) and tacrolimus (FK506) were microinjected into the medial prefrontal cortex (mPFC) in rats, and the depressive-like behavior was measured in sucrose preference test and forced swim test. Additionally, mTOR activity was tested by the levels of phosphorylation of p70s6 kinase (p70s6k) and 40S ribosomal protein S6 (rps6). RESULTS: Chronic microinjection of CsA or FK506 into mPFC increased depressive-like behaviors and decreased mTOR activity, but acute CsA or FK506 had no effects on both behavioral phenotype and mTOR activity. Furthermore, activation of mTOR by NMDA reversed the depressive-like behavior induced by chronic CsA or FK506 administration. Moreover, inhibition of mTOR by rapamycin reversed the antidepressant effects of ketamine. Finally, traditional antidepressant venlafaxine prevented the depressive-like performance induced by chronic CsA or FK506 treatment. CONCLUSION: These findings indicate that calcineurin-inhibition-induced depressive-like behavior is mediated by blockade of the mTOR signaling pathway and raise the possibility that stimulation of specific brain mTOR may be sufficient to decrease risk of affective disorders in patients treated with calcineurin inhibitor.

Disease-syndrome combination clinical study of psoriasis: present status, advantages, and prospects.

Psoriasis is an immune-abnormal, chronic, proliferative skin disease determined by polygenic inheritance and induced by a number of environmental factors. It causes worldwide concern because of its high-prevalence, harmful and incurable characteristics. Over the years, Chinese medicine (CM) treatment of psoriasis has accumulated a wealth of clinical experience. Disease-syndrome combination, which achieves more satisfactory clinical effect, is the basis to highlight the special CM advantages in treating psoriasis. In this paper, we review the advantages of treating psoriasis with the combination of disease and syndrome, analyze the prospects of research on treating psoriasis combining disease with syndrome. We also make a point that there are several key points for the clinical research of combination of disease and syndrome. It can be expected that carrying out clinical research on the combination of disease and syndrome will help improve the clinical efficacy of medical treatment of psoriasis, which will be the main direction of research in the future.