A single-centre, open-label, single-arm, fixed-sequence pharmacokinetic study of SHR3680 on repaglinide and bupropion in prostate cancer patients.

To evaluate the pharmacokinetic effects of SHR3680 on repaglinide and bupropion and its metabolite hydroxybupropion. METHODS: A single-centre, open-label, single-arm, fixed-sequence clinical trial in 18 patients with prostate cancer. RESULTS: After a single oral dose of 0.5 mg repaglinide and SHR3680, geometric mean peak plasma concentration (Cmax ) of plasma repaglinide was 14.240 and 5.887 ng/mL, geometric mean area under the concentration-time curve (AUC0-t )was 20.577 and 7.320 h ng/mL, geometric mean AUC0-∞ was 20.949 and 7.451 h ng/mL, mean half-life (t1/2 ) was 1.629 and 1.195 hours, and geometric mean oral clearance (CL/F) was 23.867 and 67.107 L/h, respectively. After a single oral administration of 150 mg bupropion and SHR3680, geometric mean Cmax of plasma bupropion was 85.430 and 33.747 ng/mL, geometric mean AUC0-t was 1003.896 and 380.158 h ng/mL, geometric mean AUC0-∞ was 1038.054 and 401.387 h ng/mL, mean t1/2 was 22.533 and 17.733 hours, and geometric mean CL/F was 144.501 and 373.705 L/h, respectively. The plasma geometric mean Cmax of its main active metabolic hydroxybupropion was 268.113 and 177.318 ng/mL, geometric mean AUC0-t was 14 283.087 and 5420.219 h ng/mL, geometric mean AUC0-∞ was 15 218.158 and 5364.625 h ng/mL, mean t1/2 were 36.069 and 16.688 hours, and geometric mean CL/F was 8.623 L/h and 27.961 L/h, respectively. CONCLUSION: Coadministration of SHR3680 with repaglinide or bupropion significantly shortened the elimination half-lives, significantly increased the apparent clearance rate, and significantly decreased the in vivo exposure of repaglinide, bupropion and hydroxybupropion compared with single administration of repaglinide or bupropion.

Opuntia dillenii Haw. Polysaccharide Promotes Cholesterol Efflux in THP-1-Derived Foam Cells via the PPARγ-LXRα Signaling Pathway.

There is increasing evidence supporting a role for enhanced macrophage cholesterol efflux in ameliorating atherosclerosis. Opuntia dillenii Haw. polysaccharide (ODP-Ia), the most important functional component obtained from Opuntia dillenii Haw. stem, has anti-atherosclerosis effects. Therefore, we propose that ODP-Ia could promote cholesterol efflux via the PPARγ-LXRα signaling pathway. In this study, THP-1 foam cells derived from macrophages were treated with different concentrations of ODP-Ia, GGPP (antagonist of LXRα) and GW9662 (antagonist of PPARγ), with or without 15 nmol ODP-Ia. The total cholesterol content in the cells was measured. The mRNA of ABCA1, ABCG1, PPARγ, LXRα and their protein levels in the foam cells were detected by RT−PCR and Western blot, respectively. The results showed that ODP-Ia plays a role in significantly promoting cholesterol efflux (p < 0.05) by upregulating the expression of ABCA1, ABCG1, SR-BI, PPARγ, PPARα and LXRα. Meanwhile, PPARγ and LXRα antagonists dramatically interfered the cholesterol efflux mediated by ODP-Ia (p < 0.05) and dramatically inhibited the upregulating effect of ODP-Ia on the expression of PPARγ, LXRα, ABCA1 and ABCG1 at both protein and mRNA levels (p < 0.05). In conclusion, ODP-Ia promotes cholesterol efflux in the foam cells through activating the PPARγ-LXRα signaling pathway. This bioactivity suggested that ODP-Ia may be of benefit in treating atherosclerosis.

The impact of packaging recyclable ability on environment: Case and scenario analysis of polypropylene express boxes and corrugated cartons.

With the push for sustainable design strategies, recyclable packaging is widely favored by the public in the express delivery industry due to its potential for lowering environmental burden and solving climatic challenges. The goal of this paper was to quantify and integrate the environmental footprints of polypropylene hollow board express box (PPH-EB) and establish evaluation model between the recyclable ability and environment performance (EMRE) based on life cycle assessment. This work was carried out by multiple indicators to avoid environmental problem-shifting, and corrugated cartons express box (C-EB) was taken as control objects. The results show that integrated index of PPH-EB is 94.42% lower than that of C-EB. Industrial Water Use (IWU), Primary Energy Demand (PED) and SO2 are major factors affecting results of PPH-EB, which mainly come from polypropylene particles and water resource consumption from recycle process. The most obvious advantage of PPH-EB compared with C-EB is the nearly 1700 times difference in normalized COD index caused by direct emission of paper preparation process. Scenario analysis showed that integrated index of PPH-EB was lower than that of traditional corrugated cartons after more than twice of use, but if the recycling times of PPH-EB continued to increase, the effect on reducing environmental burden was no longer significant. Therefore, although the recyclable times plays a role in decreasing the environmental impact, it is not a permanent strategy. In the design stage of the recyclable express box, the recyclable ability should be reasonably designed through EMRE, so as to minimize the environmental burden.

SQLE Mediates Metabolic Reprogramming to Promote LN Metastasis in Castration-Resistant Prostate Cancer.

BACKGROUND: Almost all metastatic hormone-sensitive prostate cancers (mHSPC) will develop into metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT). The expression level of squalene monooxygenase (SQLE) is increased in CRPC cells and regulates cholesterol metabolism. This study verified the biological function and mechanisms of SQLE in CRPC. METHODS: The expression of SQLE in human prostate cancer cells was overexpressed or silenced and its efficacy on cell survival was determined by the MTS test. Energy metabolism phenotype test was evaluated by XF real-time ATP rate assay, XF cell mitochondrial stress test, XF glycolysis stress test and XF mito fuel flex test. Cell migration and invasion were evaluated by colony formation assays and transwell assays; the expression of mRNA and protein was assessed by RT-qPCR and Western blot, respectively. Moreover, BALB/c nude mice model was performed to evaluate the lymph node metastasis. RESULTS: In our study, we found that the expression level of SQLE was significantly increased in bicalutamide-resistant-C4-2B cells compared to LNCaP cells. SQLE knockdown partly restored the sensitivity of drug-resistant cells to bicalutamide and reduced lymph node metastasis by inhibiting fatty acid oxidation in mitochondria. We also found that terbinafine, the specific inhibitor of SQLE, can enhance the sensitivity of prostate cancer cells to bicalutamide. CONCLUSION: Our study revealed that SQLE is involved in the progression of castration resistance in CRPC through mediating metabolic reprogramming, presenting SQLE as a new target for the treatment of mCRPC.

Environmental impacts of functional fillers in polylactide (PLA)-based bottles using life cycle assessment methodology.

The use of functional fillers added to PLA-based products can be beneficial in terms of cost reduction and properties improvement. The existing life cycle assessment of PLA containers mainly focuses on the greenhouse gas (GHG) emission of PLA material model without fillers, and overlooked environmental impacts of functional fillers and the significant environmental problem-shifting on other indicators. This paper presents a life cycle assessment (LCA) of cooking oil bottles made from PLA, PLA/Fibers and PLA/CaCO3 considering a wide spectrum impacts, and compares the environmental profile of them based on normalization and weighting analysis. The functional unit was set at 1000 bottles of 900 mL. The system boundary is from cradle to gate, including PLA-based particles production, bottle processing and transportation. The results showed that the contribution of the primary energy demand (PED) index of PLA-based bottles accounted for 159% to 192% of the global warming potential (GWP) index, which may be overlooked in previous studies. Compared to PLA and PLA/Fibers bottles, PLA/CaCO3 bottles have lower environmental impacts in most categories and the lowest integrated impact index. In terms of PLA/CaCO3 bottles, PLA particles and electricity contributed the most to energy conservation and emission reduction (ECER) results, accounting for 63.09% and 28.26% to the integrated impacts index, respectively. The results imply that the use of fillers in PLA bottles tends to reduce the environmental impacts, especially calcium carbonate can efficiently minimize environmental impacts of PLA-based bottles. And PED, SO2 and NOX indicators ranking above CO2 should be taken into consideration to avoid the environmental problem-shifting, which can provide valuable reference for the creation of the method of making biodegradable plastic and carbon neutral policies.

Extraction of Opuntia dillenii Haw. Polysaccharides and Their Antioxidant Activities.

Use of natural polysaccharides in medicine and food has wide interest in research. In this study, we extracted and purified some polysaccharides from cactus Opuntia dillenii Haw. (ODP). Some preliminary functions of these products were characterized. Under the optimal purification conditions, the yield of ODP extracted from the 2-4 month-old Opuntia dillenii Haw. (T-ODP) was 30.60% ± 0.40%, higher than that of ODP from the 5-10 month-old materials (O-ODP) (18.97% ± 0.58%). The extracted ODP was purified by DEAE sepharose fast flow anion exchange and Sephacryl S-400 chromatography with four fractions obtained (ODP-Ia, ODP-Ib, ODP-IIa and ODP-IIb). Analysis with UV-vis chromatography indicated that ODP-Ia and ODP-IIa were relatively homogeneous molecules with a molecular weight of 339 kD and 943 kD, respectively. Results of infrared spectroscopy indicated that ODP, ODP-Ia, and ODP-IIa were acidic polysaccharides. Further, the antioxidant activity against DPPH (1,1-diphenyl-2-picrylhydrazyl) radical, hydroxyl radicals, and superoxide radical in vitro demonstrated that the T-ODP exhibited higher antioxidant activity than the O-ODP, and the purified fraction (ODP-Ia) was superior to the ODP. These results will offer a theoretical basis for further research on the structure-function relationship of ODP and the rational utilization of Opuntia dillenii Haw.

Recurrent waist tumor subsequent to percutaneous nephrolithotomy: A case report.

The present study reports the case of a 39-year old male patient with a recurrent waist tumor that occurred subsequent to percutaneous nephrolithotomy (PCNL). The patient initially underwent PCNL for the management of right calculus of the kidney. Six years later, the patient underwent local mass resection for a tumor at the waist, which was subsequently diagnosed as adenocarcinoma. However, seven months subsequent to local resection, the patient presented to the Affiliated Cancer Hospital of Xiangya Medical School with a one-month history of a recurrent tumor located at the right waist. Physical examination identified no visible skin lesions; however, a palpable hard nodule was present over the right waist. Imaging studies, consisting of computed tomography (CT) and positron emission tomography-CT, indicated no additional metastases. Therefore, the patient underwent local mass resection of the waist tumor. Subsequent histological examination determined a diagnosis of metastatic adenocarcinoma. Considering the previously conducted PCNL surgery and the diagnosis, it is proposed that the recurrent waist tumor originated from renal cell carcinoma (RCC), also termed renal adenocarcinoma. However, no evidence of the original RCC tumor was identified. Therefore, the selection of an effective treatment strategy was challenging.

Overexpression of wip1 is associated with biologic behavior in human clear cell renal cell carcinoma.

Wild-type p53-induced phosphatase (Wip1 or PPM1D) has been reported to be aberrantly expressed in various cancers and correlated with the malignant behavior of cancer cells. However, the function of Wip1 in RCC remains unclear. The present study investigated its abnormal expression and dysfunctions in clear cell renal cell carcinoma (ccRCC) in vitro. With the combination of immunohistochemistry, western blotting, immunofluorescence, qRT-PCR, and cell proliferation, migration and invasion assays, we found that levels of Wip1 mRNA and protein were dramatically increased in human ccRCC tissues (P<0.001 for both), and upregulation of Wip1 was significantly associated with depth of invasion (P<0.001), Distant metastasis (P = 0.001), lymph node status (P<0.001) and Fuhrman grade (P<0.001). Wip1 knockdown inhibited the proliferation, migration and invasion of 786-O and RLC-310 cells, whereas Wip1 overexpression promoted the growth and aggressive phenotype of 786-O and RLC-310 cells in vitro. The uni- and multivariate analyses indicated that expression of Wip1 was an independent predictor for survival of ccRCC patients (P = 0.003, P = 0.027 respectively). Wip1- negative patients had a higher tumor-free/overall survival rate than patients with high Wip1 expression (P = 0.001, P = 0.002 respectively). Overexpression of Wip1 is useful in the prediction of survival in ccRCC patients.

Malignant priapism secondary to isolated penile metastasis from a renal pelvic carcinoma.

We report a case of isolated penile metastasis from renal pelvic carcinoma in a 69-year-old man with malignant priapism. The patient had radical resection of the renal pelvic carcinoma 2 months earlier with urothelial carcinoma (UC) and sarcomatoid differentiation histology. Physical examination showed no visible skin lesions, but a palpable hard nodule was present over the penile shaft. The imaging studies did not reveal other metastases. Cavernous-Glans shunt and nodule resection were performed, and histological examination showed metastasis UC with sarcomatoid differentiation. To our knowledge, we describe the first case of malignant priapism due to isolated penile metastasis of renal pelvic carcinoma.

Primary gastrointestinal stromal tumor of the prostate: A case report and literature review.

Extragastrointestinal stromal tumors (EGISTs) are relatively rare soft tissue neoplasms arising from the extra gastrointestinal tract. The current study presents a case of primary EGIST of the prostate observed in a 55-year-old male. Imaging studies showed a 10×10.5×9.5-cm prostate mass. On histological observation, the mass was separated from the rectum serosa and exhibited a high mitotic count (8/50 high-power fields). The results of immunohistochemical staining showed positive immunoreactivity for cluster of differentiation (CD)117 (c-kit), CD34 and DOG1 in the tumor. On mutation analysis, loss of heterozygosity of the c-kit gene was observed in the prostatic EGIST; however, the platelet-derived growth factor receptor-α (PDGFRA) gene was considered to be normal. Therefore, as EGIST of the prostate is rare, there is a requirement for the confirmation of the diagnosis to be based on immunohistochemistry and mutation analysis (of c-kit and PDGFRA).

Survivin and HLA-I expression predicts survival of patients with clear cell renal cell carcinoma.

Altered expression of survivin and leukocyte antigen class I (HLA-I) proteins is associated with tumor progression. This study investigated their expressions in clear cell renal cell carcinoma (ccRCC) tissues for association with a clinical significance of ccRCC patients. Ninety ccRCC and 20 normal tissue samples (i.e., control) were immunohistochemically stained for survivin and HLA-I expression for an association with clinicopathological data and survival of ccRCC patients. Survivin protein was expressed in 82.2 % (74/90) of ccRCC tissue samples compared to 0 % in the normal tissues, and HLA-I protein was expressed in 90 % (18/20) of the normal tissues vs. 67.8 % (61/90) in ccRCC samples. Survivin expression was associated with tumor grade, stage, and lymph node metastasis (p = 0.000, p = 0.016, and p = 0.001, respectively). Conversely, lost HLA-I expression did not have any associations with clinicopathological data (p > 0.05). Survivin-negative patients had a higher tumor-free survival rate than patients with survivin expression (p = 0.037). Patients with normal HLA-I levels had a higher tumor-free survival rate than those with reduced HLA-I levels (p = 0.02). The uni- and multivariate analyses indicated that expression of survivin and HLA-I, individually and in combination, was an independent predictor for survival of ccRCC patients. Overexpression of survivin but reduced HLA-I expression is useful in the prediction of tumor-free survival of ccRCC patients.

Hypolipidaemic effects and mechanisms of the main component of Opuntia dillenii Haw. polysaccharides in high-fat emulsion-induced hyperlipidaemic rats.

The antihyperlipidaemic effects of ODP-Ia, one of the main components of Opuntia dillenii Haw. polysaccharides, were studied. Gavage administration of ODP-Ia was observed to significantly decrease serum lipid levels and to increase serum high-density lipoprotein cholesterol level in hyperlipidaemic rats. Similar suppressive patterns were also seen in hepatic total cholesterol and triglyceride levels. Moreover, the ODP-Ia administration significantly increased serum lecithin:cholesterol acyltransferase activity, increased the production of serum NO, inhibited hepatic HMG-CoA reductase activity, augmented serum and hepatic superoxide dismutase activities and decreased the serum and hepatic malondialdehyde contents in hyperlipidaemic rats. In addition, a histopathological examination revealed that ODP-Ia administration significantly suppressed inflammatory cell infiltration and the expression of VCAM-1. Together, these results indicate that ODP-Ia is a potential natural product for the treatment of hyperlipidaemia-related diseases by improving antioxidant levels, modulating the activities of enzymes involved in cholesterol metabolism, promoting the production of NO and suppressing the expression of VCAM-1, thereby suppressing lipid accumulation and inflammatory cell infiltration.

[Immunomodulatory effects of Opuntia dillenii polysaccharides on specific immune function of mice].

OBJECTIVE: To investigate specific immune modulation of Opuntia dillenii polysaccharides (ODPs) on mice (body fluid and cells). METHODS: An immunosuppressed murine model was induced by intraperitoneal injection of cyclophosphamide (Cy, ip). The intraserous hemolysin IgM, IgG levels, the proliferation of spenocytes and the proportion of T lymphocyte subsets in peripheral blood were determined after the mice treated by ODPs. Proliferative effects of ODP-I, the main component purified from ODPs, on the lymphocytes in vitro were also studied. RESULTS: ODPs could significantly increase intraserous IgM and IgG levels, significantly enhance the proliferation of T and B lymphocytes and restore them to normal level. ODPs significantly reduced the percentage of CD4+ T lymphocytes subset, therefore significantly reduced the proportion of CD4+ and CD8+ T lymphocytes of peripheral blood from immunosuppressive mice and restored it to normal level. ODP-I significantly enhanced the natural proliferation of splenic lymphocyte and assisted the proliferation of T and B lymphocytes which induced by mitogen ConA or LPS. CONCLUSION: ODPs can enhance the specific immune function of immunosuppressed mice and the proliferation of lymphocytes in vitro.

Efficient Regeneration of Eucalyptus urophylla x Eucalyptus grandis from Stem Segment

The aim of the present study was to establish an efficient regeneration system for the hybrid E. urophylla x E. grandis by means of organogenesis. Stem segments from seedlings were used as explants and cultured in a modified Murashige and Skoog medium (MS), supplemented with 13.2 µM N-phenyl-N'-[6-(2-chlorobenzothiazol)-yl] urea (PBU) and 0.285 µM indole-3-acetic acid (IAA). PBU was a useful growth regulator. After cultivating for 5 d, 96% explants formed callus. After 30 d, the calli obtained were transferred to MS medium containing different combinations of 6-benzyladenine (BA) and naphthalene acetic acid (NAA). Compared with other growth regulator combinations, PBU stimulated more vigorous calli and restrained browning. In addition, a large percentage (91.3%) of the calli induced by PBU showed adventitious buds formation. Shoot elongation was then stimulated on half-strength MS mineral salts medium supplemented with 6.6 µM PBU and 0.285 µM IAA for 20 d. For rooting, the elongated shoots were cultivated on root induction medium containing 2.46 µM indole-3-butyric acid (IBA). Plantlets were then successfully transplanted to a greenhouse. This procedure represented an efficient way of E. urophylla x E. grandis plant regeneration.

Co-metabolic degradation of dimethoate by Raoultella sp. X1.

A bacterium Raoultella sp. X1, based on its 16S rRNA gene sequence, was isolated. Characteristics regarding the bacterial morphology, physiology, and genetics were investigated with an electron microscopy and conventional microbiological techniques. Although the isolate grew and degraded dimethoate poorly when the chemical was used as a sole carbon and energy source, it was able to remove up to 75% of dimethoate via co-metabolism. With a response surface methodology, we optimized carbon, nitrogen and phosphorus concentrations of the media for dimethoate degradation. Raoultella sp. X1 has a potential to be a useful organism for dimethoate degradation and a model strain for studying this biological process at the molecular level.

Prognostic factors for primary superficial transitional cell carcinoma of the bladder: a retrospective cohort study.

BACKGROUND: Previous studies showed that the prognostic factors for superficial transitional cell carcinoma of the bladder varied with the findings of different cohorts. Few multivariate analyses of prognostic factors for superficial bladder tumors have been reported in China and bladder preservation as a prognostic index of superficial bladder tumors is limited and scarce in Chinese patients. This study was conducted to analyze a group of risk factors for prognostic outcomes for patients with primary superficial transitional cell carcinoma of the bladder. METHODS: Between January 1980 to December 2000, 198 patients [172 men and 26 women; mean age (52.98 +/- 11.28) years] with primary superficial transitional cell carcinoma who were pathologically classified as Ta or T1 in Hunan Provincial Tumor Hospital (Changsha, China) were enrolled in this study. Surgical methods included local resection and electric coagulation of bladder tumors, transurethral resection of bladder tumors and partial cystectomy. After initial surgical treatment, patients were followed through a cystoscopy every three months during the first two years and every six months thereafter in the design of retrospective cohort. Survival analysis was performed to analyze risk factors of the prognostic outcomes for transitional cell carcinoma of the bladder. Canonical correlation analysis was conducted to present and interpret synthetically the multi-correlation between all kinds of prognostic outcomes and risk factor in multiply dimensions. RESULTS: The average follow-up period was (6.65 +/- 4.74) years. Assessments at three, five, and 10 years showed recurrence rates, respectively, of (28.32 +/- 3.45)%, (35.31 +/- 3.83)%, and (42.48 +/- 4.40)%; progression rates of (8.89 +/- 2.14)%, (15.16 +/- 2.94)%, and (23.88 +/- 4.19)%; bladder-preservation rates of (94.68 +/- 1.74)%, (93.87 +/- 1.91)%, and (91.51 +/- 2.49)%; metastasis rates of (8.25 +/- 2.05)%, (11.24 +/- 2.47)%, and (28.94 +/- 4.93)%; and cancer-related survival rates of (95.02 +/- 1.62)%, (90.70 +/- 2.45)%, and (77.14 +/- 4.88)%. The main risk factors for recurrence were histological grade, blood transfusion during surgery and the duration of symptoms. Progression was affected by blood transfusion during surgery, histological grade, the number of re-examinations, and the length of the recurrence-free period. Metastasis was associated with tumor multifocality, hydronephrosis, microscopic growth pattern, and the recurrence-free period. Cancer-related survival was influenced by microscopic growth pattern and the recurrence-free period. Bladder preservation involved only the recurrence-free period. The comprehensive results from canonical correlation analysis showed that the main prognostic outcomes were cancer-related survival, metastasis and progression respectively, while the dominate risk factors were histological grade, tumor multifocality and blood transfusion. CONCLUSIONS: The risk factors were different for each prognostic outcome of transitional cell carcinoma of the bladder. This is helpful for predicting the prognosis of transitional cell carcinoma of the bladder and designing therapeutic and follow-up strategies for this cancer.