Trilobatin attenuates cerebral ischaemia/reperfusion-induced blood-brain barrier dysfunction by targeting matrix metalloproteinase 9: The legend of a food additive.

BACKGROUND AND PURPOSE: Blood-brain barrier (BBB) breakdown is one of the crucial pathological changes of cerebral ischaemia-reperfusion (I/R) injury. Trilobatin (TLB), a naturally occurring food additive, exerts neuroprotective effects against cerebral I/R injury as demonstrated in our previous study. This study was designed to investigate the effect of TLB on BBB disruption after cerebral I/R injury. EXPERIMENTAL APPROACH: Rats with focal cerebral ischaemia caused by transient middle cerebral artery occlusion were studied along with brain microvascular endothelial cells and human astrocytes to mimic BBB injury caused by oxygen and glucose deprivation/reoxygenation (OGD/R). KEY RESULTS: The results showed that TLB effectively maintained BBB integrity and inhibited neuronal loss following cerebral I/R challenge. Furthermore, TLB increased tight junction proteins including ZO-1, Occludin and Claudin 5, and decreased the levels of apolipoprotein E (APOE) 4, cyclophilin A (CypA) and phosphorylated nuclear factor kappa B (NF-κB), thereby reducing proinflammatory cytokines. TLB also decreased the Bax/Bcl-2 ratio and cleaved-caspase 3 levels along with a reduced number of apoptotic neurons. Molecular docking and transcriptomics predicted MMP9 as a prominent gene evoked by TLB treatment. The protective effects of TLB on cerebral I/R-induced BBB breakdown was largely abolished by overexpression of MMP9, and the beneficial effects of TLB on OGD/R-induced loss of BBB integrity in human brain microvascular endothelial cells and astrocyte co-cultures was markedly reinforced by knockdown of MMP9. CONCLUSIONS AND IMPLICATIONS: Our findings reveal a novel property of TLB: preventing BBB disruption following cerebral I/R via targeting MMP9 and inhibiting APOE4/CypA/NF-κB axis.

A MnAl double adjuvant nanovaccine to induce strong humoral and cellular immune responses.

At present, the most widely used aluminum adjuvants have poor ability to induce effective Th1 type immune responses. Existing evidence suggests that manganese is a potential metal adjuvant by activating cyclic guanosine phospho-adenosine synthase (cGAS)-interferon gene stimulator protein (STING) signaling pathway to enhance humoral and cellular immune response. Hence, the effective modulation of metal components is expected to be a new strategy to improve the efficiency of vaccine immunization. Here, we constructed a manganese and aluminum dual-adjuvant antigen co-delivery system (MnO2-Al-OVA) to enhance the immune responses of subunit vaccines. Namely, the aluminum hydroxide was first fused on the surface of the pre-prepared MnO2 nanoparticles, which were synthesized by a simple redox reaction with potassium permanganate (KMnO4) and oleic acid (OA). The engineered MnO2-Al-OVA could remarkably promote cellular internalization and maturation of dendritic cells. After subcutaneous vaccination, MnO2-Al-OVA rapidly migrated into the lymph nodes (LNs) and efficiently activate the cGAS-STING pathway, greatly induced humoral and cellular immune responses. Of note, our findings underscore the importance of coordination manganese adjuvants in vaccine design by promoting the activation of the cGAS-STING-IFN-I pathway. With a good safety profile and facile preparation process, this dual-adjuvant antigen co-delivery nanovaccine has great potential for clinical translation prospects.

Smart combination of aluminum hydroxide and MF59 to induce strong cellular immune responses.

As two of the most widely used adjuvants, aluminum hydroxide and the oil-in-water emulsion MF59 have their intrinsic limitations: classical aluminum gel induces only weak cellular immune responses while MF59 cannot be used as an antigen delivery system due to its poor physical interaction with antigen molecules. Herein, we combined these two adjuvants and constructed a novel nano-vaccine delivery system by inserting aluminum hydroxide into the surface of a modified MF59 nano-emulsion (AlNEs). A model antigen ovalbumin (OVA) and an immune potentiator CpG were adsorbed on the surface of AlNEs (hereinafter AlNEs-OVA-CpG) through a facile mixing step. After subcutaneous injection, AlNEs-OVA-CpG effectively drained to lymph nodes, delivered both cargos into lymph node-resident antigen presenting cells (APCs), and escaped from lysosomes into the cytoplasm, resulting in enhanced antigen cross-presentation. Finally, AlNEs-OVA-CpG induced potent antigen-specific humoral and cellular immune responses, which significantly inhibited tumor growth and prolonged mice survival in a EG7-OVA tumor model. In sum, our results suggested that AlNEs have a great prospect to induce CD8+ T cell responses for subunit antigens.

Nanoparticles with rough surface improve the therapeutic effect of photothermal immunotherapy against melanoma.

Photothermal therapy has been intensively investigated for treating cancer in recent years. However, the long-term therapeutic outcome remains unsatisfying due to the frequently occurred metastasis and recurrence. To address this challenge, immunotherapy has been combined with photothermal therapy to activate anti-tumor immunity and relieve the immunosuppressive microenvironment within tumor sites. Here, we engineered silica-based core‒shell nanoparticles (JQ-1@PSNs-R), in which silica cores were coated with the photothermal agent polydopamine, and a bromodomain-containing protein 4 (BRD4) inhibitor JQ-1 was loaded in the polydopamine layer to combine photothermal and immune therapy for tumor elimination. Importantly, to improve the therapeutic effect, we increased the surface roughness of the nanoparticles by hydrofluoric acid (HF) etching during the fabrication process, and found that the internalization of JQ-1@PSNs-R was significantly improved, leading to a strengthened photothermal killing effect as well as the increased intracellular delivery of JQ-1. In the animal studies, the multifunctional nanoparticles with rough surfaces effectively eradicated melanoma via photothermal therapy, successfully activated tumor-specific immune responses against residual tumor cells, and further prevented tumor metastasis and recurrence. Our results indicated that JQ-1@PSNs-R could serve as an innovative and effective strategy for combined cancer therapy.

Palaeoecology of Cambrian-Ordovician acritarchs from China: evidence for a progressive invasion of the marine habitats.

Palaeozoic acritarchs mostly represent organic-walled cysts of marine phytoplankton, and therefore, as primary producers, played an important role in the evolution of marine ecosystems. In this study, we use a selection of the most abundant acritarch taxa from the Cambrian and Ordovician of China to understand the evolution of the palaeoecological patterns of the phytoplankton over the period. The taxa are attributed to 40 easily distinguishable morphotypes, of which the precise palaeoenvironmental distribution from 60 localities is available. By placing the 40 morphotypes on inshore-offshore transects it can be concluded that acritarch microfloras were limited to inshore environments during the early Cambrian, and progressively extended from inshore environments to offshore marine habitats during the later parts of the Cambrian and towards the Early Ordovician, with a prominent shift near the Cambrian-Ordovician boundary, confirming the onset of the 'Ordovician plankton revolution'. In addition, the acritarch morphotypes evolved from low-diversity assemblages in the early Cambrian, dominated by simple spherical forms with limited ornamentation and simple process structures, to highly diverse assemblages with very complex morphologies in the Early and Middle Ordovician. During the Ordovician, the complex acritarch assemblages occupied most marine habitats, with palaeoecological distribution patterns similar to modern dinoflagellates. This article is part of the theme issue 'The impact of Chinese palaeontology on evolutionary research'.

Engineering a sustained release vaccine with a pathogen-mimicking manner for robust and durable immune responses.

Sustained release vaccine carriers can facilitate an increased interaction time between the antigen and immune system to strengthen immune responses, but their promotion on adaptive immune responses, especially cellular immunity, are still unfavorable. Herein, we report a sustained antigen delivery vector, which carries abundant antigens, a nucleic acid adjuvant and pathogen-associated molecular patterns to simulate a natural pathogen to reinforce immune responses. Specifically, murine colorectal cancer cells MC38 lysate and Toll-like receptor 9 agonist CpG are loaded into yeast derived ß-glucan particles (GPs). After vaccination, these particles can form a vaccine depot that continuously release the antigen similar to the traditional aluminum hydroxide gel, but recruit more immune cells and induce more cytokine secretion at the injection site. Stronger antibody responses, Th1 and Th17 biased cellular immunity and immune memory are achieved compared with aluminum hydroxide gel. More importantly, treatment with these particles significantly suppress tumor growth in a therapeutic tumor model. This work shed light on the efficacy of combining sustained antigen release with pathogen-mimicking manner in vaccine design.

Highly efficient near-infrared BODIPY phototherapeutic nanoparticles for cancer treatment.

BODIPYs are highly potential photoactive agents for cancer theragnostics. The rational design of BODIPY-based photoactive nanodrugs with high efficiency and near-infrared (NIR) absorption is imperative. Herein, we developed a donor-acceptor-donor (D-A-D) organic photosensitizer (PS) (BODIPY, named NBB), which possessed strong absorption in the NIR region due to the multi-intersection of intramolecular charge transfer (ICT), photoinduced electron transfer (PET), and heavy atom effects. Through a nanoprecipitation method, NBB nanoparticles (NPs) were facilely prepared. The as-prepared NBB NPs exhibited favorable water-stability and photostability. In particular, the outstanding photon absorption capacity endows the NPs with high photothermal conversion efficiency (η = 53.8%) and active singlet oxygen (1O2) generation ability upon 808 nm laser irradiation, and promotes their tumour inhibition efficiency via the combination of photothermal/photodynamic therapy (half-maximal inhibitory concentration IC50 = 8.11 and 7.77 µM for HeLa and HepG2 cells, respectively). Together with the favorable synthetic yield and excellent antitumour effect, we envision that this exploration can provide beneficial guidance for the clinical translation of BODIPY-based PSs for phototherapy.

Red fluorescent pyrazoline-BODIPY nanoparticles for ultrafast and long-term bioimaging.

Fluorescence bioimaging is very significant in studying biological processes. Fluorescent nanoparticles (NPs) manufactured from aggregation-induced emission (AIE) materials, as promising candidates, have attracted more attention. However, it is still a challenge to explore suitable AIE NPs for bioimaging. Herein, we synthesized pyrazoline-BODIPY (PZL-BDP) with a donor and acceptor (D-A) structure by a condensation reaction, cultured its single crystal, and studied its twisted intramolecular charge transfer (TICT) and AIE effects. PZL-BDP could self-assemble to form red fluorescent nanoparticles (PZL-BDP NPs) which showed a good fluorescence quantum yield of 15.8% in water. PZL-BDP NPs with excellent stability and biocompatibility exhibited a large Stokes shift (Δλ = 111 nm) which resulted in the reduction of external interference and enhancement of the fluorescence contrast. Furthermore, these nanoparticles could be readily internalized by HeLa cells and they stain the cells in just five seconds, indicating an ultrafast bioimaging protocol. Moreover, long-term tracking fluorescence signals in vivo for about 12 days were obtained. The bright red fluorescence, ultrafast cell staining ability, and long-term in vivo tracking competence outline the great potential of rational design nanomaterials with AIE characteristics for monitoring biological processes.

Self-quenching synthesis of coordination polymer pre-drug nanoparticles for selective photodynamic therapy.

The design and preparation of a photoactive coordination polymer nanoplatform with tumor-related stimuli-activatability and biodegradability is highly desirable for achieving highly precise photodynamic therapy (PDT). Herein, novel "pre-photodynamic" nanoparticles (Fe-IBDP NPs) with a tumor microenvironment (TME)-activatable PDT and good biodegradability were synthesized by carrying out facile coordination assembly of an IBDP photosensitizer with an Fe3+ quenching agent. After being taken up by cancer cells, our "inactive" Fe-IBDP NPs were activated by the TME and as a result decomposed and released the photoactive carboxyl-functionalized diiodo-substituted BODIPY (IBDP) photosensitizer, which generated cytotoxic singlet oxygen (1O2) under light irradiation. By contrast, these NPs showed relatively low cytotoxicity in normal cells. This work also provided a feasible method for preparing the next generation of photoactive nanomedicines for use in precise phototherapy.

Comparative study of two near-infrared coumarin-BODIPY dyes for bioimaging and photothermal therapy of cancer.

Near-infrared (NIR) responsive agents for cancer bioimaging and photothermal therapy are available and significant. Herein, we employed two easily available dyes, boron-dipyrromethane and coumarin, to synthesize a pair of coumarin-borondipyrromethane dyes with different conjugate degrees (BDC and BSC). The difference in conjugate degree made their photophysical properties poles apart. After the self-assembling of BDC and BSC, the newly constructed nanoparticles (BDC NPs and BSC NPs) demonstrated good biocompatibility. Moreover, BDC NPs exhibited a good photothermal effect under irradiation of 808 nm laser, which could effectively inhibit the growth of HeLa cells, and BSC NPs could quickly show a conspicuous fluorescence in the HeLa cells. The exploration demonstrates that the two organic dyes prepared with different conjugation degrees could provide new options for photothermal therapy of cancer and rapid bioimaging.

An aluminum adjuvant-integrated nano-MOF as antigen delivery system to induce strong humoral and cellular immune responses.

Metal-organic frameworks (MOFs) have high surface area, tunable pore size, and high loading capacity, making them promising for drug delivery. However, their synthesis requires organic solvents, high temperature and high pressure that are incompatible with biomacromolecules. Zeolitic imidazole frameworks (ZIF-8) which forms through coordination between zinc ions and 2-methylimidazole (MeIM) have emerged as an advanced functional material for drug delivery due to its unique features such as high loading and pH-sensitive degradation. In this study, we took advantage of a natural biomineralization process to create aluminum-containing nanoZIF-8 particles for antigen delivery. Without organic solvents or stabilizing agent, nanoparticles (ZANPs) were synthesized by a mild and facile method with aluminum, model antigen ovalbumin (OVA) and ZIF-8 integrated. A high antigen loading capacity (%) of 30.6% and a pH dependent antigen release were achieved. A Toll-like receptor 9 agonist cytosine-phosphate-guanine oligodeoxynucleotides (CpG) was adsorbed on the surface of ZANPs (hereafter CpG/ZANPs) to boost the immune response. After subcutaneous injection in vivo, CpG/ZANPs targeted lymph nodes (LNs), where their cargo was efficiently internalized by LN-resident antigen-presenting cells (APCs). ZANPs decomposition in lysosomes released antigen into the cytoplasm and enhanced cross-presentation. Moreover, CpG/ZANPs induced strong antigen-specific humoral and cytotoxic T lymphocyte responses that significantly inhibited the growth of EG7-OVA tumors while showing minimal cytotoxicity. We demonstrate that ZANPs may be a safe and effective vehicle for the development of cancer vaccines.

CALD1, CNN1, and TAGLN identified as potential prognostic molecular markers of bladder cancer by bioinformatics analysis.

BACKGROUND: Bladder cancer (BC) is one of the most common malignant neoplasms in the genitourinary tract. We employed the GSE13507 data set from the Gene Expression Omnibus (GEO) database in order to identify key genes related to tumorigenesis, progression, and prognosis in BC patients. METHODS: The data set used in this study included 10 normal bladder mucosae tissue samples and 165 primary BC tissue samples. Differentially expressed genes (DEGs) in the 2 types of samples were identified by GEO2R. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the online website DAVID. The online website STRING was used to construct a protein-protein interaction network. Moreover, the plugins in MCODE and cytoHubba in Cytoscape were employed to find the hub genes and modules in these DEGs. RESULTS: We identified 154 DEGs comprising 135 downregulated genes and 19 upregulated genes. The GO enrichment results were mainly related to the contractile fiber part, extracellular region part, actin cytoskeleton, and extracellular region. The KEGG pathway enrichment results mainly comprised type I diabetes mellitus, asthma, systemic lupus erythematosus, and allograft rejection. A module was identified from the protein-protein interaction network. In total, 15 hub genes were selected and 3 of them comprising CALD1, CNN1, and TAGLN were associated with both overall survival and disease-free survival. CONCLUSION: CALD1, CNN1, and TAGLN may be potential biomarkers for diagnosis as well as therapeutic targets in BC patients.

Au-aided reduced graphene oxide-based nanohybrids for photo-chemotherapy.

Graphene-based nanomaterials show great potential in photo-chemotherapy, but their photo-thermal effect is not very satisfactory. Herein, we presented a facile and low-cost strategy to grow Au clusters on the reduced graphene oxide (rGO) sheets aiming to improve photothermal effect. Au clusters with low-concentration was directly conjugated on the surface of rGO by electrostatic forces. To improve its biocompatibility, 3­(3­phenylureido) propanoic acid (PPA)-PEG (PPEG) had been introduced as biodegradable backbone to form rGO/Au/PPEG nanohybrids via π-π accumulation. The obtained rGO-based nanohybrids showed excellent biocompatibility, stability, low cytotoxicity, and enhanced photo-thermal conversion efficiency. To verify the synergistic photo-chemotherapy, doxorubicin (DOX) as a drug model had been loaded in rGO/Au/PPEG nanohybrids. The results indicated that rGO/Au/PPEG/DOX exhibited synergistic therapeutic efficacy compared with single chemotherapy or photothermal therapy, endowing this designed rGO-based nanohybrids with great potential for cancer treatments.

Combined delivery of a TGF-ß inhibitor and an adenoviral vector expressing interleukin-12 potentiates cancer immunotherapy.

Cancer immunotherapy appears to have a promising future, but it can be thwarted by secretion of immunosuppressive factors, such as transforming growth factor-ß (TGF-ß), which inhibits local immune responses to tumors. To weaken immune resistance of tumors and simultaneously strengthen immune responses, we developed a multifunctional polymer that could co-deliver hydrophobic TGF-ß inhibitor and an adenovirus gene vector to tumor sites. This co-delivery system sustainably released TGF-ß inhibitor SB-505124 and effectively transferred the adenovirus vector carrying the interleukin-12 gene. In addition, it significantly delayed growth of B16 melanoma xenografts in mice and increased animal survival. Mechanistic studies showed that this combination therapy enhanced anti-tumor immune response by activating CD4+ and CD8+ T cells, natural killer cells and interferon-γ secretion in the tumor microenvironment. STATEMENT OF SIGNIFICANCE: To weaken immune resistance of tumors and simultaneously strengthen tumors' immune responses, we synthesized a structurally simple, low-toxic but functional polymer ß-cyclodextrin-PEI to encapsulate a hydrophobic TGF-ß inhibitor SB-505124 and to complex adenovirus vectors expressing IL-12. This is the first report demonstrating that combining TGF-ß inhibitor with IL-12 could provide effective immunotherapy against melanoma by the sustainable release of SB-505124 and the effectible transduction of IL-12 gene in tumor cells. The rational delivery system presented a comprehensive and valued platform to be a candidate vector for co-delivering hydrophobic small-molecule drugs and therapeutic genes for treating cancer, providing a new approach for cancer immunotherapy.

[Effect of silencing the VDR gene on the migration and invasion of prostate cancer cells].

OBJECTIVE: To investigate the effect of small interfering RNA silencing the vitamin D receptor (VDR) on the biological behavior of prostate cancer PC-3 cells. METHODS: We constructed the VDR-shRNA lentiviral vector and determined the mRNA and protein expressions of VDR by RT-PCR and Western blot. Using scratch wound healing and Transwell chamber assays, we detected the changes in the migration and invasiveness of the PC-3 cells after silencing VDR. RESULTS: The VDR-shRNA plasmid significantly interfered the VDR expression and successfully screened the cell lines with stable VDR-shRNA interference. The rate of scratch wound healing was markedly lower in the VDR interference group than in the blank control and LV3 negative control groups (59% vs 73.6% and 77.8%, P <0.05), but with no statistically significant difference between the latter two (P >0.05), and so was the count of permeable cells (P <0.05), but with no significant difference between the latter two groups, either (P >0.05). The migration ability and invasiveness of the VDR-treated cells were remarkably decreased as compared with those of the control cells. CONCLUSIONS: Down-regulated expression of the VDR gene may reduce the migration and invasiveness of prostate cancer cells.

[Indirect comparison of different adjuvant chemotherapies for stage II-III gastric cancer after D2 gastrectomy in Asian patients].

OBJECTIVE: To compare efficacy of different adjuvant chemotherapy regimens for stage II-III gastric cancer after D2 gastrectomy in Asian patients. METHODS: Associated literatures were searched through electronic databases and hand-searching. Prospective randomized clinical trials (RCTs) comparing adjuvant chemotherapy after D2 gastrectomy with surgery alone were included in the study. Overall survival and disease-free survival were chosen as the endpoints. Relative hazard was analyzed by Bucher adjusted indirect comparison. RESULTS: Two RCTs were selected, including comparison between S-1 versus surgery alone and comparison between XELOX versus surgery alone. There was no statistical difference in overall survival between the two regimens (HR=0.94, 95%CI:0.62-1.44, P=0.79). The recurrence risk of S-1 was slightly higher as compared to XELOX, but no statistical difference was found (HR=1.11, 95%CI:0.80-1.53, P=0.54). CONCLUSION: The adjuvant chemotherapy with S-1 is similar to XELOX for stage II-III gastric cancer after D2 gastrectomy in Asian patients.

No survival benefit from adding cetuximab or panitumumab to oxaliplatin-based chemotherapy in the first-line treatment of metastatic colorectal cancer in KRAS wild type patients: a meta-analysis.

BACKGROUND: The efficacy of combined therapies of oxaliplatin-based chemotherapy and anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies (MAbs) remains controversial in colorectal cancer (CRC). The aim of this study is to estimate the efficacy and safety of adding cetuximab or panitumumab to oxaliplatin-based chemotherapy in the first line treatment in KRAS wild type patients with metastatic colorectal cancer (mCRC) through meta-analysis. METHODS: Medline, EMBASE, and Cochrane library, American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) were searched. Eligible studies were randomized controlled trials (RCTs) which evaluated oxaliplatin-based chemotherapy with or without anti-EGFR drugs (cetuximab or panitumumab) in untreated KRAS wild type patients with mCRC. The outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicities. Hazard ratios (HR) and risk ratio (RR) were used for the meta-analysis and were expressed with 95% confidence intervals. RESULTS: This meta-analysis included four RCTs with 1270 patients, and all of the patients were administered oxaliplatin-based chemotherapy regimens with or without anti-EGFR MAbs. The result of heterogeneity of OS was not significant. Compared with chemotherapy alone, the addition of cetuximab or panitumumab didn't result in significant improvement in OS (HR = 1.00, 95%CI [0.88, 1.13], P = 0.95) or PFS (HR = 0.86, 95%CI [0.71, 1.04], P = 0.13). The subgroup analysis of cetuximab also revealed no significant benefit in OS (HR = 1.02, 95%CI [0.89, 1.18], P = 0.75) or in PFS (HR = 0.87, 95%CI [0.65, 1.17], P = 0.36). Patients who received combined therapy didn't have a higher ORR (Risk Ratio = 1.08, 95%CI [0.86, 1.36]). Toxicities slightly increased in anti-EGFR drugs group. CONCLUSIONS: The addition of cetuximab or panitumumab to oxaliplatin-based chemotherapy in first-line treatment of mCRC in wild type KRAS population did not improve efficacy in survival benefit and response rate. More RCTs are warranted to evaluate the combination of chemotherapy and targeted therapy.

Efficacy and adverse effects of transdermal fentanyl and sustained-release oral morphine in treating moderate-severe cancer pain in Chinese population: a systematic review and meta-analysis.

BACKGROUND: Previous meta-analysis suggested that transdermal fentanyl was not inferior to sustained-release oral morphine in treating moderate-severe cancer pain with less adverse effects. Now, we updated the data and performed a systematic review. METHODS: Updated cohort studies on transdermal fentanyl and oral morphine in the treatment of cancer pain were searched in electronic databases including CBMdisc, CNKI, VIP, Medline, EMBASE and Cochrane Library. Primary end points assessed by meta-analysis were remission rate of pain and incidence of adverse effects. Quality of life was assessed by systematic review, which was the second end point. RESULTS: 32 cohort studies, which included 2651 patients, were included in present study. The remission rate in transdermal fentanyl group and sustained-release oral morphine group were 86.60% and 88.31% respectively, there was no significant difference [RR = 1.13, 95% CI (0.92, 1.38), P = 0.23]. Compared with oral morphine group, there were less adverse effects in terms of constipation [RR = 0.35, 95% CI (0.27, 0.45), P < 0.00001], nausea/vomiting [RR = 0.57, 95% CI (0.49, 0.67), P < 0.00001], and vertigo/somnolence [RR = 0.59, 95% CI (0.51, 0.68), P < 0.00001] in transdermal fentanyl group. Six of selected trials supported either transdermal fentanyl or sustained-release oral morphine improved QOL of cancer patients and one of them showed more patients got better QOL after sustained-release oral morphine transferred to transdermal fentanyl. CONCLUSIONS: Our study showed again that both transdermal fentanyl and oral morphine had the same efficacy in the treatment of moderate-severe cancer pain in Chinese population, but the former might have less adverse effects and better quality of life.

Gemcitabine-based cytotoxic doublets chemotherapy for advanced pancreatic cancer: updated subgroup meta-analyses of overall survival.

OBJECTIVE: Previous meta-analyses showed a survival advantage with gemcitabine (GEM)-based combinations over GEM in advanced pancreatic cancer. Therefore, it would be valuable to explore the specific active regimens based on a subgroup meta-analysis. METHODS: Updated data by comprehensive search of the literature from databases and conference proceedings. Subgroup meta-analysis compared GEM with GEM-based doublets chemotherapy in terms of 6-month overall survival (OS) and 1-year OS. RESULTS: Eighteen randomized controlled trials with 4237 patients were included, which were divided into five subgroups: GEM/capecitabine, GEM/cisplatin, GEM/5-fluorouracil, GEM/irinotecan and GEM/oxaliplatin. In each subgroup, risk ratios (RRs) for 6-month OS were 0.85 (P = 0.04), 0.99 (P = 0.88), 0.95 (P = 0.46), 1.03 (P = 0.77) and 0.80 (P = 0.001), respectively, and RRs for 1-year OS were 0.94 (P = 0.14), 0.99 (P = 0.75), 0.96 (P = 0.19), 1.00 (P = 0.97) and 0.93 (P = 0.05), respectively. A meta-analysis of the trials with adequate information on performance status (PS) was performed in four trials with 1325 patients. Patients with a good PS did not show a survival benefit when receiving combination chemotherapy. RRs for 6-month and 1-year OS were 0.82 (P = 0.18) and 0.93 (P = 0.08). In contrast, application of combination chemotherapy to patients with a poor PS appeared to be harmful. RRs were 1.17 (P = 0.04) for 6-month OS and 1.09 (P = 0.04) for 1-year OS. CONCLUSIONS: The meta-analysis indicated a significant survival benefit when GEM was either combined with capcitabine or oxaliplatin. On the basis of a preliminary subgroup analysis, pancreatic cancer patients with a poor PS appeared to have a worse survival benefit from GEM-based cytotoxic doublets.