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Program death receptor-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing protein-3 (Tim-3) play an important role in tumor immune evasion. PD-1 blockade could produce an effective anti-tumor effect but the response rate was low due to lacking of tumor infiltrating lymphocytes (TILs) and existing of other negative regulatory pathways. Streptavidin(SA)-GM-CSF surface-anchored tumor cells vaccine could induce specific anti-tumor immune response. However, this vaccine failed to induce regression of established tumor because it also up-regulated PD-1 expression on tumor cells dependent on IFNγ and up-regulated PD-1/Tim-3 expression on CD8+ TILs. Subsets of CD8+ TILs assay showed that PD-1 expression was closely associated with CD8+ TILs exhaustion, and Tim-3 expression was closely correlated with secretion function but not proliferation of CD8+ TILs. Sequential administration of anti-PD-1 and anti-Tim-3 could further improve the efficacy of SA-GM-CSF-anchored vaccine therapy, and tumor regression was noted in over 50%. This triple therapy improves the specific cytotoxic activity and decreased the apoptosis of CD8+ TILs. These findings indicated that this triple therapy could induce a more robust anti-tumor immune response.

The diagenesis and diagenetic facies of shale reservoirs in Lucaogou Formation of Jimusar Sag were studied by means of microscopic observation and identification of ordinary thin sections and cast thin sections, X-ray diffraction, scanning electron microscope and electron probe tests. The results show that alkaline and acidic diagenetic processes occurred alternately during the deposition of Permian Lucaogou Formation in Jimusar Sag. The evolution of porosity in the shale reservoirs was influenced by compaction and alternate alkaline and acidic diagenetic processes jointly, and has gone through three stages, namely, stage of porosity reduction and increase caused by alkaline compaction, stage of porosity increase caused by acid dissolution, and stage of porosity increase and reduction caused by alkaline dissolution. Correspondingly, three secondary pore zones developed in Lucaogou Formation. The shale reservoirs are divided into three diagenetic facies: tuff residual intergranular pore-dissolution pore facies, tuff organic micrite dolomite mixed pore facies, and micrite alga-dolomite intercrystalline pore facies. With wide distribution, good pore structure and high oil content, the first two facies are diagenetic facies of favorable reservoirs in Lucaogou Formation. The research results provide a basis for better understanding and exploration and development of the Lucaogou Formation shale reservoirs.

The main objective of a confirmatory multiregional clinical trial (MRCT) is to demonstrate the overall efficacy of test drugs in all participating regions as well as to evaluate the possibility of extrapolating the overall results to each region. With the emergence of the demands of biosimilar drugs development, some guidelines recommended using equivalence design to demonstrate the comparability of efficacy between biosimilar and reference drugs. Previous discussions about assessing regional consistency in MRCT are mainly focused on superiority or non-inferiority designs, while the extensions to equivalence designs were limited. In this work, we proposed a flexible regional consistency criterion for the MRCT with equivalence design. Based on this criterion, sample size determination and sample allocation were also discussed.

SUMMARY Brachypodium distachyon is an annual C3 grass used as a monocot model system in functional genomics research. Insertional mutagenesis is a powerful tool for both forward and reverse genetics studies. In this study, we explored the possibility of using the tobacco retrotransposon Tnt1 to create a transposon‐based insertion mutant population in B. distachyon. We developed transgenic B. distachyon plants expressing Tnt1 (R0) and in the subsequent regenerants (R1) we observed that Tnt1 actively transposed during somatic embryogenesis, generating an average of 6.37 insertions per line in a population of 19 independent R1 regenerant plants analyzed. In seed‐derived progeny of R1 plants, Tnt1 segregated in a Mendelian ratio of 3:1 and no new Tnt1 transposition was observed. A total of 126 flanking sequence tags (FSTs) were recovered from the analyzed R0 and R1 lines. Analysis of the FSTs showed a uniform pattern of insertion in all the chromosomes (1–5) without any preference for a particular chromosome region. Considering the average length of a gene transcript to be 3.37 kb, we estimated that 29 613 lines are required to achieve a 90% possibility of tagging a given gene in the B. distachyon genome using the Tnt1‐based mutagenesis approach. Our results show the possibility of using Tnt1 to achieve near‐saturation mutagenesis in B. distachyon, which will aid in functional genomics studies of other C3 grasses., Significance Statement Retrotransposable elements transpose from one position in the DNA to another during embryogenesis, causing mutations at the genomic landing site. Here we show that Tnt1, a retrotransposable element from tobacco, can transpose in a monocot plant, Brachypodium distachyon. Based on the analyses of Tnt1 insertions in B. distachyon, we estimated that 29 613 lines would be needed to achieve a 90% probability of tagging every gene in the B. distachyon genome.

Emerging evidences have indicated that long non-coding RNAs (lncRNAs) are potential biomarkers, playing important roles in the development of cancer. LncRNA Activated in RCC with Sunitinib Resistance (lncARSR) is a novel lncRNA that functions as a potential biomarker and is involved in the progression of cancers. However, the clinical significance and molecular mechanism of lncARSR in bladder cancer (Bca) remains unknow. In this study, we discovered that lncARSR was significantly up-regulated in bladder cancer. In addition, increased expression of lncARSR was positively correlated with higher histological grade and larger tumor size. Further experiments demonstrated that suppression of lncARSR attenuated the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) process of Bca cells. Mechanistically, lncARSR was mainly located in the cytoplasm and acted as a miRNA sponge to positively modulate the expression of Sex-determining region Y-related high-mobility-group box transcription factor 4 (SOX4) via sponging miR-129-5p and subsequently promoted the proliferation and metastasis of Bca cells, thus playing an oncogenic role in Bca pathogenesis. In conclusion, our study indicated that lncARSR plays a critical regulatory role in Bca cells and lncARSR may serve as a potential diagnostic biomarker and therapeutic target for bladder cancer.

Background To investigate the associations of lens power with age, axial length (AL), and Type 2 diabetes mellitus (DM) in Chinese adults aged 50 and above. Methods Random clustering sampling was used to identify adults aged 50 years and above in urban regions of Shanghai. The participants underwent a comprehensive ophthalmic examination including subjective refraction, autorefraction, and IOL-Master. The crystalline lens power was calculated using Bennett’s formula. Results A total of 4177 adults were included. A linear decrease in lens power was observed both with age and with AL, followed by a stop of lens power loss after the age of 70 or when AL ≥ 25 mm, respectively. Participants with Type 2 DM presented higher lens power (0.43 diopter (D), p p p p p = 0.122) or with AL ≥ 25 mm (p = 0.172). Conclusions The lens power in adults aged 50 and above exhibited two stages with age and with AL. Type 2 DM caused an increase in lens power, which was not seen in participants aged ≥ 75 years or with AL ≥ 25 mm.

Huang-huai sheep are a new multiparous mutton sheep breed that has been cultivated by domestic scientific research institutes, governments, and sheep farms in China. Huang-huai sheep were bred using Dorper sheep as a sire and Small-tailed Han sheep as a dam. The breeding of Huang-huai sheep started in 2003, and three stages have been carried out: crossbreeding innovation, fixation in a two-way-crossbred closed flock, and herd propagation. A pilot test of Huang-huai sheep was conducted on 6 sheep farms from 2017 to 2018, and hereditary properties and production performance were evaluated in 2019. Huang-huai sheep were identified on site by the National Livestock and Poultry Resources Committee of China in December 2019 and approved as a new multiparous mutton sheep breed in China. The genetic distance showed that Huang-huai sheep are most closely related to Dorper sheep, Luxi black-headed sheep, and Small-tailed Han sheep, but the genetic distances are subspecies (0.02–0.20) each other. The body weights of adult Huang-huai sheep are 98.1 ± 5.2 kg (♂) and 71.7 ± 3.5 kg (♀), and those of 6-month-old Huang-huai sheep are 58.50 ± 6.55 kg (♂) and 52.45 ± 5.67 kg (♀). The slaughter rates of 6-month-old sheep are 56.02 ± 1.25% (♂) and 53.19 ± 1.19% (♀). The estrus cycle of Huang-huai sheep is 19.32 ± 2.8 days, the first estrus cycle occurs at 168 ± 12 days, the annual lambing rate of ewes is 252.82% ± 10.69%, the survival rate of lambs is 95.79 ± 0.95%, and the number of weaned lambs per ewe per year is 2.38 ± 0.14. The growth performance, carcass quality, and reproductive performance of Huang-huai sheep have been improved, resulting in considerable economic and social benefits and broader market prospects. This breed represents a new multiparous mutton sheep breed adapted for industrial sheep farms in China.

The deactivation of SIRT3, a novel deacetylase located in mitochondria, can aggravate multiple organ dysfunction. However, the role of SIRT3 and its downstream targets in ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) remain unknown.I/R was reproduced in a rat model using a clamp placed on the left and right renal pedicles for 40 min. The rats were intraperitoneally injected with either the vehicle or a selective SIRT3 inhibitor (3-TYP) and scarified at different time points (4, 8, and 24 h after I/R). A portion of the renal tissue was extracted for histological analysis, and another portion was collected for the isolation of renal tubular epithelial cells for Western blotting, SOD2 and SIRT3 activity, cell apoptosis, and the determination of oxidative stress.The I/R-induced AKI model was successfully reproduced and SIRT3 activity was considerably reduced than control (sham operated) group, accompanied by increased acetylation of SOD2 and p53, as well as their elevated physical interaction in extracted mitochondrial protein (all P values 0.05). Moreover, SIRT3 suppression by 3-TYP treatment (comparing with the vehicle treatment group) aggravated AKI, as evidenced by increased indicators of oxidative stress (increased mitochondrial red fluorescence MitoSOX and decreased reduced glutathione/oxidized glutathione ratio, all P values 0.01).The elevation of SOD2 and p53 protein acetylation in the mitochondria of renal tubular epithelial cells is an important signaling event in the pathogenesis of I/R-induced AKI. Thus, deacetylase SIRT3 may be an upstream regulator of both SOD2 and p53, and the SIRT3 deactivation may aggravate AKI.

Immunotherapy may be an effective way to prevent postoperative recurrence of renal cell carcinoma. Streptavidin-interleukin-2 (SA-IL-2) surface-modified tumor cell vaccine developed through our protein-anchor technology could induce specific antitumor T-cell responses, but this immunotherapy cannot completely eradicate the tumor. These effector T cells highly expressed programmed death receptor-1 (PD-1), and the expression of programmed death ligand-1 (PD-L1) in the tumor environment also was upregulated after SA-IL-2-modified vaccine therapy. PD-1/PD-L1 interaction promotes tumor immune evasion. Adding PD-1 blockade to SA-IL-2-modified vaccine therapy increased the number of CD4+ , CD8+ and CD8+ interferon-γ+ but not CD4+ Foxp3+ T cells. PD-1 blockade could rescue the activity of tumor-specific T lymphocytes induced by the SA-IL-2-modified vaccine. Combination therapy delayed tumor growth and protected mice against a second Renca cells but not melanoma cells challenge. Taken together, PD-1 blockade could reverse immune evasion in the treatment with SA-IL-2-modified vaccine, and eventually induce a stronger specific antitumor immune response against renal cell carcinoma.

Purpose: To investigate whether PD-L1 mediated adaptive resistance could occur in treatment with Anchored-GM-CSF vaccine and whether PD-1 blockade combined with Anchored-GM-CSF vaccine could induce a greater anti-tumor immune response than either immunotherapy alone. Materials and Methods: After establishing long-established subcutaneous metastasis bladder cancer models, mice were treated with Anchored-GM-CSF vaccine and/or anti-PD-1 antibody. T-lymphocyte-cytotoxicity, flow cytometric analysis, immunohistochemical, immunofluorescence staining, CD8+ -T cell apoptosis and enzyme-linked immunosorbent assays were performed to evaluate the efficacy of combination therapy with anchored-GM-CSF vaccine and PD-1 blockade and to explore the related mechanism. Results: Anchored-GM-CSF vaccine could significantly increase the number of mature DCs and up-regulate PD-L1 expression dependent on IFN-γ released from CD8+ T cells. Anchored-GM-CSF vaccine combined with anti-PD-1 antibody could effectively inhibit tumor growth and even cause regression of the established tumor. More CD4+ and CD8+ T cells appeared at tumor sites and in peripheral blood in the combination therapy group than in the control groups. Splenocytes from mice of the combination therapy group exhibited the most potent cytotoxicity to MB49 cells. Apoptotic assays showed that PD-1 blockade could significantly reduce CD8+ T cells apoptosis. Conclusions: Anchored-GM-CSF vaccines and anti-PD-1 antibodies have synergistic effects in metastatic bladder cancer treatment. PD-1 blockade can overcome immune resistance in treatment with the Anchored-GM-CSF vaccine, while Anchored-GM-CSF vaccine can enhance the efficacy of PD-1 blockade therapy.

The aim of our study was to investigate the effect of hypertension on health-related quality of life (HRQoL) among different age subgroups of people in Shanghai using subpopulation treatment effect pattern plot (STEPP) methodology. We utilized data from the fifth Health Service Survey of Shanghai, 2013, which utilizes a cross-sectional study design. The participants were selected into the survey by using a three-stage, stratified, random sampling method. HRQoL was evaluated by the EuroQol five-dimensional 3 level (EQ-5D-3L) questionnaire, and the EuroQol-visual analog scales (EQ-VAS) score was the main outcome. A generalized estimating equations (GEE) model adjusted for socio-demographic covariates was used to determine the effect of hypertension on HRQoL. STEPP analysis was performed to explore the effect of hypertension within overlapping age subpopulations. Subgroup analyses for gender were conducted for the main outcome. A total of 28,730 residents who were 18 years or older were included in our study. The results of the multivariate GEE model showed that hypertension negatively affected HRQoL in the study population (estimate = −1.85, p

Norcantharidin (NCTD) is a promising antitumor drug with low toxicity. It was reported to be able to regulate immunity, but the mechanism is not yet clear. Here we explored whether NCTD could enhance the antitumor immunity induced by prostate cancer cell vaccine. The results of the in vitro study showed that NCTD induced apoptosis and inhibited proliferation of regulatory T cells (Tregs). Mechanistic research showed that NCTD inhibited Akt activation and activated FOXO1 transcription, resulting in a pro‐apoptotic effect. The results of the in vivo study showed that more tumor‐infiltrating Tregs existed within peripheral blood and tumor tissue after treatment with the vaccine. Adding NCTD to vaccine treatment could decrease the number of tumor‐infiltrating Tregs and increase the number of CD4+ and CD8+ T cells. Combination therapy with NCTD and vaccine was more effective in inhibiting tumor growth than the vaccine alone. In general, this is the first report that NCTD could induce apoptosis of Tregs and enhance the vaccine‐induced immunity.

Eliminating cancer stem cells (CSCs) is a key issue in eradicating tumor. The streptavidin-granulocyte-macrophage-colony stimulating factor (SA-GM-CSF) surface-modified bladder CSCs vaccine previously developed using our protein-anchor technology could effectively induce specific immune response for eliminating CSCs. However, program death receptor-1 (PD-1)/program death ligand 1 (PD-L1) signaling in tumor microenvironment results in tumor-adaptive immune resistance. Although the CSCs vaccine could increase the number of CD8+ T cells, a part of these CD8+ T cells expressed PD-1. Moreover, the CSCs vaccine upregulated the PD-L1 expression of tumor cells, resulting in immune resistance. Adding PD-1 blockade to the CSCs vaccine therapy increased the population of CD4+ , CD8+ and CD8+ IFN-γ+ but not CD4+ Foxp3+ T cells and induced the highest production of IFN-γ. PD-1 blockade could effectively enhance the functions of tumor-specific T lymphocytes generated by the CSCs vaccine. This combination therapy improved the cure rate among mice and effectively protected the mice against a second CSCs cell challenge, but not a RM-1 cell challenge. These results indicate that PD-1 blockade combined with the GM-CSF-modified CSCs vaccine effectively induced a strong and specific antitumor immune response against bladder cancer.

Program death receptor-1 (PD-1)/program death ligand 1 (PD-L1) signaling plays an important role in tumor adaptive immune resistance. The streptavidin-granulocyte-macrophage colony stimulating factor (SA-GM-CSF) surface-modified tumor cells vaccine developed through our novel protein-anchor technology could significantly promote the activation of dendritic cells. Although GM-CSF vaccine could significantly increase the number of tumor-specific CD8+T-cells, the majority of these CD8+T-cells expressed PD-1. Moreover, GM-CSF vaccine up-regulated the PD-L1 expression of tumor cells, resulting in immune resistance. Adding PD-1/PD-L1 blockade to GM-CSF vaccine therapy could significantly increase the population of CD4+ T, CD8+ T and CD8+ IFN-γ+ T but not CD4+ Foxp3+ T-cells and induced the highest production of IFN-γ. PD-1/PD-L1 blockade could effectively rescue the tumor-specific T lymphocytes generated by the GM-CSF vaccine, resulting in consistent tumor rejection. Taken together, PD-1/PD-L1 blockade combined with SA-GM-CSF-modified vaccine could effectively induce a strong specific antitumor immune response against prostate cancer.

ObjectivesMembers living in the same household tend to share some similar behaviours and environment. We want to quantitatively assess the associations of chronic conditions to investigate the concordance of disease status among the household members.SettingShanghai, China.ParticipantsOur data were from the fifth Health Service Survey in Shanghai in 2013. 12 002 households with 31 531 residents were selected in this survey by using a three-stage, stratified, random sampling method.Outcome measuresFive highly prevalent chronic conditions, namely hypertension, diabetes, ischaemic heart disease (IHD), cerebrovascular disease (CVD) and obesity were chosen. The generalised estimating equations (GEE) model was used to estimate the associations adjusted for age, gender, education status, health insurance status, smoking and drinking. Using a subsample of adult children with parents’ chronic conditions as the key risk factor and a subsample of wives with the chronic conditions of the husband as key risk factor, we reran our GEE models to explore chronic condition concordance within these relationships.ResultsA total of 10 198 households with 27 010 adult participants were included. Using all adult household members, we found positive statistically significant associations between one’s chronic conditions and the same disease status of their household members (hypertension (OR=3.26, 95% CI 3.02 to 3.52); diabetes (OR=1.68, 95% CI 1.40 to 2.01); IHD (OR=5.31, 95% CI 3.56 to 7.92); CVD (OR=3.40, 95% CI 1.99 to 5.80); obesity (OR=3.41, 95% CI 2.34 to 4.96)). The results of analysing ad-child subsample and spouse subsample also showed similar associations. Moreover, the potential concordance of different chronic conditions was found between hypertension and diabetes.ConclusionsWe found chronic condition concordance within households. This study provides evidence that the chronic conditions of other members of a household may be a significant risk factor for a household member’s own health.

Purpose To evaluate and compare the functional outcomes of ileal and sigmoid neobladders in patients underwent radical cystectomy. Methods Relevant studies were identified by searching PubMed, Embase, and Cochrane Library. The studies comparing the functional outcomes of sigmoid neobladder (SN) and ileal neobladder (IN) in patients underwent radical cystectomy were included. Results A total of 12 cohort studies were included in this meta-analysis. From our analysis, more early complications were observed in SN group than in IN group (RR = 1.37, 95% CI: 1.03–1.81). Both daytime and nighttime continence rates were significantly better in IN group than in SN group (RR = 0.87, 95%CI: 0.81–0.94) (RR = 0.73, 95%CI: 0.60–0.90). More patients could spontaneous voiding in SN group than in IN group (RR = 1.12, 95%CI: 1.00–1.26). According to the urodynamic study, ileal neobladder exhibited bigger capacity (WMD = −84.93, 95%CI: −160.36 to −9.50), lower pressure at capacity (WMD = 11.18, 95%CI: 4.29–18.06), better compliance (WMD = −25.55, 95%CI: −32.45 to −18.64), and greater post-void residual volume(WMD = −23.48, 95%CI: −36.75 to −10.21); There was no significant difference in the max voiding flow rate or void volume between the two groups (WMD = −1.00, 95%CI: -3.73-1.73) (WMD = −27.00, 95%CI: 70.05-16.06). No significant difference was found in the serum creatinine between the two groups (WMD = −0.05, 95%CI: -0.12-0.03). Conclusions Ileal neobladder seems able to provide more favorable patient's satisfaction, while sigmoid neobladder may provide a better chance of spontaneous voiding. This meta-analysis may provide some useful evidences for urological surgeons to choose the ideal bladder substitute for patients underwent radical cystectomy.

Programmed death receptor-1 (PD-1) and T cell immunoglobulin and mucin domain-containing protein-3 (Tim-3) play important roles in tumor immune evasion. PD-1 blockade could produce an effective antitumor effect in many solid tumors except prostate cancer (PCa) because of rare programmed death ligand-1 (PD-L1) expression on PCa cells. Streptavidin (SA)-GM-CSF surface-anchored tumor cell (Anchored GM-CSF) vaccines could increase the number of tumor-infiltrating lymphocytes (TILs) and induce specific antitumor immune responses. The Anchored-GM-CSF vaccine and anti-PD-1 antibodies exerted synergistic effects in mouse models of PCa metastasis. However, the response rate was low due to the presence of other negative regulatory pathways. Tim-3 expression could be upregulated at resistance to combination therapy with anti-PD-1 antibodies and the Anchored GM-CSF vaccine. Sequential administration of anti-PD-1 and anti-Tim-3 antibodies could further improve the efficacy of the Anchored GM-CSF vaccine therapy, and tumor regression was noted in over 60% of animals. This triple therapy improved the specific cytotoxic activity, proliferation and secretion of CD8+ TILs and reduced the production of tumor-promoting cytokines. These findings indicated that this triple therapy could induce a robust antitumor immune response in mouse models of PCa.

Liver ischemia-reperfusion injury is an important clinical complication in which excessive inflammation is a key factor; however, few studies have provided effective means of its regulation. As previous studies suggested that electro-acupuncture (EA) is able control excessive inflammation, the present study aimed to explore its effects on liver ischemia-reperfusion injury in experimental rats. The animals were randomly divided into surgery and sham groups, which were further divided into four sub-groups, including a non-treatment (NT), a non-point acupuncture (NPA), the non-selective nicotinic acetylcholine receptor (AChR) agonist 1,1-dimethyl-4-phenyl L-pioperazinium iodide (DMPPI) and an EA group. The alanine aminotransferase (ALT), serum cytokine and myeloperoxidase (MP) levels and the tissue pathology were evaluated after 90 min of ischemia followed by a 4, 8 or 24 h reperfusion. The results demonstrated that EA and DMPPI suppressed serum ALT elevation at 4 and 8 h reperfusion, whereas NPA did not. I/R induced hepatocellular necrosis, and cytoplasmic vacuolization and sinusoidal congestion was ameliorated by EA treatment after an 8 and 24 h reperfusion. In addition, EA also inhibited liver neutrophil accumulation, evidenced by a decreased MPO level at 8 h reperfusion. EA also suppressed the release of serum inflammatory factors TNF-α and IL-6 for the duration of reperfusion. However, little influence on IL-10 was observed. Mechanistically, vagus block by subphrenic vagotomy or mecamylamine hydrochloride abolished EA effect on liver damage, neutrophil accumulation and inflammatory factor release. In conclusion, it was demonstrated that EA protects the liver against I/R induced injury by inhibiting the inflammatory response, which is associated with the vagus.

The aim of our study was to investigate the effect of hypertension on health-related quality of life (HRQoL) among different age subgroups of people in Shanghai using subpopulation treatment effect pattern plot (STEPP) methodology. We utilized data from the fifth Health Service Survey of Shanghai, 2013, which utilizes a cross-sectional study design. The participants were selected into the survey by using a three-stage, stratified, random sampling method. HRQoL was evaluated by the EuroQol five-dimensional 3 level (EQ-5D-3L) questionnaire, and the EuroQol-visual analog scales (EQ-VAS) score was the main outcome. A generalized estimating equations (GEE) model adjusted for socio-demographic covariates was used to determine the effect of hypertension on HRQoL. STEPP analysis was performed to explore the effect of hypertension within overlapping age subpopulations. Subgroup analyses for gender were conducted for the main outcome. A total of 28,730 residents who were 18 years or older were included in our study. The results of the multivariate GEE model showed that hypertension negatively affected HRQoL in the study population (estimate = -1.85, p 0.0001). According to the STEPP analysis, we found that the EQ-VAS score in the hypertension group was lower than that in non-hypertension group for every age group. Additionally, the results of subgroup analyses indicated that the difference of score between two groups was larger among young women. When compared to respondents without hypertension, respondents with hypertension experienced lower HRQoL regardless of gender or any range of age. Furthermore, the impact of hypertension on HRQoL of young women might be more obvious.

Background: The Oxaliplatin plus 5-Fluorouracil /Leucovorin (FOLFOX4) regimen have been approved by Chinese Food and Drug Administration (CFDA), and covered by health insurance for patients with advanced hepatocellular carcinoma (HCC) in China. However, the efficacy of FOLFOX4 for HCC patients is still under debate. In this study, we aimed to establish a nomogram to identify HCC patients who might benefit from FOLFOX4 chemotherapy base on individual profile. Methods: A total of 184 patients from the EACH study who were treated with FOLFOX4 were included in this analysis. Backward Cox proportional hazards regression combined with clinical experience was used to select variables for construction of the nomogram. The nomogram performance was assessed in terms of discrimination and calibration. The results were validated using bootstrap resampling. Results: Six variables were included in the prognostic models based on their clinical relevance: age, maximum tumor diameter, lymph node status, aspartate aminotransferase (AST), total bilirubin (TBIL) and alpha-fetoprotein (AFP). The calibration curve showed that the predicted survival probabilities closely matched the actual observations. The C-index of the model was 0.75 (95% CI:0.71-0.80). This value was significantly superior to the one for the following staging systems: BCLC (0.67, P=0.004), CUPI (0.66, P

Background: Fatal adverse events (FAEs) have been reported with sorafenib, a vascular endothelial growth factor receptor kinase inhibitor (VEGFR TKI). We here performed an up-to-date and detailed meta-analysis to determine the overall risk of FAEs associated with sorafenib. Methods: Databases, including PubMed, Embase and Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings were searched to identify relevant studies. Eligible studies included randomized controlled trials evaluating sorafenib effects in patients with all malignancies. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated for FAEs. In addition, subgroup analyses were performed according to tumor type and therapy regimen. Results: 13 trials recruiting 5,546 patients were included in our analysis. The overall incidence of FAEs with sorafenib was 1.99% (95%CI, 0.98-4.02%). Patients treated with sorafenib had a significantly increased risk of FAEs compared with patients treated with control medication, with an RR of 1.77 (95%CI 1.25-2.52, P=0.001). Risk varied with tumour type, but appeared independent of therapy regimen. A significantly increased risk of FAEs was observed in patients with lung cancer (RR 2.26; 95% CI 1.03-4.99; P= 0.043) and renal cancer (RR 1.84; 95% CI 1.15-2.94; P= 0.011). The most common causes of FAEs were hemorrhage (8.6%) and thrombus or embolism (4.9%). Conclusions: It is important for health care practitioners to be aware of the risks of FAEs associated with sorafenib, especially in patients with renal and lung cancer.

Whether an endobronchial ultrasound (EBUS) is required for transbronchial needle aspiration (TBNA) in the diagnosis of mediastinal masses is currently a disputed subject. Previous studies have demonstrated that EBUS-TBNA performs better compared to conventional TBNA as it is capable of sampling in real-time compared with conventional TBNA. However, some clinicians consider conventional TBNA to be sufficient for diagnosis. In this meta-analysis, we evaluated these two methods according to diagnostic yield. A search was conducted through PubMed, Embase and the proceedings of major conferences, for studies comparing TBNA with EBUS-TBNA in the diagnosis of mediastinal masses. The identified studies were evaluated for publication bias and heterogeneity. The primary outcome was diagnostic yield. Pooled odds ratio (OR) estimated with 95% confidence intervals (CIs) was calculated using the fixed-effects model. Five studies, including a total of 407 patients, were included in the meta-analysis. The EBUS-TBNA arm was associated with a significantly higher OR compared to that of the TBNA arm in terms of diagnostic yield (OR=2.72, 95% CI: 1.72–4.30, P

Objectives Many strategies are pursued to enhance tumor vaccine immune response, including the utilization of cytokines. We have developed a novel protein-anchor technology to immobilize cytokines on tumor cell surface. Here we reported the preparation of tumor cell vaccines by immobilizing GM-CSF or IL-2 on MB49 bladder cancer cells and evaluated their antitumor efficacy (administrated alone or sequentially) in a metastatic mouse model. Materials and methods SA-mGM-CSF or SA-hIL-2 surface-modified MB49 cells were prepared as vaccine. Mice were treated with MB49 cell vaccines (administrated alone or sequentially). Survival time, tumor growth, flow cytometry, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and cytotoxic T lymphocytes (CTL) assay were used to evaluate the antitumor efficiency of the vaccines in the pulmonary metastatic model of bladder cancer. Results GM-CSF vaccine induced more mature dendritic cells in the mice spleen. Combination with subsequent IL-2 vaccine significantly increased CD4 + , CD8 + , and IFN-γ + CD8 + T but not CD4 + Foxp3 + T cell population and induced the highest production of IFN-γ, IL-12, but not IL-10. Furthermore, the splenocytes from the sequentially combined vaccines group showed the most potent cytotoxicity on MB49 cells. Finally, the sequentially combined vaccines evidently extended the survival time of mice (the median survival time of PBS, ethanol-fixed, anchored GM-CSF, anchored IL-2, and anchored GM-CSF + anchored IL-2 groups were 34, 37, 45, 47, and 59 days, respectively) and effectively protected the mice against a second MB49 cells but not RM-1 cells challenge. Conclusions This study demonstrated that sequential administration of GM-CSF and IL-2 surface-modified MB49 cells vaccines could effectively induce specific antitumor immune response.

The findings of epidemiologic studies on the association between egg consumption and bladder cancer risk remain conflicting. We conducted a meta-analysis to clarify the potential association between egg consumption and bladder cancer risk. Four cohort studies and 9 case-control studies in the PubMed database through February 2012 were identified on egg consumption and risk of bladder cancer involving 2715 cases and 184,727 participants. Random-effects models were used to calculate the summary relative risk estimates (SRRE) based on the highest compared with the lowest category of egg consumption. In addition, we performed stratified analyses and sensitivity and dose-response analyses to examine the association. Overall, no significant association was observed between egg consumption and bladder cancer (SRRE = 1.11 95% CI: 0.90-1.35). However, increased risk of bladder cancer was detected in North/South America (SRRE = 1.40 95% CI: 1.05-1.86) and, moreover, fried egg intake positively associated with bladder cancer as well (SRRE = 2.04, 95% CI: 1.41-2.95). In conclusion, our findings suggest no significant association between egg consumption and bladder cancer risk, except for a possible positive relationship with the intake of fried eggs based on the limited number of studies. Additional studies, especially large prospective cohort studies, are warranted to confirm these findings.

The method of time-to-onset (TTO) has been proposed to overcome the drawbacks of traditional disproportionality analyses (DPAs), and it has been used for detecting safety signals of vaccines and some non-vaccine products in spontaneous reporting systems (SRSs). However, there is no consensus on its superiority over DPAs. Further, it is still not clear whether this novel approach can be generalized to the entire national SRS database. The purpose of this study was to generalize the TTO method to the Chinese SRS and to identify suitable parameters for its optimal performance. Reports submitted to the national SRS of China in 2014 were used as the data source for analysis. We evaluated the performance of TTO by using product labels as proxies for the gold standard. A series of values of significance level and time windows were explored to identify the most suitable parameters for TTO based on Youden’s index, a statistic that summarizes the performance of a diagnostic test. Additionally, we compared TTO with traditional DPAs and explored the characteristics of signals detected by these methods. Compared with DPAs, TTO had a lower sensitivity, but higher specificity and positive predictive value. At a significance level of 0.2 and no restrictions on time windows, TTO had the highest Youden’s index. The kappa coefficients between TTO and DPAs were rather low, indicating poor agreement between the two methods. More than 30% of the true signals detected by TTO were not identified by DPAs. Furthermore, TTO needed more number of reports to be able to detect signals. TTO can detect signals missed by traditional DPAs and could be an important complementary tool to the currently used DPAs in the SRS of China. We recommend a significance level of 0.2 and no restrictions on time windows for TTO.

Background We aimed to investigate the management of hypertension in Shanghai, China and to examine whether there was any difference of hypertension management among people enrolled in different health insurances. Methods In this cross-sectional study, a total of 31,531 residents were selected in Shanghai, using a randomized, stratified, multi-stage sampling method, and were asked to provide their status of hypertension, condition of hypertension management, health insurances and other demographic information. A weighted propensity score model was used to adjust confounders and to analyze the differences on hypertension management among hypertension patients enrolled in different health insurances. Results In Shanghai, most hypertension patients achieved good management of hypertension. However, patients enrolled in the New Cooperative Medical Scheme or the Urban Resident Basic Medical Insurance scheme were more likely to achieve publicity of precautionary knowledge about hypertension (OR = 2.36 [95 % CI :1.96,2.85] and 1.28 [95 % CI:1.12,1.45], respectively) and had their blood pressure under control (OR = 1.33 [95 % CI :1.09,1.62] and 1.22 [95 % CI:1.05,1.42], respectively) than patients enrolled in the Urban Employee Basic Health Insurance scheme. Conclusion The study provided a comprehensive description of hypertension in Shanghai, China. To support the management of hypertension, publicity of hypertension prevention knowledge should be improved, especially to people enrolled in the Urban Employee Basic Health Insurance scheme. Electronic supplementary material The online version of this article (doi:10.1186/s12889-016-3627-3) contains supplementary material, which is available to authorized users.

Immunotherapy is considered effective for muscle invasive bladder cancer mini metastasis. We developed what is to our knowledge a novel technology by which streptavidin tagged mouse GM-CSF was displayed on the surface of biotinylated bladder cancer cells to induce antitumor immunity.Mouse subcutaneous and lung metastasis bladder cancer models were established. Mice were injected subcutaneously with 1 × 10(6) mouse GM-CSF surface modified MB49 bladder cancer cells and monitored for tumor growth and survival. Immunohistochemical and flow cytometric assay were done to assess the proportion of T lymphocytes. The T-lymphocyte cytotoxicity assay was performed to assess MB49 specific cytotoxicity. On day 60 after MB49 implantation the vaccine cured mice were injected subcutaneously with MB49 or RM-1 cells in the left or right hind leg, respectively. They were monitored for survival and T-lymphocyte cytotoxicity.Mouse GM-CSF surface modified vaccine significantly inhibited tumor growth in the subcutaneous model and extended survival in the lung model. More CD4 and CD8 T cells appeared at tumor sites and in peripheral blood in the vaccine treated group than in other control groups. Splenocytes from the vaccine treated group showed the most potent cytotoxicity on MB49 cells. Cured mice in the vaccine treated group resisted the second injection of MB49 bladder cancer cells but not the RM-1 prostate cancer cell challenge.Mouse GM-CSF surface modified MB49 bladder cancer cell vaccine induced specific antitumor immunity and was efficient for metastatic bladder cancer.

Background Maintenance therapy for patients with non-small cell lung cancer (NSCLC) has gained extensive interest. Varying results for this treatment underpin the need for a synthesis of evidence. Methods Trials investigating maintenance therapy with either a continuous or a switch strategy for patients with nonprogressing NSCLC compared with placebo or observation were identified. The primary outcome was overall survival (OS), and secondary outcomes included progression-free survival (PFS) and toxicity. Results Eight trials of 3,736 patients were included in the analysis. Switch maintenance therapy substantially improved OS compared with placebo or observation (hazard ratio [HR], 0.85; 95% CI, 0.79-0.92; P Conclusions Maintenance therapy with either a continuous or a switch strategy significantly increases OS and PFS compared with placebo or observation. However, the benefits must be balanced against toxicity.

Non-parametric methods have been well recognised as useful tools for time-to-event (survival) data analysis because they provide valid statistical inference with few assumptions. Tangen and Koch have proposed the use of the method of non-parametric covariance for time-to-event data in a traditional superiority setting. In this article, we extended their method to assess non-inferiority of two treatments. To evaluate this non-parametric method versus the classical semi-parametric Cox proportional hazards regression model, simulations in terms of the Type 1 error rate and power were performed and compared. The results showed that the two methods were generally comparable regarding the Type 1 error rate when adjustment for the covariates correlated with the survival time was made. In the non-inferiority setting, the covariate-adjusted non-parametric analysis was shown to always increase power. However, this was not necessarily the case for the adjusted Cox model where results were inconsistent to those seen in the superiority setting. For illustration, an application of the proposed non-parametric method to a trial involving pemetrexed, a recently approved drug for first-line treatment of non-small cell lung cancer, is included.

P-Values for the Differences Before and After Correction on the Multiple propensity score. (DOCX 15 kb)

ORs in different outcome models. (DOCX 19 kb)

Background: Adjuvant transcatheter arterial chemoembolization (TACE) is associated with better outcome and reduced tumor recurrence in hepatocellular carcinoma (HCC) patients. This study aimed to investigate the relationship between glutamine synthetase (GS) expression and survival of HCC patients after postoperative adjuvant TACE. Methods: We retrospectively analyzed 554 HCC patients in two independent cohorts who underwent curative resection. Immunohistochemistry assay was used to investigate the expression of GS protein and evaluate the association with survival and the response to adjuvant TACE. Results: In training cohort, patients with low GS expression who received postoperative adjuvant TACE showed a better overall survival (OS) (P

Aims The objective of this review was to assess glucagon-like peptide-1 receptor agonists (GLP-1 RAs), basal insulin, and premixed insulin among participants with type 2 diabetes inadequately controlled with metformin and/or a sulfonylurea. Methods We searched PubMed, EmBase, and the Cochrane Library to identify eligible randomized controlled trials (RCTs) for a network meta-analysis. Results A total of 17 RCTs involving 5874 adult individuals were included. Compared with placebo, all three therapies showed a significant effect on achieving target glycated hemoglobin (HbA1c) (GLP-1 RAs: 31.7%, 95% CI, 24.7–38.6%; premixed insulin: 31.1%, 95% CI, 20.4–41.8%; basal insulin: 26.0%, 95% CI, 16.4–35.7%). However, there was no significant difference between the three therapies. A similar result was found in HbA1c reduction. The use of GLP-1 RAs resulted in significant body weight loss (−3.73kg, 95% CI, −4.52 to −2.95kg vs. basal insulin and −5.27kg, 95% CI, −6.17 to −4.36kg vs. premixed insulin) but there was a higher drop-out rate of participants. Premixed insulin seemed associated with more severe hypoglycemic episodes. Conclusions The three injectables had similar impact on glycemic control but other differentiating features relevant to the management of type 2 diabetes with GLP-1 RAs having the most favorable profile.

SummaryObjective Follicle-stimulating hormone plays a crucial role in spermatogenesis. The aim of this study was to evaluate the efficacy of treatment with FSH in Chinese infertility population. Design Prospective, randomized, double-blind, placebo-controlled clinical study. Patients A total of 354 men affected by idiopathic oligozoospermia from three medical centres. Measurements This study contained three parts: (i) treatment with different doses of rhFSH (50 IU, 100 IU, 200 IU and 300 IU); (ii) the efficacy of rhFSH at different periods (2, 3, 4, 5 months); (iii) FSH treatment in patients with different levels of inhibin B (normal-level group, low-level group and high-level group). Semen parameters were evaluated in all subjects. The patients who had not reached spontaneous pregnancy underwent assisted reproductive techniques. Results Sperm number was significantly increased after treatment with FSH at doses of at least 200 IU, and the improvement was observed beginning at the third month. The significant improvement in both morphology and forward motility was observed beginning at the fifth month. Moreover, 300 IU rhFSH administration for 5 months could significantly improve the spontaneous pregnancy rate (12/40) and ART pregnancy rate (14/28), while the rates for placebo group were two of twenty-nine and five of twenty-seven, respectively. The seminal parameters (total sperm count, sperm concentration, forward motility and morphology) were significantly improved in the normal- and low-level inhibin B groups, but no significant variation was observed in the high-level group at the end of the study. Conclusions The efficacy of FSH treatment was associated with the dose of FSH and duration of treatment, and FSH therapy was more effective in patients with normal level and low level of inhibin B.

Background Dual anti-human epidermal growth factor receptor 2 (HER2) therapies have been shown to improve outcomes of HER2-positive breast cancer patients. We undertook a systematic review to compare treatment outcomes for patients who received single or combined anti-HER2 therapies. Methods We identified randomized control trials that compared dual anti-HER2 therapy and anti-HER2 monotherapy in patients with HER2-positive breast cancer. Outcomes included pathologic complete response (pCR), overall survival (OS), progression-free survival (PFS), and adverse events. Included in the analysis were seven trials that recruited 2,609 patients. Results In the neoadjuvant setting, the pooled pCR rate in the dual anti-HER2 therapy and monotherapy groups in combination with chemotherapy was 54.8% and 36%, respectively. This difference was statistically significant (relative risk, 1.56; 95% confidence interval (CI), 1.23–1.97; p

The association between tea consumption and bladder cancer has been confirmed in several animal studies, but one epidemiological study in 2001 showed no association between them. In order to provide an accurate assessment of this, we conducted a meta-analysis on tea consumption and bladder cancer risk. Studies were identified by a literature search in PubMed from January 1980 to March 2012 and the reference lists of relevant studies. Random effect models were used to calculate summary relative risk estimates (RR) and their corresponding 95% confidence intervals (CI) based on high contrast to low intake values. Twenty-four publications (6 cohort studies and 18 case-control studies) based on consumption of overall tea, black tea, and green tea to bladder cancer risk were included in this analysis. For overall tea, the summary RR indicated no association between tea consumption and bladder cancer (RR= 1.09, 95%CI: 0.85-1.40). In subgroup analyses, we found a moderate increase of bladder cancer risk in smoking group (RR= 1.77, 95%CI: 1.04-3.01). In the black tea group, no statistically significant association was observed (RR= 0.84, 95%CI: 0.70-1.01). Interestingly, in the subgroup of sex, a protective effect was observed between tea consumption and bladder cancer risk in female (RR= 0.61, 95%CI: 0.38- 0.98). For green tea group, there was no relationship associated with bladder cancer risk (RR= 1.03, 95%CI: 0.82- 1.31). In conclusion, our data suggest that high overall tea intake in smokers increased the risk of bladder cancer, and high black tea intake in female may reduce the risk of bladder cancer.

Objective Phase IV trials are often used to investigate drug safety after approval. However, little is known about the characteristics of contemporary phase IV clinical trials and whether these studies are of sufficient quality to advance medical knowledge in pharmacovigilance. We aimed to determine the fundamental characteristics of phase IV clinical trials that evaluated drug safety using the ClinicalTrials.gov registry data. Methods A data set of 19 359 phase IV clinical studies registered in ClinicalTrials.gov was downloaded. The characteristics of the phase IV trials focusing on safety only were compared with those evaluating both safety and efficacy. We also compared the characteristics of the phase IV trials in three major therapeutic areas (cardiovascular diseases, mental health and oncology). Multivariable logistic regression was used to evaluate factors associated with the use of blinding and randomisation. Results A total of 4772 phase IV trials were identified, including 330 focusing on drug safety alone and 4392 evaluating both safety and efficacy. Most of the phase IV trials evaluating drug safety (75.9%) had enrolment

Vandetanib, an oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling, has attracted wide interest in treatment of advanced non-small-cell lung cancer (NSCLC). We aimed to assess its efficacy and safety via a systematic review and meta-analysis.Trials comparing vandetanib-based therapy and non-vandetanib therapy for advanced NSCLC were identified. Endpoints evaluated were progression-free survival (PFS), overall survival (OS), objective tumor response rate (ORR), and toxicity.Seven trials including 4,492 patients were included in the analysis. As compared with placebo, vandetanib yielded a clear benefit for ORR (odds ratio (OR) = 2.04; 95% CI, 1.60-2.61; P0.001), and a clinically and statistically significant 25% improvement in PFS (hazard ratio (HR) = 0.75; 95% CI, 0.66- 0.85; P0.001). However, these benefits did not translate into a significant improvement in OS (HR = 0.95; 95% CI, 0.88-1.04; P = 0.291). Subgroup analyses showed that vandetanib 100mg/d was associated with greater antitumor activity than 300 mg/d when given in combination with chemotherapy. In addition, the pooled results demonstrated no statistically significant difference between vandetanib and single-targeted agents in PFS, ORR or OS. Vandetanib was associated with more frequent adverse events.Vandetanib, as compared with placebo, significantly increases ORR and PFS, but does not improve OS in the treatment of advanced NSCLC. As compared with single-targeted agent, vandetanib does not provide any efficacy advantage. Furthermore grade 3 or greater toxicity proved greater in the vandetanib arm.