Modulatory Effects of XIAOPI Formula on CXCL1 and Selected Outcomes in Triple-Negative Breast Cancer: A Randomized Controlled Clinical Trial.

Background: Triple-negative breast cancer (TNBC) is the most aggressive malignancy. Psychological distress and elevated CXCL1 level have been reported to be closely associated with the poor prognosis and quality of life of patients with TNBC. In preclinical studies using xenograft mouse models, XIAOPI formula, a nationally approved drug prescribed to patients at high risk for breast cancer, inhibited CXCL1 expression and improved survival. Traditional Chinese medicine has unique advantages in improving patients' emotional disorders and quality of life. However, the impact of XIAOPI formula on the serum level of CXCL1, psychological distress, and quality of life among patients with TNBC is currently unknown. Methods: In this study, we designed a randomized, double-blind, placebo-controlled trial. Patients with TNBC were randomly assigned to receive either the XIAOPI formula or a placebo for three months. The primary outcomes include serum CXCL1 expression, Self-Rating Anxiety Scale (SAS), and the Self-Rating Depression Scale (SDS). Secondary outcomes included the Pittsburgh Sleep Quality Index (PSQI) and the Functional Assessment of Cancer Therapy-Breast (FACT-B). Results: A total of 60 patients with TNBC were enrolled in the investigation. The results showed that the XIAOPI formula significantly decreased CXCL1 expression compared with the control group. Moreover, in comparison to the placebo, the XIAOPI formula increased FACT-B scores while decreasing SDS, SAS, and PSQI scores. Conclusion: In patients with TNBC, XIAOPI formula may be effective in reducing CXCL1 levels, enhancing psychological well-being, and quality of life. While our research offers a natural alternative therapy that may enhance the prognosis of TNBC, future validation of its therapeutic effects will require large-scale, long-term clinical trials. Clinical Registration Number: Registration website: www.chictr.org.cn, Registration date: 2018-1-19, Registration number: ChiCTR1800014535.

Comprehensive pan-cancer analysis reveals prognostic implications of TMEM92 in the tumor immune microenvironment.

BACKGROUND: Transmembrane protein 92 (TMEM92) has been implicated in the facilitation of tumor progression. Nevertheless, comprehensive analyses concerning the prognostic significance of TMEM92, as well as its role in immunological responses across diverse cancer types, remain to be elucidated. METHODS: In this study, data was sourced from a range of publicly accessible online platforms and databases, including TCGA, GTEx, UCSC Xena, CCLE, cBioPortal, HPA, TIMER2.0, GEPIA, CancerSEA, GDSC, exoRBase, and ImmuCellAI. We systematically analyzed the expression patterns of TMEM92 at both mRNA and protein levels across diverse human organs, tissues, extracellular vesicles (EVs), and cell lines associated with multiple cancer types. Subsequently, analyses were conducted to determine the relationship between TMEM92 and various parameters such as prognosis, DNA methylation, copy number variation (CNV), the tumor microenvironment (TME), immune cell infiltration, genes with immunological relevance, tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and half-maximal inhibitory concentration (IC50) values. RESULTS: In the present study, we observed a pronounced overexpression of TMEM92 across a majority of cancer types, which was concomitantly associated with a less favorable prognosis. A notable association emerged between TMEM92 expression and both DNA methylation and CNV. Furthermore, a pronounced relationship was discerned between TMEM92 expression, the TME, and the degree of immune cell infiltration. Intriguingly, while TMEM92 expression displayed a positive correlation with macrophage presence, it inversely correlated with the infiltration level of CD8 + T cells. Concurrently, significant associations were identified between TMEM92 and the major histocompatibility complex, TMB, MSI, and MMR. Results derived from Gene Set Enrichment Analysis and Gene Set Variation Analysis further substantiated the nexus of TMEM92 with both immune and metabolic pathways within the oncogenic context. CONCLUSIONS: These findings expanded the understanding of the roles of TMEM92 in tumorigenesis and progression and suggest that TMEM92 may have an immunoregulatory role in several malignancies.

Ecosystem service tradeoff and synergistic relationship in the Yellow River Delta High-Efficiency Eco-Economic Zone.

Exploring the tradeoff and synergy relationship among ecosystem services in the Yellow River Delta High-Efficiency Eco-Economic Zone is of great practical significance for regional ecosystem service function zoning and high-quality development. Using the InVEST model, spatial auto-correlation and trade-off synergism (ESTD) model, we analyzed the spatial and temporal variations of five ecosystem services (habitat quality, carbon storage, soil conservation, water conservation, and water purification), as well as their trade-off and synergistic relationships at the township scale from 2000 to 2020. The results showed that habitat quality, carbon storage, and nitrogen and phosphorus output decreased as a whole from 2000 to 2020, and soil conservation and water purification increased. Habitat quality showed a distribution pattern of high in the north and low in the south, and carbon sto-rage, nitrogen and phosphorus output, soil conservation and water purification showed a pattern of low in the north and high in the south. During the study period, synergistic relationships among the five ecosystem services were predominant in both time cross-section and time period, but there were still differences, with synergistic relationships mainly between carbon storage and other services in time cross-section, and between habitat quality and other ser-vices in time period. Our results can provide theoretical guidance and practical reference for the enhancement of ecosystem services and the zoning of ecosystem functions, as well as basic support for the optimization of spatial patterns of national territory.

Bacterial butyrate mediates the anti-atherosclerotic effect of silybin.

Silybin (SIL) is a versatile bioactive compound used for improving liver damage and lipid disorders and is also thought to be beneficial for atherosclerosis (AS). The goal of this study was to investigate the efficacy of SIL in the treatment of AS in ApoE-/-mice fed a high-fat diet and explore the mechanism underlying treatment outcomes. We found that SIL significantly alleviated AS-related parameters, including the extent of aortic plaque formation, hyperlipidemia, and adhesion molecule secretion in the vascular endothelium. 16 S rRNA gene sequencing analysis, together with the application of antibiotics, showed that intestinal butyrate-producing bacteria mediated the ameliorative effect of SIL on AS. Further analysis revealed that SIL facilitated butyrate production by increasing the level of butyryl-CoA: acetate CoA-transferase (BUT). The increased expression of monocarboxylic acid transporter-1 (MCT1) induced by butyrate and MCT4 induced by SIL in the apical and basolateral membranes of colonocytes, respectively, resulted in enhanced absorption of intestinal butyrate into the circulation, leading to the alleviation of arterial endothelium dysfunction. Moreover, the SIL-mediated increase in intestinal butyrate levels restored gut integrity by upregulating the expression of tight junction proteins and promoting gut immunity, thus inhibiting the AS-induced inflammatory response. This is the first study to show that SIL can alleviate AS by modulating the production of bacterial butyrate and its subsequent absorption.

The efficacy of modified binding technique for renorrhaphy during robotic partial nephrectomy: surgical and functional outcomes from single-center experience.

BACKGROUND: To compare the traditional single-layer and double-layer suture renorrhaphy with modified "Binding" suture renorrhaphy (whole rim of the wound was closed by the all-layer flow suture starting from the parenchyma cut edges to hilum, followed by the final defect closure) in robotic partial nephrectomy (RPN) for treating localized renal cell carcinoma in our large institutional experience. METHODS: We retrospectively reviewed clinical data of 406 consecutive patients who underwent RPN from May 2018 and December 2020 in our center. The demographic and oncologic outcome variables were compared between different renal reconstruction groups and the effect of these suture techniques on renal function outcomes was also evaluated. RESULTS: For the single-layer group, median operative time and warm ischemic time were significantly less than that of the double-layer and "Binding" groups (p < 0.001), while the significantly lower eGFR drop (p = 0.014) was also detected within postoperative 3 months from baseline, but this difference lost its statistical significance from 3th month to the last follow-up. The changes in postoperative creatinine values were clinically insignificant among the three groups. In a sub-analysis over 258 patients with moderate/high nephrometry score, those patients who underwent "Binding" suture had an undifferentiated warm ischemic time, estimated blood loss, and length of hospitalization stay with a decreased risk of Grade III complications (postoperative hemorrhage requiring intervention) and improved renal function recovery during the whole follow-up. CONCLUSION: Single-layer suture renorrhaphy may be associated with better renal functional preservation and could prove to be reliable in patients with low-complexity tumor (RENAL score ≤ 6). Patients with moderate/high-complexity tumor (RENAL score ≥ 7) might represent a subgroup of patients having a functional benefit after "Binding" suture renorrhaphy even in the long-term period.

[Expression and significance analysis of GDF3 in testicular cancer based on TCGA and GTEx databases].

OBJECTIVE: To investigate the expression and significance of GDF3 in testicular cancer through bioinformatics analysis. METHODS: Using the TCGA and GTEx databases, differential expression analysis and pan-cancer analysis were performed to identify the target gene GDF3, and the clinical relevance of GDF3 in testicular cancer was analyzed using the UALCAN database. Based on the R packages "org.Hs.eg.db" and "clusterProfiler," gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to explore the potential functions of GDF3 in testicular cancer. The correlation of GDF3 with immune chemokines and immune inhibitors in testicular cancer was investigated using the TISIDB database. RESULTS: The GDF3 was significantly upregulated in testicular cancer (P<0.001) and closely associated with clinical staging (P<0.05) and tumor subtypes (P<0.001). The immune-related analysis revealed that GDF3 was strongly correlated with immune chemokines CCL26 (rho=0.599, P<0.001), CCL7 (rho=0.525, P<0.001), immune inhibitor ADORA2A (rho=0.723, P<0.001), and PVRL2 (rho=0.585, P<0.001). CONCLUSION: The GDF3 is closely related to the occurrence, development, and immune microenvironment of testicular cancer.

[Size Distribution and Source Appointment of Road Particles During Winter in Tianjin].

The significant role of traffic emissions mixed from various sources in urban air pollution has been widely recognized. However, the corresponding contributions to the roadside particle distribution are poorly understood due to the mixed impacts of various sources. Particle number concentrations of different sizes at the roadside in Nankai District of Tianjin were continuously monitored using a portable aerosol particle spectrometer during the morning rush hour (07:30-09:20) from Nov. 9, 2018 to Jan. 6, 2019. Characteristic and influencing factors of particle size distributions were discussed combined with temperature and relative humidity data, while potential sources of particles at the roadside were identified based on size distribution analysis. The results showed that the average total particle number concentrations were 502 cm-3, and the concentrations of the accumulation mode and coarse mode were 500 cm-3 and 2 cm-3, respectively. The distribution of number concentrations at the roadside was unimodal and primarily concentrated at 0.25-0.50 µm, with peak sizes at 0.28-0.30 µm. The same distribution trend of particle number concentration and difference in the concentration in the same segment size were observed at different periods. Vehicle activity level was the main influencing factor of road particulate matter concentration on different weekdays; the probability of the high value of road particulate matter concentration was reduced by a reasonable combination of the vehicle tail numbers. Temperature and relative humidity were both found to be positively correlated with the number concentration of particles. With the increase in temperature and relative humidity, the total and peak particle number concentration showed an overall upward trend. In addition, the peak particle size increased from 0.28-0.30 µm to 0.35-0.40 µm when relative humidity was higher than 80%. Three sources, including road dust, brake and tire wear, and the aging particles from vehicle exhaust, were identified using positive matrix factorization in this study. Road dust contributed 8.6% of the total number concentration, which mainly consisted of particles with sizes above 5.00 µm. Brake and tire wear contributed 2.8% of the total number concentration of particles with a size range of 0.80-4.00 µm. The aging particles from vehicle exhaust contributed the most (88.5%), with a peak at 0.25-0.65 µm. The sources of roadside particles were mainly related to vehicle activity, whereas temperature and relative humidity also affected the particle number size distribution.

Clinical efficacy of immunotherapy combined with chemotherapy in patients with advanced gastric cancer, its effect on nutritional status and Changes of peripheral blood T lymphocyte subsets.

OBJECTIVES: To evaluate the clinical efficacy of immunotherapy combined with chemotherapy in patients with advanced gastric cancer and its effect on nutritional status and changes of peripheral blood T lymphocyte subsets. METHODS: Sixty patients with locally advanced gastric cancer who were admitted by Affiliated Hospital of Hebei University from March 2020 to February 2021 were enrolled and randomly divided into two groups, with 30 cases in each group. The control group was treated with FOLFOX4 chemotherapy, while the experimental group was additively treated with cindilizumab on the basis of control group. The incidence of adverse reactions, clinical efficacy, improvement of nutritional and physical status, and changes in the levels of T lymphocyte subgroups in the two groups were compared and analyzed. RESULTS: The total effective rate was 70% in the experimental group, which was better than 43.3% of the control group (p=0.04). The improvement rate of performance status (ECOG) score and nutritional indicators in the experimental group was significantly better than that in the control group (p<0.05). Moreover, the indicators of CD3+, CD4+, CD4+/CD8+ in the experimental group were significantly higher than those in the control group after treatment, with statistically significant differences (CD3+, p=0.01; CD4 +, p= 0.02; CD4+/CD8+, p=0.01). CONCLUSION: Immunotherapy combined with chemotherapy has a significant effect on locally advanced gastric cancer patients, with significant improvement in physical strength and nutritional status, significant improvement in T lymphocyte function, and no obvious adverse reactions. It is worth promoting in clinical application.

Influence of GSTP-1 Polymorphism on the Prognosis of Patients with High-Grade Glioma Who Received Temozolomide Plus Radiotherapy Adjuvant Treatment.

BACKGROUND: Glutathione S-Transferase P 1 (GSTP-1) gene plays an important physiological role in the body. The present study was conducted to identify the clinical implication of GSTP-1 gene polymorphism on the prognosis of patients with high-grade glioma (HGG) who received temozolomide plus radiotherapy adjuvant treatment. METHODS: This study recruited a total of 186 patients with HGG who were treated with temozolomide plus radiotherapy adjuvant regimen (retrospectively). Baseline clinical characteristics were obtained and the prognostic data of the patients were collected. Peripheral blood specimen of patients was preserved for genotyping of GSTP-1 polymorphism during hospitalization. Correlation analysis was carried out accordingly. Additionally, fresh peripheral blood specimens that were available for mRNA expression analysis were collected for the mRNA expression analysis. RESULTS: The median progression-free survival (PFS) and overall survival (OS) of the 186 patients with HGG who received temozolomide plus radiotherapy regimen was 8.5 months (95% CI: 5.95-11.05) and 15.5 months (95% CI: 11.49-19.51), respectively. The prevalence of 313A>G among 186 patients with glioma was AA genotype: 126 cases (67.7%), AG genotype: 54 cases (29.1%), GG genotype: 6 cases (3.2%), minor allele frequency of 313A>G was 0.18. Association analysis suggested that the median PFS of patients with AA and AG/GG genotypes was 11.2 and 5.0 months, respectively (χ2=11.17, P=0.001). Furthermore, the median OS of patients with AA and AG/GG genotypes was 18.9 and 10.5 months, respectively (χ2=12.684, P<0.001). Besides, when adjusted for PFS in multivariate Cox regression analysis, AG/GG genotype was an independent factor for PFS (HR=0.48, P=0.006). The mRNA expression results indicated that mRNA expression of GSTP-1 in patients with AG/GG genotypes of 313A>G was significantly higher than that of patients with AA genotype (P<0.001). CONCLUSION: GSTP-1 polymorphism 313A>G might be used as a potential biomarker to predict the prognosis of patients with HGG who received temozolomide plus radiotherapy adjuvant treatment.

HIF-1α-BNIP3-mediated mitophagy in tubular cells protects against renal ischemia/reperfusion injury.

In the present study, we hypothesized that hypoxia-inducible factor 1α (HIF-1α)-mediated mitophagy plays a protective role in ischemia/reperfusion (I/R)-induced acute kidney injury (AKI). Mitophagy was evaluated by measuring the changes of mitophagy flux, mitochondria DNA copy number, and the changes of mitophagy-related proteins including translocase of outer mitochondrial membrane 20 (TOMM20), cytochrome c oxidase IV (COX IV), microtubule-associated protein 1 light chain 3B (LC3B), and mitochondria adaptor nucleoporin p62 in HK2 cells, a human tubular cell line. Results show that HIF-1α knockout significantly attenuated hypoxia/reoxygenation (H/R)-induced mitophagy, aggravated H/R-induced apoptosis, and increased the production of reactive oxygen species (ROS). Similarly, H/R induced significantly increase in Bcl-2 19-kDa interacting protein 3 (BNIP3), a downstream regulator of HIF-1α. Notably, BNIP3 overexpression reversed the inhibitory effect of HIF-1α knockout on H/R-induced mitophagy, and prevented the enhancing effect of HIF-1α knockout on H/R-induced apoptosis and ROS production. For in vivo study, we established HIF-1αflox/flox; cadherin-16-cre mice in which tubular HIF-1α was specifically knockout. It was found that tubular HIF-1α knockout significantly inhibited I/R-induced mitophagy, and aggravated I/R-induced tubular apoptosis and kidney damage. In contrast, adenovirus-mediated BNIP3 overexpression significantly reversed the decreased mitophagy, and prevented enhanced kidney damage in tubular HIF-1α knockout mice with I/R injury. In summary, our study demonstrated that HIF-1α-BNIP3-mediated mitophagy in tubular cells plays a protective role through inhibition of apoptosis and ROS production in acute kidney damage.

Severe fever with thrombocytopenia syndrome virus infection during pregnancy in C57/BL6 mice causes fetal damage.

BACKGROUND: Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel tick-borne phlebovirus, which is listed in the most dangerous pathogens by the World Health Organization, and has 12-30% fatality rates. SFTSV antibodies were reported in minks that experienced abortion or reproductive failure. The aim of this study was to determine whether SFTSV infection causes an adverse pregnancy outcome in the fetus using a pregnant mouse model. METHODOLOGY/PRINCIPAL FINDINGS: We found SFTSV in the fetus after infection in pregnant mice, and some dams showed adverse pregnancy outcomes after infection with SFTSV including placental damage, fetal reabsorption, and fetal intrauterine growth restriction (IUGR). SFTSV had obvious tropism characteristics in the placenta, especially in the labyrinth. In early-gestation, pregnant mice infected with SFTSV had fetal IUGR and a high viral load in the fetus. The virus widely spread in infected fetuses, including the hindbrain, thymus, heart, spinal cord, and liver. CONCLUSIONS: Our study demonstrated that SFTSV was vertically transmitted to the fetus through the placental barrier of immunocompetent mice, and resulted in adverse pregnancy outcomes.

Enterovirus 71 VP1 Protein Regulates Viral Replication in SH-SY5Y Cells via the mTOR Autophagy Signaling Pathway.

BACKGROUND: Enterovirus 71 (EV71) is the main pathogen that causes severe hand, foot, and mouth disease with fatal neurological complications. However, its neurovirulence mechanism is still unclear. Candidate virulence sites were screened out at structural protein VP1, but the function of these candidate virulence sites remains unclear. Several studies have shown that autophagy is associated with viral replication. However, the relationship between VP1 and autophagy in human neurons has not been studied. METHODS: A recombinant virus-SDLY107-VP1, obtained by replacing the VP1 full-length gene of the SDLY107 strain with the VP1 full-length gene of the attenuated strain SDJN2015-01-was constructed and tested for replication and virulence. We then tested the effect of the recombinant virus on autophagy in nerve cells. The effect of autophagy on virus replication was detected by western blot and plaque test. Finally, the changes of mTOR signaling molecules during EV71 infection and the effect of mTOR on virus replication at the RNA level were detected. RESULTS: Viral recombination triggered virulence attenuation. The replication ability of recombinant virus SDLY107-VP1 was significantly weaker than that of the parent strain SDLY107. The SDLY107 strain could inhibit autophagic flux and led to accumulation of autophagosomes, while the SDLY107-VP1 strain could not cause autophagosome accumulation. The synthesis of EV71 RNA was inhibited by inhibiting mTOR. CONCLUSIONS: Replacement of VP1 weakened the replication ability of virulent strains and reduced the level of autophagy in nerve cells. This autophagy facilitates the replication of virulent strains in nerve cells. VP1 is an important neurovirulence determinant of EV71, which affects virus replication by regulating cell autophagy. mTOR is a key molecule in this type of autophagy.

The untranslated regions of EV-A71 contribute to its pathogenicity and virulence.

Enterovirus A71 (EV-A71) is known for its manifestation as hand foot and mouth disease (HFMD), which has caused countless large-scale epidemic outbreaks throughout the world. However, the molecular pathogenesis of EV-A71 infection is still elusive. Previous studies found that the biological characteristics of a mild EV-A71 strain (SDLY1) and a severe EV-A71 strain (SDLY107) are significantly different, and sequence analysis showed that there are several differences in nucleotide sites of UTRs (88 nt, 123 nt, 143 nt, 154 nt, 187 nt, 241 nt, 243 nt, 253 nt, 291 nt, 438 nt, 440 nt, 571 nt, 579 nt, 602 nt, 658 nt, 664 nt, 690 nt, 696 nt, 7328 nt, 7335 nt, 7367 nt, and 7395 nt). The aim of this study was to determine whether these amino sites in UTRs are associated with the pathogenesis of EV-A71 and are responsible for different clinical manifestations. Based on the reverse genetics technology, we rescued two chimeric viruses SDLY107(1-5'UTR) and SDLY107(1-3'UTR) by replacing 5'UTR/3'UTR gene fragments of an infectious cDNA clone. Replication kinetics and cytotoxicity assays showed that the virulence of the two chimeric strains significantly changed in vitro. The viral loads of the two chimeric strains in infected ICR mice were reduced and pathological damage in the brains, lungs, intestinal tissues, and muscles were lightened. Our findings suggest that some nucleotide sites in UTRs may have a function in the pathogenicity and virulence of EV-A71.

Nonstructural protein 2A modulates replication and virulence of enterovirus 71.

Enterovirus 71 (EV71) can cause hand, foot, and mouth disease in children, and severe infections can induce neurological complications and even death. However, the pathogenesis of EV71 remains unknown. The 2A proteinase (2Apro) of EV71 plays an important role in segmenting the precursor polyprotein during viral replication, inhibiting host protein synthesis, and evading innate immunity. This study was to determine the function of EV71 2Apro in replication and virulence. A chimeric strain (SDLY 107-2A-1) was recombined by replacing 2Apro of a severe strain (SDLY107) with that of a mild strain (SDLY1) based on an infectious cDNA clone. The replication kinetics of the chimeric strain in vitro and in vivo were determined by qRT-PCR, which showed that the chimeric strain replicated slower and generated less viral RNA than the severe strain. The pathological change and viral load of chimeric strain infected mice were intermediate between severe strain infected mice and mild strain infected mice. Cellular cytotoxicity assays revealed that 2Apro was associated with the neurotoxicity of EV71. Histopathological and immunohistochemical assays detected tissue pathological damage in the lungs, muscles, brain, and intestinal tissues. Together, these results suggest that 2Apro modulates replication and virulence of EV71. This provides a theoretical basis for virulence determination of EV71.

Contribution of 3CD Region to the Virulence of Enterovirus 71.

Enterovirus 71 is a neuroinvasive virus that is associated with severe neurological complications. We had earlier suggested that the replication capacity of a severe strain was higher than that of a mild strain. The recombinant 3CRV and 3CDRV virus strains were successfully rescued in our previous study. In the present study, we found no difference in virulence between 3CRV and severe strains. However, the capacity of replication and to cause cell injury of 3CDRV strain decreased in vitro, especially at 39.5 °C. Replacement of 3CD region in the severe strain led to milder symptoms, less body weight loss, and lower viral load in ICR mice. Histopathological findings indicated less severe injury in mice infected with 3CDRV strain. This study suggests that the 3CD region contributes to the attenuation of the severe strain, including its replication capacity and temperature sensitivity.

Experimental Study on Fatigue Behaviour of Shot-Peened Open-Hole Steel Plates.

This paper presents an experimental study on the fatigue behaviour of shot-peened open-hole plates with Q345 steel. The beneficial effects induced by shot peening on the fatigue life improvement are highlighted. The characteristic fatigue crack initiation and propagation modes of open-hole details under fatigue loading are revealed. The surface hardening effect brought by the shot peening is analyzed from the aspects of in-depth micro-hardness and compressive residual stress. The fatigue life results are evaluated and related design suggestions are made as a comparison with codified detail categories. In particular, a fracture mechanics theory-based method is proposed and demonstrated its validity in predicting the fatigue life of studied shot-peened open-hole details.

Dynamic contrast-enhanced MRI to predict response to vinorelbine-cisplatin alone or with rh-endostatin in patients with non-small cell lung cancer and bone metastases: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Metastatic bone disease is a frequent complication of advanced non-small-cell lung cancer and causes skeletal-related events which result in a poor prognosis. A standard method to assess the therapeutic response of bone metastases does not currently exist. We used dynamic contrast-enhanced MRI to obtain quantitative measures to assess the suitability of this technique to gauge therapeutic response to vinorelbine-cisplatin plus rh-endostatinfor previously untreated non-small cell lung cancer with bone metastases. METHODS: We did a phase 4, randomised, prospective, double-blind, placebo-controlled clinical trial in Shanghai Sixth People's Hospital, Shanghai, China. Inclusion criteria were non-small-cell lung cancer patients with bone metastases confirmed by pathology or cytology; available imaging data of pelvic metastatic lesions; aged 18 to 75 years old; expected survival at least 3 months; not receiving taxane, bevacizumab, thalidomide, rh-endostatin, or bisphosphonate; not having radiation therapy within 3 months of enrollment into study; normal results of routine blood tests, liver and kidney function, and electrocardiogram; absence of cardiovascular disease, autoimmune disease, vasculitis, severe infection, diabetes, and other concomitant disease; and signed informed consent. Exclusion criteria were receiving granulocyte colony stimulating factor or granulocyte-macrophage colony stimulating factor during chemotherapy, intolerance to adverse reaction, and allergy to contrast agents. Patients were randomly assigned to treatment group and control group at a ratio of 2:1 by random code generation by an independent biostatistician in a double-blind fashion. Participants received either vinorelbine-cisplatin plus rh-endostatin or vinorelbine-cisplatin plus placebo. Vinorelbine (25 mg/m2) and cisplatin (75 mg/m2) were administered intravenously on the first day of a 21 day cycle. Patients received rh-endostatin (7·5 mg/m2) or placebo on days 1-14 of a cycle. The primary end points were objective response rate (complete remission+partial remission)/total × 100) and disease control rate (complete remission+partial remission+stable disease)/total × 100). Measurements including Ktrans, Kep, and Ve were evaluated by dynamic contrast-enhanced MRI before treatment and after completion of 2 treatment cycles. Blood concentrations of bone metabolites, tumour markers, and tumour vascular growth related factors were measured before and after treatment. Comparisons were made using paired t-test. Kaplan-Meier survival analysis was used to indicate the correlation between some measurements and progression-free survival or overall survival. The difference in Ktrans between patients who had partial remission or stable disease group and those who had disease progression was tested using the Chi-square test. All statistical analyses were performed with SPSS version 21.0. This trial was approved by the State Food and Drug Administration (No: S20050088) and China State Food and Drug Administration. The trial is registered with China Clinical Trials Registry, number chictr-ctr-09000569. Written informed consent and ethical approval was obtained. FINDINGS: We enrolled 33 patients (aged 52-70, 15 men and 18 women) of whom 28 were evaluable (20 in treatment group and 8 in control group). Five patients were excluded: 2 patients in treatment group and 1 patient in control group used granulocyte-macrophage colony stimulating factor, and 2 patients in the control group refused treatment. Objective response rate was higher (30% vs 0%; p<0·00001), mean overall survival was longer (21·44 [SD 17·28] vs 7·71 [4·68] months, p=0·008), and reduction in capillary permeability (measured by Ktrans) was greater (60·0% vs 4·4%; p=0·026) in the group given rh-endostatin than in the control group. Disease control rate was 80% in the treatment group and 75% in the control group (p=0·07). Overall survival was longer in patients with a greater than 50% reduction in Ktrans than in patients with a decrease of up to 50% (13·2 [1·8] vs 9·8 [0·2] months, p=0·026). INTERPRETATION: Addition of rh-endostatin to treatment with vinorelbine-cisplatin increased the treatment response in patients with non-small cell lung cancer and bone metastases. Quantitative analysis using dynamic contrast-enhanced MRI can be used to evaluate therapeutic response and to predict survival of bone metastases after anti-angiogenesis therapy. Limitations of this study include the small number of patients and the single-centre design. FUNDING: National Natural Science Foundation of China [grant number 81201628].

Expression of miRNA-630 in bladder urothelial carcinoma and its clinical significance.

Many studies informed that microRNAs (miRNAs) could function as diagnostic and prognostic indicators in several cancers. The aims of this study were to explore the expression of miR-630 in bladder urothelial carcinoma and its clinical significance for the evaluation of cancer prognosis. A total of 116 patients with bladder urothelial carcinoma were obtained in this retrospective study between May, 2012 and Sep. 2015. Quantitative real-time PCR (qRT-PCR) was conducted to evaluate the expression level of miR-630. The chi-square test was used to examine the associations between miR-630 expression and the clinicopathological features. The Kaplan-Meier method was conducted to explore the survival status of urothelial carcinoma patients. The log-rank test was used to analyze differences in survival rate. The results showed an obvious increase in miR-630 expression from normal bladder to bladder urothelial carcinoma (P=0.027). Additionally, patients with higher miR-630 expression had significantly shorter disease-free survival (DFS) (P=0.043) and overall survival (OS) (P=0.038) than those with lower miR-630 expression. Furthermore, multivariate analysis revealed that up-regulation of miR-630 was an independent prognostic factor for both DFS (P=0.042) and OS (P=0.046). It was demonstrated that miR-630 may be a novel and valuable prognostic factor for bladder urothelial carcinoma.

The effect of non-small cell lung cancer histology on survival as measured by the graded prognostic assessment in patients with brain metastases treated by hypofractionated stereotactic radiotherapy.

BACKGROUND: The purpose of this study was to investigate the impact of histology on survival stratified by the Graded Prognostic Assessment (GPA) for non-small cell lung cancer (NSCLC) in a group of selected patients treated recently. METHODS: A total of 171 NSCLC patients with brain metastases treated by hypofractionated stereotactic radiotherapy with or without whole-brain radiotherapy between 2001 and 2011 were included. The GPA score was calculated for each patient. Tumor histologies were categorized into adenocarcinoma (ADCA) and non-ADCA. Median survival time (MST, in months) was calculated using the Kaplan-Meier method. The log-rank test was used to determine statistical differences. RESULTS: MSTs by histology were: ADCA 15 (n = 92) and non-ADCA 10 (n = 79) (p < 0.001). For all patients, the MSTs by GPA score were: GPA 3.5-4, 24; GPA 2.5-3, 15; GPA 1.5-2, 9 and GPA 0-1, 6 (p < 0.001). The histology of ADCA showed a statistically significant higher MST than non-ADCA for patients with GPA 2.5-4. For GPA 2.5-3, MSTs were: ADCA 18, non-ADCA 10 (p = 0.007); for GPA 3.5-4, MSTs were: ADCA 30, non-ADCA 17 (p = 0.046). For GPA 0-2, MSTs did not differ significantly by histology. For GPA 0-1, MSTs were: ADCA 8, non-ADCA 4 (p = 0.146); GPA 1.5-2, MSTs were: ADCA 10, non-ADCA 8 (p = 0.291). We further found that non-ADCA in upper GPA class (3.5-4) had similar survival with ADCA in lower GPA class (2.5-3) (MSTs were 17 and 18, respectively, p = 0.775). This phenomenon also happened between patients of non-ADCA in upper GPA class (2.5-3) and those of ADCA in lower GPA class (1.5-2) (MSTs were both 10, p = 0.724). CONCLUSIONS: We confirmed that the histology of NSCLC had effect on the GPA in these selected patients treated recently. ADCA showed a statistically significant higher MST than non-ADCA with GPA 2.5-4. The non-ADCA in upper GPA classes (3.5-4 and 2.5-3) had similar survival to ADCA in lower GPA classes (2.5-3 and 1.5-2, respectively). The histology as a new factor should be added to the original GPA for NSCLC.

Usefulness of dynamic contrast-enhanced magnetic resonance imaging for predicting treatment response to vinorelbine-cisplatin with or without recombinant human endostatin in bone metastasis of non-small cell lung cancer.

Metastatic bone disease is a frequent complication of advanced non-small cell lung cancer (NSCLC) and causes skeletal-related events, which result in a poor prognosis. Currently, no standard method has been developed to precisely assess the therapeutic response of bone metastases (BM) and the early efficacy of anti-angiogenic therapy, which does not conform to the concept of precision medicine. This study aimed to investigate the usefulness of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for precise evaluation of the response to chemotherapy with anti-angiogenic agents in NSCLC patients with BM. Patients were randomly assigned to a treatment group (vinorelbine + cisplatin [NP] + recombinant human endostatin [rh-endostatin]) or a control group (NP + placebo). All patients were evaluated before treatment and after 2 cycles of treatment using DCE-MRI quantitative analysis technology for BM lesions and chest computed tomography (CT). Correlations between changes in the DCE-MRI quantitative parameters and treatment effect were analyzed. We enrolled 33 patients, of whom 28 were evaluable (20 in the treatment group and 8 in the control group). The results suggested a higher objective response rate (30% vs. 0%), better overall survival (21.44 ± 17.28 months vs. 7.71 ± 4.68 months), and a greater decrease in the transport constant (Ktrans) value (60% vs. 4.4%) in the treatment group than in the control group (P < 0.05). The Ktrans values in the "partial remission plus stable disease (PR + SD)" group were significantly lower after treatment (P < 0.05). Patients with a decrease of > 50% in the Ktrans value showed a significantly better overall survival than those with a decrease of ≤ 50% (13.2 vs. 9.8 months, P < 0.05). Ktrans as a DEC-MRI quantitative parameter could be used for the precise evaluation of BM lesions after anti-angiogenic therapy and as a predictor of survival. In addition, we reconfirmed the anti-angiogenic effect of rh-endostatin in NSCLC patients with BM.