Obovatol inhibits proliferation, invasion and immune escape of hepatocellular carcinoma cells through modulating the JAK/STST3/PD-L1 pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer that is fatal and has a dismal prognosis. Obovatol (Ob), a novel lignan derived from the leaf and stem bark of Magnolia obovata Thunb, has exhibited anti-tumor effect on diverse tumors. However, its effect and mechanisms on HCC remain to be further explored. METHODS: Huh7 and Hep3B cells, as well as BALB/c nude mice were used to determine the function and mechanisms of Ob on growth, invasion and immune escape by cell counting kit-8, transwell, enzyme-linked immunosorbent assay (ELISA) and western blot experiments. RESULTS: Ob reduced the cell viability of Huh7 and Hep3B cells, with a IC50 value of 57.41 µM and 62.86 µM, respectively. Ob declined the invasion ability, the protein expression of N-cadherin and the concentrations of IL-10 and TGF-ß, whereas increased the E-cadherin expression and the contents of IFN-γ and IL-2 in Hep3B and Huh7 cells. Mechanically, Ob decreased the protein level of p-JAK/JAK, p-STAT3/STAT3 and PD-L1, which was partly restored with the treatment of RO8191, an activator of JAK/STAT3 axis. The effect of Ob on the cell viability, the invasion ability, the protein level of N-cadherin and E-cadherin, and the concentrations of IL-10, TGF-ß, IFN-γ and IL-2 in both Hep3B and Huh7 cells was reversed with the management of RO8191. In vivo, Ob reduced tumor volume and weight, the level of N-cadherin, PD-L1, p-JAK/JAK, and p-STAT3/STAT3, with an elevated expression of E-cadherin and IFN-γ. CONCLUSION: Ob downregulated the JAK/STST3/PD-L1 pathway to attenuate the growth, invasion and immune escape of HCC.

Dynamic evolution and spatial spillover effect of agricultural green development on eight economic regions in China.

Promoting the green development of agriculture is of great significance to realize agricultural and rural modernization in China. Based on the existing research, this paper innovatively explores the dynamic and spatial effects of agricultural green development in the eight newly zoned regions of China's economy. Based on the panel data of 30 provinces in China from 2013 to 2022, this paper selects 20 indicators to measure the level of agricultural green development from five dimensions such as ecological protection, resource conservation, environment-friendly, green supply and economic growth by entropy weight method and uses non-parametric estimation method to analyze the dynamic evolution trend of agricultural green development in the whole country and its eight economic regions. Then, a spatial econometric model is constructed to further explore the influence mechanism and spatial spillover effect of each influencing factor on agricultural green development. The findings demonstrate that the level of agricultural green development in 30 provinces of China continuously improved during the study period, but the dynamic evolution trend characteristics in the whole country and its eight economic regions are not the same. Specifically, the development differences between the whole country, the northeast region, the eastern coast, the southern coast and the northwest region increased, while that between the northern coast, the Yellow River basin and the middle reaches of the Yangtze River first increased and then decreased, and that in the southwestern region gradually narrowed. There is a significant spatial spillover effect on agricultural green development and its influencing factors. Moreover, there is heterogeneity in the influence characteristics and spatial spillover effects of various influencing factors on agricultural green development among the eight economic regions. Therefore, it is proposed that eight economic regions in China should formulate differentiated development strategies, focus on educational and technological innovation etc., and further promote agricultural green development.

How does climate change affect potential yields of four staple grain crops worldwide by 2030?

Global food security basically depends on potential yields of staple grain crops worldwide, especially under climate change. However, most scholars use various models of production function in which climatic factors are often considered to estimate crop yield mostly at local or regional level. Therefore, in this paper: Potential yields of rice, wheat, maize and soybean worldwide by 2030 are projected creatively using Auto-regressive Integrated Moving Average and Trend Regressed (ARIMA-TR) model in which actual yields in recent two years are used for testing the reliability of projection and Gray System (GS) model for validating the test; Especially individual impacts of climate change on the productions of rice, wheat, maize and soybean worldwide since 1961 are analyzed by using unary regression model in which global mean temperature and land precipitation are independent variable while the yield of crop being dependent one, respectively. Results show that: by 2030, the ratio between average and top yields of world rice is projected to be 50.6% increasing, while those of world wheat, world maize and world soybean are projected to be 38.0% increasing, 14.7% decreasing and 72.5% increasing, respectively. Since 1961 global warming has exerted a negative impact on average yield of world rice less than on its top, a positive effect on average yield of world wheat while a negative impact on its top, a positive effect on average yield of world maize less than on its top, and a positive influence on average yield of world soybean while a negative one on its top, which might be slightly mitigated by 'Carbon Peak' target. The fluctuation of global rainfall contributes to the productions of these crops much less than global warming during same period. Our findings indicate that: to improve global production of four staple grain crops by 2030, the priorities of input should be given to either rice or wheat in both high and low yield countries, whereas to maize in high yield countries and to soybean in low yield countries. These insights highlight some difference from previous studies, and provide academia with innovative comprehension and policy-decision makers with supportive information on sustainable production of these four staple grain crops for global food security under climate change in the future.

Erratum: [Corrigendum] PF­2341066 combined with celecoxib promotes apoptosis and inhibits proliferation in human cholangiocarcinoma QBC939 cells.

[This corrects the article DOI: 10.3892/etm.2018.5967.].

Innovative measurement, trade-off-synergy relationship and influencing factors for agricultural net carbon emissions and effective supply of agricultural products in China.

Sensitive zone of global climate change has been formed in China, and it has become a hot topic how can agriculture ensure food security and the supply of important agricultural products while achieving the "Dual Carbon" goal in the country. Based on such background, this paper uses the IPCC carbon emission calculation method, environmental input-output model and economic-water-carbon coefficient method to measure agricultural net carbon emissions, adopts bivariate spatial auto-correlation analysis and SYS-GMM to explore separately the relationship between agricultural net carbon emissions and effective supply of agricultural products, as well as the carbon reduction effect, growth effect and reasonable range of green technology innovation. The results show that: (1) China's agricultural net carbon emissions reveal a spatial distribution of "higher in the east than in the west than in the center" and a temporal characteristic of increasing year by year; China's effective supply of agricultural products shows an increasing trend and a spatial distribution of "higher in the east than in the center than in the west" in 2006-2012 and "higher in the east than in the west than in the center" in 2013-2020. (2) In 2006, 2010, 2015 and 2020, the number of provinces that belong to low-low agglomeration trade-off zone, low-high agglomeration synergy zone, non-significant zone, high-low agglomeration non-trade-off-synergy zone and high-high agglomeration trade-off zone averagely accounted for 12.500 %, 30.000 %, 26.667 %, 9.167 % and 21.667 % of the totality, respectively. (3) The carbon reduction and production growth effects of green technology innovation both show an inverted "U-shape", and green technology innovation is conducive to both reducing agricultural net carbon emissions and improving supply of agricultural products when it is within a reasonable range of greater than 0.930. (4) Green technology innovation not only has significant spatial and temporal heterogeneity impact, but also exhibits a differential effect on productive agricultural carbon emissions, agricultural trade carbon emissions, agricultural carbon sinks, total output of agricultural products and agricultural net imports in international trade. Therefore, it is proposed that China should establish and improve green technology innovation incubation platforms, guide all participants to ensure the investment and application of green technology products within a reasonable range, formulate and implement regional differential policies and plan in accordance with local conditions, drive ultimately coordinated promotion of agricultural carbon emission reduction and product supply guarantee and lay an important foundation for achieving high-quality economic development and efficient ecological protection.

Mutational spectrum for guiding the decision of adjuvant treatment in patients with resected biliary tract carcinoma.

BACKGROUND: Systemic chemotherapy or chemoradiation therapy has proven to be effective in treating advanced biliary tract carcinoma (BTC). However, its efficacy in the adjuvant setting remains controversial. Therefore, this study aimed to determine the prognostic significance of genomic biomarkers in resected BTC and their potential role in stratifying patients for adjuvant treatment. METHODS: We retrospectively reviewed 113 BTC patients who underwent curative-intent surgery and had available tumor sequencing data. Disease-free survival (DFS) was the primary outcome examined and univariate analysis was used to identify gene mutations with prognostic value. Favorable and unfavoratble gene subsets were distinguished from the selected genes through grouping, respectively. Multivariate Cox regression was used to identify independent prognostic factors of DFS. RESULTS: Our results indicated that mutations in ACVR1B, AR, CTNNB1, ERBB3, and LRP2 were favorable mutations, while mutations in ARID1A, CDKN2A, FGFR2, NF1, NF2, PBRM1, PIK3CA, and TGFBR1 were unfavorable mutations. In addition to age, sex, and node positive, favorable genes (HR = 0.15, 95% CI = 0.04-0.48, p = 0.001) and unfavorable genes (HR = 2.86, 95% CI = 1.51-5.29, p = 0.001) were identified as independent prognostic factors for DFS. Out of the 113 patients, only 35 received adjuvant treatment whereas the majority (78) did not. For patients with both favorable and unfavorable mutations undetected, adjuvant treatment showed negative effect on DFS (median DFS: S441 vs. 956 days, p = 0.010), but there was no significant difference in DFS among those in other mutational subgroups. CONCLUSIONS: Genomic testing might be useful in guiding the decisions regarding adjuvant treatment in BTC.

Tear proteomic analysis of young glasses, orthokeratology, and soft contact lens wearers.

Contact lens-related ocular surface complications occur more often in teenagers and young adults. The purpose of this study was to determine changes in tear proteome of young patients wearing glasses (GL), orthokeratology lenses (OK), and soft contact lenses (SCL). Twenty-two young subjects (10-26 years of age) who were established GL, OK, and SCL wearers were recruited. Proteomic data were collected using a data-independent acquisition-parallel accumulation serial fragmentation workflow. In total, 3406 protein groups were identified, the highest number of proteins identified in Schirmer strip tears to date. Eight protein groups showed higher abundance, and 11 protein groups showed lower abundance in the SCL group compared to the OK group. In addition, the abundance of 82 proteins significantly differed in children compared to young adult GL wearers, among which 67 proteins were higher, and 15 proteins were lower in children. These 82 proteins were involved in inflammation, immune, and glycoprotein metabolic biological processes. In summary, this work identified over 3000 proteins in Schirmer Strip tears. The results indicated that tear proteomes were altered by orthokeratology and soft contact wear and age, which warrants further larger-scale study on the ocular surface responses of teenagers and young adults separately to contact lens wear. SIGNIFICANCE: In this work, we examined the tear proteomes of young patients wearing glasses, orthokeratology lenses, and soft contact lenses using a data-independent acquisition-parallel accumulation serial fragmentation (diaPASEF) workflow and identified 3406 protein groups in Schirmer strip tears. Nineteen protein groups showed significant abundance changes between orthokeratology and soft contact lens wearers. Moreover, eighty-two protein groups significantly differed in abundance in children and young adult glasses wearers. As a pilot study, this work provides a deep coverage of tear proteome and suggests the need to investigate ocular responses to contact lens wear separately for children and young adults.

Subcellular redox responses reveal different Cu-dependent antioxidant defenses between mitochondria and cytosol.

Excess intracellular Cu perturbs cellular redox balance and thus causes diseases. However, the relationship between cellular redox status and Cu homeostasis and how such an interplay is coordinated within cellular compartments has not yet been well established. Using combined approaches of organelle-specific redox sensor Grx1-roGFP2 and non-targeted proteomics, we investigate the real-time Cu-dependent antioxidant defenses of mitochondria and cytosol in live HEK293 cells. The Cu-dependent real-time imaging experiments show that CuCl2 treatment results in increased oxidative stress in both cytosol and mitochondria. In contrast, subsequent excess Cu removal by bathocuproine sulfonate, a Cu chelating reagent, lowers oxidative stress in mitochondria but causes even higher oxidative stress in the cytosol. The proteomic data reveal that several mitochondrial proteins, but not cytosolic ones, undergo significant abundance change under Cu treatments. The proteomic analysis also shows that proteins with significant changes are related to mitochondrial oxidative phosphorylation and glutathione synthesis. The differences in redox behaviors and protein profiles in different cellular compartments reveal distinct mitochondrial and cytosolic response mechanisms upon Cu-induced oxidative stress. These findings provide insights into how redox and Cu homeostasis interplay by modulating specific protein expressions at the subcellular levels, shedding light on understanding the effects of Cu-induced redox misregulation on the diseases.

The elevation of different myocardial biomarkers on admission is associated with disease features and different outcomes in aneurysmal subarachnoid hemorrhage.

Test of different myocardial biomarkers is commonly arranged in patients with aneurysmal subarachnoid hemorrhage (aSAH). We sought to figure out whether different myocardial biomarkers' elevation is related to characteristics of ruptured aneurysms and patients' clinical outcomes. Patients with aSAH admitted in the Neurosurgery Department of West China Hospital from September 2019 to March 2020 were screened. Those who have one clear responsible aneurysm and met inclusion criteria were included. Clinical characteristics, site and size of the aneurysm, modified Fisher scale, troponin T (TPN-T), creatine kinase MB (CK-MB), and myoglobin (Myo) levels at admission, clinical outcomes (3-month mRS) were collected and compared. The study included 124 patients. After multivariate logistic regression, Hunt & Hess grade (per unit grade, OR 1.68, 95% CI 1.14-2.49), the size of ruptured aneurysm (equal to or more than 7 mm, OR 3.07, 95% CI 1.32-7.10) was highly predictive of myocardial biomarker elevation. All three biomarkers (TPN-T, CK-MB, Myo) were associated with unfavorable prognoses. Higher mortality (37.2% vs. 18.6%, P = 0.036) and a lower rate of good outcomes (41.9% vs. 71.2%, P = 0.003) were observed in patients with any positive myocardial biomarkers at admission. The clinical outcomes of patients with positive troponin T and negative creatine kinase MB were especially unfavorable. Our study demonstrates that the degree of neurological injury and size of ruptured aneurysm are strong predictors of myocardial biomarkers elevation, the site of ruptured aneurysm may not be associated with heart injury after SAH. The outcomes of patients with different combinations of abnormal biomarker levels may have significant differences and deserve further study.

Morphological transitions of micelles induced by the block arrangements of copolymer blocks: dissipative particle dynamics simulation.

Polymer micelles with distinct morphologies and unique microphase separation microstructures can exhibit different properties and functions, holding great promise for a range of biomedical applications. In the current work, the topological effects of grafted triblock copolymers on the morphologies and microphase separation microstructures of micelles, including block arrangements and grafting arrangements of hydrophobic side chains, are systematically studied. Using common copolymer components of typical drug carriers, micelles with interesting geometries are achieved, such as raspberry, multicompartment, ellipsoidal and dumbbell shapes, in which the relationship between micelle morphology and copolymer topology is verified. With further exploration of the grafting position and amount of hydrophobic side chains, the microstructure influencing mechanism of copolymer micelles in self-assembly is discussed. The block arrangements of hydrophobic side chains determine the configurations of copolymers (zigzag/bridge) inside micelles, which in turn affect the morphological transitions (from spherical to ringed short-rods and then to cylinders) and the size of the hydrophobic ring, which further gradually change into hydrophobic cage. This study provides insight into the microstructure of hydrophobic side chain grafted copolymer micelles and further helps to understand the mechanism of controlling the morphology of micelles, which might be useful to guide the molecular design and experimental preparation of micelles with controllable morphology for drug encapsulation and delivery.

Comprehensive spectral libraries for various rabbit eye tissue proteomes.

Rabbits have been widely used for studying ocular physiology and pathology due to their relatively large eye size and similar structures with human eyes. Various rabbit ocular disease models, such as dry eye, age-related macular degeneration, and glaucoma, have been established. Despite the growing application of proteomics in vision research using rabbit ocular models, there is no spectral assay library for rabbit eye proteome publicly available. Here, we generated spectral assay libraries for rabbit eye compartments, including conjunctiva, cornea, iris, retina, sclera, vitreous humor, and tears using fractionated samples and ion mobility separation enabling deep proteome coverage. The rabbit eye spectral assay library includes 9,830 protein groups and 113,593 peptides. We present the data as a freely available community resource for proteomic studies in the vision field. Instrument data and spectral libraries are available via ProteomeXchange with identifier PXD031194.

Expression of Microtubule-Associated Proteins in Relation to Prognosis and Efficacy of Immunotherapy in Non-Small Cell Lung Cancer.

BACKGROUND: Microtubule-associated proteins (MAPs) have been considered to play significant roles in the tumor evolution of non-small cell lung cancer (NSCLC). Nevertheless, mRNA transcription levels and prognostic value of distinct MAPs in patients with NSCLC remain to be clarified. METHODS: In this study, the Oncomine database, Gene Expression Profiling Interactive Analysis (GEPIA) database, and Human Protein Atlas were utilized to analyze the relationship between mRNA/protein expression of different MAPs and clinical characteristics in NSCLC patients, including tumor type and pathological stage. The correlation between the transcription level of MAPs and overall survival (OS) of NSCLC patients was analyzed by Kaplan-Meier plotter. Besides, 50 frequently altered neighbor genes of the MAPs were screened out, and a network has been constructed via the cBioPortal and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) dataset. Meanwhile, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis on the expression data of MAPs and their 50 frequently altered neighbor genes in NSCLC tissues. Furthermore, The Cancer Immunome Atlas (TCIA) was utilized to analyze the relationship between MAP expression and the response to immunotherapy. Finally, we used reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to verify the expression of MAPs in 20 patients with NSCLC. RESULTS: The present study discovered that the mRNA transcription levels of MAP7/7D2 were enriched in NSCLC tissues, while those of the MAP2/4/6/7D3 were lower in NSCLC specimens than those in control specimens. The mRNA transcription level of MAP6 was significantly associated with the advanced stage of NSCLC. Besides, survival analysis indicated that higher mRNA expressions of MAP2/4/6/7/7D3 were correlated considerably with favorable OS of NSCLC patients, whereas increased mRNA expression levels of MAP1A/1S were associated with poor OS. Moreover, the expression of MAP1A/1B/1S/4/6/7D1/7D3 was significantly correlated with immunophenoscore (IPS) in NSCLC patients. CONCLUSIONS: Our analysis indicated that MAP1A/1S could serve as potential personalized therapeutic targets for patients with NSCLC, and the enriched MAP2/4/6/7/7D3 expression could serve as a biomarker for favorable prognosis in NSCLC. Besides, the expression of MAP1A/1B/1S/4/6/7D1/7D3 was closely related to the response to immunotherapy. Taken together, MAP expression has potential application value in the clinical treatment and prognosis assessment of NSCLC patients, and further verifiable experiments can be conducted to verify our results.

The influence of STK11 mutation on acquired resistance to immunotherapy in advanced non-small cell lung cancer with Lynch syndrome: a case report and literature review.

Immune checkpoint inhibitors (ICI) monotherapy or combination therapies have become increasingly popular in patients with advanced non-small cell lung cancer (NSCLC). However, there are still many unknowns concerning the predictive bio-markers and resistance mechanisms to immunotherapy. Patients with primary tumor STK11 mutation reportedly to have a lower response rate than the STK11 wild-type and possibly a primary resistance mechanism to ICIs. However, there is presently no data regarding the contribution of STK11 to acquired resistance to ICIs. Herein we report on a patient who was diagnosed with advanced lung squamous cell carcinoma accompanied by Lynch syndrome. The patient developed an STK11 mutation after receiving pembrolizumab as a first-line treatment. Programmed death ligand 1 (PD-L1) was highly expressed (50%) in the biopsy. HRAS Q61L and TP53 R158L were mainly detected. Unexpectedly, the patient carried an MSH6 heterozygous germline mutation, and was classified as proficient mismatch repair (pMMR). The patient subsequently received pembrolizumab (200 mg, ivgtt, q3w) as first line therapy and achieved stable disease (SD) as the best response. After eight treatment cycles, the patient suffered disease progression (PD), and an STK11 frameshift mutation was newly identified in his plasma circulating tumor deoxyribonucleic acid (ctDNA). This case study suggests that STK11 could contribute to pembrolizumab acquired resistance. Furthermore, the patient was also diagnosed with Lynch syndrome, which rarely occurs in lung cancer.

The impact of baseline brain metastases on clinical benefits and progression patterns after first-line crizotinib in anaplastic lymphoma kinase-rearranged non-small cell lung cancer.

ABSTRACT: Baseline brain metastasis (BBM) commonly occurs in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer. Crizotinib prolongs the survival of patients with ALK rearrangement but lacks significant effect on brain metastasis. It remains unclear whether BBM and local therapy affect therapeutic outcomes and progression patterns during crizotinib treatment.Patients with ALK-positive (immunotherapy) non-small cell lung cancer were screened from West China Hospital between May 2013 and January 2019. A total of 155 patients were enrolled in this research, with entirely recorded statistics to analyze retrospectively.Baseline brain metastasis occurred in 64 patients (55.7%). Thirty-seven patients received local therapy, while 24 patients did not. We observed higher overall response rate in patients receiving local therapy (70.2% vs. 41.7%, P = .026), but no statistical difference was found in median progression free survival (mPFS) (12.0 months vs 13.0 months, P = .633). A significantly shorter mPFS was found in patients not receiving local treatment compared with the 16.5 months mPFS of patients without BBM (P = .029). Intracranial progressions were recorded in 35 patients with BBM (71%) and 16 patients who don't have (30%). As for extracranial progression, there is a higher occurrence rate (75.5%) in patients who had baseline extracranial metastases versus 49.0% in BBM patients. A significantly higher occurrence rate of multiple progression was noted in patients with BBM (14/49 vs. 6/53).Baseline intracranial metastasis changes the location and number of progressions after the first-line crizotinib and results in poor prognosis. There is no evidence that local treatment for brain metastasis had a protective effect on intracranial progression.

Duration and choices of prophylactic anticonvulsants in subarachnoid hemorrhage: a systematic review and meta-analysis.

The use of prophylactic anticonvulsants among patients with subarachnoid hemorrhage (SAH) is controversial. We sought to assess the effectiveness of different durations of prophylactic antiepileptic drug (AED) use among SAH patients. We searched the MEDLINE, Embase, Cochrane, and ClinicalTrials.gov databases until March 1, 2020. Randomized controlled trials or observational studies comparing different durations or different drugs were selected. The primary outcome was poor clinical outcomes. The secondary outcome was in-hospital seizure. Bayesian network meta-analysis was also performed to indirectly compare the effectiveness of different prophylaxes. A total of 5 papers were included. Three studies with a total of 959 patients were included in the analysis of the primary outcome; the results showed that long-term exposure to prophylactic AEDs (more than 3 days) led to poor clinical outcomes (OR 1.55; 95% CI 1.01-2.39; p = 0.045). Four studies with 1024 patients were included in the analysis of the secondary outcome; the results showed no association between the duration of prophylactic AED use and the occurrence of in-hospital seizures (OR 0.62; 95% CI 0.18-2.15; p = 0.447). In the network meta-analysis, no significant difference was found among the four different prophylaxes. Our findings suggested that, when compared with the short-term use, the long-term use of prophylactic AEDs in SAH patients has a similar effect on in-hospital seizure prevention but is associated with poor clinical outcomes. However, these findings were based on a small number of available studies with obvious heterogeneity in study design and different prescription regimens. Further well-designed studies are warranted to elucidate these questions.

Distribution and therapeutic outcomes of intergenic sequence-ALK fusion and coexisting ALK fusions in lung adenocarcinoma patients.

INTRODUCTION: Patients with ALK rearranged non-small-cell lung cancer (NSCLC) show survival benefits from tyrosine-kinase inhibitor (TKI). Widely application of DNA sequencing revealed various rearrangement pattern in addition to single EML4-ALK fusion. Here, we retrospectively analyzed the distribution and coexistence of ALK rearrangement and therapeutic outcome of patients with ALK rearranged NSCLC. METHOD: ALK positive NSCLC patients were screened at West China Hospital. NGS was performed on pre-treatment samples. Clinical characteristics and therapeutic outcomes were collected to retrospectively analyzed. RESULTS: Among the 89 patients with 22 ALK rearrangements, fusions of intergenic sequences with ALK were found in 15 (16.85 %). Non-EML4-ALK fusions were present in 18 patients (20.22 %). Coexistence of rearrangements were present in 16 patients (17.98 %). Intergenic sequence-ALK and non-EML4-ALK fusions occurred at higher rates in patients with at least two fusions (62.5 % versus 6.85 % for intergenic sequence-ALK, 62.5 % versus 10.96 % for non-EML4-ALK). There were 40 ALK-rearranged NSCLC patients receiving the first-line crizotinib. The median progression-free survival (PFS) was 9.7 months when excluding three lost patients. In the seven patients who had at least two fusions, the median PFS was 11.9 months, compared with 9.0 months among those with single (p = 0.336). No significant difference in median PFS was found between patients with and without intergenic-ALK fusion (12.0 months versus 9.6 months, p = 0.989). The median PFS was 9.0 months in patients harboring a single EML4-ALK fusion versus 13.0 months in those with other ALK alterations (P = 0.890). The PFS of patients with single intergenic sequence-ALK fusion reached to 2.9 months, 27 months, and 28.9 months respectively. CONCLUSION: Our study reports the distribution of intergenic sequence-ALK and coexisting fusions in ALK-rearranged NSCLC. Intergenic sequence-ALK and non-EML4-ALK are prone to coexist with other fusions. Neither intergenic sequence-ALK nor coexistence of fusions had a significant effect on the therapeutic benefit of treatment with crizotinib.

Coexisting of COX7A2L-ALK, LINC01210-ALK, ATP13A4-ALK and Acquired SLCO2A1-ALK in a Lung Adenocarcinoma with Rearrangements Loss During the Treatment of Crizotinib and Ceritinib: A Case Report.

ALK rearrangements account for ~5% of non-small-cell lung cancer (NSCLC). Numerous rearrangement partners have been discovered. Here, we describe a 53-year-old nonsmoker with NSCLC, in whom we identified four novel rearrangements. The patient was diagnosed as adenocarcinoma in the right middle lobe of lung, with metastases in subcarinal lymph node, ipsilateral lung, pleura and contralateral rib (cT4N2M1, stage IV). Next-generation sequencing (NGS) identified three baseline ALK fusions: COX7A2L-ALK (C[intragenic]:A20), LINC01210-ALK (L[intergenic]:A20) and ATP13A4-ALK (A9:A19). The patient exhibited 12 months of progression-free survival (PFS) and a partial response (PR) to first-line crizotinib therapy. We then discovered a new SLCO2A1-ALK fusion (S[intergenic]:A18) and a missense mutation C1156Y after resistance developed. Sequential ceritinib resulted in further 8 months of PFS, after which NGS results demonstrated the loss of ATP13A4-ALK and SLCO2A1-ALK. This is the first description a NSCLC patient harbors four ALK fusions and was sensitive to tyrosine kinase inhibitors (TKIs). Acquisition and loss of ALK fusions after ALK inhibitors may account for resistance.

Ortho-Substituted α-Phenyl Mannoside Derivatives Promoted Early-Stage Adhesion and Biofilm Formation of E. coli 83972.

Prevention of catheter-associated urinary tract infection (CAUTI) over long-term usage of urinary catheters remains a great challenge. Bacterial interference using nonpathogenic bacteria, such as E. coli 83972, have been investigated in many pilot-scale clinical studies as a potentially nonantibiotic based strategy for CAUTI prevention. We have demonstrated that preforming a dense and stable biofilm of the nonpathogenic E. coli greatly enhances their capability to prevent pathogen colonization. Such nonpathogenic biofilms were formed by E. coli 83972 expressing type 1 fimbriae (fim+ E. coli 83972) on mannoside-presenting surfaces. In this work, we report the synthesis of a series of mannoside derivatives with a wide range of binding affinities, all being equipped with a handle for covalent attachment to silicone surfaces. We established a high-throughput competitive assay based on mannoside-modified particles and flow-cytometry to directly measure the binding affinity between the mannoside ligands and fim+ E. coli 83972. We demonstrated that the bacterial adhesion and biofilm formation were strongly correlated to the binding affinity of the immobilized mannoside ligands. Mass spectrometry based proteomic analysis indicated a substantial difference in the proteome of the extracellular polymeric substance (EPS) secreted by biofilms on different mannoside surfaces, which might be related to the biofilm stability.

A phase I dose-reduction study of apatinib combined with pemetrexed and carboplatin in untreated EGFR and ALK negative stage IV non-squamous NSCLC.

Objective Apatinib is an oral small molecule anti-angiogenic drug. This phase I study aimed to establish the feasible dose of apatinib in combination with pemetrexed plus carboplatin as first-line therapy for epidermal growth factor receptor (EGFR) and anaplasticlymphoma kinase (ALK) negative stage IV non-squamous non-small cell lung cancer (NSCLC). Methods Using a 3 + 3 dose-reduction design, patients received oral apatinib at four dose levels: 750 mg qd, 500 mg qd, 500 mg/day two weeks on/one week off schedule (500 mg schedule 2/1) or 250 mg qd. Pemetrexed (500 mg/m2) plus carboplatin (AUG = 5) was administered every three weeks. Maintenance therapy by apatinib or pemetrexed could be carried on until disease progression or unacceptable toxicity. The feasible dose was determined based on cycle 1 dose-limiting toxicities (DLT); other assessments included safety and antitumor activity according to response evaluation criteria in solid tumors. Result A total of twelve patients were enrolled and cycle 1 DLTs were observed in two patients at 750 mg qd dosage of apatinib (both Grade 3 hypertension), two patients at 500 mg qd (Grade 3 hypertension and Grade 3 hand-foot syndrome), and only one of six patients at 500 mg/day schedule 2/1 (Grade 3 hypertension). The most frequently drug-related adverse events (AEs) were hematological toxicity, hypertension, hand-foot syndrome, and hepatic transaminases elevation. Partial response was observed in four patients of eleven evaluable patients (objective response rate 36.4%), and six patients exhibited stable disease (disease control rate 90.9%). Conclusion In patients with advanced non-squamous NSCLC, the feasible dose of apatinib given with standard-dose pemetrexed and carboplatin was 500 mg/day schedule 2/1. The schedule was generally well tolerated and demonstrated promising clinical benefit in NSCLC.

Characterization of protective antigen CbpB as an adhesin and a plasminogen-binding protein of Erysipelothrix rhusiopathiae.

Erysipelothrix rhusiopathiae is the causative agent of animal erysipelas and human erysipeloid. E. rhusiopathiae CbpB has been reported to be a protective antigen, but its pathogenic roles are not known. The aim of this study was to evaluate the ability of CbpB to act as an adhesin in E. rhusiopathiae adhesion to porcine endothelial cells as well as a host plasminogen- and fibronectin- binding protein. Recombinant CbpB (rCbpB) was successfully obtained, and it was found that E. rhusiopathiae CbpB was located on the cell surface of E. rhusiopathiae. Moreover, CbpB exhibited binding activity to porcine endothelial cells. Recombinant CbpB successfully bound to host plasminogen but was unable to bind to fibronectin. In conclusion, our work suggested that CbpB is a virulence factor of E. rhusiopathiae.