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Background Reported mortalities and morbidities of therapeutic procedures for liver tumors vary between studies, because of different designs and small sample sizes. We investigated the mortalities and complication rates for hepatectomy, radiofrequency ablation (RFA), and trans-catheter arterial embolization (TAE) for hepatocellular carcinoma (HCC) in a large sample, using a nationwide Japanese database (the Diagnosis Procedure Combination database). Methods Data from the Diagnosis Procedure Combination database were analyzed for July 1 to December 31, 2007 and the same period in 2008. We identified 54,145 patients with HCC who underwent hepatectomy ( n  = 5,270), RFA ( n  = 11,688), or TAE ( n  = 37,187). In-hospital mortality and morbidity were analyzed for each procedure. The relationships between mortality and factors including patient characteristics and procedural backgrounds were assessed. Results In-hospital mortalities associated with hepatectomy, RFA, and TAE were 2.6 % [95 % confidence interval (CI) 2.2–3.1], 0.3 % (0.2–0.4), and 1.0 % (0.9–1.1), and post-procedural complication rates were 14.5 % (13.5–15.5), 4.5 % (4.2–4.9), and 4.5 % (4.3–4.7), respectively. Increased mortality following hepatectomy was significantly associated with older age, extended lobectomy (vs. partial hepatectomy; odds ratio [OR] 3.80, p  < 0.001), lower hospital volume (OR 2.74, p  < 0.001), and renal comorbidity (OR 3.01, p  = 0.02). Older age and cardiac comorbidity (OR 5.14, p  = 0.001) were significantly associated with RFA-related mortality, and lower hospital volume was significantly associated with TAE-related mortality (OR 1.60, p  < 0.001). Conclusions Mortalities and morbidities associated with therapeutic procedures for liver tumors were acceptably low in Japan, but were affected by patient and institutional characteristics.

In recent years, China’s influence as the dominant importer of waste products has reshaped global waste trade through restrictive programs such as Operation Green Fence in 2013 and National Sword in 2017. These restrictions have greatly affected not only China’s import of waste products but also the international trade and global logistics of these products. China’s import restrictions in 2017 decreased the country’s import of waste plastic by 92% and used paper by 56%. It also increased the unit value of these two categories of waste by 27% and 13%, respectively, showing an improvement in the quality of imported waste. Most of these impacts originate from intensive margins. The restrictions diverted the flow of waste mostly to the low- and middle-income countries of the East Asian and Pacific regions along with Europe and Central Asia, as their imports increased by 161% and 266% for waste plastic and 101% and 77% for used paper, respectively. Compared with Operation Green Fence, the impact of the 2017 National Sword has been much higher, with shipping companies faced with a lack of products on backhaul routes and forced to change their longstanding practices.

Engineering the microbial production of secondary metabolites is limited by the known reactions of correctly annotated enzymes. Therefore, the machine learning discovery of specialized enzymes offers great potential to expand the range of biosynthesis pathways. Benzylisoquinoline alkaloid production is a model example of metabolic engineering with potential to revolutionize the paradigm of sustainable biomanufacturing. Existing bacterial studies utilize a norlaudanosoline pathway, whereas plants contain a more stable norcoclaurine pathway, which is exploited in yeast. However, committed aromatic precursors are still produced using microbial enzymes that remain elusive in plants, and additional downstream missing links remain hidden within highly duplicated plant gene families. In the current study, machine learning is applied to predict and select plant missing link enzymes from homologous candidate sequences. Metabolomics-based characterization of the selected sequences reveals potential aromatic acetaldehyde synthases and phenylpyruvate decarboxylases in reconstructed plant gene-only benzylisoquinoline alkaloid pathways from tyrosine. Synergistic application of the aryl acetaldehyde producing enzymes results in enhanced benzylisoquinoline alkaloid production through hybrid norcoclaurine and norlaudanosoline pathways. Producing plant secondary metabolites by microbes is limited by the known enzymatic reactions. Here, the authors apply machine learning to predict missing link enzymes of benzylisoquinoline alkaloid (BIA) biosynthesis in Papaver somniferum , and validate the specialized activities through heterologous production.

Cancer-associated fibroblasts (CAFs) are important components in the tumor microenvironment, and we sought to identify effective therapeutic targets in CAFs for non-small cell lung cancer (NSCLC). In this study, we established fibroblast cell lines from the cancerous and non-cancerous parts of surgical lung specimens from patients with NSCLC and evaluated the differences in behaviors towards NSCLC cells. RNA sequencing analysis was performed to investigate the differentially expressed genes between normal fibroblasts (NFs) and CAFs, and we identified that the expression of periostin (POSTN), which is known to be overexpressed in various solid tumors and promote cancer progression, was significantly higher in CAFs than in NFs. POSTN increased cell proliferation via NSCLC cells’ ERK pathway activation and induced epithelial-mesenchymal transition (EMT), which improved migration in vitro. In addition, POSTN knockdown in CAFs suppressed these effects, and in vivo experiments demonstrated that the POSTN knockdown improved the sensitivity of EGFR-mutant NSCLC cells for osimertinib treatment. Collectively, our results showed that CAF-derived POSTN is involved in tumor growth, migration, EMT induction, and drug resistance in NSCLC. Targeting CAF-secreted POSTN could be a potential therapeutic strategy for NSCLC.Key messages• POSTN is significantly upregulated in CAFs compared to normal fibroblasts in NCSLC.• POSTN increases cell proliferation via activation of the NSCLC cells’ ERK pathway.• POSTN induces EMT in NSCLC cells and improves the migration ability.• POSTN knockdown improves the sensitivity for osimertinib in EGFR-mutant NSCLC cells.

The BioBank Japan (BBJ) Project was launched in 2003 with the aim of providing evidence for the implementation of personalized medicine by constructing a large, patient-based biobank (BBJ). This report describes the study design and profile of BBJ participants who were registered during the first 5-year period of the project. The BBJ is a registry of patients diagnosed with any of 47 target common diseases. Patients were enrolled at 12 cooperative medical institutes all over Japan from June 2003 to March 2008. Clinical information was collected annually via interviews and medical record reviews until 2013. We collected DNA from all participants at baseline and collected annual serum samples until 2013. In addition, we followed patients who reported a history of 32 of the 47 target diseases to collect survival data, including cause of death. During the 5-year period, 200,000 participants were registered in the study. The total number of cases was 291,274 at baseline. Baseline data for 199,982 participants (53.1% male) were available for analysis. The average age at entry was 62.7 years for men and 61.5 years for women. Follow-up surveys were performed for participants with any of 32 diseases, and survival time data for 141,612 participants were available for analysis. The BBJ Project has constructed the infrastructure for genomic research for various common diseases. This clinical information, coupled with genomic data, will provide important clues for the implementation of personalized medicine. •The BioBank Japan Project (BBJ) enrolled 200,000 patients with 47 target diseases.•The BBJ is one of the largest patient-based biobanks in the world.•The BBJ may allow for personalized medicine in the future.

Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we investigated the possible mechanisms acquired for crizotinib in MET -amplified lung carcinoma cell lines. Two MET -amplified lung cancer cell lines, EBC-1 and H1993, were established for acquired resistance to MET-TKI crizotinib and were functionally elucidated. Genomic and transcriptomic data were used to assess the factors contributing to the resistance mechanism, and the alterations hypothesized to confer resistance were validated. Multiple mechanisms underlie acquired resistance to crizotinib in MET -amplified lung cancer cell lines. In EBC-1-derived resistant cells, the overexpression of SERPINE1, the gene encoding plasminogen activator inhibitor-1 (PAI-1), mediated the drug resistance mechanism. Crizotinib resistance was addressed by combination therapy with a PAI-1 inhibitor and PAI-1 knockdown. Another mechanism of resistance in different subline cells of EBC-1 was evaluated as epithelial-to-mesenchymal transition with the upregulation of antiapoptotic proteins. In H1993-derived resistant cells, MEK inhibitors could be a potential therapeutic strategy for overcoming resistance with downstream mitogen-activated protein kinase pathway activation. In this study, we revealed the different mechanisms of acquired resistance to the MET inhibitor crizotinib with potential therapeutic application in patients with MET -amplified lung carcinoma.

BackgroundThe presence of tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) in tumor tissue has been related to the prognosis in various malignancies. Meanwhile, neutrophil-to-lymphocyte ratio (NLR) as a systemic inflammation marker also has been associated with the prognosis in them. However, few reports have investigated the relationship between pulmonary metastases from sarcoma and these biomarkers.MethodsWe retrospectively recruited 102 patients undergoing metastasectomy for pulmonary metastases from uterine leiomyosarcoma at Okayama University Hospital from January 2006 to December 2019. TILs and TLSs were evaluated by immunohistochemical staining of surgically resected specimens of pulmonary metastases using anti-CD3/CD8/CD103/Foxp3/CD20 antibodies. NLR was calculated from the blood examination immediately before the most recent pulmonary metastasectomy. We elucidated the relationship between the prognosis and these factors. Because we considered that the status of tumor tissue and systemic inflammation were equally valuable, we also assessed the impact of the combination of TILs or TLSs and NLR on the prognosis.ResultsAs for TILs, CD3-positive cells and CD8-positive cells were correlated with the prognosis. The prognosis was significantly better in patients with CD3-high group, CD8-high group, TLSs-high group, and NLR-low group, respectively. The prognosis of CD8-high/NLR-low group and TLSs-high/NLR-low group was significantly better than that of CD8-low/NLR-high group and TLSs-low/NLR-high group, respectively.ConclusionsCD3-positive TILs, CD8-positive TILs, TLSs, and NLR are correlated with the prognosis, respectively. The combination of CD8-positive TILs or TLSs and NLR may be the indicators to predict the prognosis of patients with pulmonary metastases from uterine leiomyosarcoma.