The objectives of this study were to propose a clinical prognostic scoring system applicable for intrahepatic cholangiocarcinoma (ICC) and to evaluate the prognostic validity of the American Joint ...Committee on Cancer (AJCC) 7th edition staging system.
Retrospective univariate and multivariate survival analyses were conducted for 344 patients with ICC who underwent hepatectomy. A simple clinical prognostic scoring system (Fudan score) was developed based on the independent predictors. The prognostic validity was assessed in 74 patients with unresected tumors and compared with the AJCC 6th and 7th edition systems.
In the training set, serum alkaline phosphatase level, carbohydrate antigen 19-9 level, tumor boundary type, tumor size, and number of intrahepatic tumors were independent predictive factors of survival in ICC and were incorporated into the Fudan score. Three hundred forty-four patients were categorized into four subsets with 5-year overall survival rates of 48.6%, 25.6%, 10.3%, and 0.0% for low-, intermediate-, high-, and extremely high-risk groups, respectively. The discriminative ability of the Fudan score was better than that of the AJCC staging system and well applied in the unresected patient set.
A Fudan score based on clinical factors may provide a relatively accurate prognostic prediction for ICC patients regardless of resection status.
The biological and functional heterogeneity between tumors—both across and within cancer types—poses a challenge for immunotherapy. To understand the factors underlying tumor immune heterogeneity and ...immunotherapy sensitivity, we established a library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma. These clones generated tumors that recapitulated T cell-inflamed and non-T-cell-inflamed tumor microenvironments upon implantation in immunocompetent mice, with distinct patterns of infiltration by immune cell subsets. Co-injecting tumor cell clones revealed the non-T-cell-inflamed phenotype is dominant and that both quantitative and qualitative features of intratumoral CD8+ T cells determine response to therapy. Transcriptomic and epigenetic analyses revealed tumor-cell-intrinsic production of the chemokine CXCL1 as a determinant of the non-T-cell-inflamed microenvironment, and ablation of CXCL1 promoted T cell infiltration and sensitivity to a combination immunotherapy regimen. Thus, tumor cell-intrinsic factors shape the tumor immune microenvironment and influence the outcome of immunotherapy.
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•Generated a library of congenic pancreatic cancer cell clones derived from KPC mice•Each tumor elicited unique immune infiltration correlating with therapeutic response•Tumors lacking T cells exhibit different epigenetic and transcriptomic status•CXCL1 was increased in therapy-resistant tumors that lacked T cell infiltration
Using a library of pancreatic cancer cell clones, Li et al. identify heterogeneous and multifactorial pathways regulating tumor-cell-intrinsic mechanisms that dictate the immune microenvironment and thereby responses to immunotherapy. This tumor clone library provides a tool for identifying new targets responsible for thwarting responses to immunotherapy in resistant tumors.
Sperm contributes diverse RNAs to the zygote. While sperm small RNAs have been shown to impact offspring phenotypes, our knowledge of the sperm transcriptome, especially the composition of long RNAs, ...has been limited by the lack of sensitive, high-throughput experimental techniques that can distinguish intact RNAs from fragmented RNAs, known to abound in sperm. Here, we integrate single-molecule long-read sequencing with short-read sequencing to detect sperm intact RNAs (spiRNAs). We identify 3440 spiRNA species in mice and 4100 in humans. The spiRNA profile consists of both mRNAs and long non-coding RNAs, is evolutionarily conserved between mice and humans, and displays an enrichment in mRNAs encoding for ribosome. In sum, we characterize the landscape of intact long RNAs in sperm, paving the way for future studies on their biogenesis and functions. Our experimental and bioinformatics approaches can be applied to other tissues and organisms to detect intact transcripts.
Epithelial-mesenchymal transition (EMT) has been recognized as a key element of cell migration and invasion in lung cancer; however, the underlying mechanisms are not fully elucidated. Recently, ...emerging evidence suggest that miRNAs have crucial roles in control of EMT and EMT-associated traits such as migration, invasion and chemoresistance. Here, we found that miR-218 expression levels were significantly downregulated in lung cancer tissues compared with adjacent non-cancerous tissues, and the levels of miR-218 were significantly associated with histological grades and lymph node metastasis. Overexpression of miR-218 inhibited cell migration and invasion as well as the EMT process. Of particular importance, miR-218 was involved in the metastatic process of lung cancer cells in vivo by suppressing local invasion and distant colonization. We identified Slug and ZEB2 as direct functional targets of miR-218. Inverse correlations were observed between miR-218 levels and Slug/ZEB2 levels in cancer tissue samples. In addition, overexpression of miR-218 in H1299 increased chemosensitivity of cells to cisplatin treatment through suppression of Slug and ZEB2. These findings highlight an important role of miR-218 in the regulation of EMT-related traits and metastasis of lung cancer in part by modulation of Slug/ZEB2 signaling, and provide a potential therapeutic strategy by targeting miR-218 in NSCLC.
Abstract
The dynamics of a nuclear open quantum system could be revealed in the correlations between the breakup fragments of halo nuclei. The breakup mechanism of a proton halo nuclear system is of ...particular interest as the Coulomb polarization may play an important role, which, however, remains an open question. Here we use a highly efficient silicon detector array and measure the correlations between the breakup fragments of
8
B incident on
120
Sn at near-barrier energies. The energy and angular correlations can be explained by a fully quantum mechanical method based on the state-of-the-art continuum discretized coupled channel calculations. The results indicate that, compared to the neutron halo nucleus
6
He,
8
B presents distinctive reaction dynamics: the dominance of the elastic breakup. This breakup occurs mainly via the short-lived continuum states, almost exhausts the
7
Be yield, indicating the effect of Coulomb polarization on the proton halo state. The correlation information reveals that the prompt breakup mechanism dominates, occurring predominantly on the outgoing trajectory. We also show that, as a large environment, the continuum of
8
B breakup may not significantly influence elastic scattering and complete fusion.
Giant Piezoelectricity on Si for Hyperactive MEMS Baek, S. H.; Park, J.; Kim, D. M. ...
Science (American Association for the Advancement of Science),
11/2011, Volume:
334, Issue:
6058
Journal Article
Peer reviewed
Microelectromechanical systems (MEMS) incorporating active piezoelectric layers offer integrated actuation, sensing, and transduction. The broad implementation of such active MEMS has long been ...constrained by the inability to integrate materials with giant piezoelectric response, such as Pb(MG 1/3 Nb 2/3 )O₃-PbTiO₃ (PMN-PT). We synthesized high-quality PMN-PT epitaxial thin films on vicinal (001) Si wafers with the use of an epitaxial (001) SrTiO₃ template layer with superior piezoelectric coefficients (e 31,f = -27 ± 3 coulombs per square meter) and figures of merit for piezoelectric energy-harvesting systems. We have incorporated these heterostructures into microcantilevers that are actuated with extremely low drive voltage due to thin-film piezoelectric properties that rival bulk PMN-PT single crystals. These epitaxial heterostructures exhibit very large electromechanical coupling for ultrasound medical imaging, microfluidic control, mechanical sensing, and energy harvesting.
Diffuse large B cell lymphoma (DLBCL) is a biologically heterogeneous and clinically aggressive disease. Here, we explore the role of bromodomain and extra-terminal domain (BET) proteins in DLBCL, ...using integrative chemical genetics and functional epigenomics. We observe highly asymmetric loading of bromodomain 4 (BRD4) at enhancers, with approximately 33% of all BRD4 localizing to enhancers at 1.6% of occupied genes. These super-enhancers prove particularly sensitive to bromodomain inhibition, explaining the selective effect of BET inhibitors on oncogenic and lineage-specific transcriptional circuits. Functional study of genes marked by super-enhancers identifies DLBCLs dependent on OCA-B and suggests a strategy for discovering unrecognized cancer dependencies. Translational studies performed on a comprehensive panel of DLBCLs establish a therapeutic rationale for evaluating BET inhibitors in this disease.
•BET inhibition exhibits antitumor efficacy in vitro and in vivo•BRD4 localizes in an asymmetric manner to massively overloaded enhancer regions•Genes with adjacent BRD4-loaded super-enhancers are sensitive to BET inhibition•Cancer dependencies are found among super-enhancer-marked genes
This study aimed to assess the efficacy and safety of intrathecal (IT) morphine for postoperative pain control in adults undergoing spinal surgeries. We searched the electronic databases of PubMed, ...Embase, and CENTRAL up to 1st January 2021 for randomized controlled trials (RCTs) or controlled clinical trials (CCTs) comparing IT morphine with placebo or other analgesics. Twelve studies were included. Eleven were RCTs and one was a CCT. Our meta-analysis indicated a statistically significant reduction of pain scores with IT morphine at 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours; but no significant difference at 48 hours. Meta-analysis indicated a statistically significant reduction in analgesic consumption with IT morphine as compared to control. Pooled analysis indicated that IT morphine had no statistically significant effect on length of hospital stay. Our analysis indicated no statistically significant difference in the risk of nausea, vomiting, sedation, respiratory depression, headache, and urinary retention between IT morphine and control groups. The incidence of pruritis was significantly increased in the IT morphine group. The certainty of the evidence was judged to be "moderate" for pain scores at 12 hours, 24 hours, and analgesic consumption. To conclude, our review indicates that IT morphine results in significantly better pain control in the first 24 hours after spinal surgery. The risk of pruritis is significantly increased with the use of IT morphine but not for other opioid-related adverse events. Future RCTs should focus on finding the most optimal dose of IT morphine for spinal surgeries.
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