Abstract
Cytokinins are one of the most important phytohormones and play essential roles in multiple life processes in planta. Root-derived cytokinins are transported to the shoots via long-distance ...transport. The mechanisms of long-distance transport of root-derived cytokinins remain to be demonstrated. In this study, we report that OsABCG18, a half-size ATP-binding cassette transporter from rice (Oryza sativa L.), is essential for the long-distance transport of root-derived cytokinins. OsABCG18 encodes a plasma membrane protein and is primarily expressed in the vascular tissues of the root, stem, and leaf midribs. Cytokinin profiling, as well as 14Ctrans-zeatin tracer, and xylem sap assays, demonstrated that the shootward transport of root-derived cytokinins was significantly suppressed in the osabcg18 mutants. Transport assays in tobacco (Nicotiana benthamiana) indicated that OsABCG18 exhibited efflux transport activities for various substrates of cytokinins. While the mutation reduced root-derived cytokinins in the shoot and grain yield, overexpression of OsABCG18 significantly increased cytokinins in the shoot and improved grain yield. The findings for OsABCG18 as a transporter for long-distance transport of cytokinin provide new insights into the cytokinin transport mechanism and a novel strategy to increase cytokinins in the shoot and promote grain yield.
OsABCG18 is essential for long-distance transport of cytokinins from root to shoot, and promotes grain yield in rice.
Recently, a new photoelectric phenomenon dubbed in-plane photoelectric (IPPE) effect has been demonstrated experimentally. In this work, we investigate the IPPE effect in a zigzag-edged or ...armchair-edged phosphorene nanoribbons (ZPNRs or APNRs) that is modulated by a step barrier. Based on the Floquet theory, we calculate the directed photocurrent Ī|| (Ī⊥) generated by a non-resonant linearly-polarized light with polarization vector in parallel with (perpendicular to) the nanoribbon direction. We find that such a photocurrent depends on the edge type of the nanoribbon and the polarization direction of light. At high Fermi energies, the IPPE current Ī|| in APNRs is significantly stronger than that in ZPNRs under the same conditions. In APNRs, both Ī|| and Ī⊥ always have the same direction and |Ī||:Ī⊥|>10. In contrast, in ZPNRs Ī⊥ can reverse its direction (becoming negative) and is comparable to Ī|| in amplitude. The negative photocurrent arises from both the photon-emission and photon-absorption process related to the quasi-flat-band in ZPNRs. This indicates that the mid-gap states can be detected by the IPPE effect. The energy scope and amplitude of negative photocurrent can be tuned by adjusting the height of the step barrier, the light frequency, and the light intensity.
•Floquet theory is used to study in-plane photoelectric effect in phosphorene ribbons.•The photocurrent depends strongly on edge type and polarization direction of light.•Negative current can occur in zigzag nanoribbons and is related to quasi-flat band.•The photocurrent can be tuned by varying parameters of the step barrier and light.
Intrahepatic cholangiocarcinomas (ICCs) are primary liver tumors with a poor prognosis. The development of effective therapies has been hampered by a limited understanding of the biology of ICCs. ...Although ICCs exhibit heterogeneity in location, histology, and marker expression, they are currently thought to derive invariably from the cells lining the bile ducts, biliary epithelial cells (BECs), or liver progenitor cells (LPCs). Despite lack of experimental evidence establishing BECs or LPCs as the origin of ICCs, other liver cell types have not been considered. Here we show that ICCs can originate from fully differentiated hepatocytes. Using a mouse model of hepatocyte fate tracing, we found that activated NOTCH and AKT signaling cooperate to convert normal hepatocytes into biliary cells that act as precursors of rapidly progressing, lethal ICCs. Our findings suggest a previously overlooked mechanism of human ICC formation that may be targetable for anti-ICC therapy.
Background & Aims Cancer cells often lose contact inhibition to undergo anchorage-independent proliferation and become resistant to apoptosis by inactivating the Hippo signaling pathway, resulting in ...activation of the transcriptional co-activator yes-associated protein (YAP). However, the oncogenic mechanisms of YAP activity are unclear. Methods By using cross-species analysis of expression data, the Notch ligand Jagged-1 (Jag-1) was identified as a downstream target of YAP in hepatocytes and hepatocellular carcinoma (HCC) cells. We analyzed the functions of YAP in HCC cells via overexpression and RNA silencing experiments. We used transgenic mice that overexpressed a constitutively activated form of YAP (YAPS127A ), and measured protein levels in HCC, colorectal and pancreatic tumor samples from patients. Results Human HCC cell lines and mouse hepatocytes that overexpress YAPS127A up-regulated Jag-1, leading to activation of the Notch pathway and increased proliferation. Induction of Jag-1, activation of Notch, and cell proliferation required binding of YAP to its transcriptional partner TEA domain family member 4 (TEAD4); TEAD4 binding required the Mst1/2 but not β-catenin signaling. Levels of YAP correlated with Jag-1 expression and Notch signaling in human tumor samples and correlated with shorter survival times of patients with HCC or colorectal cancer. Conclusions The transcriptional regulator YAP up-regulates Jag-1 to activate Notch signaling in HCC cells and mouse hepatocytes. YAP-dependent activity of Jag-1 and Notch correlate in human HCC and colorectal tumor samples with patient survival times, suggesting the use of YAP and Notch inhibitors as therapeutics for gastrointestinal cancer. Transcript profiling: microarray information was deposited at the Gene Expression Omnibus database ( http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=jxepvsumwosqkve&acc=GSE35004 ).
The tumor microenvironment (TME) has been shown to strongly influence treatment outcome for cancer patients in various indications and to influence the overall survival. However, the cells forming ...the TME in gastric cancer have not been extensively characterized.
We combine bulk and single-cell RNA sequencing from tumors and matched normal tissue of 24 treatment-naïve GC patients to better understand which cell types and transcriptional programs are associated with malignant transformation of the stomach. Clustering 96,623 cells of non-epithelial origin reveals 81 well-defined TME cell types. We find that activated fibroblasts and endothelial cells are most prominently overrepresented in tumors. Intercellular network reconstruction and survival analysis of an independent cohort imply the importance of these cell types together with immunosuppressive myeloid cell subsets and regulatory T cells in establishing an immunosuppressive microenvironment that correlates with worsened prognosis and lack of response in anti-PD1-treated patients. In contrast, we find a subset of IFNγ activated T cells and HLA-II expressing macrophages that are linked to treatment response and increased overall survival.
Our gastric cancer single-cell TME compendium together with the matched bulk transcriptome data provides a unique resource for the identification of new potential biomarkers for patient stratification. This study helps further to elucidate the mechanism of gastric cancer and provides insights for therapy.
HIPEC is an emerging procedure to treat peritoneal metastasis of gastric cancer. Data about HIPEC in locally advanced gastric cancer is scarce. The purpose of this trial is to evaluate the safety and ...toxicity of prophylactic HIPEC with cisplatin for patients with locally advanced gastric cancer.
From March 2015 to November 2016, a prospective, randomized phase II trial was conducted. After radical gastrectomy, patients in the experimental group underwent HIPEC with cisplatin followed by adjuvant chemotherapy with SOX regime. Patients in the other group were treated with SOX regime alone. Postoperative complications and patient survival were compared.
In total, 50 patients were eligible for analyses. No significant difference was found in the incidence of postoperative complications including anastomotic/intestinal leakage, liver dysfunction, bone marrow suppression, wound infection and ileus (P > 0.05). Mean duration of hospitalization after radical gastrectomy was 11.7 days. 12.2 days in experimental group and 10.8 days in control group respectively (P = 0.255). The percentage of patients with elevated tumor markers was 12.1% in experimental group, which was significantly lower than 41.2% in control group (P = 0.02). 3-year RFS of patients who treated with or without prophylactic HIPEC were 84.8 and 88.2% respectively (P = 0.986). In the multivariate analysis, pathological T stage was the only independent risk factor for the RFS of patients (P = 0.012, HR =15.071).
Additional intraoperative HIPEC with cisplatin did not increase postoperative complications for locally advanced gastric cancer after curative surgery. Prophylactic HIPEC with cisplatin was safe and tolerable, while it did not reduce the risk of peritoneal recurrence in this trial, supporting further studies to validate the efficacy of it.
Chinese Clinical Trial Registry, ChiCTR2000038331. Registered 18 September 2020 - Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=59692 .
Background
Long non-coding RNA (lncRNA) ASB16 antisense RNA 1 (ASB16-AS1) is recognized as an oncogene in several cancer types, but its relation to GC is unknown. Tripartite motif containing 37 ...(TRIM37) has been proven to accelerate the development of gastric cancer (GC), whereas the molecular mechanism assisted ASB16-AS1 and TRIM37 in regulating GC progression remains unclear.
Methods
Differentially expressed lncRNAs in GC samples were analyzed based on Gene Expression Omnibus (GEO) data. CCK-8 and colony formation assays were applied to determine the proliferative ability of GC cells. Stem cell-like phenotype of GC cells was assessed by sphere formation assay and flow cytometry analysis. Luciferase reporter assay, RNA immunoprecipitation (RIP), pulldown, and co-immunoprecipitation (Co-IP) were performed to verify the interplay of RNA molecules.
Results
ASB16-AS1 was upregulated in GC samples according to GEO data and qRT-PCR analysis. ASB16-AS1 strengthened the proliferative ability and stem cell-like characteristics in GC cells. More importantly, ASB16-AS1 encouraged GC cell growth in vivo. Mechanistically, ASB16-AS1 strengthened TRIM37 expression by sequestering miR-3918 and miR-4676-3p. ASB16-AS1 activated NF-kappa B (NF-κB) pathway by cooperating with ATM serine/threonine kinase (ATM) to induce TRIM37 phosphorylation.
Conclusion
In summary, ASB16-AS1 exerted oncogenic functions in GC through modulating TRIM37 expression at both mRNA and protein levels.
Graphic abstract
MUC1, a member of the mucin family, is expressed in tumors of various human organs and may function as an antiadhesion molecule that inhibits cell-to-cell adhesion, inducing tumor metastasis, and ...served as a potential biomarker of tumor progression in early gastric cancer. However, its prognostic significance in gastric cancer is still in dispute. We performed a meta-analysis to evaluate the relationship between MUC1 expression and prognosis of gastric cancer. A total of ten eligible studies with 834 cases and 548 controls were included. MUC1 positive cases were highly positive in intestinal-type carcinomas (OR = 1.76, 95% CI: 1.27–2.44, P=0.0008 fixed-effect), higher rate of vascular invasion (OR = 1.64, 95% CI: 1.13–2.39, P=0.009 fixed-effect), and lymph node metastasis (OR = 2.10, 95% CI: 1.20–3.67, P=0.01 random-effect), as well as lower 5-year survival rate (HR = 0.27, 95% CI: 0.11–0.66, P=0.004 random-effect). However, the presence of MUC1 was not associated with gender, tumor size, histologic differentiation, and clinical stage. In summary, MUC1 is a prognostic factor in gastric cancer, which acts as a marker of poor outcome in patients with gastric cancer. Further clinical studies are needed to confirm the role of MUC1 in clinical practice.
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•A novel mouse model of intrahepatic cholangiocarcinoma (ICC) was established.•Hydrodynamic transfection of activated forms of AKT and Yap was used to induce ICC.•This model ...recapitulates many morphological and molecular features of human ICC.•MLN0128 may be superior to gemcitabine/oxaliplatin based chemotherapy to treat ICC.•The efficacy of MLN0128 is mainly attributed to induction of apoptosis of ICC cells.
Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy without effective treatment options. MLN0128, a second generation pan-mTOR inhibitor, shows efficacy for multiple tumor types. We evaluated the therapeutic potential of MLN0128 vs. gemcitabine/oxaliplatin in a novel ICC mouse model.
We established a novel ICC mouse model via hydrodynamic transfection of activated forms of AKT (myr-AKT) and Yap (YapS127A) protooncogenes (that will be referred to as AKT/YapS127A). Genetic approaches were applied to study the requirement of mTORC1 and mTORC2 in mediating AKT/YapS127A driven tumorigenesis. Gemcitabine/oxaliplatin and MLN0128 were administered in AKT/YapS127A tumor-bearing mice to study their anti-tumor efficacy in vivo. Multiple human ICC cell lines were used for in vitro experiments. Hematoxylin and eosin staining, immunohistochemistry and immunoblotting were applied for the characterization and mechanistic study.
Co-expression of myr-AKT and YapS127A promoted ICC development in mice. Both mTORC1 and mTORC2 complexes were required for AKT/YapS127A ICC development. Gemcitabine/oxaliplatin had limited efficacy in treating late stage AKT/YapS127A ICC. In contrast, partial tumor regression was achieved when MLN0128 was applied in the late stage of AKT/YapS127A cholangiocarcinogenesis. Furthermore, when MLN0128 was administered in the early stage of AKT/YapS127A carcinogenesis, it led to disease stabilization. Mechanistically, MLN0128 efficiently inhibited AKT/mTOR signaling both in vivo and in vitro, inducing strong ICC cell apoptosis and only marginally affecting proliferation.
This study suggests that mTOR kinase inhibitors may be beneficial for the treatment of ICC, even in tumors that are resistant to standard of care chemotherapeutics, such as gemcitabine/oxaliplatin-based regimens, especially in the subset of tumors exhibiting activated AKT/mTOR cascade.
Lay summary: We established a novel mouse model of intrahepatic cholangiocarcinoma (ICC). Using this new preclinical model, we evaluated the therapeutic potential of mTOR inhibitor MLN0128 vs. gemcitabine/oxaliplatin (the standard chemotherapy for ICC treatment). Our study shows the anti-neoplastic potential of MLN0128, suggesting that it may be superior to gemcitabine/oxaliplatin-based chemotherapy for the treatment of ICC, especially in the tumors exhibiting activated AKT/mTOR cascade.
Now that the debate about the safety and effectiveness of laparoscopic versus open surgery is over, attention has turned to innovations that can verify whether minimizing the impact of laparoscopy on ...the abdominal wall can further reduce pain, improve patient comfort, lead to superior cosmesis, and reduce morbidity. The aim of this study was to further explore the application value of totally laparoscopic right hemicolectomy with transcolonic natural orifice specimen extraction (NOSE) and to evaluate the short-term efficacy of transcolonic NOSE surgery for resecting specimens of ascending colon cancer.
From January 2016 to May 2017, a retrospective study was conducted in Guangxi. Propensity score matching was used to minimize the bias from nonrandomized treatment assignment. Patients were followed up through May 2020.
Forty-nine patients underwent totally laparoscopic right hemicolectomy with transcolonic NOSE and 116 patients laparoscopic right hemicolectomy with mini-laparotomy (ML) procedures at our institution. After propensity score matching, each group included 45 patients, and all covariate imbalances were alleviated. The transcolonic NOSE group and the ML group did not differ significantly in terms of baseline clinical characteristics. The transcolonic NOSE group was associated with a shorter time to first flatus (NOSE vs ML: 1.8 ± .5 vs 3.2 ± .8, P = .032), a shorter length of hospital stay (11.3 ± 2.5 days vs 13.0 ± 3.1 days, P = .034), a shorter time to first liquid intake (2.6 ± .8 vs 3.8 ± .9, P = .068), less pain (1.8 ± .8 vs 4.2 ± .7, P = .013), less analgesia requirement (6 13.3% vs 21 46.7%, P = .001), and lower C-reactive protein levels on postoperative day 1 (3.6 ± 1.7 vs 8.2 ± 2.2, P = .001) and postoperative day 3 (NOSE 2.4 ± 1.4 vs M: 4.6 ± 1.7 P = .013) than the ML group. The median follow-up was 28.4 months (interquartile range, 18.0-36.0). The 3-year overall survival rates were similar between the transcolonic NOSE group and the ML group.
In total, laparoscopic right hemicolectomy with transcolonic specimen extraction appears to be safe for selected patients with ascending colon cancer as a minimally invasive surgery.
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