We report the first results of a light weakly interacting massive particles (WIMPs) search from the CDEX-10 experiment with a 10 kg germanium detector array immersed in liquid nitrogen at the China ...Jinping Underground Laboratory with a physics data size of 102.8 kg day. At an analysis threshold of 160 eVee, improved limits of 8×10^{-42} and 3×10^{-36} cm^{2} at a 90% confidence level on spin-independent and spin-dependent WIMP-nucleon cross sections, respectively, at a WIMP mass (m_{χ}) of 5 GeV/c^{2} are achieved. The lower reach of m_{χ} is extended to 2 GeV/c^{2}.
Background
Postoperative complications have a great impact on the postoperative course and oncological outcomes following major cancer surgery. Among them, infective complications play an important ...role. The aim of this study was to evaluate whether postoperative infective complications influence long‐term survival after liver resection for hepatocellular carcinoma (HCC).
Methods
Patients who underwent resection with curative intent for HCC between July 2003 and June 2016 were identified from a multicentre database (8 institutions) and analysed retrospectively. Independent risk factors for postoperative infective complications were identified. After excluding patients who died 90 days or less after surgery, overall survival (OS) and recurrence‐free survival (RFS) were compared between patients with and without postoperative infective complications within 30 days after resection.
Results
Among 2442 patients identified, 332 (13·6 per cent) had postoperative infective complications. Age over 60 years, diabetes mellitus, obesity, cirrhosis, intraoperative blood transfusion, duration of surgery exceeding 180 min and major hepatectomy were identified as independent risk factors for postoperative infective complications. Univariable analysis revealed that median OS and RFS were poorer among patients with postoperative infective complications than among patients without (54·3 versus 86·8 months, and 22·6 versus 43·2 months, respectively; both P < 0·001). After adjustment for other prognostic factors, multivariable Cox regression analyses identified postoperative infective complications as independently associated with decreased OS (hazard ratio (HR) 1·20, 95 per cent c.i. 1·02 to 1·41; P = 0·027) and RFS (HR 1·19, 1·03 to 1·37; P = 0·021).
Conclusion
Postoperative infective complications decreased long‐term OS and RFS in patients treated with liver resection for HCC.
From a multi‐institutional database, 2442 patients who underwent resection with curative intent for hepatocellular carcinoma between 2003 and 2016 were analysed retrospectively. Among them, 332 patients (13·6 per cent) had postoperative infective complications within 30 days after surgery. Multivariable Cox regression revealed that postoperative infective complications decreased long‐term overall and recurrence‐free survival after liver resection for hepatocellular carcinoma.
Complications decrease long‐term overall survival
The DNA damage response (DDR) induces the expression of type I interferons (IFNs), but the underlying mechanisms are poorly understood. Here, we show the presence of cytosolic DNA in different mouse ...and human tumor cells. Treatment of cells with genotoxic agents increased the levels of cytosolic DNA in a DDR-dependent manner. Cloning of cytosolic DNA molecules from mouse lymphoma cells suggests that cytosolic DNA is derived from unique genomic loci and has the potential to form non-B DNA structures, including R-loops. Overexpression of Rnaseh1, which resolves R-loops, reduced the levels of cytosolic DNA, type I Ifn transcripts, and type I IFN-dependent rejection of lymphoma cells. Live-cell imaging showed a dynamic contact of cytosolic DNA with mitochondria, an important organelle for innate immune recognition of cytosolic nucleotides. In summary, we found that cytosolic DNA is present in many tumor cells and contributes to the immunogenicity of tumor cells.
MicroRNAs have been shown to play an important role in normal hematopoisis and leukemogenesis. Here, we report function and mechanisms of miR-181 family in myeloid differentiation and acute myeloid ...leukemia (AML). The aberrant overexpression of all the miR-181 family members (miR-181a/b/c/d) was detected in French-American-British M1, M2 and M3 subtypes of adult AML patients. By conducting gain- and loss-of-function experiments, we demonstrated that miR-181a inhibits granulocytic and macrophage-like differentiation of HL-60 cells and CD34+ hematopoietic stem/progenitor cells (HSPCs) by directly targeting and downregulating the expression of PRKCD (which then affected the PRKCD-P38-C/EBPα pathway), CTDSPL (which then affected the phosphorylation of retinoblastoma protein) and CAMKK1. The three genes were also demonstrated to be the targets of miR-181b, miR-181c and miR-181d, respectively. Significantly decreases in the expression levels of the target proteins were detected in AML patients. Inhibition of the expression of miR-181 family members owing to Lenti-miRZip-181a infection in bone marrow blasts of AML patients increased target protein expression levels and partially reversed myeloid differentiation blockage. In the mice implanted with AML CD34+ HSPCs, expression inhibition of the miR-181 family by Lenti-miRZip-181a injection improved myeloid differentiation, inhibited engraftment and infiltration of the leukemic CD34+ cells into the bone marrow and spleen, and released leukemic symptoms. In conclusion, our findings revealed new mechanism of miR-181 family in normal hematopoiesis and AML development, and suggested that expression inhibition of the miR-181 family could provide a new strategy for AML therapy.
Despite significant advances in the treatment of multiple myeloma (MM), most patients succumb to disease progression. One of the major immunosuppressive mechanisms that is believed to play a role in ...myeloma progression is the expansion of regulatory T cells (Tregs). In this study, we demonstrate that myeloma cells drive Treg expansion and activation by secreting type 1 interferon (IFN). Blocking IFN α and β receptor 1 (IFNAR1) on Tregs significantly decreases both myeloma-associated Treg immunosuppressive function and myeloma progression. Using syngeneic transplantable murine myeloma models and bone marrow (BM) aspirates of MM patients, we found that Tregs were expanded and activated in the BM microenvironment at early stages of myeloma development. Selective depletion of Tregs led to a complete remission and prolonged survival in mice injected with myeloma cells. Further analysis of the interaction between myeloma cells and Tregs using gene sequencing and enrichment analysis uncovered a feedback loop, wherein myeloma-cell-secreted type 1 IFN induced proliferation and expansion of Tregs. By using IFNAR1-blocking antibody treatment and IFNAR1-knockout Tregs, we demonstrated a significant decrease in myeloma-associated Treg proliferation, which was associated with longer survival of myeloma-injected mice. Our results thus suggest that blocking type 1 IFN signaling represents a potential strategy to target immunosuppressive Treg function in MM.
We present results on light weakly interacting massive particle (WIMP) searches with annual modulation (AM) analysis on data from a 1-kg mass p-type point-contact germanium detector of the CDEX-1B ...experiment at the China Jinping Underground Laboratory. Datasets with a total live time of 3.2 yr within a 4.2-yr span are analyzed with analysis threshold of 250 eVee. Limits on WIMP-nucleus (χ-N) spin-independent cross sections as function of WIMP mass (m_{χ}) at 90% confidence level (C.L.) are derived using the dark matter halo model. Within the context of the standard halo model, the 90% C.L. allowed regions implied by the DAMA/LIBRA and CoGeNT AM-based analysis are excluded at >99.99% and 98% C.L., respectively. These results correspond to the best sensitivity at m_{χ}<6 GeV/c^{2} among WIMP AM measurements to date.
In contrast to plants, algae and cyanobacteria that contain glycolipids as the major lipid components in their photosynthetic membranes, phospholipids are the dominant lipids in the membranes of ...anoxygenic purple phototrophic bacteria. Although the phospholipid compositions in whole cells or membranes are known for a limited number of the purple bacteria, little is known about the phospholipids associated with individual photosynthetic complexes. In this study, we investigated the phospholipid distributions in both membranes and the light-harvesting 1-reaction center (LH1-RC) complexes purified from several purple sulfur and nonsulfur bacteria. 31P NMR was used for determining the phospholipid compositions and inductively coupled plasma atomic emission spectroscopy was used for measuring the total phosphorous contents. Combining these two techniques, we could determine the numbers of specific phospholipids in the purified LH1-RC complexes. A total of approximate 20–30 phospholipids per LH1-RC were detected as the tightly bound lipids in all species. The results revealed that while cardiolipin (CL) exists as a minor component in the membranes, it became the most abundant phospholipid in the purified core complexes and the sum of CL and phosphatidylglycerol accounted for more than two thirds of the total phospholipids for most species. Preferential association of these anionic phospholipids with the LH1-RC is discussed in the context of the recent high-resolution structure of this complex from Thermochromatium (Tch.) tepidum. The detergent lauryldimethylamine N-oxide was demonstrated to selectively remove phosphatidylethanolamine from the membrane of Tch. tepidum.
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•PE, PG and PC are the major phospholipids in the photosynthetic membranes.•Approximately 20–30 phospholipids are tightly bound to the purified LH1-RC.•Cardiolipin (CL) is the most abundant phospholipid in the purified LH1-RC.•Anionic CL and PG account for more than two thirds of total phospholipids in LH1-RC.
Various factors and cellular components in the tumor microenvironment are key drivers associated with drug resistance in many cancers. Here, we analyzed the factors and molecular mechanisms involved ...in chemoresistance in patients with esophageal squamous cell carcinoma (ESCC). We found that interleukin 6 (IL6) derived mainly from cancer-associated fibroblasts played the most important role in chemoresistance by upregulating C-X-C motif chemokine receptor 7 (CXCR7) expression through signal transducer and activator of transcription 3/nuclear factor-κB pathway. CXCR7 knockdown resulted in the inhibition of IL6-induced proliferation and chemoresistance. In addition, CXCR7 silencing significantly decreased gene expression associated with stemness, chemoresistance and epithelial-mesenchymal transition and suppressed the proliferation ability of ESCC cells in three-dimensional culture systems and angiogenesis assay. In clinical samples, ESCC patients with high expression of CXCR7 and IL6 presented a significantly worse overall survival and progression-free survival upon receiving cisplatin after operation. These results suggest that the IL6-CXCR7 axis may provide a promising target for the treatment of ESCC.
Although surgery remains the mainstay of curative treatment for colorectal cancer (CRC), many patients still have high chance to experience disease relapse. It is therefore imperative to identify ...prognostic markers that can help predict the clinical outcomes of CRC. Aberrant microRNA expression holds great potential as diagnostic and prognostic biomarker for CRC. Here we aimed to investigate clinical potential of miR-34a-5p as a prognostic marker for CRC recurrence and its functional significance. First, we validated that miR-34a-5p was downregulated in CRC tumour tissues (P<0.05). The expression level of tissue miR-34a-5p was then evaluated in two independent cohorts of 268 CRC patients. miR-34a-5p expression was positively correlated with disease-free survival in two independent cohorts (cohort I: n=205, P<0.001; cohort II: n=63, P=0.006). Moreover, the expression of miR-34a-5p was an independent prognostic factor for CRC recurrence by multivariate analysis (P<0.001 for cohort I, P=0.007 for cohort II). Ectopic expression of miR-34a-5p in p53 wild-type colon cancer cell HCT116 significantly inhibited cell growth, migration, invasion and metastasis. miR-34a-5p induced cell apoptosis, cell cycle arrest at G1 phase and p53 transcription activity in HCT116 cells, but not in the HCT116 p53 knockout (p53(-/-)) cells. miR-34a-5p significantly suppressed the HCT116 growth in vivo, whereas it showed no effect on the HCT116 p53(-/-) xenograft, indicating that the growth-inhibiting effect by miR-34a-5p was dependent on p53. In addition, the expression level of miR-34a-5p in patients with p53-positive expression was higher than that in patients with p53-negative expression (P<0.01). In conclusion, miR-34a-5p inhibits recurrence of CRC through inhibiting cell growth, migration and invasion, inducing cell apoptosis and cell cycle arrest in a p53-dependent manner.
The immunoreceptor NKG2D originally identified in natural killer (NK) cells recognizes ligands that are upregulated on tumor cells. Expression of NKG2D ligands (NKG2DL) is induced by the DNA damage ...response (DDR), which is often activated constitutively in cancer cells, revealing them to NK cells as a mechanism of immunosurveillance. Here, we report that the induction of retinoic acid early transcript 1 (RAE1) ligands for NKG2D by the DDR relies on a STING-dependent DNA sensor pathway involving the effector molecules TBK1 and IRF3. Cytosolic DNA was detected in lymphoma cell lines that express RAE1 and its occurrence required activation of the DDR. Transfection of DNA into ligand-negative cells was sufficient to induce RAE1 expression. Irf3(+/-);Eμ-Myc mice expressed lower levels of RAE1 on tumor cells and showed a reduced survival rate compared with Irf3(+/+);Eμ-Myc mice. Taken together, our results suggest that genomic damage in tumor cells leads to activation of STING-dependent DNA sensor pathways, thereby activating RAE1 and enabling tumor immunosurveillance.
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