Studies of gene rearrangements and the consequent oncogenic fusion proteins have laid the foundation for targeted cancer therapy. To identify oncogenic fusions associated with glioma progression, we ...catalogued fusion transcripts by RNA-seq of 272 gliomas. Fusion transcripts were more frequently found in high-grade gliomas, in the classical subtype of gliomas, and in gliomas treated with radiation/temozolomide. Sixty-seven in-frame fusion transcripts were identified, including three recurrent fusion transcripts: FGFR3-TACC3, RNF213-SLC26A11, and PTPRZ1-MET (ZM). Interestingly, the ZM fusion was found only in grade III astrocytomas (1/13; 7.7%) or secondary GBMs (sGBMs, 3/20; 15.0%). In an independent cohort of sGBMs, the ZM fusion was found in three of 20 (15%) specimens. Genomic analysis revealed that the fusion arose from translocation events involving introns 3 or 8 of PTPRZ and intron 1 of MET. ZM fusion transcripts were found in GBMs irrespective of isocitrate dehydrogenase 1 (IDH1) mutation status. sGBMs harboring ZM fusion showed higher expression of genes required for PIK3CA signaling and lowered expression of genes that suppressed RB1 or TP53 function. Expression of the ZM fusion was mutually exclusive with EGFR overexpression in sGBMs. Exogenous expression of the ZM fusion in the U87MG glioblastoma line enhanced cell migration and invasion. Clinically, patients afflicted with ZM fusion harboring glioblastomas survived poorly relative to those afflicted with non-ZM-harboring sGBMs (P < 0.001). Our study profiles the shifting RNA landscape of gliomas during progression and reveled ZM as a novel, recurrent fusion transcript in sGBMs.
Deceptive pollination is key to the species richness of Orchidaceae. However, the genetic basis of species diversification is still under study. Section Trigonopedia is a monophyletic clade of genus ...Cypripedium distributed in the southwest of China. The species of this section are pollinated by different flies. Pollinator differentiation makes section Trigonopedia an ideal group for studying the genetic basis underlying species diversification. Here, we sequenced the transcriptomes of eight species of the genus Cypripedium, including six co-flowering species of section Trigonopedia and two species outside this section as an outgroup. We reconstructed the phylogeny of the section with the combined 1572 single-copy genes extracted from the eight species and produced a highly resolved tree of the section. Furthermore, we combined substitution rate estimation and differential expression analysis to identify candidate genes, including genes related to floral scent synthesis and environmental adaptation, involved in species differentiation. Field investigations showed that these species have adapted to different habitats. We propose that the species diversification in this section is initiated by floral scent differentiation, followed by habitat differentiation, finally leading to speciation. This study sheds novel light on the diversification of closely related orchid species in the Qinghai-Tibetan region.
The present study is the first phase II clinical trial aimed to evaluate the efficacy and safety of S‐1 plus nanoparticle albumin‐bound paclitaxel (Nab‐PTX) as first‐line chemotherapy for advanced ...gastric cancer (AGC). Previously untreated patients with metastatic gastric adenocarcinoma received S‐1 in oral doses of 40 mg (BSA <1.25 m2), 50 mg (1.25 ≤ BSA < 1.50 m2) and 60 mg (BSA ≥1.50 m2) b.i.d. on days 1‐14 in combination with Nab‐PTX (120 mg/m2, on days 1 and 8) for each 21‐day cycle. Primary endpoint was progression‐free survival (PFS), and secondary endpoints were overall response rate (ORR), overall survival (OS), disease control rate (DCR), and toxicity. A total of 73 gastric cancer patients with metastatic and measurable lesions were enrolled in the first‐line setting. Median PFS and OS were 9.63 months and 14.60 months, respectively. Four (5.5%) patients had complete responses, 39 (53.4%) had partial responses (PRs), 21 (28.8%) had stable disease, four (5.5%) progressed and five (6.8%) were not evaluable. ORR and DCR were 58.9% and 87.7%, respectively. Most toxicities were mild, and no treatment‐related deaths occurred. Grade 3 to 4 toxicities occurred in 22 patients (30.1%) as follows: leukopenia (13.7%), neutropenia (12.3%), anemia (5.5%), thrombocytopenia (1.4%), diarrhea (6.8%), vomiting (2.7%), stomatitis (1.4%), peripheral neuropathy (1.4%), and hand‐foot syndrome (1.4%). Seven patients achieved good responses and underwent gastrectomy plus metastasectomy. Thirty (41.1%) patients had S‐1 maintenance with a median of four cycles. S‐1 plus Nab‐PTX is an efficient and safe regimen as first‐line treatment for patients with AGC.
As the first phase II study of fluoropyrimidines plus nanoparticle albumin‐bound paclitaxel (Nab‐PTX) in gastric cancer patients, this study found that S‐1 plus Nab‐PTX is an efficient and safe regimen as first‐line treatment for patients with advanced gastric cancer.
Organic-inorganic hybrid materials have received extensive interest due to their easily adjustable structures, environmentally friendly features and excellent properties. Recently, plenty of ...organic-inorganic hybrids have been reported. However, low phase transition temperature and limited properties restrict their applications. Therefore, improving the phase transition temperature and enriching optoelectronics properties have become the top priorities. Herein, we have successfully synthesized two bilayer (2D/3D) perovskites, (MACH)
2
·CsPb
2
Br
7
(Prv-2) and (BMACH)·CsPb
2
Br
7
(Prv-3), based on a single layer perovskite, (MACH)
2
·PbBr
4
(Prv-1), (MACH = cyclohexanemethylaminium and BMACH = 1,3-cyclohexanedimethanaminium). The experimental results show that the phase transition temperature (385-415 K) of bilayer perovskites has been significantly improved by increasing the thickness of the inorganic framework. Meanwhile, the offset of the mineralizer (Cs
+
, (0.5, 0.5, 0.5) → (0.5, 0.76, 0.47)) in the Prv-3 makes it crystallize in the polar space group (
Pmc
2
1
). Therefore, the SHG (second harmonic generation) measurement indicates that it possesses 0.5 times the signal intensity compared to KDP. Finally, optical characterization and theoretical calculation synergistically verify that all three perovskites belong to direct bandgap semiconductors. Consequentially, the strategies in this work might pave the way for the design and construction of multifunctional materials with a narrow band gap, non-linear optics and ferroelectricity.
Improving the phase transition temperature and enriching optoelectronics properties have become the top priorities. Herein, we have successfully synthesized two bilayer (2D/3D) perovskite materials based on a single layer perovskite.
Sirtuin 3 involved in development of various diseases, but its role in inflammatory bowel disease is still unknown. We used inflammatory bowel disease biopsies, colitis animal model, and vitro cells ...RAW264.7 to study the role of Sirtuin 3 in the pathophysiology of inflammatory bowel disease. Sirtuin 3 negatively correlated with intestinal TNF-α. Sirt3 was less pronounced in pediatric and adult inflammatory bowel disease patients compared with corresponding control group. Sirtuin 3 activator Honokiol suppressed dextran sulfate sodium induced colonic manifestations, while Sirt3 inhibitor caused opposite results. Honokiol inhibited colonic oxidative stress by and reduced intestinal permeability. Honokiol repressed inflammatory response by reducing macrophage infiltration, pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 levels, and inhibiting activation of NF-κB p65 in the colitis mice. However, Sirt3 inhibitor amplified colonic oxidative stress and inflammatory response. In vitro study, Sirt3 inhibitor or siRNA Sirtuin 3 activated NF-κB p65 and enhanced TNF-α, IL-1β, and IL-6 secretion from LPS stimulated RAW264.7, while Honokiol remarkably attenuated these pro-inflammatory cytokines secretion. Finally, knockdown of Sirt3 in Caco-2 cells enhanced TNF-α induced intestinal barrier integrity injury. Sirtuin 3 negatively regulates inflammatory bowel disease progression via reducing colonic inflammation and oxidative stress. Sirtuin 3 is a promising therapeutic target in clinical application for inflammatory bowel disease therapy.
The prognostic value and clinical relevance of tertiary lymphoid structures (TLSs) in intrahepatic cholangiocarcinoma (iCCA) remain unclear. Thus, we aimed to investigate the prognostic value and ...functional involvement of TLSs in iCCA.
We retrospectively included 962 patients from 3 cancer centers across China. The TLSs at different anatomic subregions were quantified and correlated with overall survival (OS) by Cox regression and Kaplan-Meier analyses. Multiplex immunohistochemistry (mIHC) was applied to characterize the composition of TLSs in 39 iCCA samples.
A quaternary TLS scoring system was established for the intra-tumor region (T score) and peri-tumor region (P score) respectively. T scores positively correlated with favorable prognosis (p <0.001), whereas a high P score signified worse survival (p <0.001). mIHC demonstrated that both T follicular helper and regulatory T cells were significantly increased in intra-tumoral TLSs compared to peri-tumoral counterparts (p <0.05), and regulatory T cell frequencies within intra-tumoral TLSs were positively associated with P score (p <0.05) rather than T score. Collectively, the combination of T and P scores stratified iCCAs into 4 immune classes with distinct prognoses (p <0.001) that differed in the abundance and distribution pattern of TLSs. Patients displaying an immune-active pattern had the lowest risk, with 5-year OS rates of 68.8%, whereas only 3.4% of patients with an immune-excluded pattern survived at 5 years (p <0.001). The C-index of the immune class was statistically higher than the TNM staging system (0.73 vs. 0.63, p <0.001). These results were validated in an internal and 2 external cohorts.
The spatial distribution and abundance of TLSs significantly correlated with prognosis and provided a useful immune classification for iCCA. T follicular helper and regulatory T cells may play a critical role in determining the functional orientation of spatially different TLSs.
Tertiary lymphoid structures (TLSs) are associated with favorable prognosis in a number of cancers. However, their role in intrahepatic cholangiocarcinoma (iCCA) remains unclear. Herein, we comprehensively evaluated the spatial distribution, abundance, and cellular composition of TLSs in iCCA, and revealed the opposite prognostic impacts of TLSs located within or outside the tumor. This difference could be mediated by the different immune cell subsets present within the spatially distinct TLSs. Based on our analysis, we were able to stratify iCCAs into 4 immune subclasses associated with varying prognoses.
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•Tertiary lymphoid structures (TLSs) within and outside the tumor have opposite prognostic impacts on patients with iCCA.•The heterogeneous distribution of Tfh and Treg cells within distinct TLSs might be a determinant of their functional state.•The geographic integration of TLSs stratified iCCAs into 4 immune subclasses with distinct clinical outcomes.
A novel chiral spirocyclic amide (SPA)-derived triazolium organocatalyst has been designed and demonstrated to effect asymmetric homo- and heterodialkylations of various bisoxindoles, enabling ...enantioselective construction of vicinal all-carbon quaternary stereocenters. These reactions feature excellent enantio- and diastereoselectivities (up to 99% ee and >20:1 dr) as well as good to high yields (up to 89% over two steps). As an application of this methodology, the first asymmetric total synthesis of (−)-chimonanthidine has been achieved.
Highly reactive metastable intermixed composites (MICs) have attracted much attention in the past decades. The MIC family of materials mainly includes traditional metal‐based nanothermites, novel ...core–shell‐structured, 3D ordered macroporous‐structured, and ternary nanocomposites. By applying special fabrication approaches, highly reactive MICs with uniformly dispersed reactants, “layer‐by‐layer” or “core–shell” structures, can be prepared. Thus, the combustion performance can be greatly improved, and the ignition characteristics and safety can be precisely controlled by using a certain preparation strategy. Here, the preparation and characterization of the MICs that have been developed during the past few decades are summarized. Traditional preparation methods for MICs generally include physical mixing, high‐energy ball milling, sol–gel synthesis, and vapor deposition, while the novel methods include self‐assembly, electrophoretic deposition, and electrospinning. Various preparation procedures and the ignition and combustion performance of different MIC reactive systems are compared and discussed. In particular, the advantages of novel structured MICs in terms of safety and combustion efficiency are clarified, based on which suggestions regarding the possible future research directions are proposed.
Highly reactive metastable intermixed composites (MICs) prepared by different strategies show various characteristics and properties. By applying special fabrication approaches, highly reactive MICs with uniformly dispersed reactants, assembled in either layer‐by‐layer or core–shell structure, can be prepared. Thus, the improved and desired performances can be achieved by using a certain preparation strategy.
An organocatalyzed asymmetric dearomative 3+2 annulation reaction of electron‐deficient 2‐nitrobenzo heteroarenes including 2‐nitrobenzofurans, 2‐nitrobenzothiophenes and 2‐nitroindoles with ...3‐isothiocyanato oxindoles was developed. With a multiple hydrogen‐bonding bifunctional thiourea as the catalyst, the reaction displays broad substrate scope and provides an access to structurally diverse polycyclic spirooxindoles containing three contiguous stereogenic centers in high yields with good diastereo‐ and enantioselectivities (up to 99% yield, 94:6 dr, and 97% ee). This organocatalysis protocol is able to afford the products with complementarily diastereoselectivity versus the previous work with transition metal catalysis.
An increasing amount of evidence suggests that high‐density lipoprotein cholesterol (HDL‐C) is related to a positive prognosis in various cancers. However, the correlation between HDL‐C and the ...immune signature and the prognostic role of HDL‐C in stage II/III colorectal cancer (CRC) has not been previously reported. A total of 667 CRC patients were enrolled and divided into two groups based on the lower limit of normal HDL‐C values (0.78 mmol/L). We used Kaplan‐Meier curves and the Cox regression model to analyze the prognostic role of HDL in both disease‐free survival (DFS) and overall survival (OS). Fifty‐five pairs of tumor tissues were selected according to the variation in HDL‐C levels (high or low) and the matched characterizes (ages, T stage, and N stage). Using immunohistochemistry, tumor tissues were stained with antibodies against CD3, CD8, CD163, iNOS, Forkhead box P3 (FOXP3), and CD33. We calculated the density of positively‐stained infiltrating cells in the tumor center (TC) and invasive margin (IM). We then used Spearman rank correlation to further investigate the relationship between HDL‐C levels and the immune signatures. Our results revealed that compared to patients with high HDL‐C levels, patients with low HDL‐C levels had poor 3‐year DFS (68.9% vs 83.1%, P = 0.032) and 5‐year OS rates (66.6% vs 85.3%, P = 0.002). We also identified a positive correlation between HDL‐C and CD3+, CD8+ and iNOS+ cells and a negative correlation between HDL‐C and CD163+ cells in both the TC and IM. This study reveals that a low HDL‐C level in stage II/III CRC patients predicts poor prognosis. The correlation between the HDL‐C level and immune signature in tissue specimens suggested that HDL‐C is likely to play an inhibitory role in tumor development via affecting immune responses.
This study reveals that a low HDL‐C level in stage II/III CRC patients predicts poor prognosis. The correlation between the HDL‐C level and immune signature in tissue specimens supports the hypothesis that HDL‐C is likely to play an inhibitory role in tumour development via affecting immune responses.
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