An electron-insulating Li2O protection layer endowing a Li-Cu-Zn ternary alloy composite anode with high performance.

We report an electron-insulating layer of Li2O nanoparticles passivating a Li-rich Li-Cu-Zn ternary alloy as an advanced Li anode. The insulating layer ensures Li deposition below the top protective layer and inhibits side reactions effectively. Additionally, the ternary alloy framework offers superior lithiophilicity and robust mechanical stability. Galvanostatic measurements demonstrate a prolonged lifespan of symmetric cells for over 1200 h at 1 mA cm-2 and 1 mA h cm-2.

Tumors cells with mismatch repair deficiency induce hyperactivation of pyroptosis resistant to cell membrane damage but are more sensitive to co-treatment of IFN-γ and TNF-α to PANoptosis.

Hypermutated neoantigens in cancers with DNA mismatch repair deficiency (dMMR) are prerequisites for favorable clinical responses to immune-checkpoint blockade (ICB) therapy. However, TMB is not significantly associated with favorable prognosis from Preclinical and clinical studies. It implies that except for TMB, other mechanisms should be needed to contribute to successful cancer immunotherapy. We found that the hyperactivation of PANoptotic effective molecules in dMMR tumor cells caused cell membrane damage, induced ESCRT-mediated membrane repair, and protected tumor cells from the damage caused by Triton X-100, while DNA mismatch repair proficient (pMMR) tumor cells were sensitive to Triton X-100 mediating cell membrane damage due to the lack of ESCRT-mediated membrane repair. There was hyperactivation of GSDMD, GSDME, and p-MLKL in dMMR tumor cells. Co-treatment of IFN-γ and TNF-α induced rapid death of dMMR tumor cells by inducing PANoptosis including pyroptosis, apoptosis, and no necrosis. pMMR tumor cells had defects in the PANoptosis pathway and were resistant to co-treatment of IFN-γ and TNF-α. In conclusion, we can activate immune cells to release IFN-γ and TNF-α to overcome resistance to ICB treatment.

P4HA3 promotes colon cancer cell escape from macrophage phagocytosis by increasing phagocytosis immune checkpoint CD47 expression.

Cancer immunotherapies have greatly changed the prospects for the therapy of many malignancies, including colon cancer. Macrophages as the effectors of cancer immunotherapy provide considerable promise for cancer treatment. Prolyl 4-hydroxylase subunit alpha 3 (P4HA3) plays a cancer-promoting role in a variety of cancers, including colon cancer. In the present work, we provided evidence for the first time that P4HA3 promoted colon cancer cell escape from macrophage phagocytosis, and preliminarily explored its possible molecular mechanism. Immunohistochemistry was used to detect the expression of P4HA3 in tissues. Bioinformatics methods were used to analyze the tumor public databases (including TCGA database and GEO database). Macrophage phagocytosis assay and flow cytometric analysis were used to detect the phagocytic capacity of macrophages. Western blot and qRT-PCR were used to detect the expression of related markers (such as P4HA3, CD47, CD24, IL-34, and M-CSF). First, we found that P4HA3 was significantly and highly expressed in both colon cancer tissues and cells, and that P4HA3 had a positive correlation with lymph node metastasis, Dukes stage and also strongly correlated with poorer survival. Subsequently, we found that P4HA3 was strongly associated with the macrophage infiltration level in colon cancer. Immediately we also found that decreasing P4HA3 expression promoted macrophage phagocytosis in colon cancer cells, whereas P4HA3 overexpression produced the opposite effect. Finally, we demonstrated that P4HA3 promoted the expression of cluster of differentiation 47 (CD47) in colon cancer cells. Moreover, P4HA3 caused colon cancer cells to secrete Interleukin 34 (IL34) and Macrophage colony stimulating factor (M-CSF), which further induced macrophages to differentiate to M2 type and thereby contributed to the progression of colon cancer. We have demonstrated that P4HA3-driven CD47 overexpression may act as an escape mechanism, causing colon cancer cells to evade phagocytosis from macrophages.

Digital cholangioscopy-assisted, direct visualization-guided, radiation-free, endoscopic retrograde intervention for cholelithiasis: technical feasibility, efficacy, and safety.

BACKGROUND: Nonradiation, digital cholangioscope (DCS)-assisted endoscopic intervention for cholelithiasis has not been widely performed. For this study, we aimed to report the feasibility, efficacy, and safety of an established DCS-guided lithotomy procedure. METHODS: Data relating to biliary exploration, stone clearance, adverse events, and follow-up were obtained from 289 patients. The choledocholithiasis-related outcomes via the DCS-guided procedure were subsequently compared to those via conventional endoscopic retrograde cholangiopancreatography (ERCP). RESULTS: Biliary access was achieved in 285 patients. The technical success rate for the exploration of the common bile duct, the cystic stump, the hilar ducts, and secondary radicals was 100%. Moreover, the success rates were 98.4%, 61.7%, and 20.7%, for the exploration of the cystic duct, complete cystic duct, and gallbladder, respectively. Suspicious or confirmed suppurative cholecystitis, cholesterol polyps, and hyperplastic polyps were detected in 42, 23, and 5 patients, respectively. Stone clearance was achieved in one session in 285 (100%), 11 (100%), 13 (100%), 7 (100%), 6 (100%), and 3 (14.3%) patients with choledocholithiasis and hepatolithiasis, cystic duct stump stones, nondiffuse located intrahepatic lithiasis, a single cystic duct stone, a single gallbladder stone, and diffuse located intrahepatic lithiasis, respectively. Complete stone clearance for diffuse intrahepatic lithiasis was achieved in 19 (90.5%) patients, and fractioned re-lithotomy was performed in 16 (76.2%) patients. One patient developed mild acute cholangitis, and 12 developed mild pancreatitis. Stones recurred in one patient. Compared with conventional ERCP, DCS-guided lithotomy has the advantages of clearing difficult-to-treat choledocholithiasis and revealing concomitant biliary lesions, and this technique has fewer complications and a decreased risk of stone recurrence. CONCLUSIONS: The technical profile, efficacy, and safety of nonradiation-guided and DCS-guided lithotomy are shown in this study. We provide a feasible modality for the endoscopic removal of cholelithiasis.

In Situ Growth of Sodium Manganese Hexacyanoferrate on Carbon Nanotubes for High-Performance Sodium-Ion Batteries.

Sodium manganese hexacyanoferrate (NaMnHCF) has emerged as a research hotspot among Prussian blue analogs for sodium-ion battery cathode materials due to its advantages of high voltage, high specific capacity, and abundant raw materials. However, its practical application is limited by its poor electronic conductivity. In this study, we aim to solve this problem through the in situ growth of NaMnHCF on carbon nanotubes (CNTs) using a simple coprecipitation method. The results show that the overall electronic conductivity of NaMnHCF is significantly improved after the introduction of CNTs. The NaMnHCF@10%CNT sample presents a specific capacity of 90 mA h g-1, even at a current density of 20 C (2400 mA g-1). The study shows that the optimized composite exhibits a superior electrochemical performance at different mass loadings (from low to high), which is attributed to the enhanced electron transport and shortened electron pathway. Surprisingly, the cycling performance of the composites was also improved, resulting from decreased polarization and the subsequent reduction in the side reactions at the cathode/electrolyte interface. Furthermore, we revealed the evolution of potential plateau roots from the extraction of crystal water during the charge-discharge process of NaMnHCF based on the experimental results. This study is instructive not only for the practical application of NaMnHCF materials but also for advancing our scientific understanding of the behavior of crystal water during the charge-discharge process.

Dendrite-Free Dual-Phase Li-Ba Alloy Anode Enabled by Ordered Array of Built-in Mixed Conducting Microchannels.

The development and application of lithium (Li) anode is hindered by volumetric variation, dendritic Li growth, and parasitic reactions. Herein, a dual-phase Li-barium (Ba) alloy with self-assembled microchannels array is synthesized through a one-step thermal fusion method to investigate the inhibition effect of lithiophilic composite porous array on Li dendrites. The Li-rich Li-Ba alloy (BaLi24) as composite Li electrode exhibits an ordered porous structure of BaLi4 intermetallic compound after delithiation, which acts as a built-in 3D current collector during Li plating/striping process. Furthermore, the lithiophilic BaLi4 alloy scaffold is a mixed conductor, featuring with Li+ ions diffusion capability, which can efficiently transport the reduced Li to the interior of the electrode structure. This unique top-down growth mode can effectively prohibit Li dendrites growth and improve the space utilization of 3D electrode structure. The spin-polarized density functional theory (DFT) calculations suggest that the absorption capability of BaLi4 benefits the deposition of Li metal. As a result, the cell performance with the dual-phase Li-Ba alloy anode is significantly improved.

A hybrid polymer protective layer with uniform Li+ flux and self-adaption enabling dendrite-free Li metal anodes.

Lithium (Li) metal is considered as an ideal negative electrode material for next-generation secondary batteries; however, the hideous dendrite growth and parasitic reactions hinder the practical applications of Li metal batteries. Herein, a hybrid polymer film composed of polyvinyl alcohol (PVA) and polyacrylic acid (PAA) is adopted as an artificial protective layer to inhibit the dendritic formation and side reactions in Li metal anodes. PVA with large quantities of polar functional groups can induce even distribution of Li ions (Li+). Alternatively, PAA can in situ react with Li metal to form highly elastic and ionic conducting lithium polyacrylic acid (LiPAA), thereby enabling tight contact and flexible self-adaption with Li metal anodes. Therefore, such a rationally designed functional composite layer, with good binding ability and relatively high Li+ conductivity, as well as excellent capability of homogenizing Li+ flow, accordingly enables Li metal anodes to reveal dendrite-free plating/stripping behaviours and minimum volume variation. As a result, the PVA-PAA modified Li metal anode delivered stable cycling for 700 and 250 h, respectively, at current densities of 1 and 3 mA cm-2 under an areal capacity of 1 mA h cm-2, in a carbonate ester-based electrolyte without any additive, exhibiting boosted cycling and rate performances. The Li anode with a functional PVA-PAA hybrid interlayer can maintain the dense and smooth texture without dendrite formation after long cycles. The full cell of Li|LiFeO4 with our modified Li anode and a cathode with a high areal capacity of 2.45 mA h cm-2 delivers, change to achieved a long-term lifespan of 180 cycles at 1.0 C, with a capacity retention of 96.7%. This work demonstrates a simple and effective strategy of designing multi-functional artificial protective layers, targeting dendrite-free Li anodes.

The Pillar Effect of Large-Size Alkaline Ions on the Electrochemical Stability of Sodium Manganese Hexacyanoferrate for Sodium-Ion Batteries.

Sodium manganese hexacyanoferrate (NaMnHCF) is an attractive candidate as a cathode material for sodium-ion batteries due to its low cost and high energy density. However, its practical application is hindered by poor electrochemical stability caused by the Jahn-Teller effect of Mn and the unstable structure of NaMnHCF. Here, this paper aims to address this issue by introducing highly stable AMnHCF (where A = K, Rb, or Cs) through a facile method to composite with NaMnHCF. The findings reveal that all AMnHCFs have a "pillar effect" on the crystal structure of NaMnHCF. It is observed that the degree of pillar effect varies depending on the specific AMnHCF used. The less electrochemically inactive the alkaline ion is and the greater the degree of compositing with NaMnHCF, the more dramatic the pillar effect. KMnHCF shows limited pillar effect due to its rough composition with NaMnHCF and the loss of K+ upon (de)intercalation. RbMnHCF has lower electrochemical activity and can be better composited with NaMnHCF. On the other hand, CsMnHCF exhibits the strongest pillar effect due to the inactivation of Cs+ and the excellent coherent structure formed by CsMnHCF and NaMnHCF. This research provides a new perspective on stabilizing NaMnHCF with other alkaline elements.

EphB6 deficiency in intestinal neurons promotes tumor growth in colorectal cancer by neurotransmitter GABA signaling.

EphB6 belongs to the receptor tyrosine kinase, whose low expression is associated with shorter survival of colorectal cancer (CRC) patients. But the role and mechanism of EphB6 in the progression of CRC need further study. In addition, EphB6 was mainly expressed in intestinal neurons. But how EphB6 is involved in functions of intestinal neurons has not been known. In our study, we constructed a mouse xenograft model of CRC by injecting CMT93 cells into the rectum of EphB6-deficient mice. We found that the deletion of EphB6 in mice promoted tumor growth of CMT93 cells in a xenograft model of CRC, which was independent of changes in the gut microbiota. Interestingly, inhibition of intestinal neurons by injecting botulinum toxin A into rectum of EphB6-deficient mice could eliminate the promotive effect of EphB6 deficiency on tumor growth in the xenograft model of CRC. Mechanically, the deletion of EphB6 in mice promoted the tumor growth in CRC by increasing GABA in the tumor microenvironment. Furthermore, EphB6 deficiency in mice increased the expression of synaptosomal-associated protein 25 in the intestinal myenteric plexus, which mediated the release of GABA. Our study concluded that EphB6 knockout in mice promotes tumor growth of CMT93 cells in a xenograft model of CRC by modulating GABA release. Our study found a new regulating mechanism of EphB6 on the tumor progression in CRC that is dependent on intestinal neurons.

Machine learning-based automated sponge cytology for screening of oesophageal squamous cell carcinoma and adenocarcinoma of the oesophagogastric junction: a nationwide, multicohort, prospective study.

BACKGROUND: Oesophageal squamous cell carcinoma and adenocarcinoma of the oesophagogastric junction have a dismal prognosis, and early detection is key to reduce mortality. However, early detection depends on upper gastrointestinal endoscopy, which is not feasible to implement at a population level. We aimed to develop and validate a fully automated machine learning-based prediction tool integrating a minimally invasive sponge cytology test and epidemiological risk factors for screening of oesophageal squamous cell carcinoma and adenocarcinoma of the oesophagogastric junction before endoscopy. METHODS: For this multicohort prospective study, we enrolled participants aged 40-75 years undergoing upper gastrointestinal endoscopy screening at 39 tertiary or secondary hospitals in China for model training and testing, and included community-based screening participants for further validation. All participants underwent questionnaire surveys, sponge cytology testing, and endoscopy in a sequential manner. We trained machine learning models to predict a composite outcome of high-grade lesions, defined as histology-confirmed high-grade intraepithelial neoplasia and carcinoma of the oesophagus and oesophagogastric junction. The predictive features included 105 cytological and 15 epidemiological features. Model performance was primarily measured with the area under the receiver operating characteristic curve (AUROC) and average precision. The performance measures for cytologists with AI assistance was also assessed. FINDINGS: Between Jan 1, 2021, and June 30, 2022, 17 498 eligible participants were involved in model training and validation. In the testing set, the AUROC of the final model was 0·960 (95% CI 0·937 to 0·977) and the average precision was 0·482 (0·470 to 0·494). The model achieved similar performance to consensus of cytologists with AI assistance (AUROC 0·955 [95% CI 0·933 to 0·975]; p=0·749; difference 0·005, 95% CI, -0·011 to 0·020). If the model-defined moderate-risk and high-risk groups were referred for endoscopy, the sensitivity was 94·5% (95% CI 88·8 to 97·5), specificity was 91·9% (91·2 to 92·5), and the predictive positive value was 18·4% (15·6 to 21·6), and 90·3% of endoscopies could be avoided. Further validation in community-based screening showed that the AUROC of the model was 0·964 (95% CI 0·920 to 0·990), and 92·8% of endoscopies could be avoided after risk stratification. INTERPRETATION: We developed a prediction tool with favourable performance for screening of oesophageal squamous cell carcinoma and adenocarcinoma of the oesophagogastric junction. This approach could prevent the need for endoscopy screening in many low-risk individuals and ensure resource optimisation by prioritising high-risk individuals. FUNDING: Science and Technology Commission of Shanghai Municipality.

A functional loop between YTH domain family protein YTHDF3 mediated m6A modification and phosphofructokinase PFKL in glycolysis of hepatocellular carcinoma.

BACKGROUND & AIMS: N6-methyladenosine (m6A) modification plays a critical role in progression of hepatocellular carcinoma (HCC), and aerobic glycolysis is a hallmark of cancer including HCC. However, the role of YTHDF3, one member of the core readers of the m6A pathway, in aerobic glycolysis and progression of HCC is still unclear. METHODS: Expression levels of YTHDF3 in carcinoma and surrounding tissues of HCC patients were evaluated by immunohistochemistry. Loss and gain-of-function experiments in vitro and in vivo were used to assess the effects of YTHDF3 on HCC cell proliferation, migration and invasion. The role of YTHDF3 in hepatocarcinogenesis was observed in a chemically induced HCC model with Ythdf3-/- mice. Untargeted metabolomics and glucose metabolism phenotype assays were performed to evaluate relationship between YTHDF3 and glucose metabolism. The effect of YTHDF3 on PFKL was assessed by methylated RNA immunoprecipitation assays (MeRIP). Co-immunoprecipitation and immunofluorescence assays were performed to investigate the connection between YTHDF3 and PFKL. RESULTS: We found YTHDF3 expression was greatly upregulated in carcinoma tissues and it was correlated with poor prognosis of HCC patients. Gain-of-function and loss-of-function assays demonstrated YTHDF3 promoted proliferation, migration and invasion of HCC cells in vitro, and YTHDF3 knockdown inhibited xenograft tumor growth and lung metastasis of HCC cells in vivo. YTHDF3 knockout significantly suppressed hepatocarcinogenesis in chemically induced mice model. Mechanistically, YTHDF3 promoted aerobic glycolysis by promoting phosphofructokinase PFKL expression at both mRNA and protein levels. MeRIP assays showed YTHDF3 suppressed PFKL mRNA degradation via m6A modification. Surprisingly, PFKL positively regulated YTHDF3 protein expression, not as a glycolysis rate-limited enzyme, and PFKL knockdown effectively rescued the effects of YTHDF3 overexpression on proliferation, migration and invasion ability of Sk-Hep-1 and HepG2 cells. Notably, co-immunoprecipitation assays demonstrated PFKL interacted with YTHDF3 via EFTUD2, a core subunit of spliceosome involved in pre-mRNA splicing process, and ubiquitination assays showed PFKL could positively regulate YTHDF3 protein expression via inhibiting ubiquitination of YTHDF3 protein by EFTUD2. CONCLUSIONS: our study uncovers the key role of YTHDF3 in HCC, characterizes a positive functional loop between YTHDF3 and phosphofructokinase PFKL in glucose metabolism of HCC, and suggests the connection between pre-mRNA splicing process and m6A modification.

Real-Time NURBS Interpolation under Multiple Constraints.

NURBS interpolation is superior to traditional linear or circular interpolation in terms of code size, surface quality, and machining efficiency. However, with the increasing demands for high-accuracy and efficient machining, NURBS interpolation has faced a growing number of challenges. Many researchers are actively involved in this field with great interest. Due to the special form of NURBS curve, there is a nonlinear relationship between its curve and arc length; feed fluctuations and mechanical shocks which are caused during the interpolation process will seriously affect the surface accuracy and quality of machined parts. To solve these problems, a real-time NURBS interpolation is proposed under multiple constraints (RNIC) in this paper. First, the formulas of the constrained feedrate under geometric errors, kinematic constraints, drive constraints, and contour errors are given. Then, the two stages for the proposed interpolation are established. The former stage is offline preprocessing stage, which aims to quickly find feedrate sensitive areas (FSAs), while the latter online stage is the real-time interpolation, which is responsible for smoothing the velocity. In the preprocessing stage, we utilized FSA scan module and feedrate adjustment module to detect the FSAs and adjust the feedrate at the start/end of each subsegment by a bidirectional scanning algorithm. Each segment contains acceleration and deceleration (some contains uniform speed) stages, which can be well matched with the processing process of acceleration and deceleration. Finally, according to the proposed method and the adaptive speed adjustment method, the simulation of a "butterfly-shaped" NURBS curve using the S-shaped ACC/DEC algorithm is carried out, which verifies the reliability and effectiveness of the proposed algorithm.

miR-1266-3p Suppresses Epithelial-Mesenchymal Transition in Colon Cancer by Targeting P4HA3.

Numerous studies have been conducted to demonstrate that miRNA is strongly related to colon cancer progression. Nevertheless, there are few studies regarding the function for miR-1266-3p in colon cancer, and the molecular mechanism remains poorly know. Our study was designed to examine the level of miR-1266-3p expression among the colon cancer tissue and cell and to study the role and regulatory mechanism for miR-1266-3p among colon cancer's malignant biologic behavior. First, we found that miR-1266-3p expression was distinctly lower in colonic carcinoma tissues and cells than in nontumor ones, and the prognosis of low miR-1266-3p patients was distinctly worse than that of high miR-1266-3p patients. Second, we predicted that the target gene of miR-1266-3p was prolyl 4-hydroxylase subunit alpha 3 (P4HA3) through bioinformatics, and the targeting relationship between the two was verified by a dual luciferase assay report. Furthermore, miR-1266-3p inhibited the growth and metastasis of colon cancer in vitro as well as in vivo, and this effect could be alleviated by overexpressing P4HA3. Even more importantly, our study demonstrated that miR-1266-3p inhibited epithelial-mesenchymal transition (EMT) by targeting P4HA3. In conclusion, miR-1266-3p could inhibit growth, metastasis, and EMT in colon cancer by targeting P4HA3. Our discoveries might offer a novel target for colon cancer diagnosis and treatment.

Prolyl 4-hydroxylase subunit alpha 3 facilitates human colon cancer growth and metastasis through the TGF-ß/Smad signaling pathway.

Prolyl 4-hydroxylase subunit alpha 3 (P4HA3) has been known to be associated with a variety of human cancers. However, the role of P4HA3 on colon cancer growth and metastasis is unclear. In this study, we investigated the effect of P4HA3 on the growth and metastasis of colon cancer and its possible molecular mechanism. First of all, we demonstrated that P4HA3 expression was greatly higher in cells and tissues of colon cancer than that in non-tumor tissues and cells, and the prognosis of patients who had higher P4HA3 was distinctively poorer than patients who had lower level of P4HA3. Second, it was shown that P4HA3 knockdown strongly inhibited the migration, proliferation and invasion ability of colon cancer cells. However, P4HA3 over-expression accelerated the abilities. Meanwhile, P4HA3 could promote subcutaneous tumorigenesis in nude mice in vivo. In addition, P4HA3 knockdown significantly decreased mesenchymal markers Vimentin, N-cadherin and Snail expression and increased epithelial marker E-cadherin expression. And conversely, over-expression of P4HA3 produced the opposite effects. In the current study, there was further evidence that down-regulating P4HA3 significantly reduced both TGF-ß and its following molecules including p-Smad2 as well as p-Smad3. However, overexpression of P4HA3 showed the opposite effect. In conclusion, this study shows that P4HA3 promotes the human colon cancer growth and metastasis by affecting TGF-ß/Smad signaling pathway. P4HA3 may become a new target for early diagnosis, treatment and prognosis assessment of colon cancer.

Recent Advances and Perspectives in Lithium-Sulfur Pouch Cells.

Lithium-sulfur batteries (LSBs) are considered one of the most promising candidates for next-generation energy storage owing to their large energy capacity. Tremendous effort has been devoted to overcoming the inherent problems of LSBs to facilitate their commercialization, such as polysulfide shuttling and dendritic lithium growth. Pouch cells present additional challenges for LSBs as they require greater electrode active material utilization, a lower electrolyte-sulfur ratio, and more mechanically robust electrode architectures to ensure long-term cycling stability. In this review, the critical challenges facing practical Li-S pouch cells that dictate their energy density and long-term cyclability are summarized. Strategies and perspectives for every major pouch cell component-cathode/anode active materials and electrode construction, separator design, and electrolyte-are discussed with emphasis placed on approaches aimed at improving the reversible electrochemical conversion of sulfur and lithium anode protection for high-energy Li-S pouch cells.

Confined Polysulfides in N-Doped 3D-CNTs Network for High Performance Lithium-Sulfur Batteries.

Improving the utilization efficiency of active materials and suppressing the dissolution of lithium polysulfides into the electrolyte are very critical for development of high-performance lithium-sulfur batteries. Herein, a novel strategy is proposed to construct a three-dimensional (3D) N-doped carbon nanotubes (CNTs) networks to support lithium polysulfides (3D-NCNT-Li2S6) as a binder-free cathode for high-performance lithium-sulfur batteries. The 3D N-doped CNTs networks not only provide a conductive porous 3D architecture for facilitating fast ion and electron transport but also create void spaces and porous channels for accommodating active sulfur. In addition, lithium polysulfides can be effectively confined among the networks through the chemical bond between Li and N. Owing to the synergetic effect of the physical and chemical confinement for the polysulfides dissolution, the 3D-NCNT-Li2S6 cathodes exhibit enhanced charge capacity and cyclic stability with lower polarization and faster redox reaction kinetics. With an initial discharge capacity of 924.8 mAh g-1 at 1 C, the discharge capacity can still maintain 525.1 mAh g-1 after 200 cycles, which is better than that of its counterparts.

A single-cell atlas of liver metastases of colorectal cancer reveals reprogramming of the tumor microenvironment in response to preoperative chemotherapy.

Metastasis is the primary cause of cancer-related mortality in colorectal cancer (CRC) patients. How to improve therapeutic options for patients with metastatic CRC is the core question for CRC treatment. However, the complexity and diversity of stromal context of the tumor microenvironment (TME) in liver metastases of CRC have not been fully understood, and the influence of stromal cells on response to chemotherapy is unclear. Here we performed an in-depth analysis of the transcriptional landscape of primary CRC, matched liver metastases and blood at single-cell resolution, and a systematic examination of transcriptional changes and phenotypic alterations of the TME in response to preoperative chemotherapy (PC). Based on 111,292 single-cell transcriptomes, our study reveals that TME of treatment-naïve tumors is characterized by the higher abundance of less-activated B cells and higher heterogeneity of tumor-associated macrophages (TAMs). By contrast, in tumors treated with PC, we found activation of B cells, lower diversity of TAMs with immature and less activated phenotype, lower abundance of both dysfunctional T cells and ECM-remodeling cancer-associated fibroblasts, and an accumulation of myofibroblasts. Our study provides a foundation for future investigation of the cellular mechanisms underlying liver metastasis of CRC and its response to PC, and opens up new possibilities for the development of therapeutic strategies for CRC.

Targeting cholesterol biosynthesis promotes anti-tumor immunity by inhibiting long noncoding RNA SNHG29-mediated YAP activation.

Anti-tumor immunity through checkpoint inhibitors, specifically anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) interaction, is a promising approach for cancer therapy. However, as early clinical trials indicate that colorectal cancers (CRCs) do not respond well to immune-checkpoint therapies, new effective immunotherapy approaches to CRC warrant further study. Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (CoA) reductase (HMGCR), the rate-limiting enzyme of the mevalonate (MVA) pathway for the cholesterol biosynthesis. However, little is known about the functions of simvastatin in the regulation of immune checkpoints or long noncoding RNA (lncRNA)-mediated immunoregulation in cancer. Here, we found that simvastatin inhibited PD-L1 expression and promoted anti-tumor immunity via suppressing the expression of lncRNA SNHG29. Interestingly, SNHG29 interacted with YAP and inhibited phosphorylation and ubiquitination-mediated protein degradation of YAP, thereby facilitating downregulation of PD-L1 transcriptionally. Patient-derived tumor xenograft (PDX) models and the clinicopathological analysis in samples from CRC patients further supported the role of the lncRNA SNHG29-mediated PD-L1 signaling axis in tumor microenvironment reprogramming. Collectively, our study uncovers simvastatin as a potential therapeutic drug for immunotherapy in CRC, which suppresses lncRNA SNHG29-mediated YAP activation and promotes anti-tumor immunity by inhibiting PD-L1 expression.

Pregnancy and birth outcomes of multiple gestations with PPROM occurred within 24 h after fetal reduction: A case series.

OBJECTIVE: The study aims to analyze the pregnancy outcomes of multiple gestations with preterm premature rupture of membranes (PPROM) that occurred within 24 h after fetal reduction with potassium chloride (KCL). MATERIALS AND METHODS: We identified and evaluated the outcomes of 16 retrospectively recorded multigestational pregnancies that met the inclusion criteria between 2006 and 2016, from the Obstetrics Department of Shandong Provincial Hospital. A total of 16 patients carrying twins or higher order multiple gestations experienced PPROM within 24 h after fetal reduction, and all of them received expectant management after understanding the relevant risks. The maternal and neonatal records were retrospectively collected and reviewed. Every surviving child was followed up to at least 2 years old. RESULT: Of the 16 cases, 12 cases (75%) ended in successful pregnancy, resulting in the delivery of at least 1 child surviving from a multiple gestational pregnancy. All cases of successful pregnancies were either term (≥37 weeks) or near-term (36+5 weeks) at delivery. And of those 20 infants delivered, only 3 were low birth weight infants (<2500g) (15%), None of the 16 women had fever, or other clinical symptoms and signs of chorioamnionitis during hospital stay. Postnatal follow-up of the surviving babies showed no obvious sequelae thus far. No newborn baby had neonatal complications, or needed to be transferred to neonatal intensive care unit. CONCLUSION: Overall, our data demonstrate that dichorionic diamniotic (DCDA) twins or higher-order gestations who experienced PPROM of the reduced fetus within 24 h after selective reduction with KCL had relatively good outcomes with expectant management alone.