Molecular basis for recognition of Gly/N-degrons by CRL2ZYG11B and CRL2ZER1.

N-degron pathways are a set of proteolytic systems that target the N-terminal destabilizing residues of substrates for proteasomal degradation. Recently, the Gly/N-degron pathway has been identified as a new branch of the N-degron pathway. The N-terminal glycine degron (Gly/N-degron) is recognized by ZYG11B and ZER1, the substrate receptors of the Cullin 2-RING E3 ubiquitin ligase (CRL2). Here we present the crystal structures of ZYG11B and ZER1 bound to various Gly/N-degrons. The structures reveal that ZYG11B and ZER1 utilize their armadillo (ARM) repeats forming a deep and narrow cavity to engage mainly the first four residues of Gly/N-degrons. The α-amino group of the Gly/N-degron is accommodated in an acidic pocket by five conserved hydrogen bonds. These structures, together with biochemical studies, decipher the molecular basis for the specific recognition of the Gly/N-degron by ZYG11B and ZER1, providing key information for future structure-based chemical probe design.

Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction.

Aerobic glycolysis regulates T cell function. However, whether and how primary cancer alters T cell glycolytic metabolism and affects tumor immunity in cancer patients remains a question. Here we found that ovarian cancers imposed glucose restriction on T cells and dampened their function via maintaining high expression of microRNAs miR-101 and miR-26a, which constrained expression of the methyltransferase EZH2. EZH2 activated the Notch pathway by suppressing Notch repressors Numb and Fbxw7 via trimethylation of histone H3 at Lys27 and, consequently, stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling. Moreover, small hairpin RNA-mediated knockdown of human EZH2 in T cells elicited poor antitumor immunity. EZH2(+)CD8(+) T cells were associated with improved survival in patients. Together, these data unveil a metabolic target and mechanism of cancer immune evasion.

Single-cell RNA profiling reveals classification and characteristics of mononuclear phagocytes in colorectal cancer.

Colorectal cancer (CRC) is a major cause of cancer mortality and a serious health problem worldwide. Mononuclear phagocytes are the main immune cells in the tumor microenvironment of CRC with remarkable plasticity, and current studies show that macrophages are closely related to tumor progression, invasion and dissemination. To understand the immunological function of mononuclear phagocytes comprehensively and deeply, we use single-cell RNA sequencing and classify mononuclear phagocytes in CRC into 6 different subsets, and characterize the heterogeneity of each subset. We find that tissue inhibitor of metalloproteinases (TIMPs) involved in the differentiation of proinflammatory and anti-inflammatory mononuclear phagocytes. Trajectory of circulating monocytes differentiation into tumor-associated macrophages (TAMs) and the dynamic changes at levels of transcription factor (TF) regulons during differentiation were revealed. We also find that C5 subset, characterized by activation of lipid metabolism, is in the terminal state of differentiation, and that the abundance of C5 subset is negatively correlated with CRC patients' prognosis. Our findings advance the understanding of circulating monocytes' differentiation into macrophages, identify a new subset associated with CRC prognosis, and reveal a set of TF regulons regulating mononuclear phagocytes differentiation, which are expected to be potential therapeutic targets for reversing immunosuppressive tumor microenvironment.

Two-Year Outcomes and Biomarker Analysis of Locally Advanced Gastric and Gastroesophageal Junction Adenocarcinoma After Neoadjuvant Chemotherapy and Immunotherapy from the Phase II WuhanUHGI001 Trial.

BACKGROUND: This study reports the 2-year outcomes and biomarker analysis results of patients with locally advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma who received neoadjuvant chemotherapy and immunotherapy in a phase II WuhanUHGI001 trial. METHODS: Eligible patients with cT3/4aN+M0 locally advanced G/GEJ adenocarcinoma were screened, enrolled, and treated with 3 cycles of neoadjuvant tislelizumab and SOX followed by D2 gastrectomy and another 5 cycles of postoperative adjuvant SOX. The primary endpoint was major pathological response. RESULTS: Of the 49 included patients, 24 (49.0%) achieved major pathological response and 13 (26.5%) achieved pathological complete response. During a median follow-up of 26.8 months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 69.4% and 81.2%, respectively. Grade 3-4 adverse events occurred in six patients (12.2%) during the neoadjuvant period, eight patients (17.0%) during the postoperative period, and seven patients (15.2%) during the adjuvant period. Biomarker analysis revealed that the pathological complete response showed no association with 2-year PFS and OS. Major pathological response showed a potentially strong association with improved 2-year PFS and OS rates. In addition, preoperative circulating tumor cells combined with pathological responses are helpful in prognosis assessment. In addition, our results showed that T downstaging, lymphocyte-to-monocyte ratio, and CD3+ T cells were independent factors that affect PFS. The signet ring cell component (SRCC), T downstaging, and neutrophil-to-lymphocyte ratio were independent factors affecting OS. Prognostic nomograms of PFS and OS constructed based on the multivariate Cox regression results demonstrated suitable calibration and discrimination ability. CONCLUSIONS: Neoadjuvant tislelizumab plus SOX exhibits promising efficacy and acceptable toxicity in patients with locally advanced G/GEJ adenocarcinoma. In addition, our study established a prognostic risk signature and nomograms based on clinicopathological characteristics, which can accurately predict patient outcomes and aid in personalized treatment planning.

Let-7c-5p down-regulates immune-related CDCA8 to inhibit hepatocellular carcinoma.

OBJECTIVE: The aim of this study is to investigate the effect of let-7c-5p on the malignant behaviors of hepatocellular carcinoma (HCC) and its specific molecular pathway. METHODS: Differential expression and survival analysis of let-7c-5p were obtained from The Cancer Genome Atlas database, and then its expression level was preliminarily verified through qPCR. The effect of let-7c-5p on the malignant phenotype of HCC cells was subsequently evaluated using CCK-8, transwell, wound healing, and flow cytometry assays. Downstream mRNA regulated by let-7c-5p was identified and confirmed by ENCORI database, dual-luciferase reporter, and western blot assays. The immunocorrelation of genes was evaluated by Xiantao tool, and TIMER and TISIDB databases. RESULTS: The expression level of let-7c-5p in HCC was obviously reduced, which was found to be closely associated with the short survival time of HCC patients. Cell phenotypic experiments showed that let-7c-5p inhibited proliferation, invasion, and migration and promoted apoptosis of HCC cells. Dual-luciferase reporter and western blot analysis demonstrated that CDCA8 is a downstream mRNA of let-7c-5p and is negatively regulated by it. Rescue experiment revealed that CDCA8 reversed the effect of let-7c-5p on the malignant phenotype of HCC cells. Furthermore, analysis of the public database revealed that CDCA8 is related to some immune cells and immunomodulators, and that it may participate in the regulation of some immune pathways and immune functions. CONCLUSION: Let-7c-5p has been proved to suppress HCC by down-regulating immune-related CDCA8, which will help understand the pathogenesis of HCC and develop drugs for its treatment.

High level of tumor marker CA19-9 returned to normal after cholecystectomy in calculous cholecystitis patients.

BACKGROUND: High serum CA19-9 is usually caused by pancreaticobiliary malignancies, but it has also been found in a tiny minority of calculous cholecystitis patients. AIMS: To clarify the relationship between calculous cholecystitis and serum CA19-9. METHODS: Clinical data of calculous cholecystitis patients with high serum CA19-9 (high group, n = 20) and normal serum CA19-9 (normal group, n = 40) who underwent cholecystectomy were analyzed. Serum CA19-9 of high group were followed-up and gallbladder specimens were analyzed by immunohistochemistry. RESULTS: Serum CA19-9 in the high group ranged from 105 to 1635 U/ml, of which 30% exceeded 1000 U/ml. Follow-up results showed that 20 patient's serum CA19-9 returned to normal after cholecystectomy, including 4 closely followed-up patients whose serum CA19-9 recovered within one month. Immunohistochemical results revealed that CA19-9 was mildly positive only in mucosal epithelial cells in the normal group, but positive in mucosal epithelial cells, vascular endothelial cells, and intercellular substances in the high group, accounting for high serum CA19-9. CONCLUSION: Serum CA19-9 is proved to be associated with calculous cholecystitis for the first time, so that clinicians should consider calculous cholecystitis associated CA19-9 elevation in the clinic practice besides other CA19-9 related diseases.

Helmet-Wearing Tracking Detection Based on StrongSORT.

Object detection based on deep learning is one of the most important and fundamental tasks of computer vision. High-performance detection algorithms have been widely used in many practical fields. For the management of workers wearing helmets in construction scenarios, this paper proposes a framework model based on the YOLOv5 detection algorithm, combined with multi-object tracking algorithms, to monitor and track whether workers wear safety helmets in real-time video. The improved StrongSORT tracking algorithm of DeepSORT is selected to reduce the loss of the tracked object caused by the occlusion, trajectory blur, and motion scale of the object. The safety helmet dataset is trained with YOLOv5s, and the best result of training is used as the weight model in the StrongSORT tracking algorithm. The experimental results show that the mAP@0.5 of all classes in the YOLOv5s model can reach 95.1% in the validation dataset, mAP@0.5:0.95 is 62.1%, and the precision of wearing helmet is 95.7%. After the box regression loss function was changed from CIOU to Focal-EIOU, the mAP@0.5 increased to 95.4%, mAP@0.5:0.95 increased to 62.9%, and the precision of wearing helmet increased to 96.5%, which were increased by 0.3%, 0.8% and 0.8%, respectively. StrongSORT can update object trajectories in video frames at a speed of 0.05 s per frame. Based on the improved YOLOv5s combined with the StrongSORT tracking algorithm, the helmet-wearing tracking detection can achieve better performance.

Effect of abnormal values of three temperature indicators on ischemic stroke hospital admissions in Guangzhou, China.

Abnormal temperature has important effects on the occurrence of ischemic stroke (IS). However, relatively less efforts have been taken to systematically unravel the association between various abnormal temperature and IS hospital admission. Focusing on three temperature indicators (i.e., mean temperature, maximum temperature, and minimum temperature), this study attempts to analyse how their abnormal values affect IS hospital admission. The dataset covers the period between September 17, 2012 and August 28, 2018, and includes a total of 1464 cases who were admitted to the hospital for the first onset of IS and lived in the main urban area of Guangzhou. The study adopts the time-stratified case-crossover analysis. Abnormal values of temperature were measured using the 2.5th and 97.5th quantile values of each temperature indicator, with the former refers to a low value whereas the latter a high one. The effects of abnormal temperature on IS hospital admission were assessed through calculating the relative risks induced by the low and high values (the median values of each temperature indicators were taken as the references). The results show that the risk window periods for IS hospital admission associated with the low values of the temperature indicators are the lags of 3-7 days and 18-19 days. The risks of high temperature values on IS admission, however, are insignificant with either one-day lag or cumulative lag. As to different population groups, females show higher risks of IS hospital admission at low temperature values than males; and elderly people, compared with young people, are more vulnerable to low temperature values. To cities with similar climate of Guangzhou, particular attention should be paid to the impact of low temperature values, especially the low value of minimum temperature, on IS admission, and to females and elderly people who are more sensitive to abnormal temperatures.

Identification of Aging and Young Subtypes for Predicting Colorectal Cancer Prognosis and Immunotherapy Responses.

Colorectal cancer (CRC) is critically related to aging and severely threatens human lives. To better explore the effects of aging on CRC progression and therapy outcome, a reliable aging subtypes identification of CRC is urgently desired. Here, 28 aging-related genes associated with the CRC prognosis were selected by univariate Cox analyses. Based on these 28 genes, CRC patients were divided into the aging subtype and young subtype by non-negative matrix factorization clustering. Aging subtype and young subtype of CRC were identified with distinct molecular features and clinical prognosis. The aging subtype was characterized by upregulation of senescence-associated secretory phenotype, higher frequencies of TP53 and immune checkpoint molecules, and high sensitivity to protein kinase and angiogenesis inhibitors. Furthermore, 14 genes were selected by LASSO penalized Cox regression analyses for aging-related risk signature construction. The constructed aging risk signature exhibited good prediction and the nomogram showed robust discrimination power over the traditional CRC staging system. In conclusion, this study successfully established aging subtype and young subtype of CRC, which is helpful to identify patients with aging characteristics to evaluate prognosis and treatment outcomes. Introducing aging-based subtypes into clinical concern and patient prognostication provides new opportunities for personalized CRC treatment.

Tumour-associated neutrophils secrete AGR2 to promote colorectal cancer metastasis via its receptor CD98hc-xCT.

OBJECTIVE: Reciprocal cellular crosstalk within the tumour microenvironment (TME) actively participates in tumour progression. The anterior gradient-2 (AGR2) can be secreted to extracellular compartments and contribute to colorectal cancer (CRC) metastasis. We investigated the cellular source for secreted AGR2 in the TME and underlying mechanisms mediating secreted AGR2's effects. DESIGN: Tissue microarray, tumour tissues, blood samples and tumour-associated neutrophils (TANs) from patients with CRC were isolated for phenotypical and functional analyses. The role of TAN-secreted AGR2 was determined in neutrophil-specific Agr2 knockout (Agr2f/f;Mrp-Cre) mice. The biological roles and mechanisms of secreted AGR2 in CRC metastasis were determined in vitro and in vivo. RESULTS: TANs were a predominant cell type for secreting AGR2 in the TME of CRC. TANs-secreted AGR2 promoted CRC cells' migration. Neutrophils-specific ablation of Agr2 in mice ameliorated CRC liver metastases. The heavy chain of CD98 (CD98hc) served as the functional receptor for secreted AGR2. Mechanistically, secreted AGR2 increased xCT activity in a CD98hc-dependent manner, subsequently activating Ras homologue family member A/Rho-associated protein kinase 2 cascade. CRC cells actively recruited TANs through the C-X-C motif chemokine 2. Moreover, CRC-derived transforming growth factor beta 1 (TGF-ß1) educated peripheral blood neutrophils to become AGR2+ TANs that secrete AGR2. Abundant infiltration of AGR2+ TANs and high expression of TGF-ß1 and CD98hc-xCT were correlated with poor prognosis of patients with CRC. CONCLUSIONS: Our study unveils a novel crosstalk between TANs and CRC cells involving the secreted AGR2-CD98hc-xCT axis that promotes metastasis and impacts the outcomes of patients with CRC.

Copper-Based Metal-Organic Framework Overcomes Cancer Chemoresistance through Systemically Disrupting Dynamically Balanced Cellular Redox Homeostasis.

Chemodrug resistance is a major reason accounting for tumor recurrence. Given the mechanistic complexity of chemodrug resistance, molecular inhibitors and targeting drugs often fail to eliminate drug-resistant cancer cells, and sometimes even promote chemoresistance by activating alternative pathways. Here, by exploiting biochemical fragility of high-level but dynamically balanced cellular redox homeostasis in drug-resistant cancer cells, we design a nanosized copper/catechol-based metal-organic framework (CuHPT) that effectively disturbs this homeostasis tilting the balance toward oxidative stress. Within drug-resistant cells, CuHPT starts disassembly that is triggered by persistent consumption of cellular glutathione (GSH). CuHPT disassembly simultaneously releases two structural elements: catechol ligands and reductive copper ions (Cu+). Both of them cooperatively function to amplify the production of intracellular radical oxidative species (ROS) via auto-oxidation and Fenton-like reactions through exhausting GSH. By drastically heightening cellular oxidative stress, CuHPT exhibits selective and potent cytotoxicity to multiple drug-resistant cancer cells. Importantly, CuHPT effectively inhibits in vivo drug-resistant tumor growth and doubles the survival time of tumor-bearing mice. Thus, along with CuHPT's good biocompatibility, our biochemical, cell biological, preclinical animal model data provide compelling evidence supporting the notion that this copper-based MOF is a predesigned smart therapeutic against drug-resistant cancers through precisely deconstructing their redox homeostasis.

Pentraxin-3 as a predictive marker of mortality in sepsis: an updated systematic review and meta-analysis.

BACKGROUND: The purpose of this study was to clarify the prognostic value of Pentraxin-3 (PTX3) on the mortality of patients with sepsis. METHODS: Publications published up to January 2021 were retrieved from PubMed, EMBASE, and the Cochrane library. Data from eligible cohort and case-control studies were extracted for the meta-analysis. Multivariate regression analysis was used to evaluate the correlation of the outcomes with sample size and male proportion. RESULTS: A total of 17 studies covering 3658 sepsis patients were included. PTX3 level was significantly higher in non-survivor compared to survivor patients (SMD (95% CI): -1.06 (-1.43, -0.69), P < 0.001). Increased PTX3 level was significantly associated with mortality (HR (95% CI): 2.09 (1.55, 2.81), P < 0.001). PTX3 showed good predictive capability for mortality (AUC:ES (95% CI): 0.73 (0.70, 0.77), P < 0.001). The outcome comparing PTX3 level in non-survivors vs. survivors and the outcome of the association between PTX3 and mortality were associated with sample size but not male proportion. AUC was associated with both sample size and male proportion. CONCLUSIONS: PTX3 level was significantly higher in non-survivor compared to survivor patients with sepsis. Elevated PTX3 level was significantly associated with mortality. Furthermore, the level of PTX3 might predict patient mortality.

Transcriptome analysis of Mythimna separata: De novo assembly and detection of genes related to beta-cypermethrin resistance.

The oriental armyworm Mythimna separata (Walker) is a devastating pest of cereal crops mainly in Asia and Oceania and recently become resistant to beta-cypermethrin (beta-CP). However, molecular biological studies of its response to beta-CP are scarce, and related genomic information is not available. In this study, we sequenced and de novo assembled the transcriptome of beta-CP susceptible M. separata (MsS-whole, abbr. MsS-W). A total of 30,486 unigenes were obtained, with an N50 length of 506 bp. A number of 21,051 unigenes were matched to public databases, of which 10,107 were classified into 59 gene ontology subcategories, 5792 were assigned into 25 clusters of orthologous groups of proteins subgroups and 12,123 were assigned to 257 Kyoto Encyclopedia of Genes and Genomes pathways. A total of 729 simple sequence repeats were detected. In addition, a total of 323 cytochrome P450-associated sequences from nine lepidopterous species, of which 130 were from M. separata, were analyzed using the maximum likelihood method and Bayesian inference. Among the 130 cytochrome P450-associated sequences from M. separata, 60 were dropped into CYP3 clan, which is associated with metabolizing xenobiotics and plant natural compounds. Furthermore, the beta-CP susceptible (MsS-2) and resistant (MsR-2) M. separata population transcriptomes were sequenced. Certain critical genes involved in beta-CP detoxification were detected and verified by quantitative real-time polymerase chain reaction. Collectively, our results provided a basis for further studies of the molecular mechanism of insecticide resistance in M. separata.

Oxygen-Generating Cyanobacteria Powered by Upconversion-Nanoparticles-Converted Near-Infrared Light for Ischemic Stroke Treatment.

Stroke is one of most common causes of death and disability. Most of neuroprotective agents fail to rescue neurons from cerebral ischemic insults, mainly because of targeting downstream cascading events, such as excitotoxicity, oxidative and nitrosative stress, and inflammation, rather than improving hypoxia that initially occurs. Here, we report a near-infrared light (NIR)-driven nanophotosynthesis biosystem capable of generating oxygen and absorbing carbon dioxide, thus rescuing neurons from ischemia toward treating stroke. Through cerebral delivery of S. elongatus that spontaneously photosynthesize and upconversion nanoparticles (UCNPs), NIR with excellent tissue penetrating capability is converted to visible light by UCNPs to activate S. elongatus generating oxygen in vivo, enhancing angiogenesis, reducing infarction, and facilitating repair of brain tissues, thus improving neuronal function recovery. The combination of cell-biological, biochemical, and animal-level behavioral data provides compelling evidence demonstrating that this oxygen-generating biosystem through jointly utilizing microorganism and nanotechnology represents a novel approach to stroke treatment.

Ursodeoxycholyl lysophosphatidylethanolamide protects against hepatic ischemia/reperfusion injury via phospholipid metabolism-mediated mitochondrial quality control.

Mitochondrial dysfunction is the leading cause of reactive oxygen species (ROS) burst and apoptosis in hepatic ischemia/reperfusion (I/R) injury. Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a hepatotargeted agent that exerts hepatoprotective roles by regulating lipid metabolism. Our previous studies have shown that UDCA-LPE improves hepatic I/R injury by inhibiting apoptosis and inflammation. However, the role of UDCA-LPE in lipid metabolism and mitochondrial function in hepatic I/R remains unknown. In the present study, we investigated the role of UDCA-LPE in hepatic I/R by focusing on the interface of phospholipid metabolism and mitochondrial homeostasis. Livers from 28-week-old mice, primary hepatocytes and HepG2 cells were subjected to in vivo and in vitro I/R, respectively. Analyses of oxidative stress, imaging, ATP generation, genetics, and lipidomics showed that I/R was associated with mitochondrial dysfunction and a reduction in phospholipids. UDCA-LPE alleviated mitochondria-dependent oxidative stress and apoptosis and prevented the decrease of phospholipid levels. Our study found that cytosolic phospholipase A2 (cPLA2 ), a phospholipase that is activated during I/R, hydrolyzed mitochondrial membrane phospholipids and led to mitochondria-mediated oxidative stress and apoptosis. UDCA-LPE inhibited the interaction between cPLA2 and mitochondria and reduced phospholipid hydrolysis-mediated injury. UDCA-LPE might regulate the crosstalk between the phospholipid metabolism and the mitochondria, restore mitochondrial function and ameliorate I/R injury.

Kupffer cell-targeting strategy for the protection of hepatic ischemia/reperfusion injury.

The aim of this study is to evaluate the effect of rare earth upconversion nanoparticles (UCNs) on hepatic ischemia reperfusion injury (IRI) and explore its possible mechanism. Hepatic IRI seriously affects the prognosis of patients undergoing liver surgery. Liver-resident Kupffer cells have been reported to promote IRI. Nanomedicines are known to be effective in the treatment of liver diseases, however, Kupffer cell-targeting nanomedicines for the treatment of IRI are yet to be developed. As potential bioimaging nanomaterials, UCNs have been found to specifically deplete Kupffer cells, but the underlying mechanism is unknown. In this study, we found that UCNs specifically depleted Kupffer cells by pyroptosis, while the co-administration of the caspase-1 inhibitor VX-765 rescued the UCN-induced Kupffer cell pyroptosis in mice. Furthermore, the pre-depletion of Kupffer cells by the UCNs significantly suppressed the release of inflammatory cytokines and effectively improved hepatic IRI. The rescue of the pyroptosis of the Kupffer cells by VX-765 abrogated the protective effect of UCNs on the liver. These results suggest that UCNs are highly promising for the development of Kupffer cell-targeting nanomedicines for intraoperative liver protection.

Uhrf1-Mediated Tnf-α Gene Methylation Controls Proinflammatory Macrophages in Experimental Colitis Resembling Inflammatory Bowel Disease.

Macrophages drive the pathological process of inflammatory bowel diseases (IBD) mostly by secreting proinflammatory cytokines, such as Tnf-α. Recent studies have indicated the association between epigenetic modifications and macrophage functions. However, epigenetic mechanisms regulating macrophages' functional involvement in IBD remain unknown. In this study, we investigated whether the epigenetic regulator Uhrf1 plays a role in innate immunity by functionally regulating macrophages in intestines. We employed two transgenic strains of mice (one with Uhrf1 deficiency in macrophages [Uhrf1fl/flLyz2-Cre mice] and the other with the two mutations at Uhrf1's DNA methylation regulatory site [Uhrf1YP187/188AA mice]) to assess their susceptibility to dextran sodium sulfate-induced colitis. We examined the cytokines derived from Uhrf1fl/flLyz2-Cre and Uhrf1YP187/188AA macrophages in response to LPS stimulation. We also analyzed the effects of proinflammatory cytokines on Uhrf1 expression in macrophages. The data demonstrated that Uhrf1 deficiency and Uhrf1YP187/188AA mutation resulted in severe colitis in the dextran sodium sulfate-treated mice. In vitro analysis revealed the hypomethylation of Tnf-α promoter and the increased Tnf-α expression in Uhrf1fl/flLyz2-Cre and Uhrf1YP187/188AA macrophages in response to LPS stimulation, and anti-Tnf-α therapy implied the key role of Tnf-α to the aggravated colitis in Uhrf1-deficient mice. Exogenous Tnf-α destabilized Uhrf1 protein through ubiquitination-mediated protein degradation, triggering macrophage activation. In conclusion, we identified that Uhrf1-mediated DNA methylation controls Tnf-α expression of macrophages in the experimental colitis resembling IBD. The epigenetic mechanisms that activate macrophages may provide new therapeutic targets for IBD treatment.

Risk and prognostic nomograms for colorectal neuroendocrine neoplasm with liver metastasis: a population-based study.

PURPOSE: Liver metastasis (LM) significantly shortens the survival time of colorectal neuroendocrine neoplasms (NENs) patients. This research aimed to explore risk and prognostic factors in colorectal NENs patients with LM and develop nomograms for predicting the risk of LM and survival probability quantitatively. METHODS: A total of 9926 colorectal NENs patients registered in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2017 were included. Risk factors for LM in colorectal NENs patients were identified by multivariate logistic regression analysis. Potential prognostic factors for colorectal NENs patients with LM were identified by multivariable Cox regression analysis. Nomograms were constructed for quantifying the probability of LM occurrence and survival. RESULTS: At diagnosis, 8.7% of colorectal NENs patients suffered LM, with 1-, 3-, and 5-year cancer-specific survival (CSS) rates of 44.3%, 26.5%, and 18.0%, respectively. Factors associated with LM occurrence included gender, age at diagnosis, primary tumor location, carcinoembryonic antigen (CEA), histological differentiation, T stage, and N stage. Age at diagnosis, race, histological differentiation, N stage, tumor size, primary tumor location, primary site surgery, and extraliver metastasis were prognostic factors of cancer-specific mortality. The area under the receiver operating characteristics (ROC) curve of the nomogram for predicting LM was 0.888 (95% CI: 0.877-0.898), and the C-index of the nomogram for estimating CSS probability was 0.705 (95% CI: 0.682-0.729). CONCLUSIONS: This research identified the risk and prognostic factors in colorectal NENs patients with LM. The nomograms constructed by this study can be convenient tools for facilitating clinical decision-making.

Safety and feasibility of prolonged versus early laparoscopic cholecystectomy for acute cholecystitis: a single-center retrospective study.

BACKGROUND: Laparoscopic cholecystectomy (LC) is the standard treatment for acute cholecystitis (AC), and it should be performed within 72 h of symptoms onset if possible. In many undesired situations, LC was performed beyond the golden 72 h. However, the safety and feasibility of prolonged LC (i.e., performed more than 72 h after symptoms onset) are largely unknown, and therefore were investigated in this study. METHODS: We retrospectively enrolled the adult patients who were diagnosed as AC and were treated with LC at the same admission between January 2015 and October 2018 in an emergency department of a tertiary academic medical center in China. The primary outcome was the rate and severity of adverse events, while the secondary outcomes were length of hospital stay and costs. RESULTS: Among the 104 qualified patients, 70 (67.3%) underwent prolonged LC and 34 (32.7%) underwent early LC (< 72 h of symptom onset). There were no differences between the two groups in mortality rate (none for both), conversion rates (prolonged LC 5.4%, and early LC 8.8%, P = 0.68), intraoperative and postoperative complications (prolonged LC 5.7% and early LC 2.9%, P ≥ 0.99), operation time (prolonged LC 193.5 min and early LC 198.0 min, P = 0.81), and operation costs (prolonged LC 8,700 Yuan, and early LC 8,500 Yuan, P = 0.86). However, the prolonged LC was associated with longer postoperative hospitalization (7.0 days versus 6.0 days, P = 0.03), longer total hospital stay (11.0 days versus 8.0 days, P < 0.01), and subsequently higher total costs (40,400 Yuan versus 31,100 Yuan, P < 0.01). CONCLUSIONS: Prolonged LC is safe and feasible for patients with AC for having similar rates and severity of adverse events as early LC, but it is also associated with longer hospital stay and subsequently higher total cost.

Acute respiratory distress syndrome emerging after surgical debridement in a patient with extranodal natural killer/T cell lymphoma.

BACKGROUND: Extranodal natural killer/T cell lymphoma (ENKL) is a rare subtype of non-Hodgkin lymphoma, and lung involvement is extremely rare. The patients with pulmonary ENKL always presented unspecific symptoms of the respiratory system, such as cough with sputum and varying degrees of fever, while developing into acute respiratory distress (ARDS) was seldomly reported, especially promoted by the surgical procedure. CASE PRESENTATION: Here we describe a patient with nasal ENKL and most likely lung dissemination that was regarded as an infection at first. After nonresponse to a period of anti-infective therapy, this patient received surgical debridement. While the histopathology did not show the evidence of infection, but consistent with ENKL. The patient got refractory hypoxemia rapidly after surgery, with the LDH surging to a much higher level than before surgery. The ARDS was diagnosed, and he died on the 5th day after surgery. We postulate that ARDS was due to aggressive lymphoma proliferation promoted by the surgical procedure. CONCLUSIONS: Pulmonary ENKL developing into ARDS was scarce, and was likely attributed to the aggressive tumor cell proliferation after surgery in this case.