Hypoxia exosome derived CEACAM5 promotes tumor-associated macrophages M2 polarization to accelerate pancreatic neuroendocrine tumors metastasis via MMP9.

Exosomes play significant roles in the communications between tumor cells and tumor microenvironment. However, the specific mechanisms by which exosomes modulate tumor development under hypoxia in pancreatic neuroendocrine tumors (pNETs) are not well understood. This study aims to investigate these mechanisms and made several important discoveries. We found that hypoxic exosomes derived from pNETs cells can activate tumor-associated macrophages (TAM) to the M2 phenotype, in turn, the M2-polarized TAM, facilitate the migration and invasion of pNETs cells. Further investigation revealed that CEACAM5, a protein highly expressed in hypoxic pNETs cells, is enriched in hypoxic pNETs cell-derived exosomes. Hypoxic exosomal CEACAM5 was observed to induce M2 polarization of TAM through activation of the MAPK signaling pathway. Coculturing pNETs cells with TAM or treated with hypoxic exosomes enhanced the metastatic capacity of pNETs cells. In conclusion, these findings suggest that pNETs cells generate CEACAM5-rich exosomes in a hypoxic microenvironment, which in turn polarize TAM promote malignant invasion of pNETs cells. Targeting exosomal CEACAM5 could potentially serve as a diagnostic and therapeutic strategy for pNETs.

FOXA2-initiated transcriptional activation of INHBA induced by methylmalonic acid promotes pancreatic neuroendocrine neoplasm progression.

Pancreatic neuroendocrine neoplasms (PanNENs) are a group of highly heterogeneous neoplasms originating from the endocrine islet cells of the pancreas with characteristic neuroendocrine differentiation, more than 60% of which represent metastases when diagnosis, causing major tumor-related death. Metabolic alterations have been recognized as one of the hallmarks of tumor metastasis, providing attractive therapeutic targets. However, little is known about the molecular mechanism of metabolic changes regulating PanNEN progression. In this study, we first identified methylmalonic acid (MMA) as an oncometabolite for PanNEN progression, based on serum metabolomics of metastatic PanNEN compared with non-metastatic PanNEN patients. One of the key findings was the potentially novel mechanism of epithelial-mesenchymal transition (EMT) triggered by MMA. Inhibin ßA (INHBA) was characterized as a key regulator of MMA-induced PanNEN progression according to transcriptomic analysis, which has been validated in vitro and in vivo. Mechanistically, INHBA was activated by FOXA2, a neuroendocrine (NE) specific transcription factor, which was initiated during MMA-induced progression. In addition, MMA-induced INHBA upregulation activated downstream MITF to regulate EMT-related genes in PanNEN cells. Collectively, these data suggest that activation of INHBA via FOXA2 promotes MITF-mediated EMT during MMA inducing PanNEN progression, which puts forward a novel therapeutic target for PanNENs.

Hypoxia upregulating ACSS2 enhances lipid metabolism reprogramming through HMGCS1 mediated PI3K/AKT/mTOR pathway to promote the progression of pancreatic neuroendocrine neoplasms.

BACKGROUND: Pancreatic neuroendocrine neoplasms (pNENs) are relatively rare. Hypoxia and lipid metabolism-related gene acetyl-CoA synthetase 2 (ACSS2) is involved in tumor progression, but its role in pNENs is not revealed. This study showed that hypoxia can upregulate ACSS2, which plays an important role in the occurrence and development of pNENs through lipid metabolism reprogramming. However, the precise role and mechanisms of ACSS2 in pNENs remain unknown. METHODS: mRNA and protein levels of ACSS2 and 3-hydroxy-3-methylglutaryl-CoA synthase1 (HMGCS1) were detected using quantitative real-time PCR (qRT-PCR) and Western blotting (WB). The effects of ACSS2 and HMGCS1 on cell proliferation were examined using CCK-8, colony formation assay and EdU assay, and their effects on cell migration and invasion were examined using transwell assay. The interaction between ACSS2 and HMGCS1 was verified by Co-immunoprecipitation (Co-IP) experiments, and the functions of ACSS2 and HMGCS1 in vivo were determined by nude mouse xenografts. RESULTS: We demonstrated that hypoxia can upregulate ACSS2 while hypoxia also promoted the progression of pNENs. ACSS2 was significantly upregulated in pNENs, and overexpression of ACSS2 promoted the progression of pNENs and knockdown of ACSS2 and ACSS2 inhibitor (ACSS2i) treatment inhibited the progression of pNENs. ACSS2 regulated lipid reprogramming and the PI3K/AKT/mTOR pathway in pNENs, and ACSS2 regulated lipid metabolism reprogramming through the PI3K/AKT/mTOR pathway. Co-IP experiments indicated that HMGCS1 interacted with ACSS2 in pNENs. Overexpression of HMGCS1 can reverse the enhanced lipid metabolism reprogramming and tumor-promoting effects of knockdown of ACSS2. Moreover, overexpression of HMGCS1 reversed the inhibitory effect of knockdown of ACSS2 on the PI3K/AKT/mTOR pathway. CONCLUSION: Our study revealed that hypoxia can upregulate the lipid metabolism-related gene ACSS2, which plays a tumorigenic effect by regulating lipid metabolism through activating the PI3K/AKT/mTOR pathway. In addition, HMGCS1 can reverse the oncogenic effects of ACSS2, providing a new option for therapeutic strategy.

WTAP activates MAPK signaling through m6A methylation in VEGFA mRNA-mediated by YTHDC1 to promote colorectal cancer development.

N6-methyladenosine modification, especially Wilms tumor 1-associated protein (WTAP), is reportedly associated with a variety of cancers, including colorectal cancer (CRC). Angiogenesis also plays an important role in the occurrence and development of CRC. However, only a few studies have reported the biological mechanisms underlying this connection. Therefore, tissue microarray and public database were used to explore WTAP levels in CRC. Then, WTAP was down-regulated and over-expressed, respectively. CCK8, EdU, colony formation, and transwell experiments were performed to study the role of WTAP in CRC. Combined RNA sequencing and m6A RNA immunoprecipitation (MeRIP) sequencing, we found downstream molecules VEGFA. Moreover, a tube formation assay was executed for tumor angiogenesis. Finally, a subcutaneous tumorigenesis assay in nude mice was used to examine the tumor-promoting effect of WTAP in vivo. In the present study, WTAP was significantly upregulated in CRC cells and patients with CRC. Moreover, higher WTAP expression was observed in the TCGA and CPATC databases in CRC tissues. WTAP over-expression exacerbates cell proliferation, migration, invasion, and angiogenesis. Conversely, WTAP knockdown inhibited the malignant biological behavior of CRC cells. Mechanistically, WTAP positively regulated VEGFA, as identified using RNA sequencing and MeRIP sequencing. Moreover, we identified YTHDC1 as a downstream effector of the YTHDC1-VEGFA axis in CRC. Furthermore, increased WTAP expression activated the MAPK signaling pathway, which led to enhanced angiogenesis. In conclusion, our study revealed that the WTAP/YTHDC1/VEGFA axis promotes CRC development, especially angiogenesis, suggesting that it may act as a potential biomarker of CRC.

FABP5 regulates lipid metabolism to facilitate pancreatic neuroendocrine neoplasms progression via FASN mediated Wnt/ß-catenin pathway.

Pancreatic neuroendocrine neoplasms (pNENs) are among the most frequently occurring neuroendocrine neoplasms (NENs) and require targeted therapy. High levels of fatty acid binding protein 5 (FABP5) are involved in tumor progression, but its role in pNENs remains unclear. We investigated the mRNA and protein levels of FABP5 in pNEN tissues and cell lines and found them to be upregulated. We evaluated changes in cell proliferation using CCK-8, colony formation, and 5-ethynyl-2'-deoxyuridine assays and examined the effects on cell migration and invasion using transwell assays. We found that knockdown of FABP5 suppressed the proliferation, migration, and invasion of pNEN cell lines, while overexpression of FABP5 had the opposite effect. Co-immunoprecipitation experiments were performed to clarify the interaction between FABP5 and fatty acid synthase (FASN). We further showed that FABP5 regulates the expression of FASN via the ubiquitin proteasome pathway and both proteins facilitate the progression of pNENs. Our study demonstrated that FABP5 acts as an oncogene by promoting lipid droplet deposition and activating the WNT/ß-catenin signaling pathway. Moreover, the carcinogenic effects of FABP5 can be reversed by orlistat, providing a novel therapeutic intervention option.

ALKBH5 enhances lipid metabolism reprogramming by increasing stability of FABP5 to promote pancreatic neuroendocrine neoplasms progression in an m6A-IGF2BP2-dependent manner.

The process of post-transcriptional regulation has been recognized to be significantly impacted by the presence of N6-methyladenosine (m6A) modification. As an m6A demethylase, ALKBH5 has been shown to contribute to the progression of different cancers by increasing expression of several oncogenes. Hence, a better understanding of the key targets of ALKBH5 in cancer cells could potentially lead to the development of new therapeutic targets. However, the specific role of ALKBH5 in pancreatic neuroendocrine neoplasms (pNENs) remains largely unknown. Here, we demonstrated that ALKBH5 was up-regulated in pNENs and played a critical role in tumor growth and lipid metabolism. Mechanistically, ALKBH5 over-expression was found to increase the expression of FABP5 in an m6A-IGF2BP2 dependent manner, leading to disorders in lipid metabolism. Additionally, ALKBH5 was found to activate PI3K/Akt/mTOR signaling pathway, resulting in enhanced lipid metabolism and proliferation abilities. In conclusion, our study uncovers the ALKBH5/IGF2BP2/FABP5/mTOR axis as a mechanism for aberrant m6A modification in lipid metabolism and highlights a new molecular basis for the development of therapeutic strategies for pNENs treatment.

Methylmalonic acid promotes colorectal cancer progression via activation of Wnt/ß-catenin pathway mediated epithelial-mesenchymal transition.

BACKGROUND: It has been manifested in several studies that age-related metabolic reprogramming is associated with tumor progression, in particular, colorectal cancer (CRC). Here we investigated the role of upregulated metabolites of the aged serum, including methylmalonic acid (MMA), phosphoenolpyruvate (PEP), and quinolinate (QA), in CRC. METHODS: Functional assays including CCK-8, EdU, colony formation and transwell experiments were used to ascertain which upregulated metabolite of elderly serum was related to tumor progression. RNA-seq analysis was conducted to explore the potential mechanisms of MMA-induced CRC progression. Subcutaneous tumorigenesis and metastatic tumor models were constructed to verify the function of MMA in vivo. RESULTS: Among three consistently increased metabolites of the aged sera, MMA was responsible for tumorigenesis and metastasis in CRC, according to functional assays. The promotion of Epithelial-mesenchymal transition (EMT) was observed in CRC cells treated with MMA, on the basis of protein expression of EMT markers. Moreover, combined with transcriptome sequencing, Wnt/ß-catenin signaling pathway was activated in CRC cells treated with MMA, which was verified by western blot and qPCR experiments. Furthermore, animal assays demonstrated the pro-proliferation and promotion of metastasis role of MMA in vivo. CONCLUSION: We have identified that age-dependent upregulation of MMA in serum promoted the progression of CRC via Wnt/ß-catenin signaling pathway mediated EMT. These collective findings provide valuable insights into the vital role of age-related metabolic reprogramming in CRC progression and propose a potential therapeutic target for elderly CRC.

Efficacy and safety of modified endoscopic submucosal tunnel dissection for superficial esophageal circumferential lesions.

To evaluate the efficacy and safety of intra-tunnel dissection using hemostatic forceps and needle-type device for patients with esophageal circumferential lesions (ECLs). Patients with ECLs were enrolled in the study and underwent endoscopic submucosal tunnel dissection (ESTD) or hemostatic forceps-based ESTD (ESFTD). All patients were divided into three subgroups according to longitudinal length of the lesions (LLLs): >8 cm, 4-8 cm and < 4 cm. The clinical data such as gender, age, length of lesions and operating time were collected. A total of 152 patients were included in this study and comprised 80 cases of ESFTD and 72 cases of ESTD. The procedure time was markedly shorter in the ESFTD group than in the ESTD group (P < 0.001). Moreover, ESFTD significantly increased the rate of complete resection and reduced specimen injury in LLLs >8 cm and 4-8 cm subgroup compared with ESTD (P < 0.001), but not in <4 cm subgroup (P > 0.05). The perforation and infection rate were similar in ESFTD and ESTD group (P > 0.05). However, ESFTD effectively decreased the muscular injury rate' the duration of chest pain and the time from endoscopic surgery to first occurrence of esophageal stenosis compared with ESTD group (P < 0.01). ESFTD has better efficacy and safety than ESTD in the treatment of ECLs, especially for large lesions. ESFTD could be recommended for patients with ECLs.

M2 Macrophage-Derived Exosomes Facilitate HCC Metastasis by Transferring αM ß2 Integrin to Tumor Cells.

BACKGROUND AND AIMS: The development and progression of hepatocellular carcinoma (HCC) is dependent on its local microenvironment. Tumor-associated macrophages (TAMs) are deemed a key factor for the tumor microenvironment and attribute to contribute to tumor aggressiveness. However, the detailed mechanism underlying the pro-metastatic effect of TAMs on HCC remains undefined. APPROACH AND RESULTS: The present study proved that TAMs were enriched in HCC. TAMs were characterized by an M2-polarized phenotype and accelerated the migratory potential of HCC cells in vitro and in vivo. Furthermore, we found that M2-derived exosomes induced TAM-mediated pro-migratory activity. With the use of mass spectrometry, we identified that integrin, αM ß2 (CD11b/CD18), was notably specific and efficient in M2 macrophage-derived exosomes (M2 exos). Blocking either CD11b and/or CD18 elicited a significant decrease in M2 exos-mediated HCC cell metastasis. Mechanistically, M2 exos mediated an intercellular transfer of the CD11b/CD18, activating the matrix metalloproteinase-9 signaling pathway in recipient HCC cells to support tumor migration. CONCLUSIONS: Collectively, the exosome-mediated transfer of functional CD11b/CD18 protein from TAMs to tumor cells may have the potency to boost the migratory potential of HCC cells, thus providing insights into the mechanism of tumor metastasis.

Prognosis of patients with poorly differentiated gastric neuroendocrine neoplasms: a multi-center study in China.

Background: The incidence of poorly differentiated gastric neuroendocrine neoplasms (G-NENs) has been increasing during the past decades. Methods: A total of 183 patients diagnosed with poorly differentiated G-NENs were enrolled from eight hospitals during 2010-2019 in China. All cases included have accepted abdominal surgery in tertiary hospitals. Result: T3 (HR: 2.66, p = 0.019), T4 (HR: 3.62, p = 0.005), stage IV (HR: 5.67, p < 0.001), vascular invasion (HR: 1.59, p = 0.048) were independent risk factors for poor prognosis of poorly differentiated G-NENs. In stratified analysis, for patients with stage III tumors, those treated with chemotherapy had significantly longer survival than those accepting surgery alone. Conclusion: T3/T4 stage, TNM stage IV and vascular invasion were independent negative prognostic factors for patients with poorly differentiated G-NENs. Patients with stage III tumors can benefit from chemotherapy. Highly selected patients with stage IV tumors may also benefit from surgery.

This study mainly describes a rare cancerous gastric tumor. Numerous people have been diagnosed with this disease during the past decades. Owing to the small number of patients diagnosed with this disease, the treatment method is still not clear. In our study, we found that the outcome of patients who were diagnosed at late stage was much poorer than those diagnosed at early stage. So, it is important for patients to get accurate diagnosis in time. For a part of patients accepting surgery, they may benefit from chemotherapy.

Diagnosis and treatment of a small intestinal neuroendocrine neoplasm by double balloon enteroscopy combined with laparoscopy: a case report.

We report the case of a jejunum neuroendocrine neoplasm with liver metastases, the lesion showed somatostatin receptor expression in the junction of duodenum and jejunum without enlarged lymph nodes in 68Ga-DOTA-NOC PET/CT scan, definitive diagnosis and treatment depend on double-balloon enteroscopy and laparoscopy. This is a meaningful and thought-provoking process.

Colorectal cancer prompted adipose tissue browning and cancer cachexia through transferring exosomal miR-146b-5p.

Cancer cachexia is a complex syndrome that is associated with thermogenic gene regulation. Currently, although some studies have reported the link between exosomes and cancer cachexia in a few types of cancer, the underlying mechanisms remain poorly understood. In this study, we tried to identify whether exosomes derived from colorectal cancer could affect lipolysis in vitro and in vivo. Here, we collected the tissue samples from 48 patients with colorectal cancer (47.91% females and mean age 55 ± 8.20) and 48 healthy people at the First Affiliated Hospital of Nanjing Medical University to detect the miR-146-5p expression. Here, we found that cancer cells released exosomes induced white adipose tissues (WATs) browning and accelerated lipolysis. We also demonstrated that miR-146b-5p was enriched in cancer-related exosomes. Overexpression miR-146b-5p resulted in increased WAT browning, decreased oxygen consumption, and fat mass loss (14.57%). The further study identified that miR-146b-5p could directly repress the downstream gene homeodomain-containing gene C10 (HOXC10), thereby regulating lipolysis. Therefore, our results indicated that cancer cells derived from exosomal miR-146b-5p played an essential role in WAT browning. Inhibition of cancer-related exosomes might be necessary for improving the cachexia condition.

Tuning Sugar-Based Chiral and Flower-Like Microparticles.

Unique supermolecular structures as chiral and flower-like microparticles and the precise tuning of the morphologies hold immense promise for a variety of applications. Examples of such structures deriving from monosaccharides are still rare, and a general understanding is also lacking. Herein, it is shown that chiral, flower-like, or solid microparticles can be tuned by only using monosaccharide esters without external stimuli. Chiral "left-handed" (counterclockwise) and "right-handed" (clockwise) morphologies can be induced by d- and l-glucose stearoyl esters. In comparison, other monosaccharides, i.e., galactose, mannose, and xylose, cannot formed chiral particles and generated diverse other morphologies of the supermolecular microparticles based on their distinct molecular configurations. Due to the numbers of side chains and the bond orientations, microparticles with solid and porous flower-like morphologies can be obtained. While glucose and xylose esters only lead to solid microparticles, mannose and galactose generate porous flower-like particles. These findings suggest a general method to design and control the superstructures by using monosaccharide backbones with diverse molecular configurations.

Boosting Room Temperature Phosphorescence Performance by Alkyl Modification for Intravital Orthotopic Lung Tumor Imaging.

Pure organic persistent room temperature phosphorescence (RTP) materials have attracted wide attention owing to their great potential in various applications, particularly in bioimaging. However, it is still a challenge to manufacture organic RTP materials possessing quite high efficiency and long lifetime, owing to the high requirements for triplet excitons. In this study, a series of keto derivatives with efficient RTP in crystals are developed through the regulation of molecular aggregation states by simple alkyl groups, resulting in impressive luminescence performance with a longer lifetime and higher efficiency of up to 868 ms and 51.59%, respectively. All the alkyl-substituted derivatives exhibit bright RTP intensities after heavy grinding with a pestle, indicating their robust RTP features, which are suitable for many fields. Encouraged by the excellent RTP performance of these luminogens in the crystalline state, successful orthotopic lung tumor imaging with a high signal-to-background ratio (SBR) of 65 is demonstrated in this study to provide the promise of pure organic RTP materials for disease diagnosis, which hold the advantages of low autofluorescence interference and high signal-to-background ratio.

Evaporation-Induced Liquid Expansion and Bubble Formation in Binary Mixtures.

We observe an anomalous liquid expansion after quenching a binary mixture at coexistence to low pressures in the vapor phase by numerical calculations. This evaporation-induced expansion can be attributed to the pressure imbalance near the liquid-vapor interface, which originates from the interplay between the complex thermodynamics of binary mixtures both in the vapor and liquid phases, as well as their dynamical asymmetries. In addition, careful modulation of the pressure quench in the vapor phase can result in spinodal bubble formation inside liquid phase. The results indicate that the thermodynamics-kinetics interplay could foster our fundamental understanding of the evaporation process and promote its practical applications.

Development and validation of prognostic nomograms for patients with colon neuroendocrine neoplasms.

BACKGROUND: Colon neuroendocrine neoplasms (NENs) have one of the poorest median overall survival (OS) rates among all NENs. The American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system-currently the most commonly used prediction model-has limited prediction accuracy because it does not include parameters such as age, sex, and treatment. The aim of this study was to construct nomograms containing various clinically important parameters to predict the prognosis of patients with colon NENs more accurately. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, we performed a retrospective analysis of colon NENs diagnosed from 1975 to 2016. Data were collected from 1196 patients; almost half were female (617/1196, 51.6%), and the average age was 61.94 ± 13.05 years. Based on the age triple cut-off values, there were 396 (33.1%), 408 (34.1%), and 392 (32.8%) patients in age groups 0-55 years, 55-67 years, and ≥ 68 years, respectively. Patients were randomized into training and validation cohorts (3:1). Independent prognostic factors were used for construction of nomograms to precisely predict OS and cancer-specific survival (CSS) in patients with colon NENs. RESULTS: Multivariate analysis showed that age ≥ 68 years, sex, tumor size, grade, chemotherapy, N stage, and M stage were independent predictors of OS. In the validation cohort, the Concordance index (C-index) values of the OS and CSS nomograms were 0.8345 (95% confidence interval [CI], 0.8044-0.8646) and 0.8209 (95% CI, 0.7808-0.861), respectively. C-index also indicated superior performance of both nomograms (C-index 0.8347 for OS and 0.8668 for CSS) compared with the AJCC TNM classification (C-index 0.7159 for OS and 0.7366 for CSS). CONCLUSIONS: We established and validated new nomograms for more precise prediction of OS and CSS in patients with colon NENs to facilitate individualized clinical decisions.

Self-Assembly of Surface-Acylated Cellulose Nanowhiskers and Graphene Oxide for Multiresponsive Janus-Like Films with Time-Dependent Dry-State Structures.

For the first time Janus-like films of surface-acylated cellulose nanowhiskers (CNWs) with or without graphene oxide (GO) via one-step evaporation-driven self-assembly process are reported, which have reconstructible time-dependent micro-/nanostructures and asymmetric wettability. The heterogeneous aggregation of CNWs on rough Teflon substrates favors the formation of uniform films, leading to hydrophobic smooth bottom surface. The homogeneous nucleation of residual CNWs in bulk suspensions promotes the growth of patchy microspheres with an average diameter of 22.7 ± 2.1 µm, which precipitate on the top surface leading to enhanced hydrophobicity. These patchy microspheres are thermoresponsive and vanish after heating at 60 °C within 1 min, while they are reconstructed at room temperature with time-dependent evolving micro-/nanostructures in dry state within 2 d. The thermoresponsive transition of patchy microparticles leads to accompanied switchable change between transparency and opacity of Janus-like films. Furthermore, the incorporation of GO generates more patchy microspheres with an average diameter of 13.5 ± 1.3 µm on the top surface of hybrid Janus-like films. Different distributions of CNWs and GO in Janus-like films and the solvent-responsive self-assembled patchy microparticles of CNWs facilitate their reversible actuation by showing fast curling in THF within 6 s and flattening in water for at least 25 cycles.

Prediction of Kinetically Stable Nanotheranostic Superstructures: Integral of First-Passage Times from Constrained Simulations.

The kinetics of forming multifunctional nanostructures, such as nanotheranostic superstructures, is often highly protracted, involving macroscopic time scales and resulting in nanostructures that correspond to kinetically stable states rather than thermodynamic equilibrium. Predicting such kinetically stable nanostructures becomes a great challenge due to the widely different, relevant time scales that are implicated in the formation kinetics of nano-objects. We develop a methodology, integral of first-passage times from constrained simulations (IFS), to predict kinetically stable, planet-satellite nanotheranostic superstructures. The simulation results are consistent with our experimental observations. The developed methodology enables the exploration of time scales from molecular vibrations of 10-3 ns toward macroscopic scales, 1010 ns, which permits the rational design and prediction of kinetically stable nanotheranostic superstructures for applications in nanomedicine.

Trends of incidence and prognosis of gastric neuroendocrine neoplasms: a study based on SEER and our multicenter research.

BACKGROUND: To investigate the recent epidemiological trends of gastric neuroendocrine neoplasms (GNENs) and establish a new tool to estimate the prognosis of gastric neuroendocrine carcinoma (GNEC) and gastric neuroendocrine tumor (GNET). METHODS: Nomograms were established based on a retrospective study on patients diagnosed with GNENs from 1975 to 2016 in Surveillance, Epidemiology and End Results database. External validation was performed among 246 GNENs patients in Jiangsu province to verify the discrimination and calibration of the nomograms. RESULTS: The age-adjusted incidence of GNENs has increased from 0.309 to 6.149 per 1,000,000 persons in the past 4 decades. Multivariate analysis indicated independent prognostic factors for both GNEC and GNET including age, distant metastasis and surgical intervention (P < 0.05). In addition, T, N staging and grade were significantly associated with survival of GNEC, while size was a predictor for GNET (P < 0.05). The C-indexes of the nomograms were 0.840 for GNEC and 0.718 for GNET, which were higher than those of the 8th AJCC staging system (0.773 and 0.599). Excellent discrimination was observed in the validation cohorts (C-index of nomogram vs AJCC staging for GNEC: 0.743 vs 0.714; GNET: 0.945 vs 0.927). Survival rates predicted by nomograms were close to the actual survival rates in the calibration plots in both training and validation sets. CONCLUSIONS: The incidence of the GNENs is increasing steadily in the past 40 years. We established more excellent nomograms to predict the prognosis of GNENs than traditional staging system, helping clinicians to make tailored decisions.

Anomalous Ostwald Ripening Enables 2D Polymer Crystals via Fast Evaporation.

We demonstrate by molecular simulations that the Ostwald ripening of crystalline polymer nuclei within the fast-evaporation-induced 2D skin layer is retarded at suitable temperatures and evaporation rates. Such an anomalous ripening can be attributed to the interplay between the thermodynamically driven diffusion of noncrystalline fragments toward the growing nuclei and the diffusive current away from the free surface caused by the densification in the nonequilibrium skin layer. The growth orientation of the nuclei inside the skin plane can be adjusted during this anomalous ripening process, which is beneficial for fabricating 2D polymer crystals.