Tight regulation of a nuclear HAPSTR1-HUWE1 pathway essential for mammalian life.

The recently discovered HAPSTR1 protein broadly oversees cellular stress responses. This function requires HUWE1, a ubiquitin ligase that paradoxically marks HAPSTR1 for degradation, but much about this pathway remains unclear. Here, leveraging multiplexed proteomics, we find that HAPSTR1 enables nuclear localization of HUWE1 with implications for nuclear protein quality control. We show that HAPSTR1 is tightly regulated and identify ubiquitin ligase TRIP12 and deubiquitinase USP7 as upstream regulators titrating HAPSTR1 stability. Finally, we generate conditional Hapstr1 knockout mice, finding that Hapstr1-null mice are perinatal lethal, adult mice depleted of Hapstr1 have reduced fitness, and primary cells explanted from Hapstr1-null animals falter in culture coincident with HUWE1 mislocalization and broadly remodeled signaling. Notably, although HAPSTR1 potently suppresses p53, we find that Hapstr1 is essential for life even in mice lacking p53. Altogether, we identify novel components and functional insights into the conserved HAPSTR1-HUWE1 pathway and demonstrate its requirement for mammalian life.

Neuron type-specific proteomics reveals distinct Shank3 proteoforms in iSPNs and dSPNs lead to striatal synaptopathy in Shank3B-/- mice.

Combinatorial expression of postsynaptic proteins underlies synapse diversity within and between neuron types. Thus, characterization of neuron-type-specific postsynaptic proteomes is key to obtaining a deeper understanding of discrete synaptic properties and how selective dysfunction manifests in synaptopathies. To overcome the limitations associated with bulk measures of synaptic protein abundance, we developed a biotin proximity protein tagging probe to characterize neuron-type-specific postsynaptic proteomes in vivo. We found Shank3 protein isoforms are differentially expressed by direct and indirect pathway spiny projection neurons (dSPNs and iSPNs). Investigation of Shank3B-/- mice lacking exons 13-16 within the Shank3 gene, reveal distinct Shank3 protein isoform expression in iSPNs and dSPNs. In Shank3B-/- striatum, Shank3E and Shank3NT are expressed by dSPNs but are undetectable in iSPNs. Proteomic analysis indicates significant and selective alterations in the postsynaptic proteome of Shank3B-/- iSPNs. Correspondingly, the deletion of exons 13-16 diminishes dendritic spine density, reduces spine head diameter, and hampers corticostriatal synaptic transmission in iSPNs. Remarkably, reintroducing Shank3E in adult Shank3B-/- iSPNs significantly rectifies the observed dendritic spine morphological and corticostriatal synaptic transmission deficits. We report unexpected cell-type specific synaptic protein isoform expression which could play a key causal role in specifying synapse diversity and selective synapse dysfunction in synaptopathies.

Local mitochondrial replication in the periphery of neurons requires the eEF1A1 protein and thetranslation of nuclear-encoded proteins.

In neurons, it is commonly assumed that mitochondrial replication only occurs in the cell body, after which the mitochondria must travel to the neuron's periphery. However, while mitochondrial DNA replication has been observed to occur away from the cell body, the specific mechanisms involved remain elusive. Using EdU-labelling in mouse primary neurons, we developed a tool to determine the mitochondrial replication rate. Taking of advantage of microfluidic devices, we confirmed that mitochondrial replication also occurs locally in the periphery of neurons. To achieve this, mitochondria require de novo nuclear-encoded, but not mitochondrial-encoded protein translation. Following a proteomic screen comparing synaptic with non-synaptic mitochondria, we identified two elongation factors - eEF1A1 and TUFM - that were upregulated in synaptic mitochondria. We found that mitochondrial replication is impaired upon the downregulation of eEF1A1, and this is particularly relevant in the periphery of neurons.

Notch receptor-ligand binding facilitates extracellular vesicle-mediated neuron-to-neuron communication.

Extracellular vesicles (EVs) facilitate intercellular communication by transferring cargo between cells in a variety of tissues. However, how EVs achieve cell-type-specific intercellular communication is still largely unknown. We found that Notch1 and Notch2 proteins are expressed on the surface of neuronal EVs that have been generated in response to neuronal excitatory synaptic activity. Notch ligands bind these EVs on the neuronal plasma membrane, trigger their internalization, activate the Notch signaling pathway, and drive the expression of Notch target genes. The generation of these neuronal EVs requires the endosomal sorting complex required for transport-associated protein Alix. Adult Alix conditional knockout mice have reduced hippocampal Notch signaling activation and glutamatergic synaptic protein expression. Thus, EVs facilitate neuron-to-neuron communication via the Notch receptor-ligand system in the brain.

A Pathogenic Missense Mutation in Kainate Receptors Elevates Dendritic Excitability and Synaptic Integration through Dysregulation of SK Channels.

Numerous rare variants that cause neurodevelopmental disorders (NDDs) occur within genes encoding synaptic proteins, including ionotropic glutamate receptors. However, in many cases, it remains unclear how damaging missense variants affect brain function. We determined the physiological consequences of an NDD causing missense mutation in the GRIK2 kainate receptor (KAR) gene, that results in a single amino acid change p.Ala657Thr in the GluK2 receptor subunit. We engineered this mutation in the mouse Grik2 gene, yielding a GluK2(A657T) mouse, and studied mice of both sexes to determine how hippocampal neuronal function is disrupted. Synaptic KAR currents in hippocampal CA3 pyramidal neurons from heterozygous A657T mice exhibited slow decay kinetics, consistent with incorporation of the mutant subunit into functional receptors. Unexpectedly, CA3 neurons demonstrated elevated action potential spiking because of downregulation of the small-conductance Ca2+ activated K+ channel (SK), which mediates the post-spike afterhyperpolarization. The reduction in SK activity resulted in increased CA3 dendritic excitability, increased EPSP-spike coupling, and lowered the threshold for the induction of LTP of the associational-commissural synapses in CA3 neurons. Pharmacological inhibition of SK channels in WT mice increased dendritic excitability and EPSP-spike coupling, mimicking the phenotype in A657T mice and suggesting a causative role for attenuated SK activity in aberrant excitability observed in the mutant mice. These findings demonstrate that a disease-associated missense mutation in GRIK2 leads to altered signaling through neuronal KARs, pleiotropic effects on neuronal and dendritic excitability, and implicate these processes in neuropathology in patients with genetic NDDs.SIGNIFICANCE STATEMENT Damaging mutations in genes encoding synaptic proteins have been identified in various neurodevelopmental disorders, but the functional consequences at the cellular and circuit level remain elusive. By generating a novel knock-in mutant mouse, this study examined the role of a pathogenic mutation in the GluK2 kainate receptor (KAR) subunit, a subclass of ionotropic glutamate receptors. Analyses of hippocampal CA3 pyramidal neurons determined elevated action potential firing because of an increase in dendritic excitability. Increased dendritic excitability was attributable to reduced activity of a Ca2+ activated K+ channel. These results indicate that a pathogenic KAR mutation results in dysregulation of dendritic K+ channels, which leads to an increase in synaptic integration and backpropagation of action potentials into distal dendrites.

[Effects of Fertilizer Application Strategy Adjustments on Nitrogen and Phosphorus Loss from Typical Crop Systems in Taihu Lake Region].

The intensity of crop farming fertilizer input is generally high in the Taihu Lake Region, with chemical fertilizer as the main form. Due to inappropriate fertilizer application, nitrogen and phosphorus loss have occurred, causing serious agricultural non-point source pollution. The Ministry of Agriculture and Rural Affairs of China has launched the "zero-growth action for chemical fertilizer use" and "replacement action with organic fertilizer" ("two actions" for short) campaigns since 2015. Local agricultural sectors adjusted fertilizer application strategies of crop farming to respond to the call of two actions. However, the current research is still focusing on reducing the total amount of fertilizer application and increasing the area of organic fertilizer application, which is mainly based on grain crops. The study of agricultural environment problems is still lacking, especially in vegetable, orchard, and tea systems. Therefore, a study was carried out in the typical agricultural area of Suzhou City Wuzhong District from 2019 to 2021. Based on the data of the amount of nitrogen and phosphorus removal by harvest crops and soil nitrogen and phosphorus residual in paddy, vegetable, orchard, and tea systems, the loss was estimated. The responses of nitrogen and phosphorus loss from typical crop systems to fertilizer application strategy adjustments were studied through analysis of different factors. The results showed that fertilizer application rate was the key to control nitrogen and phosphorus loss. Additionally, the suitable replacement ratio of organic fertilizer could further reduce the loss risk. It should be noted that the urgent demand for nutrients in crop growth should be considered to determine the timing of organic fertilizer application, and agricultural machinery should be used to assist organic fertilizer application to reduce labor output if possible. Fertilizer efficiency was the core of environmental friendliness and economic benefits of crop farming. Hence, improving fertilizer efficiency should be the guidance of fertilizer application strategy adjustment. Our suggestions on the adjustment of fertilizer application strategy in different crop systems in the study area are as follows:attention should be paid to the nitrogen, phosphorus, and potassium input ratio in paddy systems to further reduce nitrogen and phosphorus loss. Planting structure adjustment should be emphasized in vegetable systems to promote fertilizer efficiency. The strategy to satisfy both tea and orchard growth from a composite system perspective would help to build crop systems that meet the needs of green agricultural development.

Single-center phase 2 study of PD-1 inhibitor combined with DNA hypomethylation agent + CAG regimen in patients with relapsed/refractory acute myeloid leukemia.

Anti-PD-1 monotherapy had limited clinical efficacy in relapsed/refractory (r/r) AML patients with higher PD-1 and PD-L1 expression. Hence, we investigated the efficacy and safety of PD-1 inhibitor with DNA hypomethylating agent (HMA) + CAG regimen in patients who had failed prior AML therapy. In this phase 2, single-arm study, r/r AML patients received azacitidine or decitabine plus CAG regimen with tislelizumab. Primary endpoints were efficacy (objective response rate [ORR]) and safety. Secondary endpoints included overall survival (OS), event-free survival (EFS) and duration of response (DOR). Statistical analyses were performed using Stata 14.0 and SPSS 20.0 software where P < 0.05 denoted significance. Twenty-seven patients were enrolled patients and completed 1 cycle, and 14 (51.9%) and 4 (14.8%) patients completed 2 and 3 cycles, respectively. ORR was 63% (14: complete remission [CR]/CR with incomplete hematologic recovery [CRi], 3: partial remission (PR), 10: no response [NR]). Median OS (mOS) and EFS were 9.7 and 9.2 months, respectively. With a median follow-up of 8.2 months (1.1-26.9), the mOS was not reached in responders (CR/CRi/PR) while it was 2.4 months (0.0-5.4) in nonresponders (P = 0.002). Grade 2-3 immune-related adverse events (irAEs) were observed in 4 (14.8%) patients and 3 nonresponders died of lung infection after treatment. Tislelizumab + HMA + CAG regimen showed improved outcomes in r/r AML patients with lower pretherapy leukemia burden. irAEs were mild and low-grade and higher pretherapy bone marrow CD4+ CD127+ PD-1+ T cells might serve as a predictor of treatment response.ClinicalTrials.gov identifier NCT04541277.

Rescue of neuropsychiatric phenotypes in a mouse model of 16p11.2 duplication syndrome by genetic correction of an epilepsy network hub.

Neuropsychiatric disorders (NPDs) are frequently co-morbid with epilepsy, but the biological basis of shared risk remains poorly understood. The 16p11.2 duplication is a copy number variant that confers risk for diverse NPDs including autism spectrum disorder, schizophrenia, intellectual disability and epilepsy. We used a mouse model of the 16p11.2 duplication (16p11.2dup/+) to uncover molecular and circuit properties associated with this broad phenotypic spectrum, and examined genes within the locus capable of phenotype reversal. Quantitative proteomics revealed alterations to synaptic networks and products of NPD risk genes. We identified an epilepsy-associated subnetwork that was dysregulated in 16p11.2dup/+ mice and altered in brain tissue from individuals with NPDs. Cortical circuits from 16p11.2dup/+ mice exhibited hypersynchronous activity and enhanced network glutamate release, which increased susceptibility to seizures. Using gene co-expression and interactome analysis, we show that PRRT2 is a major hub in the epilepsy subnetwork. Remarkably, correcting Prrt2 copy number rescued aberrant circuit properties, seizure susceptibility and social deficits in 16p11.2dup/+ mice. We show that proteomics and network biology can identify important disease hubs in multigenic disorders, and reveal mechanisms relevant to the complex symptomatology of 16p11.2 duplication carriers.

Response of primary tumor and lymph node in non-small cell lung cancer after neoadjuvant immunotherapy: a pooled analysis.

The good pathological response of primary tumors (PTs) to neoadjuvant immunotherapy has been acknowledged in non-small cell lung cancer (NSCLC), however, it remains unclear whether neoadjuvant immunotherapy shows consistent effects in metastatic lymph nodes (LNs). We compared the pathological response of PT and nodal downstaging using a pooled analysis to assess the effect of neoadjuvant immunotherapy on LNs. Original articles reporting the tumor major pathological response (ypT(MPR)), pathological complete response (ypT0) and nodal downstaging following neoadjuvant immunotherapy in NSCLC were retrieved. The OR and 95% CI were calculated by Review Manager V.5.3. Subgroup analysis was performed according to the neoadjuvant therapy regimen used. A total of 209 patients from 6 studies were included in this analysis. The frequency of nodal downstaging was comparable to that of ypT(MPR) (OR 1.31; 95% CI 0.84 to 2.05; p=0.24). Interestingly, ypN0 was observed more frequently than ypT0 (OR 3.26; 95% CI 2.06 to 5.16; p<0.0001). However, this difference was not observed in the subgroup of cN2 patients who underwent immune checkpoint inhibitor monotherapy (OR 1.58; 95% CI 0.56 to 4.48; p=0.39). Neoadjuvant immunotherapy results in satisfactory response in metastatic LN. Patients had a high probability of node clearance when ypT0 was confirmed, especially in patients treated with immunochemotherapy.

Integrative Analysis of Bioinformatics and Machine Learning Algorithms Identifies a Novel Diagnostic Model Based on Costimulatory Molecule for Predicting Immune Microenvironment Status in Lung Adenocarcinoma.

Costimulatory molecules are an indispensable signal for activating immune cells. However, the features of many costimulatory molecule genes (CMGs) in lung adenocarcinoma (LUAD) are poorly understood. This study systematically explored expression patterns of CMGs in the tumor immune microenvironment (TIME) status of patients with LUAD. Their expression profiles were downloaded from The Cancer Genome Atlas and the Gene Expression Omnibus databases. Two robust TIME subtypes ("hot" and "cold") were classified by K-means clustering and estimation of stromal and immune cells in malignant tumor tissues using expression data. The "hot" subtype presented higher infiltration in activated immune cells and enrichments in the immune cell receptor signaling pathway and adaptive immune response. Three CMGs (CD80, LTB, and TNFSF8) were screened as final diagnostic markers by means of Least Absolute Shrinkage Selection Operator and Support Vector Machine-Recursive Feature Elimination algorithms. Accordingly, the diagnostic nomogram for predicting individualized TIME status showed satisfactory diagnostic accuracy in The Cancer Genome Atlas training cohort as well as GSE31210 and GSE180347 validation cohorts. Immunohistochemistry staining of 16 specimens revealed an apparently positive correlation between the expression of CMG biomarkers and pathologic response to immunotherapy. Thus, this diagnostic nomogram provided individualized predictions in TIME status of LUAD patients with good predictive accuracy, which could serve as a potential tool for identifying ideal candidates for immunotherapy.

FGFR3 Nuclear Translocation Contributes to Proliferative Potential and Poor Prognosis in Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: Fibroblast growth factor receptor 3 (FGFR3) was revealed to have divergent, even opposite roles in different neoplasms. In pancreatic ductal adenocarcinoma (PDAC), its impact on biological behavior and prognosis was not well elucidated. METHODS: Fibroblast growth factor receptor 3 was downregulated by RNA interference to explore its impact on cell proliferative proclivity in PDAC cells. Furthermore, tissue microarray-based immunohistochemistry for FGFR3 was performed in 326 patients with PDAC who underwent radical resection, and its clinicopathologic and prognostic implications were then evaluated. RESULTS: First, successful FGFR3 knockdown remarkably decreased its expression, cell proliferation, and S-phase ratio in the cell cycle in 2 PDAC cell lines, BxPC-3 and AsPC-1. Meanwhile, alterations in p-Akt, cyclin D1, cyclin B1, and p21 were also observed. Subsequently, high nuclear FGFR3 expression, but not cytoplasmic, was significantly common in tumor tissues and positively associated with N stage and dismal overall survival in the entire cohort. In addition, nuclear FGFR3 expression was also prognostic in 10 of 14 subsets. Univariate and multivariate Cox regression analyses identified nuclear expression of FGFR3 as an independent prognosticator in the entire cohort. CONCLUSIONS: Our data showed that FGFR3 nuclear translocation contributes to cell proliferative potential and predicts poor long-term prognosis in PDAC after surgical resection.

An Aging-Related Gene Signature-Based Model for Risk Stratification and Prognosis Prediction in Lung Squamous Carcinoma.

Aging is an inevitable process characterized by a decline in many physiological activities, and has been known as a significant risk factor for many kinds of malignancies, but there are few studies about aging-related genes (ARGs) in lung squamous carcinoma (LUSC). We designed this study to explore the prognostic value of ARGs and establish an ARG-based prognosis signature for LUSC patients. RNA-sequencing and corresponding clinicopathological data of patients with LUSC were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The ARG risk signature was developed on the basis of results of LASSO and multivariate Cox analysis in the TCGA training dataset (n = 492). Furthermore, the GSE73403 dataset (n = 69) validated the prognostic performance of this ARG signature. Immunohistochemistry (IHC) staining was used to verify the expression of the ARGs in the signature. A five ARG-based signature, including A2M, CHEK2, ELN, FOS, and PLAU, was constructed in the TCGA dataset, and stratified patients into low- and high-risk groups with significantly different overall survival (OS) rates. The ARG risk score remained to be considered as an independent indicator of OS in the multivariate Cox regression model for LUSC patients. Then, a prognostic nomogram incorporating the ARG risk score with T-, N-, and M-classification was established. It achieved a good discriminative ability with a C-index of 0.628 (95% confidence interval [CI]: 0.586-0.671) in the TCGA cohort and 0.648 (95% CI: 0.535-0.762) in the GSE73403 dataset. Calibration curves displayed excellent agreement between the actual observations and the nomogram-predicted survival. The IHC staining discovered that these five ARGs were overexpression in LUSC tissues. Besides, the immune infiltration analysis in the TCGA cohort represented a distinctly differentiated infiltration of anti-tumor immune cells between the low- and high-risk groups. We identified a novel ARG-related prognostic signature, which may serve as a potential biomarker for individualized survival predictions and personalized therapeutic recommendation of anti-tumor immunity for patients with LUSC.

[Analysis of Factors Influencing Autologous Peripheral Blood Stem Cells Mobilization in Patients with Lymphoma and Multiple Myeloma].

OBJECTIVE: To analyze the factors influencing the mobilization of autologous peripheral blood stem cells (auto-PBSCs) in patients with lymphoma and multiple myeloma, and provide reference for optimizing the autologous stem cell mobilization regimen. METHODS: Clinical data of 33 multiple myeloma and lymphoma patients received auto-PBSCs mobilization in our center from January 2015 to December 2018 were collected, the correlation of mobilization failure rate with gender, age, courses of chemotherapy before mobilization, does of recombinant human granulocyte colony stimulating factor (rhG-CSF), type of disease, and chemotherapy regimen were retrospectively analyzed. RESULTS: Type of disease and course of pre-mobilization chemotherapy could affect the mobilization failure rate (P<0.05). The mobilization failure rate of lymphoma patients was 42.1%, which was significantly higher than 7.1% of multiple myeloma patients (P=0.026). The mobilization failure rate was higher in the group with chemotherapy courses≥5 before mobilization (P=0.016). Age, gender, dose of rhG-CSF, and chemotherapy regimen had no significant correlation with mobilization failure rate (P>0.05). CONCLUSION: Multi-course chemotherapy before collection and lymphoma patients are poor factors negatively impacting on auto-PBSCs mobilization.

Phase 2 trial of neoadjuvant toripalimab with chemotherapy for resectable stage III non-small-cell lung cancer.

Multimodality treatment provides modest survival benefits for patients with locally advanced (stage III) non-small-cell lung cancer (NSCLC). Nevertheless, preoperative immunotherapy has continuously been shown to be promising in treating resectable NSCLC.This phase 2 trial enrolled patients with AJCC-defined stage IIIA or T3-4N2 IIIB NSCLC deemed surgically resectable. Patients received three cycles of neoadjuvant treatment with intravenous PD-1 inhibitor toripalimab (240 mg), carboplatin (area under the curve 5), and pemetrexed (500 mg/m2 for adenocarcinoma) or nab-paclitaxel (260 mg/m2 for other subtypes) on day 1 of each 21-day cycle. Surgical resection was performed 4-5 weeks afterward. The primary endpoint was major pathological response (MPR), defined as less than 10% residual tumor remaining at the time of surgery.Thirty-three patients were enrolled, of whom 13 (39.4%) had T3-4N2 stage IIIB disease. Thirty (90.9%) patients underwent resection and all except one (96.7%) achieved R0 resection. Twenty patients (60.6%) in the intention-to-treat population achieved an MPR, including 15 patients (45.5%) who achieved a pathological complete response (pCR). The MPR and pCR rates in the per-protocol population were 66.7% and 50.0%, respectively. The surgical complications included three cases of arrhythmias, one case of a prolonged air leak, and one case of chylothorax. The most common grade 3 treatment-related adverse event (TRAE) was anemia (2, [6.1%]). Severe TRAEs included one (3.0%) case of grade 3 peripheral neuropathy that resulted in surgical cancellation.Toripalimab plus platinum-based doublet chemotherapy yields a high MPR rate, manageable toxicity, and feasible resection in stage III NSCLC.Trial ClinicalTrials.gov (NCT04304248).

Expression and Prognostic Value of Small Mothers Against Decapentaplegic 7, Matrix Metalloproteinase 2, and Matrix Metalloproteinase 9 in Resectable Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: Thus far, expression, clinicopathologic, and prognostic implication of small mothers against decapentaplegic 7 (Smad7), matrix metalloproteinase 2 (MMP2), and matrix metalloproteinase 9 (MMP9) in pancreatic ductal adenocarcinoma (PDAC) were rarely investigated or controversial. METHODS: Expression of Smad7, MMP2, and MMP9 was detected using immunohistochemistry in tissue microarrays based on 322 patients with curatively resected PDAC. Their expression pattern, clinicopathologic, and prognostic relevance were further evaluated. RESULTS: Smad7 expression was found to be lower in tumor than in adjacent nontumor tissues, whereas tumoral MMP2 and MMP9 staining scores were much higher than in adjacent nontumor ones. Furthermore, Smad7 was negatively associated with serum carbohydrate antigen 19-9 level. Univariate survival analyses showed that patients with high Smad7 tumors had significantly better disease-specific survival (P = 0.0007), whereas MMP2 and MMP9 predicted poor disease-specific survival (P = 0.0211 and 0.0404). In multivariate Cox regression test, Smad7 was an independent prognostic indicator (P = 0.021). In addition, these 3 proteins were also prognostic in many subgroups. CONCLUSIONS: Smad7 and MMP2/9 significantly predict good or poor prognosis in resectable PDAC, respectively. Therefore, the genes might serve as a tool or targets for molecular therapy in PDAC.

Pulmonary Metastasectomy in Patients with Lung Metastases from Nasopharyngeal Carcinoma.

BACKGROUND: Approximately 10% of patients with nasopharyngeal carcinoma (NPC) develop lung-only metastases. Data regarding the potential role of lung metastasectomy are limited. OBJECTIVE: The aim of this case-control study was to determine whether lung metastasectomy prolongs survival in patients with NPC with lung-only metastases. METHODS: The resectability of 215 consecutive patients diagnosed with lung-only metastases from 2001 to 2018 was reviewed by doctors blinded to the patient groups. The propensity score matching method was used to balance the potential probability of being assigned to treatment groups based on pretherapeutic information. Postmetastatic survival (PMS) and cumulative incidence of local failure were compared between the surgical and nonsurgical arms. RESULTS: Overall, 120 potentially resectable cases were enrolled, and 45 and 22 patients who underwent and did not undergo metastasectomy, respectively, were included in the propensity-matched cohort. Patients who underwent pulmonary resection had better PMS and a lower cumulative incidence of local failure than those who did not undergo surgery. The 5-year PMS rates were 75.53% and 47.81% in the surgical and nonsurgical arms, respectively (difference 27.72%; 95% confidence interval 3.95-51.49%). Younger patients (≤ 45 years), and those with a lower primary N stage (N0-1), longer disease-free interval (> 2 years), smaller total diameter of the metastatic lesions (≤ 3 cm), unilateral distribution of metastases, no mediastinal/hilar lymph node involvement, and adjuvant chemotherapy showed a significantly longer PMS after metastasectomy by multivariable analysis. CONCLUSIONS: Lung metastasectomy may improve PMS and decrease the chance of local treatment failure in NPC patients with potentially resectable lung-only metastases.

A Novel Inflammatory-Related Gene Signature Based Model for Risk Stratification and Prognosis Prediction in Lung Adenocarcinoma.

Inflammation is an important hallmark of cancer and plays a role in both neogenesis and tumor development. Despite this, inflammatory-related genes (IRGs) remain to be poorly studied in lung adenocarcinoma (LUAD). We aim to explore the prognostic value of IRGs for LUAD and construct an IRG-based prognosis signature. The transcriptomic profiles and clinicopathological information of patients with LUAD were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Least absolute shrinkage and selection operator (LASSO) analysis and multivariate Cox regression were applied in the TCGA set to generate an IRG risk signature. LUAD cases with from the GSE31210 and GSE30219 datasets were used to validate the predictive ability of the signature. Analysis of the TCGA cohort revealed a five-IRG risk signature consisting of EREG, GPC3, IL7R, LAMP3, and NMUR1. This signature was used to divide patients into two risk groups with different survival rates. Multivariate Cox regression analysis verified that the risk score from the five-IRG signature negatively correlated with patient outcome. A nomogram was developed using the IRG risk signature and stage, with C-index values of 0.687 (95% CI: 0.644-0.730) in the TCGA training cohort, 0.678 (95% CI: 0.586-0.771) in GSE30219 cohort, and 0.656 (95% CI: 0.571-0.740) in GSE30219 cohort. Calibration curves were consistent between the actual and the predicted overall survival. The immune infiltration analysis in the TCGA training cohort and two GEO validation cohorts showed a distinctly differentiated immune cell infiltration landscape between the two risk groups. The IRG risk signature for LUAD can be used to predict patient prognosis and guide individual treatment. This risk signature is also a potential biomarker of immunotherapy.

The Dichotomous Role of Extracellular Vesicles in the Central Nervous System.

Extracellular vesicles (EVs) are important mediators of intercellular communication. Interest in the role of central nervous system (CNS)-derived EVs has been increasing; however, some skepticism of their importance has persisted because many aspects of their biology remain elusive. This ambiguity is largely due to technical barriers that hamper our ability to achieve a comprehensive understanding of their molecular components and mechanisms responsible for their transmission and uptake. However, accumulating evidence supports the notion that EVs play important roles in basic physiological processes within the CNS during neurodevelopment and synaptic plasticity. Interestingly, EVs also act to spread toxic polypeptides in neurodegenerative diseases. Developing a more profound understanding of the role that EVs play in the CNS could lead to the identification of biomarkers and potential vehicles for drug delivery. Here we highlight our current understanding of CNS EVs and summarize our current understanding of their complex role in the CNS.

Laparoscopic assisted pancreaticoduodenectomy: an important link in the process of transition from open to total laparoscopic pancreaticoduodenectomy.

BACKGROUND: The safety of total laparoscopic pancreaticoduodenectomy still remains controversial. Laparoscopic assisted pancreaticoduodenectomy (LAPD) may be an alternative selection. The purpose of the present study is to compare a consecutive cohort of LAPD and open pancreaticoduodenectomy (OPD) from a single surgeon. METHODS: A comparison was conducted between LAPD and OPD from January 2013 to December 2018. Perioperative outcomes and short-term oncological results were compared. Univariate and multivariable analyses were performed to determine associations among variables. RESULTS: 133 patients were enrolled, 36 patients (27.1%) underwent LAPD and 97 (72.9%) underwent OPD. No 30-day and 90-day mortality occurred. LAPD was associated with decreased intraoperative estimated blood loss (300 versus 500 ml; P = 0.002), longer operative time (372 versus 305 min; P < 0.001) compared with OPD. LAPD had a conversion rate of 16.7%, and wasn't associated with an increased grade B/C pancreatic fistula rate, major surgical complications, intraoperative blood transfusion, reoperation rate or length of hospital stay after surgery. In the subset of 58 pancreatic ductal adenocarcinomas, R0 resection rate, median total harvested lymph node or lymph nodes ≥12 did not differ between the two groups. CONCLUSION: LAPD could be performed with non-inferior short-term perioperative and oncologic outcomes achieved by OPD in selected patients.