Trajectory of mid-arm subcutaneous fat, muscle mass predicts mortality in hemodialysis patients independent of body mass index.

Although decreasing body mass index (BMI) is associated with higher mortality risk in patients undergoing hemodialysis (HD), BMI neither differentiates muscle and fat mass nor provides information about the variations of fat distribution. It remains unclear whether changes over time in fat and muscle mass are associated with mortality. We examined the prognostic significance of trajectory in the triceps skinfold (TSF) thickness and mid-upper arm circumference (MUAC). In this multicenter prospective cohort study, 972 outpatients (mean age, 54.5 years; 55.3% men) undergoing maintenance HD at 22 treatment centers were included. We calculated the relative change in TSF and MUAC over a 1-year period. The outcome was all-cause mortality. Kaplan-Meier, Cox proportional hazard analyses, restricted cubic splines, and Fine and Gray sub-distribution hazards models were performed to examine whether TSF and MUAC trajectories were associated with all-cause mortality. During follow-up (median, 48.0 months), 206 (21.2%) HD patients died. Compared with the lowest trajectory group, the highest trajectories of TSF and MUAC were independently associated with lower risk for all-cause mortality (HR = 0.405, 95% CI 0.257-0.640; HR = 0.537; 95% CI 0.345-0.837; respectively), even adjusting for BMI trajectory. Increasing TSF and MUAC over time, measured as continuous variables and expressed per 1-standard deviation decrease, were associated with a 55.7% (HR = 0.443, 95% CI 0.302-0.649), and 97.8% (HR = 0.022, 95% CI 0.005-0.102) decreased risk of all-cause mortality. Reduction of TSF and MUAC are independently associated with lower all-cause mortality, independent of change in BMI. Our study revealed that the trajectory of TSF thickness and MUAC provides additional prognostic information to the BMI trajectory in HD patients.

Habitat amount modulates biodiversity responses to fragmentation.

Anthropogenic habitat destruction leads to habitat loss and fragmentation, both of which interact to determine how biodiversity changes at the landscape level. While the detrimental effects of habitat loss are clear, there is a long-standing debate about the role of habitat fragmentation per se. We identify the influence of the total habitat amount lost as a modulator of the relationship between habitat fragmentation and biodiversity. Using a simple metacommunity model characterized by colonization-competition (C-C) trade-offs, we show that the magnitude of habitat loss can induce a unimodal response of biodiversity to habitat fragmentation. When habitat loss is low, habitat fragmentation promotes coexistence by suppressing competitively dominant species, while habitat fragmentation at high levels of habitat loss can shape many smaller isolated patches that drive extinctions of superior competitors. While the C-C trade-off is not the only mechanism for biodiversity maintenance, the modulation of habitat fragmentation effects by habitat loss is probably common. Reanalysis of a globally distributed dataset of fragmented animal and plant metacommunities shows an overall pattern that supports this hypothesis, suggesting a resolution to the debate regarding the relative importance of positive versus negative fragmentation effects.

Agrin-Lrp4 pathway in hippocampal astrocytes restrains development of temporal lobe epilepsy through adenosine signaling.

BACKGROUND: Human patients often experience an episode of serious seizure activity, such as status epilepticus (SE), prior to the onset of temporal lobe epilepsy (TLE), suggesting that SE can trigger the development of epilepsy. Yet, the underlying mechanisms are not fully understood. The low-density lipoprotein receptor related protein (Lrp4), a receptor for proteoglycan-agrin, has been indicated to modulate seizure susceptibility. However, whether agrin-Lrp4 pathway also plays a role in the development of SE-induced TLE is not clear. METHODS: Lrp4f/f mice were crossed with hGFAP-Cre and Nex-Cre mice to generate brain conditional Lrp4 knockout mice (hGFAP-Lrp4-/-) and pyramidal neuron specific knockout mice (Nex-Lrp4-/-). Lrp4 was specifically knocked down in hippocampal astrocytes by injecting AAV virus carrying hGFAP-Cre into the hippocampus. The effects of agrin-Lrp4 pathway on the development of SE-induced TLE were evaluated on the chronic seizure model generated by injecting kainic acid (KA) into the amygdala. The spontaneous recurrent seizures (SRS) in mice were video monitored. RESULTS: We found that Lrp4 deletion from the brain but not from the pyramidal neurons elevated the seizure threshold and reduced SRS numbers, with no change in the stage or duration of SRS. More importantly, knockdown of Lrp4 in the hippocampal astrocytes after SE induction decreased SRS numbers. In accord, direct injection of agrin into the lateral ventricle of control mice but not mice with Lrp4 deletion in hippocampal astrocytes also increased the SRS numbers. These results indicate a promoting effect of agrin-Lrp4 signaling in hippocampal astrocytes on the development of SE-induced TLE. Last, we observed that knockdown of Lrp4 in hippocampal astrocytes increased the extracellular adenosine levels in the hippocampus 2 weeks after SE induction. Blockade of adenosine A1 receptor in the hippocampus by DPCPX after SE induction diminished the effects of Lrp4 on the development of SE-induced TLE. CONCLUSION: These results demonstrate a promoting role of agrin-Lrp4 signaling in hippocampal astrocytes in the development of SE-induced development of epilepsy through elevating adenosine levels. Targeting agrin-Lrp4 signaling may serve as a potential therapeutic intervention strategy to treat TLE.

Pan-Cancer Analysis Shows that KIFC2 is a Potential Prognostic and Immunotherapeutic Biomarker for Multiple Cancer Types Including Bladder Cancer.

KIFC2 plays an important role in prostate cancer progression and chemotherapy resistance, but the mechanism of its involvement in other malignancies remains unclear. Therefore, this study aimed to analyze and validate the mechanism of effect of KIFC2 in multiple tumors. Bioinformatic analysis was performed in conjunction with multiple databases (The Cancer Genome Atlas, Genotype-Tissue Expression Project, Human Protein Atlas, etc.) to fully explore the potential role of KIFC2 within individual tumors and to analyze the correlation with major research components such as prognosis, mutations, and the tumor microenvironment. The expression of KIFC2 demonstrates a significant correlation with the prognosis, clinical phenotype, tumor mutational burden, microsatellite instability, and tumor microenvironment across various malignancies and is associated with the modulation of diverse functional and signaling pathways. The differences in the expression of KIFC2 in the bladder cancer tissues (14 pairs) were statistically significant. The pan-cancer analysis in this study revealed the multifunctionality of KIFC2 in a variety of tumors, indicating a possible prognostic predictor and potential therapeutic target for tumors.

Complex nonmonotonic responses of biodiversity to habitat destruction.

It has typically been assumed that habitat destruction, characterized by habitat loss and fragmentation, has consistently negative effects on biodiversity. While numerous empirical studies have shown the detrimental effects of habitat loss, debate continues as to whether habitat fragmentation has universally negative effects. To explore the effects of habitat fragmentation, we developed a simple model for site-occupancy dynamics in fragmented landscapes. With the model, we demonstrate that a competition-colonization trade-off can result in nonlinear oscillatory responses in biodiversity to both habitat loss and fragmentation. However, the overall pattern of habitat loss reducing species richness is still established, in line with empirical observations. Interestingly, the existence of localized oscillations in biodiversity can explain the mixed responses of species richness to habitat fragmentation per se observed in nature, thereby reconciling the debate on the fragmentation-diversity relationship. Therefore, this study offers a parsimonious mechanistic explanation for empirically observed biodiversity patterns in response to habitat destruction.

Associations of long-term exposure to air pollution with prevalence of pulmonary nodules: A cross-sectional study in Shijiazhuang, China.

A complete understanding of the associations of ambient air pollution with prevalence of pulmonary nodule is lacking. We aimed to investigate the associations of ambient air pollutants with prevalence of pulmonary nodule. A total of 9991 health examination participants was enrolled and 3166 was elected in the final in Shijiazhuang between April 1st, 2018, and December 31st, 2018. 107 participants were diagnosed in pulmonary nodule while 3059 participants were diagnosed in non-pulmonary (named control). The individual exposure of participants was evaluation by Empirical Bayesian Kriging model according to their residential or work addresses. The pulmonary nodules were found and diagnosed by health examination through chest x-ray detection. Our results suggested that there were positive associations between prevalence of pulmonary nodules and PM2.5 (OR = 1.06, 95% CI: 1.02, 1.11) as well as O3 (OR = 1.49, 95% CI: 1.35, 1.66) levels. The platelet count (PLT) acted as the mediator of pulmonary nodules related with the PM2.5 exposure, while the neutrophil-to-lymphocyte ratio (NLR) as well as platelet-to-lymphocyte ratio (PLR) were the mediators of pulmonary nodules related with the O3 exposure. This study suggests that long-term exposure to PM2.5 and O3 may significantly associated with prevalence of pulmonary nodules, and the above associations are mediated by PLT, NLR and PLR.

LINC00958 may be a new prognostic biomarker in various cancers: A meta-analysis and bioinformatics analysis.

Background: There have been many studies on long non-coding RNAs (lncRNAs) as tumor markers. LINC00958 is a lncRNA that has been studied in a variety of tumor types. This meta-analysis aims to explore the relationship between LINC00958 and clinical prognosis and pathological characteristics in various cancers. Methods: We searched for related studies from PubMed, Web of Science, The Cochrane Library and Embase (up to October 2021). The association of LINC00958 expression with clinicopathological characteristics and prognosis was evaluated using the pooled odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs). Results: 16 studies (1,121 patients) were included in this meta-analysis, we found that overexpression of LINC00958 was associated with poor overall survival (OS) (HR = 1.84; 95% CI: 1.36-2.49; p < 0.001). We also found that LINC00958 overexpression was correlated with positive lymph node metastasis (LNM) (OR = 1.91; 95% CI: 1.39-2.63; p < 0.001), advanced degree of infiltration (OR = 1.64; 95% CI: 1.11-2.41; p = 0.013), advanced tumor-node-metastasis (TNM) stage (OR = 2.80; 95% CI: 1.48-5.33; p = 0.002). Other clinicopathological characteristics have no obvious correlation, such as age, sex, tumor size, distant metastasis, and differentiation grade (p > 0.05). Conclusion: In summary, the overexpression of LINC00958 is significantly correlated with poor OS, positive LNM, advanced degree of infiltration, and advanced TNM stage. LINC00958 might serve as a potential prognostic biomarker and therapeutic target for a variety of cancers. However, rigorous studies with large sample sizes are still needed for further research and demonstration.

HOXA-AS2 may be a potential prognostic biomarker in human cancers: A meta-analysis and bioinformatics analysis.

Background: Dysregulation of long non-coding (lncRNA) has been reported in various solid tumors. HOXA cluster antisense RNA 2 (HOXA-AS2) is a newly identified lncRNA with abnormal expression in several human malignancies. However, its prognostic value remains controversial. This meta-analysis synthesized available data to clarify the association between HOXA-AS2 expression levels and clinical prognosis in multiple cancers. Methods: Four public databases (Embase, PubMed, Web of Science, The Cochrane Library) were used to identify eligible studies. Hazard ratios (HRs) and odds ratios (ORs) with their 95% confidence intervals (CIs) were combined to assess the correlation of HOXA-AS2 expression with survival outcomes and clinicopathological features of cancer patients. Publication bias was measured using Begg's funnel plot and Egger's regression test, and the stability of the combined results was measured using sensitivity analysis. Additionally, multiple public databases were screened and extracted to validate the results of this meta-analysis. Results: The study included 20 studies, containing 1331 patients. The meta-analysis showed that the overexpression of HOXA-AS2 was associated with poor overall survival (HR = 2.06, 95% CI 1.58-2.69, p < 0.001). In addition, the high expression of HOXA-AS2 could forecast advanced tumor stage (OR = 3.89, 95% CI 2.90-5.21, p < 0.001), earlier lymph node metastasis (OR = 3.48, 95% CI 2.29-5.29, p < 0.001), larger tumor size (OR = 2.36, 95% CI 1.52-3.66, p < 0.001) and earlier distant metastasis (OR = 3.54, 95% CI 2.00-6.28, p < 0.001). However, other clinicopathological features, including age (OR = 1.09, 95% CI 0.86-1.38, p = 0.467), gender (OR = 0.92, 95% CI 0.72-1.18, p = 0.496), depth of invasion (OR = 2.13, 95% CI 0.77-5.90, p = 0.146) and differentiation (OR = 1.02, 95% CI 0.65-1.59, p = 0.945) were not significantly different from HOXA-AS2 expression. Conclusion: Our study showed that the overexpression of HOXA-AS2 was related to poor overall survival and clinicopathological features. HOXA-AS2 may serve as a potential prognostic indicator and therapeutic target for tumor treatment.

Integrative pan-cancer analysis indicates the prognostic importance of long noncoding RNA SNHG17 in human cancers.

BACKGROUND: Cancer is one of the most widespread causes of death today. Early diagnosis can dramatically reduce cancer-related mortality. Studies have shown that the lncRNA Small Nucleolar RNA Host Gene 17 (SNHG17) is aberrantly expressed in various types of solid tumors. Nevertheless, its prognostic value remains to be elucidated. The main objective of this meta-analysis was to elucidate whether SNHG17 can be considered as a potential prognostic biomarker for a variety of cancers. METHODS: Correlational studies were screened from Cochrane, Embase, PubMed, and Web of Science. Hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were pooled, and the role of SNHG17 in cancer was analyzed. The Cancer Genome Atlas (TCGA) database was employed to verify the results. RESULTS: Seventeen original papers including 1451 patients were included in the meta-analysis. SNHG17 expression was upregulated in various cancers. Overexpression of SNHG17 was significantly correlated with worse overall survival (OS) (HR = 1.92, 95% CI 1.55-2.37, P < 0.001) and relapse-free survival (RFS) (HR = 1.87, 95% CI 1.06-3.30, P = 0.030). Furthermore, overexpression of SNHG17 was predictive of earlier lymph node metastasis (LNM) (OR = 2.94, 95% CI 2.29-3.78, P < 0.001), more advanced tumor-node-metastases (TNM) stage (OR = 3.56, 95% CI 2.22-5.68, P < 0.001), larger tumor size (OR = 2.18, 95% CI 1.65-2.88, P < 0.001), worse differentiation grade (OR = 1.69, 95% CI 1.26-2.25, P < 0.001), and earlier distant metastasis (DM) (OR = 1.63, 95% CI 1.03-2.56, P = 0.033) in human cancers. Moreover, further inquiry based on TCGA dataset validated that SNHG17 was high expression in various tumors and foresaw unfavorable clinical prognosis. CONCLUSIONS: Overexpression of SNHG17 correlates with poor prognosis and advanced clinicopathological features in cancer patients and may be a potential prognostic indicator and a therapeutic target for cancer treatment.

PEG-rhG-CSF for prophylaxis of neutropenia after chemotherapy in patients with non-small cell lung cancer: A multicenter, prospective, randomized study.

BACKGROUND: To evaluate the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in preventing neutropenia during multiple cycles of chemotherapy in patients with non-small cell lung cancer (NSCLC). METHOD: In a multicenter, prospective, randomized trial, patients with NSCLC were randomly assigned in a 2:1 ratio to treatment group (PEG-rhG-CSF as primary prophylactic therapy) or control group. Patients in the control group were administered rhG-CSF when white blood cell count was <2.0 × 109 /L or absolute neutrophil count <1.0 × 109 /L. The primary endpoint was the incidence of grade 3/4 neutropenia. Secondary endpoints included the incidence and duration of grade 3/4 neutropenia in each cycle, the incidence of febrile neutropenia (FN), delay rate of chemotherapy, prolonged time of chemotherapy, and safety. RESULTS: Between January 2019 and July 2021, 130 patients were enrolled (treatment group: n = 87, control group: n = 43). The incidence of grade 3/4 neutropenia in the treatment group was significantly lower than that in the control group (1.15% vs. 11.63%, p < 0.05). The mean duration of grade 3/4 neutropenia for the treatment and control group was 2.00 and 3.75 days, respectively. There were no statistical differences in the incidence of FN, delay rate of chemotherapy, prolonged time of chemotherapy, and antibiotic use between the two groups (all p > 0.05). Adverse events were reported in 47.13% of patients in the treatment group and 48.84% patients in the control group. CONCLUSIONS: Primary prophylactic treatment with PEG-rhG-CSF could reduce the incidence of neutropenia in patients with NSCLC during multiple cycles of chemotherapy, with acceptable safety and tolerability.

Genetic instability of lung induced by carbon black nanoparticles is related with Plk1 signals changes.

As a possible carcinogen, carbon black has threatened public health. However, the evidences are insufficient and the mechanism of carcinogenesis is still not specified. Thirty rats were randomly divided into 3 groups, namely 0, 5 and 30 mg/m3 Carbon Black nanoparticles (CBNPs) groups, respectively. Rats were treated with CBNPs by nose-only inhalation for 28 days, 6 h/day. The human bronchial epithelial (16HBE) cells were treated with 0, 50, 100 and 200 µg/mL CBNPs for 24 h. Polo-like kinase 1 (PLK1) overexpression cell line was established by pcDNA3.1-PLK1 stable transfection. Our results showed that CBNPs exposure could induce DNA damage and genetic changes as well as apoptosis in vivo and in vitro. The DNA repair ability increased after CBNPs exposure. Cell cycle process was retarded at the G2/M phases in 16HBE cells after CBNPs treatment. The PLK1, ChK2 GADD45α and XRCC1 expression levels changed in rat lung and 16HBE cells after CBNPs treatment. Compared with NC 16HBE cells, DNA damage and repair, numbers of apoptotic cells and micronucleus (MN) rates, as well as the ChK2, GADD45α, XRCC1 expression levels decreased, whereas cytokinesis block proliferation index (CBPI) and replicative index (RI) increase in PLK overexpression (PLK+/+) cells after CBNPs treatment. This study highlighted that PLK1 related with the genetic toxicity of CBNPs in vitro and in vivo. Our results provided evidences supporting reclassification of carbon black as a human possible carcinogen.

The QICK (Quantum Instrumentation Control Kit): Readout and control for qubits and detectors.

We introduce a Xilinx RF System-on-Chip (RFSoC)-based qubit controller (called the Quantum Instrumentation Control Kit, or QICK for short), which supports the direct synthesis of control pulses with carrier frequencies of up to 6 GHz. The QICK can control multiple qubits or other quantum devices. The QICK consists of a digital board hosting an RFSoC field-programmable gate array, custom firmware, and software and an optional companion custom-designed analog front-end board. We characterize the analog performance of the system as well as its digital latency, important for quantum error correction and feedback protocols. We benchmark the controller by performing standard characterizations of a transmon qubit. We achieve an average gate fidelity of Favg=99.93%. All of the schematics, firmware, and software are open-source.

The regulation of autophagy by the miR-199a-5p/p62 axis was a potential mechanism of small cell lung cancer cisplatin resistance.

BACKGROUND: Autophagy has been found to be involved in the multidrug resistance (MDR) of cancers, but whether it is associated with resistance of small cell lung cancer (SCLC) has not been studied. Here, we hypothesized that a potential autophagy-regulating miRNA, miR-199a-5p, regulated cisplatin-resistant SCLC. METHODS: We validated the MDR of H446/EP using CCK-8 and LDH. We tested the binding of miR-199a-5p to p62 using the Dual-Luciferase assay and validated the association of miR-199a-5p and p62 in SCLC samples. We overexpressed (OE) and knocked down (KD) miR-199a-5p in H446 and H446/EP and determined the expression of miR-199a-5p, autophagy-related proteins, and the formation of autophagolysosomes using QPCR, western blotting, and MDC staining respectively. These results were validated in an orthotopic H446 mouse model of SCLC. RESULTS: H446/EP was resistant to cisplatin, etoposide, paclitexal, epirubicin, irinotecan, and vinorelbine. Exposure of cisplatin at 5 µg/ml for 24 h increased LC3II/LC3I, ATG5, p62, and the formation of autophagolysosomes in H446 cells, but not in H446/EP cells. The expression of miR-199a-5p was up-regulated in H446/EP compared to H446. MiR-199a-5p directly targeted the p62 gene. The expression of miR-199a-5p and p62 were correlated in SCLC samples. In H446 and H69PR, the OE of miR-199a-5p increased LC3II/LC3I, p62, and the formation of autophagolysosomes, but not ATG5, while the KD of miR-199a-5p decreased p62, but did not affect LC3II/LC3I, ATG5, and the formation of autophagolysosomes. In H446/EP, the OE of miR-199a-5p decreased p62 only. These results were generally consistent to results in the animal tumor samples. CONCLUSIONS: The regulation of autophagy by the miR-199a-5p/p62 axis was a potential mechanism of small cell lung cancer cisplatin resistance.

Curcumin increases crizotinib sensitivity through the inactivation of autophagy via epigenetic modulation of the miR-142-5p/Ulk1 axis in non-small cell lung cancer.

Drug resistance is a critical factor responsible for the recurrence of non-small cell lung cancer (NSCLC). Previous studies suggest that curcumin acts as a chemosensitizer and radiosensitizer in human malignancies, but the underlying mechanism remains elusive. In the present study, we explored how curcumin regulates the expression of miR-142-5p and sensitizes NSCLC cells to crizotinib. We found that miR-142-5p is significantly downregulated in NSCLC tissue samples and cell lines. Curcumin could increase crizotinib cytotoxicity by epigenetically restoring the expression of miR-142-5p. Furthermore, curcumin treatment suppressed the expression of DNA methylation-related enzymes, including DNMT1, DNMT3A, and DNMT3B, in NSCLC cells. In addition, the upregulation of miR-142-5p expression increased crizotinib cytotoxicity and induced apoptosis in tumor cells in a similar manner to that of curcumin. Strikingly, miR-142-5p overexpression suppressed crizotinib-induced autophagy in A549 and H460 cells. Mechanistically, miR-142-5p inhibited autophagy in lung cancer cells by targeting Ulk1. Overexpression of Ulk1 abrogated the miR-142-5p-induced elevation of crizotinib cytotoxicity in A549 and H460 cells. Collectively, our findings demonstrate that curcumin sensitizes NSCLC cells to crizotinib by inactivating autophagy through the regulation of miR-142-5p and its target Ulk1.

Structural insights into the cis and trans assembly of human trophoblast cell surface antigen 2.

Human trophoblast cell surface antigen 2 (TROP-2) is an important target of tumor therapy, and antibody-drug conjugates with sacituzumab targeting TROP-2 have been approved for the treatment of triple-negative breast cancer. Here, we report the crystal structures of TROP-2-ECD, which can be either cis- or trans-dimers depending on which distinct but overlapping interfaces is used to engage with monomers. The cis- or trans-tetrameric forms of TROP-2 can also be assembled with a non-overlapping interface with either cis- or trans-dimerization, suggesting that cis- and trans-dimers cluster on the cell surface. The binding site of sacituzumab on TROP-2 is mapped to be located on a stretched polypeptide in CPD (Q237-Q252), which is not involved in either cis- or trans-interactions. The present findings will improve understanding of the molecular assembly of TROP-2 on tumor cells and shed light on future design of biologics for tumor therapy.

Multilayer network structure enhances the coexistence of competitive species.

The concept of a multiplex network can be used to characterize the dispersal paths and states of different species in a patch habitat system. The multiplex network is one of three types of multilayer networks. In this study, the effect of a multiplex network on the long-term stable coexistence of species is investigated using the concept of metapopulation. Based on the mean field approximation, the stability analysis of a two-species system shows that, compared to the single layer network, the multiplex network is more conducive to the stable coexistence of species when one species has a stronger colonization ability. That is, in such a patch habitat system, if the dispersal paths of the stronger species are different than those of the weaker species, then the larger the heterogeneity of the dispersal network of the stronger species is, the more likely the long-term stable coexistence of species. This result provides a different perspective for understanding the biodiversity in heterogeneous habitats.

ValLAI_Crop, a validation dataset for coarse-resolution satellite LAI products over Chinese cropland.

Numerous validation efforts have been conducted over the last decade to assess the accuracy of global leaf area index (LAI) products. However, such efforts continue to face obstacles due to the lack of sufficient high-quality field measurements. In this study, a fine-resolution LAI dataset consisting of 80 reference maps was generated during 2003-2017. The direct destructive method was used to measure the field LAI, and fine-resolution LAI images were derived from Landsat images using semiempirical inversion models. Eighty reference LAI maps, each with an area of 3 km × 3 km and a percentage of cropland larger than 75%, were selected as the fine-resolution validation dataset. The uncertainty associated with the spatial scale effect was also provided. Ultimately, the fine-resolution reference LAI dataset was used to validate the Moderate Resolution Imaging Spectroradiometer (MODIS) LAI product. The results indicate that the fine-resolution reference LAI dataset builds a bridge to link small sampling plots and coarse-resolution pixels, which is extremely important in validating coarse-resolution LAI products.

Improvement of pathological staging system for neuroendocrine tumors of the lung.

BACKGROUND: Currently, the tumor, node, and metastasis (TNM) staging system has a limited value in prognostic stratification for neuroendocrine tumors of the lung (NETL). A specific pathological staging system was therefore explored. METHODS: Two cohorts were assessed: the training cohort was composed of surgically treated patients from the Surveillance, Epidemiologic, and End Results (SEER) database [2004-2015]; the Shanghai cohort included Shanghai resident patients treated at Shanghai Pulmonary Hospital [2009-2018]. Multivariable Cox regression analysis was performed to identify factors associated with overall survival. A new staging system was proposed based on survival tree, and was further compared with the 8th edition of the TNM staging system. RESULTS: In the training set (n=3,204), multivariate Cox analysis showed that tumor histotype and nodal status were independently associated with survival, but not T stage. Therefore, by incorporating NETL histotype (G1, low-grade typical pulmonary carcinoids; G2, intermediate-grade atypical pulmonary carcinoids; G3, high-grade large-cell neuroendocrine carcinomas) and N stage, a new staging system was developed: IA, G1N0; IB, G1N1 or G2N0; II, G1N2, G2N1-2, or G3N0; III, G3N1-2. Five-year survival rates were 91.2%, 81.3%, 50.2% and 27.6% for the new stages IA to III in the validation set (n=3,204), respectively (P<0.001). Additionally, the new staging system had significantly better predictive ability than the TNM staging system, in both the SEER [C-index, 0.75 vs. 0.62; net reclassification improvement (NRI), 0.62; integrated discrimination improvement (IDI), 20%] and Shanghai (IDI, 8%) cohorts. Based on the new staging system, adjuvant chemotherapy conferred a significantly better survival in stage-III NETL cases (HR =0.34, 95% CI, 0.25-0.45). CONCLUSIONS: The new pathological staging system can better predict NETL prognosis than the 8th edition of the TNM staging system, with the potential to guide postoperative treatment.

Identification of NY-ESO-1157-165 Specific Murine T Cell Receptors With Distinct Recognition Pattern for Tumor Immunotherapy.

New York esophageal squamous cell carcinoma 1 (NY-ESO-1) is a promising target for T-cell receptor-engineered T cell (TCR-T) therapy, and targeting the human leukocyte antigen (HLA)-A2 restricted NY-ESO-1157-165 epitope has yielded remarkable clinical benefits in the treatment of multiple advanced malignancies. Herein, we report the identification of two NY-ESO-1157-165 epitope-specific murine TCRs obtained from HLA-A*0201 transgenic mice. NY-ESO-1157-165 specific TCRs were isolated after vaccinating HLA-A2 transgenic mice with epitope peptides. HZ6 and HZ8 TCRs could specifically bind to NY-ESO-1157-165/HLA-A2 and were capable of cytokine secretion with engineered Jurkat T cells and primary T cells upon recognition with K562 target cells expressing the single-chain trimer (SCT) of NY-ESO-1157-165/HLA-A2. The reactivity profiles of the HZ6 and HZ8 TCRs were found to be distinct from one another when co-cultured with K562 target cells carrying alanine-substituted NY-ESO-1157-165 SCTs. The binding characterization revealed that the recognition pattern of the HZ6 TCR to NY-ESO-1157-165/HLA-A2 was substantially different from the widely used 1G4 TCR. These findings would broaden the understanding of immunogenicity of the NY-ESO-1157-165, and the two identified TCRs may serve as promising candidates for the future development of TCR-T therapy for tumors.