Single-cell profiling of response to neoadjuvant chemo-immunotherapy in surgically resectable esophageal squamous cell carcinoma.

BACKGROUND: The efficacy of neoadjuvant chemo-immunotherapy (NAT) in esophageal squamous cell carcinoma (ESCC) is challenged by the intricate interplay within the tumor microenvironment (TME). Unveiling the immune landscape of ESCC in the context of NAT could shed light on heterogeneity and optimize therapeutic strategies for patients. METHODS: We analyzed single cells from 22 baseline and 24 post-NAT treatment samples of stage II/III ESCC patients to explore the association between the immune landscape and pathological response to neoadjuvant anti-PD-1 combination therapy, including pathological complete response (pCR), major pathological response (MPR), and incomplete pathological response (IPR). RESULTS: Single-cell profiling identified 14 major cell subsets of cancer, immune, and stromal cells. Trajectory analysis unveiled an interesting link between cancer cell differentiation and pathological response to NAT. ESCC tumors enriched with less differentiated cancer cells exhibited a potentially favorable pathological response to NAT, while tumors enriched with clusters of more differentiated cancer cells may resist treatment. Deconvolution of transcriptomes in pre-treatment tumors identified gene signatures in response to NAT contributed by specific immune cell populations. Upregulated genes associated with better pathological responses in CD8 + effector T cells primarily involved interferon-gamma (IFNγ) signaling, neutrophil degranulation, and negative regulation of the T cell apoptotic process, whereas downregulated genes were dominated by those in the immune response-activating cell surface receptor signaling pathway. Natural killer cells in pre-treatment tumors from pCR patients showed a similar upregulation of gene expression in response to IFNγ but a downregulation of genes in the neutrophil-mediated immunity pathways. A decreased cellular contexture of regulatory T cells in ESCC TME indicated a potentially favorable pathological response to NAT. Cell-cell communication analysis revealed extensive interactions between CCL5 and its receptor CCR5 in various immune cells of baseline pCR tumors. Immune checkpoint interaction pairs, including CTLA4-CD86, TIGIT-PVR, LGALS9-HAVCR2, and TNFSF4-TNFRSF4, might serve as additional therapeutic targets for ICI therapy in ESCC. CONCLUSIONS: This pioneering study unveiled an intriguing association between cancer cell differentiation and pathological response in esophageal cancer patients, revealing distinct subgroups of tumors for which neoadjuvant chemo-immunotherapy might be effective. We also delineated the immune landscape of ESCC tumors in the context of clinical response to NAT, which provides clinical insights for better understanding how patients respond to the treatment and further identifying novel therapeutic targets for ESCC patients in the future.

Pan-Cancer Analysis of the LOX Family Reveals that LOX Affects Tumor Prognosis by Affecting Immune Infiltration.

The lysyl oxidase (LOX) gene family encodes for a group of copper-dependent enzymes that play a crucial role in the cross-linking of collagen and elastin fibers in the extracellular matrix (ECM). Dysregulation of LOX gene expression has been implicated in various pathological conditions, including cancer. Several studies have shown that the LOX gene family is involved in cancer progression and metastasis. The goal of this article is to conduct a comprehensive analysis of the LOX family's role in pan-cancer multiplexes. We utilized pan-cancer multi-omics sequencing data from TCGA to investigate the relationship between LOX family genes and tumors at four different levels: mutation, copy number variation, methylation, and gene expression. In addition, we also examined the relationship between LOX family genes and tumors at the cell line level using tumor cell line sequencing data from CCLE. Taking into account the impact of LOX family genes on lung cancer, we developed a LOX family lung cancer prognostic model to forecast the disease's prognosis. Our findings revealed that LOXL2 had the highest mutation frequency in tumors, while all four LOX family genes experienced some degree of copy number variation in diverse tumors. We observed that LOX, LOXL1 to LOXL3 were predominantly highly expressed in tumors including LUAD. The expression trends of LOX and LOXL1 to LOXL3 were consistent across tumor cell lines, but differed somewhat from LOXL4. Utilizing 25 LOX family-related genes, we constructed a LOX family prognostic model that performed well in predicting the prognosis of lung cancer. Through pan-cancer analysis, we gain further knowledge of the role of LOX family genes in different tumors, offering a novel pathway for future research into the relationship between LOX family genes and tumors.

Neoadjuvant Camrelizumab Plus Platinum-Based Chemotherapy vs Chemotherapy Alone for Chinese Patients With Resectable Stage IIIA or IIIB (T3N2) Non-Small Cell Lung Cancer: The TD-FOREKNOW Randomized Clinical Trial.

Importance: The benefit of neoadjuvant camrelizumab plus chemotherapy for resectable stage IIIA or IIIB non-small cell lung cancer (NSCLC) remains unknown. Objective: To assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy vs chemotherapy alone for patients with resectable stage IIIA or IIIB NSCLC. Design, Setting, and Participants: In this randomized phase 2 clinical trial conducted at 2 hospitals in China, patients aged 18 to 70 years with resectable stage IIIA or IIIB (T3N2) NSCLC were enrolled between April 7, 2020, and January 12, 2022. Interventions: Patients were randomly assigned to receive 3 cycles of camrelizumab (200 mg) plus chemotherapy (nab-paclitaxel, 130 mg/m2, and platinum [cisplatin, 75 mg/m2; carboplatin, area under the curve, 5; or nedaplatin, 100 mg/m2]) or chemotherapy alone, followed by surgery after 4 to 6 weeks. Main Outcomes and Measures: The primary end point was the pathologic complete response (pCR) rate. Secondary end points included the major pathologic response (MPR) rate, objective response rate (ORR), event-free survival (EFS), and safety. Disease-free survival (DFS, defined as the time from surgery to disease recurrence or death from any cause) was analyzed post hoc. Efficacy was assessed on a modified intention-to-treat basis. Results: Ninety-four Chinese patients were randomized, and 88 (93.6%; median age, 61 years [IQR, 54-65 years]; 74 men [84.1%]) received allocated neoadjuvant treatment (43 received camrelizumab plus chemotherapy, and 45 received chemotherapy alone). Among these 88 patients, the pCR rate was 32.6% (14 of 43; 95% CI, 19.1%-48.5%) with camrelizumab plus chemotherapy vs 8.9% (4 of 45; 95% CI, 2.5%-21.2%) with chemotherapy alone (odds ratio, 4.95; 95% CI, 1.35-22.37; P = .008). The MPR rates were 65.1% (95% CI, 49.1%-79.0%) with camrelizumab plus chemotherapy and 15.6% (95% CI, 6.5%-29.5%) with chemotherapy alone. The radiographic ORRs were 72.1% (95% CI, 56.3%-84.7%) with camrelizumab plus chemotherapy and 53.3% (95% CI, 37.9%-68.3%) with chemotherapy alone. With a median follow-up of 14.1 months (IQR, 9.2-20.9 months), the median EFS and DFS were not reached in either group. The most common neoadjuvant treatment-related adverse events of grade 3 or higher were decreased white blood cell count (6 of 43 [14.0%] in the camrelizumab plus chemotherapy group vs 2 of 45 [4.4%] in the chemotherapy group) and decreased neutrophil count (3 of 43 [7.0%] in the camrelizumab plus chemotherapy group vs 5 of 45 [11.1%] in the chemotherapy group). No treatment-related deaths were reported. Conclusions and Relevance: This randomized clinical trial found that among patients with resectable stage IIIA or IIIB (T3N2) NSCLC, camrelizumab plus chemotherapy, compared with chemotherapy alone, significantly improved the pCR rate with manageable toxic effects. Trial Registration: ClinicalTrials.gov Identifier: NCT04338620.

A multicenter, single-arm, open study of neoadjuvant or conversion atezolizumab in combination with chemotherapy in resectable small cell lung cancer (Cohort Study).

BACKGROUND: This study aimed to investigate the prospects of using chemotherapy in combination with atezolizumab in the neoadjuvant or conversion treatment of small cell lung cancer (SCLC). METHODS: Prior to surgery, untreated patients with limited-stage SCLC received three cycles of neoadjuvant or conversion atezolizumab combined with chemotherapy of etoposide and platinum. The primary endpoint of the trial was pathological complete response (pCR) in the per-protocol (PP) cohort. In addition, safety was assessed based on treatment-related adverse events (AEs) and postoperative complications. RESULTS: Overall, 13 of 17 patients (including 14 males and 3 females) underwent surgery. In the PP cohort, pCR and major pathological response were observed in 8 (8/13, 61.5%) and 12 (12/13, 92.3%) patients, respectively. According to the intention-to-treat (ITT) analysis, the pCR and major pathological response in the ITT cohort were 47.1% (8/17) and 70.6% (12/17), respectively. In addition, an overall response rate of 100% was recorded in the PP cohort. Moreover, 15 (15/17, 88.2%) patients and 1 (1/17, 5.9%) in the ITT cohort attained partial remission (PR), and complete remission, respectively, with an overall response rate of 94.1%. The median overall survival of the patients of pCR and the median event-free survival of the patients on surgery had not achieved. However, the median overall survival of the patients of non-pCR was 18.2 months and the median event-free survival of the nonsurgical patients was 9.5 months. During the neoadjuvant treatment, the incidence of grade 3 or higher AEs was 58.8% (10/17). Additionally, three patients (17.6%) developed immune-related adverse event (grades 1-2). CONCLUSION: In patients with SCLC, neoadjuvant or conversion atezolizumab combined with chemotherapy significantly improved pCR with manageable AEs. Therefore, this regimen may be considered a safe and effective treatment for SCLC.

Analysis of the 2p-manifold population distribution in a diode-pumped metastable Ar laser.

The complex excited energy levels in the diode-pumped metastable Ar laser may induce harmful effects in laser cycling. Significantly, the influence of the population distribution in 2p energy levels on the laser performance is unclear yet. In this work, the absolute populations in all the 2p states were measured online by the simultaneous applications of tunable diode laser absorption spectroscopy and optical emission spectroscopy. The results showed that most atoms were populated to the 2p8, 2p9, and 2p10 levels while lasing, and the majority of the 2p9 population was efficiently transferred to the 2p10 level with the aid of helium, which was beneficial for the laser performance.

An IL-6/STAT3/MR/FGF21 axis mediates heart-liver cross-talk after myocardial infarction.

The liver plays a protective role in myocardial infarction (MI). However, very little is known about the mechanisms. Here, we identify mineralocorticoid receptor (MR) as a pivotal nexus that conveys communications between the liver and the heart during MI. Hepatocyte MR deficiency and MR antagonist spironolactone both improve cardiac repair after MI through regulation on hepatic fibroblast growth factor 21 (FGF21), illustrating an MR/FGF21 axis that underlies the liver-to-heart protection against MI. In addition, an upstreaming acute interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway transmits the heart-to-liver signal to suppress MR expression after MI. Hepatocyte Il6 receptor deficiency and Stat3 deficiency both aggravate cardiac injury through their regulation on the MR/FGF21 axis. Therefore, we have unveiled an IL-6/STAT3/MR/FGF21 signaling axis that mediates heart-liver cross-talk during MI. Targeting the signaling axis and the cross-talk could provide new strategies to treat MI and heart failure.

Continuous Encoding for Overlapping Community Detection in Attributed Network.

Detecting overlapping communities of an attribute network is a ubiquitous yet very difficult task, which can be modeled as a discrete optimization problem. Besides the topological structure of the network, node attributes and node overlapping aggravate the difficulty of community detection significantly. In this article, we propose a novel continuous encoding method to convert the discrete-natured detection problem to a continuous one by associating each edge and node attribute in the network with a continuous variable. Based on the encoding, we propose to solve the converted continuous problem by a multiobjective evolutionary algorithm (MOEA) based on decomposition. To find the overlapping nodes, a heuristic based on double-decoding is proposed, which is only with linear complexity. Furthermore, a postprocess community merging method in consideration of node attributes is developed to enhance the homogeneity of nodes in the detected communities. Various synthetic and real-world networks are used to verify the effectiveness of the proposed approach. The experimental results show that the proposed approach performs significantly better than a variety of evolutionary and nonevolutionary methods on most of the benchmark networks.

Characteristics and Correlations of the Oral and Gut Fungal Microbiome with Hypertension.

The mycobiome is an essential constituent of the human microbiome and is associated with various diseases. However, the role of oral and gut fungi in hypertension (HTN) remains largely unexplored. In this study, saliva, subgingival plaques, and feces were collected from 36 participants with HTN and 24 healthy controls for metagenomic sequencing. The obtained sequences were analyzed using the Kraken2 taxonomic annotation pipeline to assess fungal composition and diversity. Correlations between oral and gut fungi and clinic parameters, between fungi within the same sample types, and between different sample types were identified by Spearman's correlation analysis. Overall, the subgingival fungal microbiome had substantially higher alpha diversity than the salivary and fecal fungal microbiomes. The fungal microbiomes of the three sample types displayed distinct beta diversity from each other. Oral fungi but not gut fungi in HTN had beta diversity significantly different from that of controls. Among the fungi shared in the oral cavity and gut, Exophiala was the genus with the most notable changes. Exophiala spinifera was the most abundant salivary species in HTN. Some fungal species directly correlated with blood pressure, including gut Exophiala xenobiotica and Exophiala mesophila. The markedly impaired ecological cocorrelation networks of oral and gut fungi in HTN suggested compromised association among fungal species. Most fungi were shared in the oral cavity and gut, and their correlations suggested the potential interplays between oral and gut fungi. In conclusion, the oral cavity and intestine have unique fungal ecological environments. The fungal enrichment and ecology in HTN, the correlations between oral and gut fungi, and the associations between oral and gut fungi and clinical parameters suggest an important role that the fungal microbiome may play in HTN. IMPORTANCE Our study fills the gap in human studies investigating the oral and gut fungal microbiota in association with blood pressure. It characterizes the diversity and composition of the oral and gut fungal microbiome in human subjects, elucidates the dysbiosis of fungal ecology in a hypertensive population, and establishes oral-gut fungal correlations and fungus-clinical parameter correlations. Targeting fungi in the oral cavity and/or gut may provide novel strategies for the prevention and treatment of hypertension.

Roles of oral microbiota and oral-gut microbial transmission in hypertension.

INTRODUCTION: Considerable evidence has linked periodontitis (PD) to hypertension (HTN), but the nature behind this connection is unclear. Dysbiosis of oral microbiota leading to PD is known to aggravate different systematic diseases, but the alteration of oral microbiota in HTN and their impacts on blood pressure (BP) remains to be discovered. OBJECTIVES: To characterize the alterations of oral and gut microbiota and their roles in HTN. METHODS: We performed a cross-sectional (95 HTN participants and 39 controls) and a 6-month follow-up study (52 HTN participants and 26 controls) to analyze the roles of oral and gut microbiota in HTN. Saliva, subgingival plaques, and feces were collected for 16S rRNA gene sequencing or metagenomic analysis. C57BL/6J mice were pretreated with antibiotics to deplete gut microbiota, and then transplanted with human saliva by gavage to test the impacts of abnormal oral-gut microbial transmission on HTN. RESULTS: BP in participants with PD was higher than no PD in both cross-sectional and follow-up cohort. Relative abundances of 14 salivary genera, 15 subgingival genera and 10 gut genera significantly altered in HTN and those of 7 salivary genera, 12 subgingival genera and 6 gut genera significantly correlated with BP. Sixteen species under 5 genera were identified as oral-gut transmitters, illustrating the presence of oral-gut microbial transmission in HTN. Veillonella was a frequent oral-gut transmitter stably enriched in HTN participants of both cross-sectional and follow-up cohorts. Saliva from HTN participants increased BP in hypertensive mice. Human saliva-derived Veillonella successfully colonized in mouse gut, more abundantly under HTN condition. CONCLUSIONS: PD and oral microbiota are strongly associated with HTN, likely through oral-gut transmission of microbes. Ectopic colonization of saliva-derived Veillonella in the gut may aggravate HTN. Therefore, precise manipulations of oral microbiota and/or oral-gut microbial transmission may be useful strategies for better prevention and treatment of HTN.

NCOR1 maintains the homeostasis of vascular smooth muscle cells and protects against aortic aneurysm.

Phenotypic modulation of vascular smooth muscle cells (VSMCs) plays critical roles in the pathogenesis of aortic aneurysm (AA). The function of nuclear receptor corepressor1 (NCOR1) in regulation of VSMC phenotype and AA is unclear. Herein, using smooth muscle NCOR1 knockout mice, we demonstrated that smooth muscle NCOR1 deficiency decreased both mRNA and protein levels of contractile genes, impaired stress fibers formation and RhoA pathway activation, reduced synthesis of elastin and collagens, and induced the expression and activity of MMPs, manifesting a switch from contractile to degradative phenotype of VSMCs. NCOR1 modulated VSMC phenotype through 3 different mechanisms. First, NCOR1 deficiency increased acetylated FOXO3a to inhibit the expression of Myocd, which downregulated contractile genes. Second, deletion of NCOR1 derepressed NFAT5 to induce the expression of Rgs1, thus impeding RhoA activation. Third, NCOR1 deficiency increased the expression of Mmp12 and Mmp13 by derepressing ATF3. Finally, a mouse model combined apoE knockout mice with angiotensin II was used to study the role of smooth muscle NCOR1 in the development of AA. The results showed that smooth muscle NCOR1 deficiency increased the incidence of aortic aneurysms and exacerbated medial degeneration in angiotensin II-induced AA mouse model. Collectively, our data illustrated that NCOR1 interacts with FOXO3a, NFAT5, and ATF3 to maintain contractile phenotype of VSMCs and suppress AA development. Manipulation of smooth muscle NCOR1 may be a potential approach for AA treatment.

Probabilistic Matrix Factorization for Data With Attributes Based on Finite Mixture Modeling.

Matrix factorization (MF) methods decompose a data matrix into a product of two-factor matrices (denoted as U and V ) which are with low ranks. In this article, we propose a generative latent variable model for the data matrix, in which each entry is assumed to be a Gaussian with mean to be the inner product of the corresponding columns of U and V . The prior of each column of U and V is assumed to be as a finite mixture of Gaussians. Further, we propose to model the attribute matrix with the data matrix jointly by considering them as conditional independence with respect to the factor matrix U , building upon previously defined model for the data matrix. Due to the intractability of the proposed models, we employ variational Bayes to infer the posteriors of the factor matrices and the clustering relationships, and to optimize for the model parameters. In our development, the posteriors and model parameters can be readily computed in closed forms, which is much more computationally efficient than existing sampling-based probabilistic MF models. Comprehensive experimental studies of the proposed methods on collaborative filtering and community detection tasks demonstrate that the proposed methods achieve the state-of-the-art performance against a great number of MF-based and non-MF-based algorithms.

Mineralocorticoid receptor deficiency in Treg cells ameliorates DSS-induced colitis in a gut microbiota-dependent manner.

Mineralocorticoid receptor (MR) is a classic nuclear receptor and an effective drug target in the cardiovascular system. The function of MR in immune cells such as macrophages and T cells has been increasingly appreciated. The aim of this study was to investigate the function of Treg MR in the process of inflammatory bowel disease (IBD). We treated Treg MR-deficient (MRflox/flox Foxp3YFP-Cre , KO) mice and control (Foxp3YFP-Cre , WT) mice with dextran sodium sulphate (DSS) to induce colitis and found that the severity of DSS-induced colitis was markedly alleviated in Treg MR-deficient mice, accompanied by reduced production of inflammatory cytokines, and relieved infiltration of monocytes, neutrophils and interferon γ+ T cells in colon lamina propria. Faecal microbiota of mice with colitis was analysed by 16S rRNA gene sequencing and the composition of gut microbiota was vastly changed in Treg MR-deficient mice. Furthermore, depletion of gut microbiota by antibiotics abolished the protective effects of Treg MR deficiency and resulted in similar severity of DSS-induced colitis in WT and KO mice. Faecal microbiota transplantation from KO mice attenuated DSS-induced colitis characterized by alleviated inflammatory infiltration compared to that from WT mice. Hence, our study demonstrates that Treg MR deficiency protects against DSS-induced colitis by attenuation of colonic inflammatory infiltration. Gut microbiota is both sufficient and necessary for Treg MR deficiency to exert the beneficial effects.

Tislelizumab combined with chemotherapy as neoadjuvant therapy for surgically resectable esophageal cancer: A prospective, single-arm, phase II study (TD-NICE).

BACKGROUND: Clinical benefit of neoadjuvant immunotherapy in resectable esophageal squamous cell carcinoma (ESCC). remains unclear. This study evaluated the efficacy and safety of the programmed death 1 (PD-1) inhibitor tislelizumab combined with chemotherapy as neoadjuvant therapy in patients with resectable ESCC. METHODS: Treatment-naïve patients were enrolled and eligible patients received 3 cycles of neoadjuvant therapy with tislelizumab, carboplatin, and nab-paclitaxel. The primary endpoint was surgery patients major pathological response (MPR). Subgroup analysis was stratified by tumor downstaging, circumferential resection margin (CRM), PD-ligand 1 (PD-L1) expression, and tumor mutation burden (TMB). Safety was assessed by adverse events (AEs) and postoperative complications. RESULTS: Between September 2020 and March 2021, 45 patients were enrolled. Thirty-six (80.0%) of 45 patients underwent surgery, and 29 (80.5%) underwent successful R0 resection. MPR and pathological complete response (pCR) for surgery patients were 72.0% and 50.0%, respectively. Intention to treatment (ITT) patients MPR and PCR were 57.5% and 40%. Downgrading occurred in 75% of 36 patients. MPR and pCR were identified to be associated with tumor downstaging and CRM but not PD-L1 expression or TMB. TPS levels in MPR and pCR group were significantly higher than that in Non-MPR and Non-pCR group, respectively. Treatment-related AEs of grade 3-4 and immune-related AEs occurred in 42.2% and 22.2% of 45 patients, respectively, and postoperative complications occurred in 77.8% of 36 patients. No treatment-related surgical delay or death occurred. No associations between gene mutation and pathological efficacy were observed. CONCLUSIONS: Tislelizumab plus chemotherapy as neoadjuvant therapy demonstrates promising antitumor activity for resectable ESCC with high rates of MPR, pCR, and R0 resection, as well as acceptable tolerability.

Polymorphisms of COX/PEG2 pathway-related genes are associated with the risk of lung cancer: A case-control study in China.

BACKGROUND: The COX/PGE2 pathway is widely involved in the development of tumors and the regulation of tumor immune cells such as T cells, NK cells and DCs. However, little information is available on the single nucleotide polymorphisms (SNPs) of COX/PGE2 pathway-related genes in patients with lung cancer. METHODS: Seven SNPs of the PTGS2, PTGER2 and PTGIS genes were genotyped in a case-control cohort including 600 lung cancer cases and 600 controls using the MassARRAY platform. RESULTS: The minor alleles of PTGS2-rs4648298, PTGS2-rs2745557, PTGER2-rs2075797 and PTGIS-rs6125671 were all risk alleles that led to a different degree of elevated lung cancer risk (p < 0.001). The rs4648298-TC/CC, rs2745557-GA/AA, rs2075797-CG/GG and rs6125671-TC/CC genotypes were markedly associated with an elevated risk of lung cancer (p < 0.0001). Moreover, genetic model results showed that PTGS2-rs4648298 was correlated with a 4.91-, 6.90- and 4.21-fold increased risk of lung cancer under dominant, recessive and log-additive models, respectively (p < 0.0001). Similarly, PTGS2-rs2745557, PTGER2-rs2075797 and PTGIS-rs6125671 were also related to an elevated risk of the disease under the three genetic models (p < 0.001). In addition, stratification analysis based on smoking status and pathological types showed that these four SNPs were associated with the risk of lung cancer in both smokers and nonsmokers and in all three pathological types, including adenocarcinoma, squamous cell carcinoma, and small cell lung cancer (p < 0.014). CONCLUSION: These results contribute to a better understanding of the pathogenesis of lung cancer and provide new clues for the early detection and personalized treatment of the disease.

Osteoblast MR deficiency protects against adverse ventricular remodeling after myocardial infarction.

RATIONALE: Mineralocorticoid receptor (MR) antagonists have been clinically used to treat heart failure. However, the underlying cellular and molecular mechanisms remain incompletely understood. METHODS AND RESULTS: Using osteoblast MR knockout (MRobko) mouse in combination with myocardial infarction (MI) model, we demonstrated that MR deficiency in osteoblasts significantly improved cardiac function, promoted myocardial healing, as well as attenuated cardiac hypertrophy, fibrosis and inflammatory response after MI. Gene expression profiling using RNA sequencing revealed suppressed expression of osteocalcin (OCN) in calvaria from MRobko mice compared to littermate control (MRfl/fl) mice with or without MI. Plasma levels of undercarboxylated OCN (ucOCN) were also markedly decreased in MRobko mice compared to MRfl/fl mice. Administration of ucOCN abolished the protective effects of osteoblast MR deficiency on infarcted hearts. Mechanistically, ucOCN treatment promoted proliferation and inflammatory cytokine secretion in macrophages. Spironolactone, an MR antagonist, significantly inhibited the expression and secretion of OCN in post-MI mice. More importantly, spironolactone decreased plasma levels of ucOCN and inflammatory cytokines in heart failure patients. CONCLUSIONS: MR deficiency in osteoblasts alleviates pathological ventricular remodeling after MI, likely through its regulation on OCN. Spironolactone may work through osteoblast MR/OCN axis to exert its therapeutic effects on pathological ventricular remodeling and heart failure in mice and human patients.

Association of 3D-CRT and IMRT accelerated hyperfractionated radiotherapy with local control rate and 5-year survival in esophageal squamous cell carcinoma patients.

OBJECTIVES: This retrospective study examined the relevance and prognostic factors of whole-course conformal radiotherapy (CRT) and late-course accelerated hyperfractionation radiotherapy (LCAFRT) for esophageal squamous cell carcinoma (ESCC). METHODS: A total of 110 patients with ESCC received whole-course CRT and LCAFRT between May 2004 and January 2015. All patients received conventional CRT of 2 Gy per day, up to 30-40 Gy, followed by LCAFRT using reduced fields at 1.5 Gy/fraction twice a day, up to 24-39 Gy, for a total dose of 60-69 Gy. RESULTS: The median follow-up was 85 months. The whole groups 1-, 3-, and 5-year survival rates were 81.8%, 46.4%, and 41.8%, respectively. The local control rates for the whole group at 1, 3, and 5 years were 82.7%, 70.0%, and 68.2%, respectively. There were no significant differences among survival rates and local control rates between the 3D-CRT and intensity-modulated radiotherapy (IMRT) groups. The main reactions to acute radiotherapy were acute radiation tracheitis, esophagitis, and pneumonia. The tumor location and TNM stage were independent prognostic factors for overall survival. CONCLUSION: The results showed that whole-course CRT and LCAFRT for ESCC can improve survival and local control with a tolerable acute reaction compared to previous studies. Local recurrence and distant metastasis are the main failure modes of treatment. ADVANCES IN KNOWLEDGE: Whole-course CRT and LCAFRT for ESCC can improve the survival and local control rate compared with previous studies from the 2DRT era. It might provide another treatment for patients with inoperable ESCC or refusing surgery.

IAGS: Inferring Ancestor Genome Structure under a Wide Range of Evolutionary Scenarios.

Significant improvements in genome sequencing and assembly technology have led to increasing numbers of high-quality genomes, revealing complex evolutionary scenarios such as multiple whole-genome duplication events, which hinders ancestral genome reconstruction via the currently available computational frameworks. Here, we present the Inferring Ancestor Genome Structure (IAGS) framework, a novel block/endpoint matching optimization strategy with single-cut-or-join distance, to allow ancestral genome reconstruction under both simple (single-copy ancestor) and complex (multicopy ancestor) scenarios. We evaluated IAGS with two simulated data sets and applied it to four different real evolutionary scenarios to demonstrate its performance and general applicability. IAGS is available at https://github.com/xjtu-omics/IAGS.

Improving Pareto Local Search Using Cooperative Parallelism Strategies for Multiobjective Combinatorial Optimization.

Pareto local search (PLS) is a natural extension of local search for multiobjective combinatorial optimization problems (MCOPs). In our previous work, we improved the anytime performance of PLS using parallel computing techniques and proposed a parallel PLS based on decomposition (PPLS/D). In PPLS/D, the solution space is searched by multiple independent parallel processes simultaneously. This article further improves PPLS/D by introducing two new cooperative process techniques, namely, a cooperative search mechanism and a cooperative subregion-adjusting strategy. In the cooperative search mechanism, the parallel processes share high-quality solutions with each other during the search according to a distributed topology. In the proposed subregion-adjusting strategy, a master process collects useful information from all processes during the search to approximate the Pareto front (PF) and redivide the subregions evenly. In the experimental studies, three well-known NP-hard MCOPs with up to six objectives were selected as test problems. The experimental results on the Tianhe-2 supercomputer verified the effectiveness of the proposed techniques.

Homotopic Convex Transformation: A New Landscape Smoothing Method for the Traveling Salesman Problem.

This article proposes a novel landscape smoothing method for the symmetric traveling salesman problem (TSP). We first define the homotopic convex (HC) transformation of a TSP as a convex combination of a well-constructed simple TSP and the original TSP. The simple TSP, called the convex-hull TSP, is constructed by transforming a known local or global optimum. We observe that controlled by the coefficient of the convex combination, with local or global optimum: 1) the landscape of the HC transformed TSP is smoothed in terms that its number of local optima is reduced compared to the original TSP and 2) the fitness distance correlation of the HC transformed TSP is increased. Furthermore, we observe that the smoothing effect of the HC transformation depends highly on the quality of the used optimum. A high-quality optimum leads to a better smoothing effect than a low-quality optimum. We then propose an iterative algorithmic framework in which the proposed HC transformation is combined within a heuristic TSP solver. It works as an escaping scheme from local optima aiming to improve the global searchability of the combined heuristic. Case studies using the 3-Opt and the Lin-Kernighan local search as the heuristic solver show that the resultant algorithms significantly outperform their counterparts and two other smoothing-based TSP heuristic solvers on most of the test instances with up to 20 000 cities.

Graph Neural Network Encoding for Community Detection in Attribute Networks.

In this article, we first propose a graph neural network encoding method for the multiobjective evolutionary algorithm (MOEA) to handle the community detection problem in complex attribute networks. In the graph neural network encoding method, each edge in an attribute network is associated with a continuous variable. Through nonlinear transformation, a continuous valued vector (i.e., a concatenation of the continuous variables associated with the edges) is transferred to a discrete valued community grouping solution. Further, two objective functions for the single-attribute and multiattribute network are proposed to evaluate the attribute homogeneity of the nodes in communities, respectively. Based on the new encoding method and the two objectives, a MOEA based upon NSGA-II, called continuous encoding MOEA, is developed for the transformed community detection problem with continuous decision variables. Experimental results on single-attribute and multiattribute networks with different types show that the developed algorithm performs significantly better than some well-known evolutionary- and nonevolutionary-based algorithms. The fitness landscape analysis verifies that the transformed community detection problems have smoother landscapes than those of the original problems, which justifies the effectiveness of the proposed graph neural network encoding method.