Combination of Neutrophil Count and Gensini Score as a Prognostic Marker in Patients with ACS and Uncontrolled T2DM Undergoing PCI

Background: Several biomarkers have been studied as prognostic indicators among people with diabetes and coronary artery disease (CAD). The purpose of this study was to determine the prognostic value of neutrophil counts and the Gensini score in patients with diabetes and ACS undergoing percutaneous coronary intervention (PCI). Methods: A total of 694 people with ACS and T2DM who simultaneously had elevated HBA1c received PCI. Spearman rank correlation estimates were used for correlation evaluation. Multivariate Cox regression and Kaplan-Meier analysis were used to identify characteristics associated with major adverse cardiovascular and cerebrovascular events (MACCEs) and patient survival. The effects of single- and multi-factor indices on MACCEs were evaluated through receiver operating characteristic curve analysis. Results: The Gensini score and neutrophil count significantly differed between the MACCE and non-MACCE groups among patients receiving PCI who had concomitant ACS and T2DM with elevated HBA1c (P<0.001). The Gensini score and neutrophil count were strongly associated with MACCEs (log-rank, P<0.001). The Gensini score and neutrophil count, alone or in combination, were predictors of MACCEs, according to multivariate Cox regression analysis (adjusted hazard ratio [HR], 1.005; 95% confidence interval [CI], 1.002–1.008; P=0.002; adjusted HR, 1.512; 95% CI, 1.005–2.274; P=0.047, respectively). The Gensini score was strongly associated with neutrophil count (variance inflation factor ≥ 5). Area under the curve analysis revealed that the combination of multivariate factors predicted the occurrence of MACCEs better than any single variable. Conclusion: In patients with T2DM and ACS with elevated HBA1c who underwent PCI, both the Gensini score and neutrophil count were independent predictors of outcomes. The combination of both predictors has a higher predictability

Immune-based mutation classification enables neoantigen prioritization and immune feature discovery in cancer immunotherapy.

Genetic mutations lead to the production of mutated proteins from which peptides are presented to T cells as cancer neoantigens. Evidence suggests that T cells that target neoantigens are the main mediators of effective cancer immunotherapies. Although algorithms have been used to predict neoantigens, only a minority are immunogenic. The factors that influence neoantigen immunogenicity are not completely understood. Here, we classified human neoantigen/neopeptide data into three categories based on their TCR-pMHC binding events. We observed a conservative mutant orientation of the anchor residue from immunogenic neoantigens which we termed the NP rule. By integrating this rule with an existing prediction algorithm, we found improved performance in neoantigen prioritization. To better understand this rule, we solved several neoantigen/MHC structures. These structures showed that neoantigens that follow this rule not only increase peptide-MHC binding affinity but also create new TCR-binding features. These molecular insights highlight the value of immune-based classification in neoantigen studies and may enable the design of more effective cancer immunotherapies

ASXL1 interacts with the cohesin complex to maintain chromatid separation and gene expression for normal hematopoiesis

ASXL1 is frequently mutated in a spectrum of myeloid malignancies with poor prognosis. Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice; however, the underlying molecular mechanisms remain unclear. We report that ASXL1 interacts with the cohesin complex, which has been shown to guide sister chromatid segregation and regulate gene expression. Loss of Asxl1 impairs the cohesin function, as reflected by an impaired telophase chromatid disjunction in hematopoietic cells. Chromatin immunoprecipitation followed by DNA sequencing data revealed that ASXL1, RAD21, and SMC1A share 93% of genomic binding sites at promoter regions in Lin-cKit+ (LK) cells. We have shown that loss of Asxl1 reduces the genome binding of RAD21 and SMC1A and alters the expression of ASXL1/cohesin target genes in LK cells. Our study underscores the ASXL1-cohesin interaction as a novel means to maintain normal sister chromatid separation and regulate gene expression in hematopoietic cells

Sequence analysis of the Epstein-Barr virus (EBV) BRLF1 gene in nasopharyngeal and gastric carcinomas

<p>Abstract</p> <p>Background</p> <p>Epstein-Barr virus (EBV) has a biphasic infection cycle consisting of a latent and a lytic replicative phase. The product of immediate-early gene BRLF1, Rta, is able to disrupt the latency phase in epithelial cells and certain B-cell lines. The protein Rta is a frequent target of the EBV-induced cytotoxic T cell response. In spite of our good understanding of this protein, little is known for the gene polymorphism of BRLF1.</p> <p>Results</p> <p>BRLF1 gene was successfully amplified in 34 EBV-associated gastric carcinomas (EBVaGCs), 57 nasopharyngeal carcinomas (NPCs) and 28 throat washings (TWs) samples from healthy donors followed by PCR-direct sequencing. Fourteen loci were found to be affected by amino acid changes, 17 loci by silent nucleotide changes. According to the phylogenetic tree, 5 distinct subtypes of BRLF1 were identified, and 2 subtypes BR1-A and BR1-C were detected in 42.9% (51/119), 42.0% (50/119) of samples, respectively. The distribution of these 2 subtypes among 3 types of specimens was significantly different. The subtype BR1-A preferentially existed in healthy donors, while BR1-C was seen more in biopsies of NPC. A silent mutation A/G was detected in all the isolates. Among 3 functional domains, the dimerization domain of Rta showed a stably conserved sequence, while DNA binding and transactivation domains were detected to have multiple mutations. Three of 16 CTL epitopes, NAA, QKE and ERP, were affected by amino acid changes. Epitope ERP was relatively conserved; epitopes NAA and QKE harbored more mutations.</p> <p>Conclusions</p> <p>This first detailed investigation of sequence variations in BRLF1 gene has identified 5 distinct subtypes. Two subtypes BR1-A and BR1-C are the dominant genotypes of BRLF1. The subtype BR1-C is more frequent in NPCs, while BR1-A preferentially presents in healthy donors. BR1-C may be associated with the tumorigenesis of NPC.</p

The Haploinsufficient Hematopoietic Microenvironment Is Critical to the Pathological Fracture Repair in Murine Models of Neurofibromatosis Type 1

Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a complex genetic disorder with a high predisposition of numerous skeletal dysplasias including short stature, osteoporosis, kyphoscoliosis, and fracture non-union (pseudoarthrosis). We have developed murine models that phenocopy many of the skeletal dysplasias observed in NF1 patients, including reduced bone mass and fracture non-union. We also show that the development of these skeletal manifestations requires an Nf1 haploinsufficient background in addition to nullizygous loss of Nf1 in mesenchymal stem/progenitor cells (MSCs) and/or their progenies. This is replicated in two animal models of NF1, PeriCre+;Nf1flox/− and Col2.3Cre+;Nf1flox/−mice. Adoptive transfer experiments demonstrate a critical role of the Nf1+/− marrow microenvironment in the impaired fracture healing in both models and adoptive transfer of WT bone marrow cells improves fracture healing in these mice. To our knowledge, this is the first demonstration of a non-cell autonomous mechanism in non-malignant NF1 manifestations. Collectively, these data provide evidence of a combinatory effect between nullizygous loss of Nf1 in osteoblast progenitors and haploinsufficiency in hematopoietic cells in the development of non-malignant NF1 manifestations

Spatiotemporal Variation in the Yangtze River Delta Urban Agglomeration from 1980 to 2020 and Future Trends in Ecosystem Services

Over the past 40 years of reform and opening up, human activities in the Yangtze River Delta region have caused major changes in land use patterns and ecosystem functions. Clarifying the spatiotemporal change characteristics and future development trends of ecosystem service functions is the basis for rational land development and utilization. In this study, the InVEST model and the CASA model were used to calculate habitat quality, water conservation, carbon sequestration and oxygen release, and soil conservation ecosystem services in the Yangtze River Delta urban agglomeration from 1980 to 2020. The spatial pattern, change law, and future trend of these services were analyzed using the Theil–Sen median trend analysis, Mann–Kendall test, and Hurst index analysis. The results show that the four types of ecosystems in the Yangtze River Delta urban agglomeration (habitat quality, water conservation, carbon sequestration and oxygen release, and soil conservation) exhibited an overall spatial pattern of being high in the southwest mountainous area and low in the northeast plain, and the conversion from constructed to agriculture was the most frequent type of land conversion over the past 40 years. From 1980 to 2020, the average level of habitat quality showed a downward trend and is expected to continue to deteriorate in the future. Water conservation, carbon sequestration and oxygen release, and soil conservation showed a fluctuating upward trend, with the latter two primarily predicted to have a future trend of improvement. The changes in ecosystem services exhibit gradient effects and horizontal spatial differentiation. The decline in ecosystem service functions is more pronounced in the vicinity of large cities. It is thus necessary to accelerate the transformation of the economic development model, and abandon the extensive urbanization development model, and promote high-quality urbanization development on the basis of improving resource and environmental carrying capacities

Measuring the Relationship between Physical Geographic Features and the Constraints on Ecosystem Services from Urbanization Development

Exploring the constraint relationship between physical geographic features and urbanization on ecosystem services is important for managing and optimizing regional ecosystem services. Taking Anhui Province as an example, we assessed the spatial and temporal evolution characteristics of five types of ecosystem services (habitat support, water production services, soil conservation, NPP, and carbon fixation) and five types of urbanization levels (population, economic, social, ecological, and spatial) in 2000, 2010, and 2020, and integrated the constraint line method, bivariate spatial autocorrelation model, and spatial regression model to measure the relationship between ecosystem services. The spatial constraints between ecosystem services and urbanization level and natural topography in Anhui Province were measured using the constraint line method, bivariate spatial autocorrelation model and the spatial regression model. The results show that: (1) the spatial distribution of the five types of ecosystem services in Anhui Province is characterized as &ldquo;low in the north and high in the south&rdquo;. At the provincial level, the five ecosystem services in southern and central Anhui Province are synergistic, while the five ecosystem services in northern Anhui Province show a trade-off; (2) topography has different effects on the five ecosystem services with &ldquo;exponential&rdquo; effects on water production services and NPP, &ldquo;positive convex&rdquo; effects on habitat support, and &ldquo;positive convex&rdquo; effects on habitat support&rdquo;; (3) the bivariate global autocorrelation Moran&rsquo;s I index between ecosystem services and urbanization level in Anhui Province is significant, confirming that ecosystem services and urbanization are spatially related, where the development of population urbanization, spatial urbanization, economic urbanization, and social urbanization leads to the decrease in ecosystem services, and ecological urbanization promotes the increase in ecosystem services. In the spatial regression model, the Spatial Lag Model passed the significance test, indicating that there is a spatial spillover effect between ecosystem services and urbanization. That is, changes in ecosystem services are influenced not only by their own urbanization elements, but also by urbanization elements in neighboring units or more distant units. Exploring the constraints of ecosystem services and identifying their interaction with urbanization can provide a scientific basis for land-use optimization, adjusting management measures and achieving regional sustainability

Measuring the Relationship between Physical Geographic Features and the Constraints on Ecosystem Services from Urbanization Development

Exploring the constraint relationship between physical geographic features and urbanization on ecosystem services is important for managing and optimizing regional ecosystem services. Taking Anhui Province as an example, we assessed the spatial and temporal evolution characteristics of five types of ecosystem services (habitat support, water production services, soil conservation, NPP, and carbon fixation) and five types of urbanization levels (population, economic, social, ecological, and spatial) in 2000, 2010, and 2020, and integrated the constraint line method, bivariate spatial autocorrelation model, and spatial regression model to measure the relationship between ecosystem services. The spatial constraints between ecosystem services and urbanization level and natural topography in Anhui Province were measured using the constraint line method, bivariate spatial autocorrelation model and the spatial regression model. The results show that: (1) the spatial distribution of the five types of ecosystem services in Anhui Province is characterized as “low in the north and high in the south”. At the provincial level, the five ecosystem services in southern and central Anhui Province are synergistic, while the five ecosystem services in northern Anhui Province show a trade-off; (2) topography has different effects on the five ecosystem services with “exponential” effects on water production services and NPP, “positive convex” effects on habitat support, and “positive convex” effects on habitat support”; (3) the bivariate global autocorrelation Moran’s I index between ecosystem services and urbanization level in Anhui Province is significant, confirming that ecosystem services and urbanization are spatially related, where the development of population urbanization, spatial urbanization, economic urbanization, and social urbanization leads to the decrease in ecosystem services, and ecological urbanization promotes the increase in ecosystem services. In the spatial regression model, the Spatial Lag Model passed the significance test, indicating that there is a spatial spillover effect between ecosystem services and urbanization. That is, changes in ecosystem services are influenced not only by their own urbanization elements, but also by urbanization elements in neighboring units or more distant units. Exploring the constraints of ecosystem services and identifying their interaction with urbanization can provide a scientific basis for land-use optimization, adjusting management measures and achieving regional sustainability