The cuproptosis-related gene UBE2D2 functions as an immunotherapeutic and prognostic biomarker in pan-cancer.

BACKGROUND: Cuproptosis, as a unique modality of regulated cell death, requires the involvement of ubiquitin-binding enzyme UBE2D2. However, the prognostic and immunotherapeutic values of UBE2D2 in pan-cancer remain largely unknown. METHODS: Using UCSC Xena, TIMER, Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Human Protein Atlas (HPA) databases, we aimed to explore the differential expression pattern of UBE2D2 across multiple cancer types and to evaluate its association with patient prognosis, clinical features, and genetic variations. The association between UBE2D2 and immunotherapy response was assessed by gene set enrichment analysis, tumor microenvironment, immune gene co-expression and drug half maximal inhibitory concentration (IC50) analysis. RESULTS: The mRNA and protein levels of UBE2D2 were markedly elevated in most cancer types, and UBE2D2 exhibited prognostic significance in liver hepatocellular carcinoma (LIHC), kidney chromophobe (KICH), uveal melanomas (UVM), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), and kidney renal papillary cell carcinoma (KIRP). UBE2D2 expression was correlated with clinical features, tumor mutation burden, microsatellite instability, and anti-tumor drug resistance in several tumor types. Gene enrichment analysis showed that UBE2D2 was significantly associated with immune-related pathways. The expression level of UBE2D2 was correlated with immune cell infiltration, including CD4 + T cells、Macrophages M2、CD8 + T cells in pan-cancer. PDCD1, CD274 and CTLA4 expression levels were positively correlated with UBE2D2 level in multiple cancers. CONCLUSIONS: We comprehensively investigated the potential value of UBE2D2 as a prognostic and immunotherapeutic predictor for pan-cancer, providing a novel insight for cancer immunotherapy.

Variation of peripheral blood-based biomarkers for response of anti-PD-1 immunotherapy in non-small-cell lung cancer.

PURPOSE: Immune checkpoint inhibitors (ICIs) for non-small-cell lung cancer (NSCLC) are on the rise, but unfortunately, only a small percentage of patients benefit from them in the long term. Thus, it is crucial to identify biomarkers that can forecast the efficacy of immunotherapy. METHODS: We retrospectively studied 224 patients with NSCLC who underwent anti-PD-1 therapy. The role of biomarkers and clinical characteristics were assessed in a prognostic model. RESULTS: Only 14.3% of patients had both programmed death ligand 1 (PD-L1) and tumor mutational burden (TMB) outcomes, highlighting the need to investigate more available biomarkers. Our analysis found a correlation between histological PD-L1 TPS and hematological PD-1 expression. Analysis of hematological biomarkers revealed that elevated expression of CD4/CD8 and LYM% are positively associated with effective immunotherapy, while PD-1+ on T cells, NLR, and MLR have a negative impact. Moreover, high level of ΔCEA%, CYFRA21-1 and LDH may suggest ineffective ICIs. We also observed that disparate immunotherapy drugs didn't significantly impact prognosis. Lastly, by comparing squamous carcinoma and adenocarcinoma cohorts, ΔCEA%, CD3+PD-1+, CD4+PD-1+, and CD4/CD8 are more important in predicting the prognosis of adenocarcinoma patients, while age is more significant for squamous carcinoma patients. CONCLUSION: Our research has yielded encouraging results in identifying a correlation between immunotherapy's response and clinical characteristics, peripheral immune cell subsets, and biochemical and immunological biomarkers. The screened hematological detection panel could be used to forecast an NSCLC patient's response to anti-PD-1 immunotherapy with an accuracy rate of 76.3%, which could help customize suitable therapeutic decision-making.

Driving force of deteriorated cellular environment in heart failure: Metabolic remodeling.

Heart Failure (HF) has been one of the leading causes of death worldwide. Though its latent mechanism and therapeutic manipulation are updated and developed ceaselessly, there remain great gaps in the cognition of heart failure. High morbidity and readmission rates among HF patients are waiting to be addressed. Recent studies have found that myocardial energy metabolism was closely related to heart failure, in which substrate utilization, as well as intermediate metabolism disorders, insulin resistance, oxidative stress, and mitochondrial dysfunction, might underlie systolic dysfunction and progression of HF. This article centers on the changes and counteraction of cardiac energy metabolism in the failing heart. Therefore, targeting impaired energy provision is of great potential in the treatment of HF. And shifting the objective from traditional neurohormones to improving the cellular environment is expected to further optimize the management of HF.

Driving force of deteriorated cellular environment in heart failure: Metabolic remodeling

Abstract Heart Failure (HF) has been one of the leading causes of death worldwide. Though its latent mechanism and therapeutic manipulation are updated and developed ceaselessly, there remain great gaps in the cognition of heart failure. High morbidity and readmission rates among HF patients are waiting to be addressed. Recent studies have found that myocardial energy metabolism was closely related to heart failure, in which substrate utilization, as well as intermediate metabolism disorders, insulin resistance, oxidative stress, and mitochondrial dysfunction, might underlie systolic dysfunction and progression of HF. This article centers on the changes and counteraction of cardiac energy metabolism in the failing heart. Therefore, targeting impaired energy provision is of great potential in the treatment of HF. And shifting the objective from traditional neurohormones to improving the cellular environment is expected to further optimize the management of HF.

The variation in crown-root morphology of anterior teeth assessed with cone-beam computed tomography.

OBJECTIVE: To determine the discrepancy of crown-root morphology of anterior teeth, using cone-beam computed tomography (CBCT), and to provide a guidance for proper torque expression. METHODS: A total of eligible 200 CBCT were imported into Invivo v. 5.4 software, to obtain the middle labio-lingual sections of anterior teeth. AutoCAD 2007 software was applied to measure the crown-root angulation (Collum angle) and the angle formed by a tangent to the center of the labial surface and the long axis of the crown (labial surface angle). SPSS 18.0 was used for statistical comparisons of the two measurements, at the level of p< 0.05, and the Pearson correlation analysis was applied to investigate the association between the two measurements. RESULTS: The value of Collum angle in maxillary central incisor was close to 0°. Significantly negative Collum angle in lateral incisors and maxillary canine, and positive value in mandibular canine were detected (p < 0.001). The labial surface angle in canine was significantly greater than the intra-arch incisors (p< 0.001), and no significant difference was detected between the central and lateral incisors (p > 0.05). Notably, there was also a significant positive correlation between the two measurements. CONCLUSIONS: The crown-root angulations were greatly different among anterior teeth. Accompanying the obvious crown-root angulations, the canines both in maxillary and mandibular arches presented considerable labial surface curvatures. Hence, equivalent deviation during bracket bonding might cause greater torque expression error and increase the risk of alveolar fenestration and dehiscence.

The variation in crown-root morphology of anterior teeth assessed with cone-beam computed tomography

ABSTRACT Objective: To determine the discrepancy of crown-root morphology of anterior teeth, using cone-beam computed tomography (CBCT), and to provide a guidance for proper torque expression. Methods: A total of eligible 200 CBCT were imported into Invivo v. 5.4 software, to obtain the middle labio-lingual sections of anterior teeth. AutoCAD 2007 software was applied to measure the crown-root angulation (Collum angle) and the angle formed by a tangent to the center of the labial surface and the long axis of the crown (labial surface angle). SPSS 18.0 was used for statistical comparisons of the two measurements, at the level of p< 0.05, and the Pearson correlation analysis was applied to investigate the association between the two measurements. Results: The value of Collum angle in maxillary central incisor was close to 0°. Significantly negative Collum angle in lateral incisors and maxillary canine, and positive value in mandibular canine were detected (p < 0.001). The labial surface angle in canine was significantly greater than the intra-arch incisors (p< 0.001), and no significant difference was detected between the central and lateral incisors (p > 0.05). Notably, there was also a significant positive correlation between the two measurements. Conclusions: The crown-root angulations were greatly different among anterior teeth. Accompanying the obvious crown-root angulations, the canines both in maxillary and mandibular arches presented considerable labial surface curvatures. Hence, equivalent deviation during bracket bonding might cause greater torque expression error and increase the risk of alveolar fenestration and dehiscence.

RESUMO Objetivo: Determinar a discrepância na morfologia coroa-raiz de dentes anteriores, utilizando tomografia computadorizada de feixe cônico (TCFC), e fornecer parâmetros para a expressão apropriada do torque. Método: No total, 200 tomografias elegíveis foram importadas para o software Invivo 5.4 para obtenção das secções médias vestibulolinguais dos dentes anteriores. Osoftware AutoCAD 2007 foi usado para medir a angulação coroa-raiz (ângulo Collum) e o ângulo formado por uma tangente ao centro da superfície vestibular da coroa e o longo eixo da coroa (ângulo da superfície vestibular). O software SPSS 18.0 foi utilizado para as comparações estatísticas das duas medições, com nível de significância de p< 0,05, e a análise de correlação de Pearson foi aplicada para investigar a associação entre as duas medições. Resultados: O valor do ângulo Collum do incisivo central superior foi próximo a 0°. Foram detectados valores significativamente negativos para o ângulo Collum nos incisivos laterais e caninos superiores, mas valores positivos nos caninos inferiores (p< 0,001). O ângulo da superfície vestibular no canino foi significativamente maior do que nos incisivos intra-arcada (p< 0,001), e nenhuma diferença significativa foi detectada entre incisivos centrais e laterais (p> 0,05). Também foi observada uma correlação positiva significativa entre as duas medições. Conclusões: As angulações coroa-raiz foram muito diferentes entre os dentes anteriores. Os caninos superiores e inferiores apresentaram considerável curvatura na superfície vestibular, associada a uma evidente angulação coroa-raiz. Consequentemente, desvios durante a colagem de braquetes podem desencadear maior erro na expressão de torque e aumentar o risco de fenestração alveolar e deiscência, sendo necessária uma avaliação antes da colagem.

Discovery of the fossil otter Enhydritherium terraenovae (Carnivora, Mammalia) in Mexico reconciles a palaeozoogeographic mystery.

The North American fossil otter Enhydritherium terraenovae is thought to be partially convergent in ecological niche with the living sea otter Enhydra lutris, both having low-crowned crushing teeth and a close association with marine environments. Fossil records of Enhydritherium are found in mostly marginal marine deposits in California and Florida; despite presence of very rich records of fossil terrestrial mammals in contemporaneous localities inland, no Enhydritherium fossils are hitherto known in interior North America. Here we report the first occurrence of Enhydritherium outside of Florida and California, in a land-locked terrestrial mammal fauna of the upper Miocene deposits of Juchipila Basin, Zacatecas State, Mexico. This new occurrence of Enhydritherium is at least 200 km from the modern Pacific coastline, and nearly 600 km from the Gulf of Mexico. Besides providing further evidence that Enhydritherium was not dependent on coastal marine environments as originally interpreted, this discovery leads us to propose a new east-to-west dispersal route between the Florida and California Enhydritherium populations through central Mexico. The proximity of the fossil locality to nearby populations of modern neotropical otters Lontra longicaudis suggests that trans-Mexican freshwater corridors for vertebrate species in riparian habitats may have persisted for a prolonged period of time, pre-dating the Great American Biotic Interchange.

Electronic medical records and genomics (eMERGE) network exploration in cataract: several new potential susceptibility loci.

PURPOSE: Cataract is the leading cause of blindness in the world, and in the United States accounts for approximately 60% of Medicare costs related to vision. The purpose of this study was to identify genetic markers for age-related cataract through a genome-wide association study (GWAS). METHODS: In the electronic medical records and genomics (eMERGE) network, we ran an electronic phenotyping algorithm on individuals in each of five sites with electronic medical records linked to DNA biobanks. We performed a GWAS using 530,101 SNPs from the Illumina 660W-Quad in a total of 7,397 individuals (5,503 cases and 1,894 controls). We also performed an age-at-diagnosis case-only analysis. RESULTS: We identified several statistically significant associations with age-related cataract (45 SNPs) as well as age at diagnosis (44 SNPs). The 45 SNPs associated with cataract at p<1×10(-5) are in several interesting genes, including ALDOB, MAP3K1, and MEF2C. All have potential biologic relationships with cataracts. CONCLUSIONS: This is the first genome-wide association study of age-related cataract, and several regions of interest have been identified. The eMERGE network has pioneered the exploration of genomic associations in biobanks linked to electronic health records, and this study is another example of the utility of such resources. Explorations of age-related cataract including validation and replication of the association results identified herein are needed in future studies.