Characterization of Two Ferroptosis Subtypes With Distinct Immune Infiltration and Gender Difference in Gastric Cancer

Background: Iron is an essential nutrient involved in the redox cycle and the formation of free radicals. The reprogramming of iron metabolism is the main link to tumor cell survival. Ferroptosis is an iron-dependent form of regulated cell death associated with cancer; the characteristics of ferroptosis in cancers are still uncertain. This study aimed to explore the application value and gender difference of ferroptosis in prognosis and immune prediction to provide clues for targeted therapy of gastric cancer.Methods: We comprehensively evaluated the ferroptosis levels of 1,404 gastric cancer samples from six independent GC cohorts based on ferroptosis-related specific genes and systematically correlated ferroptosis with immune cell infiltrating and gender characteristics. The ferroptosis score was constructed to quantify the ferroptosis levels of individual tumors using principal component analysis (PCA) algorithms.Results: We identified two distinct ferroptosis subtypes in gastric cancer, namely Subtype-A and Subtype-B. We found that male patients in Subtype-B had the worst prognosis in contrast with the other groups. Three sex hormone receptors (AR, ER, and PR) in Subtype-B tumor patients were higher than in Subtype-A tumor patients in GC, while the HER2 displayed an opposite trend. We developed a risk model termed ferroptosis score to evaluate ferroptosis levels within individual tumors. The low-ferroptosis score group was characterized by activation of immune cells and increased mutation burden, which is also linked to increased neoantigen load and enhanced response to anti-PD-1/L1 immunotherapy. The patients with a low-ferroptosis score showed a high microsatellite instability status (MSI-H) and had a higher response to immunotherapy. Furthermore, the patients with low-ferroptosis scores have a lower estimated IC50 in the several chemotherapy drugs, including paclitaxel, gemcitabine, and methotrexate.Conclusions: We revealed that sex hormone receptors and immune cell infiltration were markedly different between ferroptosis subtypes in GC patients. The results suggested that gender difference may be critical when the ferroptosis-related strategy is applied in GC treatment. Further, ferroptosis levels were identified with an extreme variety of prognosis and tumor immune characteristics, which might benefit GC individualized treatment.

Systematic Analysis of an Invasion-Related 3-Gene Signature and Its Validation as a Prognostic Model for Pancreatic Cancer

BackgroundPancreatic adenocarcinoma (PAAD) is a malignant tumor of the digestive system that is associated with a poor prognosis in patients owing to its rapid progression and high invasiveness.MethodsNinety-seven invasive-related genes obtained from the CancerSEA database were clustered to obtain the molecular subtype of pancreatic cancer based on the RNA-sequencing (RNA-seq) data of The Cancer Genome Atlas (TCGA). The differentially expressed genes (DEGs) between subtypes were obtained using the limma package in R, and the multi-gene risk model based on DEGs was constructed by Lasso regression analysis. Independent datasets GSE57495 and GSE62452 were used to validate the prognostic value of the risk model. To further explore the expression of the hub genes, immunohistochemistry was performed on PAAD tissues obtained from a large cohort.ResultsThe TCGA-PAAD samples were divided into two subtypes based on the expression of the invasion-related genes: C1 and C2. Most genes were overexpressed in the C1 subtype. The C1 subtype was mainly enriched in tumor-related signaling pathways, and the prognosis of patients with the C1 subtype was significantly worse than those with the C2 subtype. A 3-gene signature consisting of LY6D, BCAT1, and ITGB6 based on 538 DEGs between both subtypes serves as a stable prognostic marker in patients with pancreatic cancer across multiple cohorts. LY6D, BCAT1, and ITGB6 were over-expressed in 120 PAAD samples compared to normal samples.ConclusionsThe constructed 3-gene signature can be used as a molecular marker to assess the prognostic risk in patients with PAAD.

Origin and evolution of HIV-1 subtype A6

Background HIV outbreaks in the Former Soviet Union (FSU) countries were characterized by repeated transmission of the HIV variant AFSU, which is now classified as a distinct subtype A sub-subtype called A6. The current study used phylogenetic/phylodynamic and signature mutation analyses to determine likely evolutionary relationship between subtype A6 and other subtype A sub-subtypes. Methods For this study, an initial Maximum Likelihood phylogenetic analysis was performed using a total of 553 full-length, publicly available, reverse transcriptase sequences, from A1, A2, A3, A4, A5, and A6 sub-subtypes of subtype A. For phylogenetic clustering and signature mutation analysis, a total of 5961 and 3959 pol and env sequences, respectively, were used. Results Phylogenetic and signature mutation analysis showed that HIV-1 sub-subtype A6 likely originated from sub-subtype A1 of African origin. A6 and A1 pol and env genes shared several signature mutations that indicate genetic similarity between the two subtypes. For A6, tMRCA dated to 1975, 15 years later than that of A1. Conclusion The current study provides insights into the evolution and diversification of A6 in the backdrop of FSU countries and indicates that A6 in FSU countries evolved from A1 of African origin and is getting bridged outside the FSU region.

The Distinct Impact of TAM Infiltration on the Prognosis of Patients With Cardia and Non-Cardia Gastric Cancer and Its Association With H. pylori Infection

BackgroundIn stage III gastric cancer (GC), the role of tumor-associated macrophages (TAMs) and Helicobacter pylori (H. pylori) infection impact tumor progression; however, the specific mechanisms remain controversial. We speculated whether this controversy is caused by differences in the location of TAM infiltration (in the core (CT) and invasive margin (MI) of primary tumors) and the topographical subsites of GC (cardia and non-cardia). Therefore, in this study, we investigated TAMs in different locations and H. pylori infection status as prognostic biomarkers for GC.MethodsImmunohistochemical staining for CD68 (pan-macrophage), CD163 (M2-like macrophage), and H. pylori in 200 samples (100 cases of cardia-GC [CGC] and 100 cases of non-cardia GC [NCGC]) was performed. We compared the number of CD68+ and CD163+ macrophages that infiltrated the CT and MI in patients with the prognosis of CGC and NCGC, respectively. In addition, we analyzed the relationship between H. pylori status and the prognosis of patients with GC in different locations, as well as the correlation with TAM infiltration.ResultsThe distribution of TAMs had distinct characteristics in CGC and NCGC, especially differences between CT and MI subtype. A Kaplan–Meier analysis showed that a high number of CD68+ macrophages that infiltrated the CT in CGC was associated with a better prognosis, whereas infiltration at the MI in NCGC indicated a poor prognosis. Furthermore, a high number of CD163+ macrophages infiltrating the MI resulted in a poor prognosis in CGC and NCGC cohorts. Considering the larger differences in the relationship between the infiltration of CD68+ macrophages at different locations and prognosis, we divided the GC cases into marginal and central GC, based on this difference. This resulted in an accurate estimation of the prognosis. Moreover, positive H. pylori status in central GC was significantly associated with a better prognosis and TAM infiltration.ConclusionTAMs in different locations and H. pylori status were identified as independent prognostic markers, with an obvious correlation between them. Therefore, it is important to clarify the impact of TAM location on the prognosis of patients with GC, which contributes to the development of potential therapeutic strategies.

Identification of Immune-Related lncRNA Prognostic Signature and Molecular Subtypes for Glioblastoma

BackgroundGlioblastoma multiforme (GBM) is extensively genetically and transcriptionally heterogeneous, which poses challenges for classification and management. Long noncoding RNAs (lncRNAs) play a critical role in the development and progression of GBM, especially in tumor-associated immune processes. Therefore, it is necessary to develop an immune-related lncRNAs (irlncRNAs) signature.MethodsUnivariate and multivariate Cox regression analyses were utilized to construct a prognostic model. GBM-specific CeRNA and PPI network was constructed to predict lncRNAs targets and evaluate the interactions of immune mRNAs translated proteins. GO and KEGG pathway analyses were used to show the biological functions and pathways of CeRNA network-related immunity genes. Consensus Cluster Plus analysis was used for GBM gene clustering. Then, we evaluated GBM subtype-specific prognostic values, clinical characteristics, genes and pathways, immune infiltration access single cell RNA-seq data, and chemotherapeutics efficacy. The hub genes were finally validated.ResultsA total of 17 prognostically related irlncRNAs were screened to build a prognostic model signature based on six key irlncRNAs. Based on GBM-specific CeRNAs and enrichment analysis, PLAU was predicted as a target of lncRNA-H19 and mainly enriched in the malignant related pathways. GBM subtype-A displayed the most favorable prognosis, high proportion of genes (IDH1, ATRX, and EGFR) mutation, chemoradiotherapy, and low risk and was characterized by low expression of four high-risk lncRNAs (H19, HOTAIRM1, AGAP2-AS1, and AC002456.1) and one mRNA KRT8. GSs with poor survival were mainly infiltrated by mesenchymal stem cells (MSCs) and astrocyte, and were more sensitive to gefitinib and roscovitine. Among GSs, three hub genes KRT8, NGFR, and TCEA3, were screened and validated to potentially play feasible oncogenic roles in GBM.ConclusionConstruction of lncRNAs risk model and identification of GBM subtypes based on 17 irlncRNAs, which suggesting that irlncRNAs had the promising potential for clinical immunotherapy of GBM.

Gummy Smile Treatment by Aesthetic Crown Lengthening on Altered Passive Eruption Case

An attractive smile enhances the appearance and acceptance of an individual in society. Gum exposure more than 3 mm is generally considered unattractive and known as a gummy smile, which is usually considered an aesthetic problem. At present, patients have a greater desire for more aesthetic results that may influence the planning of dental treatments. This case report aimed to describe the surgical sequence of aesthetic crown lengthening to improve smile profile and eliminate gummy smile. We reported a 21-year-old non-smoking woman with no pertinent medical history who presented with a chief complaint of an unattractive smile due to excessive gingival display. The gingival display in the smile was 5 mm, and the width to height ratio of the central incisor was 121%. Neither periodontal problems nor teeth mobility was detected. Assessment for the condition was excessive gingival display due to altered passive eruption. The overall prognosis for this case was good. The primary treatment plan proposed to the patient was an aesthetic crown lengthening. Altered passive eruption class I subtype A was a case conclusion, and aesthetic crown lengthening with gingivectomy without osseous reduction was the selected treatment. In conclusion, aesthetic crown lengthening should be considered as a surgical component of aesthetic therapy to improve smile profile and eliminate gummy smile.

Geographic patterns of koala retrovirus genetic diversity, endogenization and subtype distributions

Koala retrovirus subtype A is the youngest endogenized retrovirus, providing a unique system to elucidate retroviral-host co-evolution. We characterised KoRV geography using faecal DNA from 192 samples across 20 populations throughout the koala’s range. We reveal an abrupt change in KoRV genetics and incidence at the Victoria/NSW state border. In northern koalas, pol gene copies were ubiquitously present at greater than 5 per-cell, consistent with endogenous KoRV. In southern koalas, pol copies were detected in only 25.8% of koalas and always at copy numbers less than one, while the env gene was detected in all animals and in a majority at copy numbers of greater than one per-cell. These results suggest that southern koalas carry partial endogenous KoRV-like sequences. Deep sequencing of the env hypervariable region revealed three putatively endogenous KoRV-A sequences in northern koalas and a single, distinct sequence present in all southern koalas. Among northern populations, env sequence diversity decreased with distance from the equator, suggesting infectious KoRV-A invaded the koala genome in northern Australia and then spread south. The previously described exogenous KoRV subtypes (B-K), two novel subtypes (L and M), and intermediate or hybrid subtypes were detected in all northern koala populations but strikingly absent from all southern animals tested. Apart from KoRV-D, these exogenous subtypes were generally locally prevalent but geographically restricted, producing KoRV genetic differentiation among northern populations. This suggests that sporadic evolution and local transmission of the exogenous subtypes has occurred within northern Australia, but this has not extended into animals within southern Australia.