Prognostic value of RNA methylation-related genes in gastric adenocarcinoma based on bioinformatics.

Background: Gastric cancer (GC) is a malignant tumor that originates from the epithelium of the gastric mucosa and has a poor prognosis. Stomach adenocarcinoma (STAD) covers 95% of total gastric cancer. This study aimed to identify the prognostic value of RNA methylation-related genes in gastric cancer. Methods: In this study, The Cancer Genome Atlas (TCGA)-STAD and GSE84426 cohorts were downloaded from public databases. Patients were classified by consistent cluster analysis based on prognosis-related differentially expressed RNA methylation genes Prognostic genes were obtained by differential expression, univariate Cox and least absolute shrinkage and selection operator (LASSO) analyses. The prognostic model was established and validated in the training set, test set and validation set respectively. Independent prognostic analysis was implemented. Finally, the expression of prognostic genes was affirmed by reverse transcription quantitative PCR (RT-qPCR). Results: In total, four prognostic genes (ACTA2, SAPCD2, PDK4 and APOD) related to RNA methylation were identified and enrolled into the risk signature. The STAD patients were divided into high- and low-risk groups based on the medium value of the risk score, and patients in the high-risk group had a poor prognosis. In addition, the RNA methylation-relevant risk signature was validated in the test and validation sets, and was authenticated as a reliable independent prognostic predictor. The nomogram was constructed based on the independent predictors to predict the 1/3/5-year survival probability of STAD patients. The gene set enrichment analysis (GSEA) result suggested that the poor prognosis in the high-risk subgroup may be related to immune-related pathways. Finally, the experimental results indicated that the expression trends of RNA methylation-relevant prognostic genes in gastric cancer cells were in agreement with the result of bioinformatics. Conclusion: Our study established a novel RNA methylation-related risk signature for STAD, which was of considerable significance for improving prognosis of STAD patients and offering theoretical support for clinical therapy.

Progression of Frailty and Cardiovascular Outcomes Among Medicare Beneficiaries.

Background: Frailty is associated with adverse cardiovascular outcomes independent of age and comorbidities, yet the independent influence of frailty progression remains uncertain. Methods: Medicare Fee-for-service beneficiaries ≥ 65 years at cohort inception with continuous enrollment from 2003-2015 were included. Frailty trajectory was measured by annualized change in a validated claims-based frailty index (CFI) over a 5-year period. Linear mixed effects models, adjusting for baseline frailty, were used to estimate CFI change over a 5-year period. Survival analysis was used to evaluate associations of frailty progression and future health outcomes (major adverse cardiovascular and cerebrovascular events [MACCE], all-cause death, heart failure, myocardial infarction, ischemic stroke, and days alive at home [DAH] within the following calendar year). Results: 26.4 million unique beneficiaries were included (mean age 75.4 ± 7.0 years, 57% female, 13% non-White). In total, 20% had frailty progression, 66% had no change in frailty, and 14% frailty regression over median follow-up of 2.4 years. Compared to those without a change in CFI, when adjusting for baseline frailty, those with frailty progression had significantly greater risk of incident MACCE (hazard ratio [HR] 2.30, 95% confidence interval [CI] 2.30-2.31), all-cause mortality (HR 1.59, 95% CI 1.58-1.59), acute myocardial infarction (HR 1.78, 95% CI 1.77-1.79), heart failure (HR 2.78, 95% CI 2.77-2.79), and stroke (HR 1.78, 95% CI 1.77-1.79). There was also a graded increase in risk of each outcome with more rapid progression and significantly fewer DAH with the most rapid vs. the slowest progression group (270.4 ± 112.3 vs. 308.6 ± 93.0 days, rate ratio 0.88, 95% CI 0.87-0.88, p < 0.001). Conclusions: In this large, nationwide sample of Medicare beneficiaries, frailty progression, independent of baseline frailty, was associated with fewer DAH and a graded risk of MACCE, all-cause mortality, myocardial infarction, heart failure, and stroke compared to those without progression.

Posttransplantation late complications increase over time for patients with SCID: A Primary Immune Deficiency Treatment Consortium (PIDTC) landmark study.

BACKGROUND: The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children in the United States and Canada onto a retrospective multicenter natural history study of hematopoietic cell transplantation (HCT). OBJECTIVE: We investigated outcomes of HCT for severe combined immunodeficiency (SCID). METHODS: We evaluated the chronic and late effects (CLE) after HCT for SCID in 399 patients transplanted from 1982 to 2012 at 32 PIDTC centers. Eligibility criteria included survival to at least 2 years after HCT without need for subsequent cellular therapy. CLE were defined as either conditions present at any time before 2 years from HCT that remained unresolved (chronic), or new conditions that developed beyond 2 years after HCT (late). RESULTS: The cumulative incidence of CLE was 25% in those alive at 2 years, increasing to 41% at 15 years after HCT. CLE were most prevalent in the neurologic (9%), neurodevelopmental (8%), and dental (8%) categories. Chemotherapy-based conditioning was associated with decreased-height z score at 2 to 5 years after HCT (P < .001), and with endocrine (P < .001) and dental (P = .05) CLE. CD4 count of ≤500 cells/µL and/or continued need for immunoglobulin replacement therapy >2 years after transplantation were associated with lower-height z scores. Continued survival from 2 to 15 years after HCT was 90%. The presence of any CLE was associated with increased risk of late death (hazard ratio, 7.21; 95% confidence interval, 2.71-19.18; P < .001). CONCLUSION: Late morbidity after HCT for SCID was substantial, with an adverse impact on overall survival. This study provides evidence for development of survivorship guidelines based on disease characteristics and treatment exposure for patients after HCT for SCID.

Cardiovascular Hospitalizations and Mortality Among Adults Aged 25 to 64 years in the United States.

BACKGROUND AND AIMS: Declines in cardiovascular mortality have stagnated in the United States since 2011. There is growing concern that these patterns reflect worsening cardiovascular health in younger adults. However, little is known about how the burden of acute cardiovascular hospitalizations and mortality have changed in this population. Changes in cardiovascular hospitalizations and mortality among adults aged 25-64 years were evaluated, overall and by community-level income. METHODS: Using the National Inpatient Sample, age-standardized annual hospitalization and inhospital mortality rates for acute myocardial infarction (AMI), heart failure, and ischemic stroke were determined among adults aged 25-64 years. Quasi-Poisson and quasi-binominal regression models were fitted to compare outcomes between individuals residing in low- and higher-income communities. RESULTS: Between 2008 and 2019, age-standardized hospitalization rates for AMI increased among younger adults from 155.0 (95% CI 154.6, 155.4) per 100,000 to 160.7 (160.3, 161.1) per 100,000 (absolute change +5.7 [5.0, 6.3], p<0.001). Heart failure hospitalizations also increased (165.3 [164.8, 165.7] to 225.3 [224.8, 225.8], absolute change +60.0 (59.3, 60.6), p<0.001), as ischemic stroke hospitalizations (76.3 [76.1, 76.7] to 108.1 [107.8, 108.5], absolute change +31.7 (31.2, 32.2), p<0.001). Across all conditions, hospitalizations rates were significantly higher among younger adults residing in low-income compared with higher-income communities, and disparities did not narrow between groups. In-hospital mortality decreased for all conditions over the study period. CONCLUSIONS: There was an alarming increase in cardiovascular hospitalizations among younger adults in the US from 2008 to 2019, and disparities between those residing in low- and higher-income communities did not narrow.

16S full-length gene sequencing analysis of intestinal flora in breast cancer patients in Hainan Province.

Breast cancer has become the number one cancer in the world, and intestinal flora may be closely linked to it. Geographic location also has an important impact on human intestinal flora. We conducted the first study on the intestinal flora of breast cancer patients and non-breast cancer patients in a tropical region - Hainan Province in China. At the same time, Pacbio platform based on third-generation sequencing was used for the first time to conduct 16S full-length sequencing of fecal microorganism DNA. We completed the species diversity analysis and differential species analysis of the intestinal flora between the two groups, inferred their functional genetic composition and performed functional difference analysis. There were statistically significant differences in alpha diversity between the two groups in Hainan Province. By species composition difference analysis, at the phylum level, Bacteroidales (P = 0.006) and Firmicutes (P = 0.002) was differed between the two groups, and at the genus level, 17 breast cancer-related differential species such as Bacteroides were screened. According to the five grouping methods including ER level, PR level, HER2 status, Ki67 index and histological grade of breast cancer patients, 4, 1, 9, 6, 5 differential microbiota were screened out respectively, which were in total 25 (P < 0.05 for all subgroups) . The functional prediction and difference analysis revealed two functional metabolisms with significant differences between the two groups of microbes (P < 0.05). These results suggest that breast cancer is associated with changes in the composition and function of intestinal flora. These microflora and functional differences may become biomarkers or new targets for diagnosis and treatment of breast cancer.

Breast cancer-derived exosomal lncRNA SNHG14 induces normal fibroblast activation to cancer-associated fibroblasts via the EBF1/FAM171A1 axis.

BACKGROUND: Exosomes released from cancer cells can activate normal fibroblasts (NFs) into cancer-associated fibroblasts (CAFs), which promotes cancer development. Our study aims to explore the role and potential mechanisms of breast cancer exosomes-delivered long non-coding RNA (lncRNA) SNHG14 in regulating CAFs transformation. METHODS: Adjacent normal tissues, cancerous and serum specimens were gathered in breast cancer patients. Exosomes and NFs were separated from breast cancer cells (SKBR-3) and normal tissues of patients, respectively. Cell viability and migration were measured with CCK-8 and Transwell assays. CAFs markers, fibroblast activation protein (FAP) and a-smooth muscle actin (α-SMA) were detected for assessing CAFs activation. The interactions between molecules were evaluated using dual luciferase reporter assay, RNA immunoprecipitation and chromatin immunoprecipitation. RESULTS: SNHG14 and FAM171A1 were upregulated in breast cancer. Exosomes secreted by SKBR-3 cells induced NFs activation in CAFs, as indicated by upregulating CAFs marker levels and facilitated cell viability and migration. Exosomal SNHG14 silencing in SKBR-3 cells inhibited CAFs activation. SNHG14 positively regulated FAM171A1 expression through EBF1. FAM171A1 overexpression eliminated the inhibition effect of exosomal SNHG14 silencing in CAFs transformation. CONCLUSION: Breast cancer-derived exosomal SNHG14 contributed to NFs transformation into CAFs by the EBF1/FAM171A1 axis.

Cardiovascular hospitalizations for Medicare advantage beneficiaries in the United States, 2009 to 2019.

BACKGROUND: Federal programs measuring hospital quality of care for acute cardiovascular conditions are based solely on Medicare fee-for-service (FFS) beneficiaries, and exclude Medicare Advantage (MA) beneficiaries. In this study we characterize the proportion of Medicare beneficiaries enrolled in MA at the time of acute myocardial infarction (AMI), heart failure (HF), and ischemic stroke hospitalization. METHODS: Retrospective cross-sectional study of short-term acute care hospitals using Medicare claims in 2009 and 2019. RESULTS: There were 2,653 hospitals in 2009 and 2,732 hospitals in 2019. Across hospitals, the proportion of Medicare beneficiaries hospitalized for AMI who were enrolled in MA increased between 2009 (hospital-level median 14.4% [IQR 5.1%-26.0%]) and 2019 (33.3% [IQR 20.6%-45.2%]), with substantial variation across hospitals. Similar patterns were observed for HF (13.0% [IQR 5.3%-24.3%] to 31.0% [IQR 20.2%-42.3%]) and ischemic stroke (14.6% [IQR 5.3%-26.7%] to 33.3% [IQR 20.9%-46.0%]). Within each hospital referral region, hospital size (large 36.3% vs small 24.5%; adjusted difference 6.7%, 95% CI, 4.5%-8.8%), teaching status (teaching 34.5% vs nonteaching 28.2%; 2.8%, 1.4%-4.1%), and ownership status (private nonprofit 32.3% vs public 24.5%; 5.2%, 3.5%-6.9%) were each associated with a higher hospital MA proportion. CONCLUSIONS: The proportion of Medicare beneficiaries hospitalized for AMI, HF, and ischemic stroke enrolled in MA doubled between 2009 and 2019, with substantial variation across hospitals. These findings have implications for federal efforts to measure and improve quality, which currently focus only on FFS beneficiaries.

Pathological complete response rate and clinical outcome after neoadjuvant therapy of HER2-low breast cancer: A National Cancer Database Analysis.

BACKGROUND: The interest in breast cancer with low HER2 expression as a distinct subtype is increasing. We aimed to explore the differences between HER2-low and HER2-zero breast cancer in their prognosis and rate of pathological complete response (pCR) after neoadjuvant therapy. METHODS: The National Cancer Database (NCDB) was used to select patients with breast cancer who received neoadjuvant therapy from 2004 to 2017. Logistic regression model was constructed for analysis of pCR. Cox proportional hazards regression model and Kaplan-Meier method were used for survival analysis. RESULTS: A total of 41500 breast cancer patients were included, among which 14814 (35.7%) had HER2-zero tumors and 26686 (64.3%) had HER2-low. HER2-low tumors were more commonly HR-positive in comparison with HER2-zero (66.3% versus 47.1%, P < 0.001). A lower rate of pCR was observed in HER2-low tumors than in HER2-zero tumors after neoadjuvant therapy in the total cohort (OR = 0.90; 95% CI [0.86-0.95]; P < 0.001) and in the subset of HR-positive (OR = 0.87; 95% CI [0.81-0.94]; P < 0.001). Patients with HER2-low tumors had a significantly superior survival than those with HER2-zero tumors (HR = 0.90; 95% CI [0.86-0.94]; P < 0.001), regardless of the HR status. Additionally, a marginal survival difference was also observed between HER2 IHC1+ and HER2 IHC2+/ISH-negative (HR = 0.91; 95% CI [0.85-0.97]; P = 0.003) cohorts. CONCLUSION: HER2-low tumors are a clinically relevant breast cancer subtype that is distinct from HER2-zero tumors. These findings may provide clues to appropriate therapeutic strategies for this subtype in the future.

Exploration of prognostic genes and risk signature in breast cancer patients based on RNA binding proteins associated with ferroptosis.

Background: Breast cancer (BRCA) is a life-threatening malignancy in women with an unsatisfactory prognosis. The purpose of this study was to explore the prognostic biomarkers and a risk signature based on ferroptosis-related RNA-binding proteins (FR-RBPs). Methods: FR-RBPs were identified using Spearman correlation analysis. Differentially expressed genes (DEGs) were identified by the "limma" R package. The univariate Cox and multivariate Cox analyses were executed to determine the prognostic genes. The risk signature was constructed and verified with the training set, testing set, and validation set. Mutation analysis, immune checkpoint expression analysis in high- and low-risk groups, and correlation between risk signature and chemotherapeutic agents were conducted using the "maftools" package, "ggplot2" package, and the CellMiner database respectively. The Human Protein Atlas (HPA) database was employed to confirm protein expression trends of prognostic genes in BRCA and normal tissues. The expression of prognostic genes in cell lines was verified by Real-time quantitative polymerase chain reaction (RT-qPCR). Kaplan-meier (KM) plotter database analysis was applied to predict the correlation between the expression levels of signature genes and survival statuses. Results: Five prognostic genes (GSPT2, RNASE1, TIPARP, TSEN54, and SAMD4A) to construct an FR-RBPs-related risk signature were identified and the risk signature was validated by the International Cancer Genome Consortium (ICGC) cohort. Univariate and multivariate Cox regression analysis demonstrated the risk score was a robust independent prognostic factor in overall survival prediction. The Tumor Mutational Burden (TMB) analysis implied that the high- and low-risk groups responded differently to immunotherapy. Drug sensitivity analysis suggested that the risk signature may serve as a chemosensitivity predictor. The results of GSEA suggested that five prognostic genes might be related to DNA replication and the immune-related pathways. RT-qPCR results demonstrated that the expression trends of prognostic genes in cell lines were consistent with the results from public databases. KM plotter database analysis suggested that high expression levels of GSPT2, RNASE1, and SAMD4A contributed to poor prognoses. Conclusion: In conclusion, this study identified the FR-RBPs-related prognostic genes and developed an FR-RBPs-related risk signature for the prognosis of BRCA, which will be of great significance in developing new therapeutic targets and prognostic molecular biomarkers for BRCA.

Quantifying the impact of reduced opioid use in patients after emergency laparotomy.

BACKGROUND: Emergency laparotomies have high rates of morbidity and mortality. The evaluation and management of pain are crucial, as poorly managed pain may contribute to postoperative complications and increase the risk of mortality. This study aims to describe the relationship between opioid use and opioid-related adverse effects and identify what constitutes appropriate dose reductions to elicit clinically relevant benefits. METHODS: This was a retrospective, observational study of patients presenting for emergency laparotomy due to trauma from 2014 to 2018. The primary objective was to define clinical outcomes that may be significantly affected by changes in milligrams of morphine equivalent during the first 72 hours postoperatively; additionally, we sought to quantify the approximate differences in morphine equivalent that correlate with clinically meaningful outcomes such as hospital length of stay, pain scores, and time to first bowel movement. For descriptive summaries, patients were categorized into low, moderate, and high groups based on morphine equivalent requirements of 0 to 25, 25 to 50, and >50, respectively. RESULTS: A total of 102 (35%), 84 (29%), and 105 (36%) patients were stratified into the low, moderate, and high groups, respectively. Mean pain scores for postoperative days 0 to 3 (P = .034), time to first bowel movement (P = .002), and nasogastric tube duration (P = .003) were the clinical outcomes found to be significantly associated with morphine equivalent. Estimated clinically significant reductions in morphine equivalent for these outcomes ranged from 194 to 464. CONCLUSION: Clinical outcomes, such as pain scores, and opioid-related adverse effects, such as time to first bowel movement and nasogastric tube duration, may be linked with the amount of opioids used.

Extracorporeal membrane oxygenation for COVID-19: An evolving experience through multiple waves.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has shown variable results in COVID-19 pneumonia however, some evidence supports benefit. Here we compare our institution's ECMO outcomes across multiple waves of the COVID-19 pandemic. METHODS: All patients who received ECMO for COVID-19 between March 1, 2020, and March 1, 2021, were reviewed. Patients received venovenous (VV) or right ventricular assist device (RVAD/ECMO) ECMO. Early (March 1-July 6, 2020, Era 1) and late (July 7, 2020-March 1, 2021, Era 2) pandemic RVAD/ECMO patients were compared. RESULTS: Fifty-four patients received ECMO of which 16 (29.6%) patients received VV ECMO and 38 (70.4%) RVAD/ECMO. Median age was 53.0 years, body mass index 36.1 kg/m2 , 41.2% female, and 49% Caucasian. The most common pre-cannulation treatments included steroids (79.6%) and convalescent plasma (70.4%). Median time from admission to cannulation was 7.0 days. Median support time was 30.5 days (VV ECMO 35.0 days, RVAD/ECMO 26.0 days). In- hospital mortality was 42.6% (39.5% RVAD/ECMO, 50.0% VV ECMO). Significant morbidities included infection (80.8%), bleeding events (74.5%), and renal replacement therapy (30.8%). Cumulative mortality 120-days post-cannulation was 45.7% (VV ECMO 60.8%, RVAD/ECMO 40.0%). RVAD/ECMO Era 1 demonstrated a significantly lower cumulative mortality (16.2%) compared to Era 2 (60.4%). Competing risk analysis found age (HR 0.95, [95% CI 0.92, 0.98] p = 0.005) to be a protective factor for survival. CONCLUSION: ECMO support for COVID-19 is beneficial but carries significant morbidity. RVAD/ECMO support demonstrated consistent advantages in survival to VV-ECMO, but with declining efficacy across time during the COVID-19 pandemic.

Corrigendum: Upregulation of CCT-3 Induces Breast Cancer Cell Proliferation Through miR-223 Competition and Wnt/b-Catenin Signaling Pathway Activation.

[This corrects the article DOI: 10.3389/fonc.2020.533176.].

[Retracted] Exosome-mediated transfer of lncRNA­SNHG14 promotes trastuzumab chemoresistance in breast cancer.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the TUNEL assay data shown in Fig. 6C were strikingly similar to images that had already appeared in Fig. 8B in another article that appeared in the journal Oncotarget [Chen W, Xu X-K, Li J-L, Kong K-K, Li H, Chen C, He J, Wang F, Li P, Ge X-S and Li F-C: MALAT1 is a prognostic factor in glioblastoma multiforme and induces chemoresistance to temozolomide through suppressing miR-203 and promoting thymidylate synthase expression. Oncotarget 8: 22783-22799, 2017]. Owing to the fact that the contentious data in the above article had already been published elsewhere prior to its submission to International Journal of Oncology, the Editor has decided that this paper should be retracted from the Journal on account of a lack of confidence in the presented data. The authors did provide an explanation to account for the duplication of the data, although this was not accepted by the Editorial Board. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 53: 1013-1026, 2018; DOI: 10.3892/ijo.2018.4467].