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ObjectivesRecently, an increasing number of studies have revealed that N6-methyladenosine (m6A) functions as a significant post-transcriptional modification which plays a critical role in the occurrence and progression of enriched tumors by regulating coding and non-coding RNA biogenesis. However, the biological function of m6A in breast cancer remains largely unclear.Materials and MethodsIn this study, we used a series of bioinformatic databases and tools to jointly analyze the expression of m6A methylation transferases (METTL3, METTL14, WTAP, RBM15, RBM15B and ZC3H13) and investigate the prognostic value of METTL14 and ZC3H13 in breast cancer. Besides, we analyzed the downstream carcinogenic molecular mechanisms related to METTL14 and ZC3H13 and their relationship with immune infiltration in breast tumor tissues.ResultsThe results showed that METTL14 and ZC3H13 were the down-regulated m6A methylation transferases in breast cancer. Survival outcome analysis suggested that abnormally low expression of METTL14 and ZC3H13 could predict unfavorable prognosis in four breast cancer subtypes. Moreover, their down-regulation was associated with ER-, PR- and triple-negative breast cancer patients, as well as tumor progression (increased Scarff, Bloom and Richardson grade status and Nottingham Prognostic Index classification). Co-expression analysis revealed that METTL14 and ZC3H13 had a strong positive correlation with APC, an antagonist of the Wnt signaling pathway, indicating they might cooperate in regulating proliferation, invasion, and metastasis of tumor cells. METTL14, ZC3H13, and APC expression levels had significant positive correlation with infiltrating levels of CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells, and negative correlation with Treg cells in breast cancer.ConclusionsThis study demonstrated that down-regulation of METTL14 and ZC3H13 which act as two tumor suppressor genes was found in breast cancer and predicted poor prognosis. Their abnormal expression promoted breast cancer invasion by affecting pathways related to tumor progression and mediating immunosuppression.

This investigation elucidated the underlying mechanisms of functional impairments in patients with heart failure (HF) by simultaneously comparing cardiac-cerebral-muscle hemodynamic and ventilatory responses to exercise among HF patients with various functional capacities. One hundred one patients with HF [New York Heart Association HF functional class II (HF-II, n = 53) and functional class III (HF-III, n = 48) patients] and 71 normal subjects [older control (O-C, n = 39) and younger control (Y-C, n = 32) adults] performed an incremental exercise test using a bicycle ergometer. A recently developed noninvasive bioreactance device was adopted to measure cardiac hemodynamics, and near-infrared spectroscopy was employed to assess perfusions in the frontal cerebral lobe (Δ[THb](FC)) and vastus lateralis muscle (Δ[THb](VL)). The results demonstrated that the Y-C group had higher levels of cardiac output, Δ[THb](FC), and Δ[THb](VL) during exercise than the O-C group. Moreover, these cardiac/peripheral hemodynamic responses to exercise in HF-III group were smaller than those in both HF-II and O-C groups. Although the change of cardiac output caused by exercise was normalized, the amounts of blood distributed to frontal cerebral lobe and vastus lateralis muscle in the HF-III group significantly declined during exercise. The HF-III patients had lower oxygen-uptake efficiency slopes (OUES) and greater Ve-Vo(2) slopes than the HF-II patients and age-matched controls. However, neither hemodynamic nor ventilatory response to exercise differed significantly between the HF-II and O-C groups. Cardiac output, Δ[THb](FC), and Δ[THb](VL) during exercise were directly related to the OUES and Vo(2peak) and inversely related to the Ve-Vco(2) slope. Moreover, cardiac output or Δ[THb](FC) was an effect modifier, which modulated the correlation status between Δ[THb](VL) and Ve-Vco(2) slope. We concluded that the suppression of cerebral/muscle hemodynamics during exercise is associated with ventilatory abnormality, which reduces functional capacity in patients with HF.

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Background: Acute xerostomia is the most common side effect of radiation therapy (RT) for head and neck (H&N) malignancies. Investigating radiation-induced changes of computed tomography (CT) radiomics in parotid glands (PGs) and saliva amount (SA) can predict acute xerostomia during the RT for nasopharyngeal cancer (NPC).Methods: CT and SA data from 35 patients with stages I-IVB were randomly collected from an NPC clinical trial registered on the clinicaltrials.gov (ID: NCT01762514). All patients received radical treatment based on intensity-modulated RT (IMRT) with a prescription dose of 68.1 Gy in 30 fractions. The patients' ages ranged 24-72 years, and each patient had five CT sets acquired at treatment position: at the 0 th , 10 th , 20 th , 30 th fractions during the RT, and at 3-month later after the RT. The PGs for each CT set were delineated by a radiation oncologist and verified independently by another. Patients' saliva was collected every other 10 days during the RT. Acute xerostomia was evaluated based on the RTOG acute toxicity scoring and the SA. In total, 1,703 radiomics features were calculated for PGs from each CT set, including feature value at 0 th fraction (FV 0F ), FV 10F , and delta FV (ΔFV 10F-0F ), respectively. Extensive experiments were conducted to achieve the optimal results. RidgeCV and Recursive Feature Elimination (RFE) were used for feature selection, while linear regression was used for predicting SA 30F . Four more patients were added for independent testing.Results: Substantial changes in various radiomics metrics of PGs were observed during the RT. Eight normalized feature value (NFV), selected from NFV 0F , predicted SA 10F with a mean square error (MSE) of 0.9042 and a R 2 score of 0.7406. Fourteen NFV, selected from ΔNFV 10F-0F , NFV 0F , and NFV 10F to predict SA 30F , showed the best predictive ability with an MSE of 0.0569. The model predicted the level of acute xerostomia with a precision of 0.9220 and a sensitivity of 100%, compared to the clinical observed SA. For the independent test, the MSE of PSA 30F was 0.0233. Conclusions:This study demonstrated that radiation-induced acute xerostomia level could be early predicted based on the SA and radiomics changes of the PGs during IMRT delivery. SA, NFV 0F , NFV 10F , and especially ΔNFV 10F-0F provided the best performance on acute xerostomia prediction for individual patient based on RidgeCV_RFE_LinearRegression method of delta radiomics.

ObjectiveMany primary tumors have insufficient supply of molecular oxygen, called hypoxia. Hypoxia is one of the leading characteristics of solid tumors resulting in a higher risk of local failure and distant metastasis. It is quite necessary to investigate the hypoxia associated molecular hallmarks in breast cancer.Materials and MethodsAccording to the published studies, we selected 13 hypoxia related gene expression signature to define the hypoxia status of breast cancer using ConsensusClusterPlus package based on the data from The Cancer Genome Atlas (TCGA). Subsequently, we characterized the infiltration of 24 immune cell types under different hypoxic conditions. Furthermore, the differentially expressed hypoxia associated microRNAs, mRNAs and related signaling pathways were analyzed and depicted. On this basis, a series of prognostic markers related to hypoxia were identified and ceRNA co-expression networks were constructed.ResultsTwo subgroups (cluster1 and cluster2) were identified and the 13 hypoxia related gene signature were all up-regulated in cluster1. Thus, we defined the cluster1 as “hypoxic subgroup” compared with cluster2. The infiltration of CD8+ T cell and CD4+ T cell were lower in cluster1 while the nTreg cell and iTreg cell were higher, indicating that there was immunosuppressive status in cluster1. We observed widespread hypoxia-associated dysregulation of microRNAs and mRNAs. Next, a risk signature for predicting prognosis of breast cancer patients was established based on 12 dysregulated hypoxia associated prognostic genes. Two microRNAs, hsa-miR-210-3p and hsa-miR-190b, with the most significant absolute logFC value were related to unfavorable and better prognosis, respectively. Several long non-coding RNAs were predicted to be microRNA targets and positively correlated with two selected mRNAs, CPEB2 and BCL11A. Predictions based on the SNHG16-hsa-miR-210-3p-CPEB2 and LINC00899/PSMG3-AS1/PAXIP-AS1-hsa-miR-190b-BCL11A ceRNA regulation networks indicated that the two genes might act as tumor suppressor and oncogene, respectively.ConclusionHypoxia plays an important role in the initiation and progression of breast cancer. Our research provides potential mechanisms into molecular-level understanding of tumor hypoxia.

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