Investigation of correlation between shear wave elastography and lymphangiogenesis in invasive breast cancer and diagnosis of axillary lymph node metastasis.

BACKGROUND: Accurate evaluation of axillary lymph node metastasis (LNM) in breast cancer is very important. A large number of hyperplastic and dilated lymphangiogenesis cases can usually be found in the pericancerous tissue of breast cancer to promote the occurrence of tumor metastasis.Shear wave elastography (SWE) can be used as an important means for evaluating pericancerous stiffness. We determined the stiffness of the pericancerous by SWE to diagnose LNM and lymphangiogenesis in invasive breast cancer (IBC). METHODS: Patients with clinical T1-T2 stage IBC who received surgical treatment in our hospital from June 2020 to December 2020 were retrospectively enrolled. A total of 299 patients were eventually included in the preliminary study, which included an investigation of clinicopathological features, ultrasonic characteristics, and SWE parameters. Multivariable logistic regression analysis was used to establish diagnostic model and evaluated its diagnostic performance of LNM. The correlation among SWE values, collagen volume fraction (CVF), and microlymphatic density (MLD) in primary breast cancer lesions was analyzed in another 97 patients. RESULTS: The logistic regression model is Logit(P)=-1.878 + 0.992*LVI-2.010*posterior feature enhancement + 1.230*posterior feature shadowing + 0.102*posterior feature combined pattern + 0.009*Emax. The optimum cutoff value of the logistic regression model was 0.365, and the AUC (95% CI) was 0.697 (0.636-0.758); the sensitivity (70.7 vs. 54.3), positive predictive value (PPV) (54.0 vs. 50.8), negative predictive value (NPV) (76.9 vs. 69.7), and accuracy (65.2 vs. 61.9) were all higher than Emax. There was no correlation between the SWE parameters and MLD in primary breast cancer lesions. CONCLUSIONS: The logistic regression model can help us to determine LNM, thus providing more imaging basis for the selection of preoperative treatment. The SWE parameter of the primary breast cancer lesion cannot reflect the peritumoral lymphangiogenesis, and we still need to find a new ultrasonic imaging method.

Metabolic phenotyping to monitor chronic enteritis canceration.

INTRODUCTION: Colorectal cancer (CRC) remains an incurable disease. Previous metabolomic studies show that metabolic signatures in plasma distinguish CRC patients from healthy controls. Chronic enteritis (CE) represents a risk factor for CRC, with a 20 fold greater incidence than in healthy individuals. However, no studies have performed metabolomic profiling to investigate CRC biomarkers in CE. OBJECTIVE: Our aims were to identify metabolomic signatures in CRC and CE and to search for blood-derived metabolite biomarkers distinguishing CRC from CE, especially early-stage biomarkers. METHODS: In this case-control study, 612 subjects were prospectively recruited between May 2015 and May 2016, and including 539 CRC patients (stage I, 102 cases; stage II, 259 cases; stage III, 178 cases) and 73 CE patients. Untargeted metabolomics was performed to identify CRC-related metabolic signatures in CE. RESULTS: Five pathways were significantly enriched based on 153 differential metabolites between CRC and CE. 16 biomarkers were identified for diagnosis of CRC from CE and for guiding CRC staging. The AUC value for CRC diagnosis in the external validation set was 0.85. Good diagnostic performances were also achieved for early-stage CRC (stage I and stage II), with an AUC value of 0.84. The biomarker panel could also stage CRC patients, with an AUC of 0.72 distinguishing stage I from stage II CRC and AUC of 0.74 distinguishing stage II from stage III CRC. CONCLUSIONS: The identified metabolic biomarkers exhibit promising properties for CRC monitoring in CE patients and are superior to commonly used clinical biomarkers (CEA and CA19-9).

DecoMetDIA: Deconvolution of Multiplexed MS/MS Spectra for Metabolite Identification in SWATH-MS-Based Untargeted Metabolomics.

SWATH-MS-based data-independent acquisition mass spectrometry (DIA-MS) technology has been recently developed for untargeted metabolomics due to its capability to acquire all MS2 spectra with high quantitative accuracy. However, software tools for deconvolving multiplexed MS/MS spectra from SWATH-MS with high efficiency and high quality are still lacking in untargeted metabolomics. Here, we developed a new software tool, namely, DecoMetDIA, to deconvolve multiplexed MS/MS spectra for metabolite identification and support the SWATH-based untargeted metabolomics. In DecoMetDIA, multiple model peaks are selected to model the coeluted and unresolved chromatographic peaks of fragment ions in multiplexed spectra and decompose them into a linear combination of the model peaks. DecoMetDIA enabled us to reconstruct the MS2 spectra of metabolites from a variety of different biological samples with high coverages. We also demonstrated that the deconvolved MS2 spectra from DecoMetDIA were of high accuracy through comparison to the experimental MS2 spectra from data-dependent acquisition (DDA). Finally, about 90% of deconvolved MS2 spectra in various biological samples were successfully annotated using software tools such as MetDNA and Sirius. The results demonstrated that the deconvolved MS2 spectra obtained from DecoMetDIA were accurate and valid for metabolite identification and structural elucidation. The comparison of DecoMetDIA to other deconvolution software such as MS-DIAL demonstrated that it performs very well for small polar metabolites. DecoMetDIA software is freely available at https://github.com/ZhuMSLab/DecoMetDIA .

Development of a Correlative Strategy To Discover Colorectal Tumor Tissue Derived Metabolite Biomarkers in Plasma Using Untargeted Metabolomics.

The metabolic profiling of biofluids using untargeted metabolomics provides a promising choice to discover metabolite biomarkers for clinical cancer diagnosis. However, metabolite biomarkers discovered in biofluids may not necessarily reflect the pathological status of tumor tissue, which makes these biomarkers difficult to reproduce. In this study, we developed a new analysis strategy by integrating the univariate and multivariate correlation analysis approach to discover tumor tissue derived (TTD) metabolites in plasma samples. Specifically, untargeted metabolomics was first used to profile a set of paired tissue and plasma samples from 34 colorectal cancer (CRC) patients. Next, univariate correlation analysis was used to select correlative metabolite pairs between tissue and plasma, and a random forest regression model was utilized to define 243 TTD metabolites in plasma samples. The TTD metabolites in CRC plasma were demonstrated to accurately reflect the pathological status of tumor tissue and have great potential for metabolite biomarker discovery. Accordingly, we conducted a clinical study using a set of 146 plasma samples from CRC patients and gender-matched polyp controls to discover metabolite biomarkers from TTD metabolites. As a result, eight metabolites were selected as potential biomarkers for CRC diagnosis with high sensitivity and specificity. For CRC patients after surgery, the survival risk score defined by metabolite biomarkers also performed well in predicting overall survival time ( p = 0.022) and progression-free survival time ( p = 0.002). In conclusion, we developed a new analysis strategy which effectively discovers tumor tissue related metabolite biomarkers in plasma for cancer diagnosis and prognosis.

Correlations Between Ultrasonographic Findings of Invasive Lobular Carcinoma of the Breast and Intrinsic Subtypes.

PURPOSE: To analyze the ultrasonographic findings of invasive lobular carcinoma (ILC) of the breast in 360 women and the correlations between the characteristics and the intrinsic subtypes. MATERIALS AND METHODS: We evaluated the imaging findings according to the lexicon of the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS). The included ultrasonographic features were shape, orientation, margin, echo pattern, posterior features, calcifications, the vascularity of the masses and the presence of architectural distortions. The associations between those features and the intrinsic ILC subtypes were investigated. RESULTS: The most common manifestations of ILC on ultrasound (US) were hypoechoic masses with irregular shape, parallel orientation, spiculated margin, posterior acoustic shadowing, no calcification and blood vessels in the rim. The patients in the luminal A subtype were the youngest, and the patients in the HER2 overexpression subtype were the oldest (p = 0.01). On US, the HER2 overexpression subtype was characterized by microlobulated margins (p = 0.002), while the luminal A subtype and the luminal B subtype mostly had spiculated margins. The basal-like subtype was distinctive in that it had no posterior features (p = 0.041), rather than acoustic shadowing, and the masses in the HER2 and basal-like subtypes were larger than in the other two groups (p = 0.03). CONCLUSION: There were significant differences and several trends in the ultrasonographic characteristics of different intrinsic subtypes, which may supply accurate imaging diagnostic criteria to assist in the management of individuals with ILC.

SWATHtoMRM: Development of High-Coverage Targeted Metabolomics Method Using SWATH Technology for Biomarker Discovery.

The complexity of metabolome presents a great analytical challenge for quantitative metabolite profiling, and restricts the application of metabolomics in biomarker discovery. Targeted metabolomics using multiple-reaction monitoring (MRM) technique has excellent capability for quantitative analysis, but suffers from the limited metabolite coverage. To address this challenge, we developed a new strategy, namely, SWATHtoMRM, which utilizes the broad coverage of SWATH-MS technology to develop high-coverage targeted metabolomics method. Specifically, SWATH-MS technique was first utilized to untargeted profile one pooled biological sample and to acquire the MS2 spectra for all metabolites. Then, SWATHtoMRM was used to extract the large-scale MRM transitions for targeted analysis with coverage as high as 1000-2000 metabolites. Then, we demonstrated the advantages of SWATHtoMRM method in quantitative analysis such as coverage, reproducibility, sensitivity, and dynamic range. Finally, we applied our SWATHtoMRM approach to discover potential metabolite biomarkers for colorectal cancer (CRC) diagnosis. A high-coverage targeted metabolomics method with 1303 metabolites in one injection was developed to profile colorectal cancer tissues from CRC patients. A total of 20 potential metabolite biomarkers were discovered and validated for CRC diagnosis. In plasma samples from CRC patients, 17 out of 20 potential biomarkers were further validated to be associated with tumor resection, which may have a great potential in assessing the prognosis of CRC patients after tumor resection. Together, the SWATHtoMRM strategy provides a new way to develop high-coverage targeted metabolomics method, and facilitates the application of targeted metabolomics in disease biomarker discovery. The SWATHtoMRM program is freely available on the Internet ( http://www.zhulab.cn/software.php ).

Metabolomics approach for predicting response to neoadjuvant chemotherapy for colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) is a clinically heterogeneous disease, which necessitates a variety of treatments and leads to different outcomes. Only some CRC patients will benefit from neoadjuvant chemotherapy (NACT). OBJECTIVES: An accurate prediction of response to NACT in CRC patients would greatly facilitate optimal personalized management, which could improve their long-term survival and clinical outcomes. METHODS: In this study, plasma metabolite profiling was performed to identify potential biomarker candidates that can predict response to NACT for CRC. Metabolic profiles of plasma from non-response (n = 30) and response (n = 27) patients to NACT were studied using UHPLC-quadruple time-of-flight)/mass spectrometry analyses and statistical analysis methods. RESULTS: The concentrations of nine metabolites were significantly different when comparing response to NACT. The area under the receiver operating characteristic curve value of the potential biomarkers was up to 0.83 discriminating the non-response and response group to NACT, superior to the clinical parameters (carcinoembryonic antigen and carbohydrate antigen 199). CONCLUSION: These results show promise for larger studies that could result in more personalized treatment protocols for CRC patients.

Shaping immune landscape of colorectal cancer by cholesterol metabolites.

Cancer immunotherapies have achieved unprecedented success in clinic, but they remain largely ineffective in some major types of cancer, such as colorectal cancer with microsatellite stability (MSS CRC). It is therefore important to study tumor microenvironment of resistant cancers for developing new intervention strategies. In this study, we identify a metabolic cue that determines the unique immune landscape of MSS CRC. Through secretion of distal cholesterol precursors, which directly activate RORγt, MSS CRC cells can polarize T cells toward Th17 cells that have well-characterized pro-tumor functions in colorectal cancer. Analysis of large human cancer cohorts revealed an asynchronous pattern of the cholesterol biosynthesis in MSS CRC, which is responsible for the abnormal accumulation of distal cholesterol precursors. Inhibiting the cholesterol biosynthesis enzyme Cyp51, by pharmacological or genetic interventions, reduced the levels of intratumoral distal cholesterol precursors and suppressed tumor progression through a Th17-modulation mechanism in preclinical MSS CRC models. Our study therefore reveals a novel mechanism of cancer-immune interaction and an intervention strategy for the difficult-to-treat MSS CRC.

Prognostic value of gut microbiota-derived metabolites in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Studies about the prognostic role of gut microbiota-derived metabolites including phenylacetyl glutamine (PAGln), indoxyl sulfate (IS), lithocholic acid (LCA), deoxycholic acid (DCA), trimethylamine (TMA), trimethylamine N-oxide (TMAO), and its precursor trimethyllysine (TML) are limited in patients with ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: To examine the relationship between plasma metabolite levels and major adverse cardiovascular events (MACEs), including nonfatal MI, nonfatal stroke, all-cause mortality, and heart failure in patients with STEMI. METHODS: We enrolled 1004 patients with STEMI undergoing percutaneous coronary intervention (PCI). Plasma levels of these metabolites were determined by targeted liquid chromatography/mass spectrometry. The associations of metabolite levels with MACEs were assessed with the Cox regression model and quantile g-computation. RESULTS: During a median follow-up of 360 d, 102 patients experienced MACEs. Higher plasma PAGln (hazard ratio [HR], 3.17 [95% CI: 2.05, 4.89]; P < 0.001), IS (2.67 [1.68, 4.24], P < 0.001), DCA (2.36 [1.40, 4.00], P = 0.001), TML (2.66 [1.77,3.99], P < 0.001), and TMAO (2.61 [1.70, 4.00], P < 0.001) levels were significantly associated with MACEs independent of traditional risk factors. According to quantile g-computation, the joint effect of all these metabolites was 1.86 (95% CI: 1.46, 2.27). PAGln, IS and TML had the greatest proportional positive contributions to the mixture effect. Additionally, plasma PAGln and TML combined with coronary angiography scores including the Synergy between PCI with Taxus and cardiac surgery (SYNTAX) score (area under the curve [AUC]: 0.792 vs. 0.673), Gensini score (0.794 vs. 0.647) and Balloon pump-assisted Coronary Intervention Study (BCIS-1) jeopardy score (0.774 vs. 0.573) showed better prediction performance for MACEs. CONCLUSIONS: Higher plasma PAGln, IS, DCA, TML, and TMAO levels are independently associated with MACEs suggesting that these metabolites may be useful markers for prognosis in patients with STEMI.

Cholesterol crystals in non-culprit plaques of STEMI patients: A 3-vessel OCT study.

BACKGROUND: Cholesterol crystals (CCs) are regular microstructures found within the necrotic core of atherosclerotic plaques and have been hypothesized to be related to plaque destabilization. We attempted to investigate the potential association between CCs and non-culprit plaque vulnerability in patients with ST-segment elevated myocardial infarction (STEMI) and study morphological features of CCs in ruptured non-culprit plaques. METHODS: A total of 261 patients with ST-segment elevation myocardial infarction who underwent 3-vessel optical coherence tomography (OCT) imaging were included. Non-culprit plaques were divided into two groups according to the presence or absence of CCs in the plaque to compare the morphological characteristics of the plaques. The differences in parameters of the non-culprit plaque CCs were explored between ruptured plaques and unruptured plaques. RESULTS: Totally, 530 non-culprit plaques (29 ruptured plaques and 501 unruptured plaques) were identified by OCT. The incidence of CCs was 21.1%. Compared with non-culprit plaques without CCs, those with CCs had a larger lipid burden. Macrophages (p < 0.001) and spotty calcification (p = 0.002) were more frequently observed in non-culprit plaques with CCs. The frequency of CCs was significantly higher (p = 0.001) and the CCs were larger (p = 0.046) and more superficial (p = 0.005) in ruptured non-culprit plaques than in unruptured non-culprit plaques. The maximum lipid arc and fibrous cap thickness were independent predictors of plaque rupture, but the presence of CCs was not. CONCLUSIONS: Non-culprit plaques with CCs have more vulnerable features. CCs are more frequently found in ruptured non-culprit plaques and larger and more superficial CCs are associated with plaque rupture.

Differences in Culprit Lesions Between Premenopausal and Postmenopausal Women With Acute Coronary Syndrome: An Optical Coherence Tomography Study.

BACKGROUND: Differences in culprit lesion characteristics remain unclear between premenopausal and postmenopausal women with acute coronary syndrome (ACS). Optical coherence tomography (OCT) enables high-resolution in vivo identification of plaques. We investigated potential differences in culprit lesions between premenopausal and postmenopausal women with ACS by means of OCT. METHODS: We included 191 ACS patients who had undergone preinterventional OCT and stratified them into 2 groups according to their menopausal status: premenopausal (n = 97) and postmenopausal (n = 94). The characteristics of culprit lesions were compared between the 2 groups. RESULTS: Multivessel lesions were more commonly noted on angiography in the postmenopausal group than in the premenopausal group (40.21% vs 72.34%; P < 0.0001). On OCT, the most common type of culprit plaque was the fibrous plaque in the premenopausal group and the lipid plaque in the postmenopausal group. Compared with the premenopausal group, plaque rupture was more common in the postmenopausal group (39.18% vs 55.32%; P = 0.0254); culprit lesions had more vulnerable features, including macrophage accumulation (58.76% vs 87.23%; P < 0.0001), microchannel (38.14% vs 84.04%; P < 0.0001), cholesterol crystals (30.93% vs 62.77%; P < 0.0001), lipid-rich plaque (32.99% vs 58.51%; P < 0.0001), thin-cap fibroatheroma (3.09% vs 21.28%; P = 0.0001), and calcium (20.62% vs 44.68%; P = 0.0004); maximum lipid arc was larger (121.06 ± 110.99° vs 220.12 ± 115.47°, P < 0.0001); and lipid length was longer (5.78 ± 5.29 mm vs 12.90 ± 8.97 mm; P < 0.0001). CONCLUSIONS: Compared with premenopausal women with ACS, postmenopausal women with ACS had more vulnerable culprit lesions. These finding suggest potential optimised lipid-lowering therapy for postmenopausal women with ACS.

A Concomitant Cancer Diagnosis Is Associated With Poor Cardiovascular Outcomes Among Acute Myocardial Infarction Patients.

BACKGROUND AND AIMS: With the increasing coexistence of cardiovascular disease and cancer in contemporary clinical practice, studies on the outcomes in acute myocardial infarction (AMI) patients with cancer has not been systematically investigated. This study sought to investigated the effect of coexisting cancer on the treatment and clinical outcomes among AMI patients. METHODS: We retrospectively integrated and analyzed cardiovascular data of 6,607 AMI patients between June 2016 and December 2019. Patients with cancer were compared with pair-matched cancer-naive patients. Cox proportional hazards models were constructed to compare the differences in outcomes. RESULTS: Of 6,607 patients, 2.3% (n = 150) had been diagnosed with cancer. Patients with cancer were older (70.3 ± 10.0 vs. 63.9 ± 11.5 years, P < 0.001) and had a higher burden of comorbidities. Moreover, patients with cancer tended to receive clopidogrel (52.0 vs. 40.0%, P = 0.004) rather than ticagrelor (45.6 vs. 58.2%, P = 0.003) than those without cancer. After pairwise matching, patients with cancer were less likely to undergo in-hospital percutaneous coronary intervention (61.3 vs. 70.0%, P = 0.055). And after 3-year follow-up, the cumulative incidence of cardiovascular death (14.0 vs. 8.3%; adjusted HR, 1.93; 95% CI, 1.11-3.39; P = 0.021) among patients with cancer was significantly higher than that among the matched controls, a similar pattern was observed for the composite outcome of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (16.0 vs. 10.3%; adjusted HR, 1.98; 95% CI, 1.21-3.26; P = 0.007). Moreover, patients with a historical cancer diagnosis within 5 years had a higher risk of cardiovascular ischemic events. CONCLUSIONS: AMI patients with a concomitant diagnosis of cancer tended to be treated with conservative therapies and were at substantially higher risk for adverse cardiovascular outcomes.

Clinical and hemodynamic features of acute pulmonary embolism patients diagnosed in cold weather predicts adverse clinical outcome.

Background: Acute pulmonary embolism (APE) is associated with peak incidence and mortality rate in winter. The present study sought to characterize the clinical and hemodynamic features of cold weather on APE patients. Methods: All enrolled 224 APE patients underwent clinical and hemodynamic evaluation and baseline parameters were collected. Recruited patients were grouped by weather pattern on admission into cold and warm weather group. The correlation and prognostic values among cold weather and other variables were analyzed. Results: Compared to warm weather group, patients in cold weather group present with more severe cardiac function, with adverse WHO-functional class (P = 0.032) and higher NT-proBNP concentration [1,853.0 (398.0, 5,237.0) pg/ml vs. 847.5 (56.8, 3,090.5) pg/ml, P = 0.001]. The cold weather group also displayed much critical hemodynamic status and heavier thrombosis load, with higher mPAP (29.1 ± 11.2mmHg vs. 25.6 ± 14.2mmHg, P = 0.045), higher PVR [3.3 (1.7, 6.0) wood units vs. 1.8 (0.9, 3.8) wood units, P < 0.001], higher Miller index (21.4 ± 5.9 vs. 19.1 ± 8.0, P = 0.024), and higher D-dimer levels [2,172.0 (854.5, 3,072.5) mg/L vs. 1,094.5 (210.5, 2,914.5) mg/L, P = 0.008]. Besides, cold weather showed well correlation with the above variables. Survival analysis showed APE patients in cold weather had significantly higher clinical worsening event rate (P = 0.010) and could be an independent predictor of adverse clinical outcome in the multivariate analysis (HR 2.629; 95% CI 1.127, 6.135; P = 0.025). Conclusion: APE patients in cold weather were associated with thrombus overload, cardiac dysfunction, hemodynamic collapse and higher clinical worsening event rate. Cold weather proves to be an independent predictor of adverse clinical outcome.

Association Between Serum Carcinoembryonic Antigen Levels at Different Perioperative Time Points and Colorectal Cancer Outcomes.

BACKGROUND: Whether elevated postoperative serum carcinoembryonic antigen (CEA) levels are prognostic in patients with stage II colorectal cancer (CRC) remains controversial. PATIENTS AND METHODS: Primary and sensitivity analysis populations were obtained from a retrospective, multicenter longitudinal cohort including consecutive patients without neoadjuvant treatment undergoing curative resection for stage I-III CRC. Serum CEA levels before (CEApre-m1) and within 1 (CEApost-m1), 2-3 (CEApost-m2-3), and 4-6 months (CEApost-m4-6) after surgery were obtained, and their associations with recurrence-free survival (RFS) and overall survival (OS) were assessed using Cox regression. Sensitivity and subgroup analyses were performed. RESULTS: Primary and sensitivity analysis populations included 710 [415 men; age, 54.8 (11.6) years] and 1556 patients [941 men; age, 56.2 (11.8) years], respectively. Recurrence hazard ratios (HRs) in the elevated CEApre-m1, CEApost-m1, CEApost-m2-3, and CEApost-m4-6 groups were 1.30 (95% CI: 0.91-1.85), 1.53 (95% CI: 0.89-2.62), 1.88 (95% CI: 1.08-3.28), and 1.15 (95% CI: 0.91-1.85), respectively. The HRs of the elevated CEApre-m1, CEApost-m1, CEApost-m2-3, and CEApost-m4-6 groups for OS were 1.09 (95% CI: 0.60-1.97), 2.78 (95% CI: 1.34-5.79), 2.81 (95% CI: 1.25-6.30), and 3.30 (95% CI: 1.67-.536), respectively. Adjusted multivariate analyses showed that both in the primary and sensitivity analysis populations, elevated CEApost-m2-3, rather than CEApre-m1, CEApost-m1, and CEApost-m4-6, was an independent risk factor for recurrence, but not for OS. The RFS in the elevated and normal CEApost-m2-3 groups differed significantly among patients with stage II disease [n = 266; HR, 2.89; 95% CI, 1.02-8.24 (primary analysis); n = 612; HR, 2.69; 95% CI, 1.34-5.38 (sensitivity analysis)]. CONCLUSIONS: Elevated postoperative CEA levels are prognostic in patients with stage II CRC, with 2-3 months after surgery being the optimal timing for CEA measurement.

Plasma irisin levels are associated with hemodynamic and clinical outcome in idiopathic pulmonary arterial hypertension patients.

Irisin has been considered to reflect oxidative stress. This study aimed to show whether plasma irisin levels are correlated with hemodynamic dysfunction and predict the clinical outcome of patients with idiopathic pulmonary arterial hypertension (IPAH). A total of 68 adult IPAH patients were prospectively recruited in the present study. Plasma irisin levels were measured by the ELISA method in enrolled IPAH patients. Baseline clinical characteristics, and hemodynamic and clinical outcome were compared according to different plasma irisin levels. IPAH patients were divided into high irisin group (irisin ≥ 7.3 µg/ml) and low irisin group (irisin < 7.3 µg/ml) according to median values of irisin levels. Total plasma cholesterol levels (P = 0.027) and low-density lipoprotein cholesterol (LDL-C) levels (P = 0.042) were higher in high irisin group and were positively correlated with plasma irisin levels. IPAH patients in low irisin group had a significantly higher mean pulmonary artery pressure (mPAP, P = 0.047), systolic pulmonary artery pressure (sPAP, P = 0.022), systolic right-ventricular pressure (sRVP, P = 0.007), mean right atrial pressure (mRAP, P = 0.043), and systolic right atrial pressure (sRAP, P = 0.020). mRAP, sRAP, and diastolic right atrial pressure (dRAP) were negatively correlated with plasma irisin levels. Low irisin group predicts adverse hemodynamic status and poor free of event survival rate (P = 0.030, log-rank test). Multivariate analysis indicates plasma irisin levels to be an independent predictor of prognosis in IPAH patients after adjusting for related covariates (HR 0.786; 95% CI 0.584, 0.957; P = 0.038). Plasma irisin levels may serve as a novel biomarker in IPAH patients for hemodynamic severity assessment and clinical outcome evaluation.

Focal Geometry and Characteristics of Erosion-Prone Coronary Plaques in vivo Angiography and Optical Coherence Tomography Study.

Objective: This study compared focal geometry and characteristics of culprit plaque erosion (PE) vs. non-culprit plaques in ST-segment elevated myocardial infarction (STEMI) patients in whom optical coherence tomography (OCT) identified PE as the cause of the acute event. Background: Culprit PE is a distinct clinical entity with specific coronary risk factors and its own tailored management strategy. However, not all plaques develop erosion resulting in occlusive thrombus formation. Methods: Between January 2017 and July 2019, there were 484 STEMI patients in whom OCT at the time of primary percutaneous intervention identified culprit lesion PE to be the cause of the event; 484 culprit PE were compared to 1,132 non-culprit plaques within 1,196 imaged vessels. Results: Culprit PE were highly populated at "hot spots" within the proximal 40 mm in the left anterior descending artery (LAD) and tended to cluster proximal to a nearby bifurcation mainly in the LAD. Minimal lumen area (MLA) <2.51 mm2 and AS (area stenosis) >64.02% discriminated culprit PE from non-culprit plaques. In the multivariable analysis, focal geometry (LAD location, distance from coronary ostium <40 mm, and location proximal to a nearby bifurcation), luminal narrowing (MLA <2.51 mm2, AS > 64.02%), and TCFA phenotype were independent predictors of culprit PE overall. Cholesterol crystals were predictive of culprit PE with underlying LRP morphology while the absence of calcification and microchannels were risk factors for culprit PE with an underlying non-LRP. Similarities and differences in predictors of culprit PE were found between males and females; distance from coronary ostium <40 mm, MLA <2.51 mm2, TCFA, and less spotty calcium were risk factors of culprit PE in males, but not in females while smaller RVD was associated with culprit PE only in females. Conclusions: Irrespective of underlying lesion substrates and patient risk factors, there are lesion-specific and OCT-identifiable predictors of developing culprit PE in erosion-prone vulnerable patients.

Differential Expression and Bioinformatics Analysis of CircRNA in PDGF-BB-Induced Vascular Smooth Muscle Cells.

Atherosclerosis is mediated by various factors and plays an important pathological foundation for cardiovascular and cerebrovascular diseases. Abnormal vascular smooth muscle cells (VSMCs) proliferation and migration have an essential role in atherosclerotic lesion formation. Circular RNAs (circRNA) have been widely detected in different species and are closely related to various diseases. However, the expression profiles and molecular regulatory mechanisms of circRNAs in VSMCs are still unknown. We used high-throughput RNA-seq as well as bioinformatics tools to systematically analyze circRNA expression profiles in samples from different VSMC phenotypes. Polymerase chain reaction (PCR), Sanger sequencing, and qRT-PCR were performed for circRNA validation. A total of 22191 circRNAs corresponding to 6273 genes (host genes) in the platelet-derived growth factor (PDGF-BB) treated group, the blank control group or both groups, were detected, and 112 differentially expressed circRNAs were identified between the PDGF-BB treated and control groups, of which 59 were upregulated, and 53 were downregulated. We selected 9 circRNAs for evaluation of specific head-to-tail splicing, and 10 differentially expressed circRNAs between the two groups for qRT-PCR validation. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses enrichment analyses revealed that the parental genes of the circRNAs mainly participated in cardiac myofibril assembly and positive regulation of DNA-templated transcription, indicating that they might be involved in cardiovascular diseases. Finally, we constructed a circRNA-miRNA network based on the dysregulated circRNAs and VSMC-related microRNAs. Our study is the first to show the differential expression of circRNAs in PDGF-BB-induced VSMCs and may provide new ideas and targets for the prevention and therapy of vascular diseases.

Plasma irisin level associated with hemodynamic parameters and predict clinical outcome in patients with acute pulmonary embolism.

BACKGROUND: The purpose of the present study is to investigate the correlation of plasma irisin level and hemodynamic parameters in patients with acute pulmonary embolism (APE) and to estimate clinical outcome prediction value of plasma irisin level. METHODS: We prospectively recruited 86 adult patients with APE in the present study. All recruited patients conduct measurement of plasma irisin levels using ELISA kits. Baseline clinical characteristics, hemodynamic parameters and prognostic conditions were evaluated according to different plasma irisin levels. RESULTS: According to median values of irisin levels, APE patients were divided into high irisin group (irisin≥6.9 µg/ml) and low irisin group (irisin<6.9 µg/ml). Plasma NT-proBNP (P = 0.044), mean pulmonary artery pressure (mPAP, P = 0.013), systolic pulmonary artery pressure (sPAP, P = 0.001), mean right ventricular pressure (mRVP, P = 0.021) and systolic right ventricular pressure (sPVP, P = 0.003) were higher in low irisin group compared with high irisin group. Hemodynamic parameters of mPAP, sPAP, mRVP and sRVP were negatively correlated with plasma irisin levels. Kaplan- Meier survival analysis showed that APE patients with lower plasma irisin levels had significantly higher clinical worsening event rate (P = 0.026) and could be the independent predictor of prognosis in multivariate analysis (P = 0.035). CONCLUSION: Plasma irisin level was negatively correlated with hemodynamic parameters in patients with APE. Low irisin group patients had significantly higher clinical worsening event rate and could be the independent predictor of clinical outcome in multivariate analysis.

An Immune-Related Signature Predicts Survival in Patients With Lung Adenocarcinoma.

We investigated the local immune status and its prognostic value in lung adenocarcinoma. In total, 513 lung adenocarcinoma samples from TCGA and ImmPort databases were collected and analyzed. The R package coxph was employed to mine immune-related genes that were significant prognostic indicators using both univariate and multivariate analyses. The R software package glmnet was then used for Lasso Cox regression analysis, and a prognosis prediction model was constructed for lung adenocarcinoma; clusterProfiler was selected for functional gene annotations and KEGG enrichment analysis. Finally, correlations between the RiskScore and clinical features or signaling pathways were established. Sixty-four immune-related genes remarkably correlated with patient prognosis and were further applied. Samples were hierarchically clustered into two subgroups. Accordingly, the LASSO regression algorithm was employed to screen the 14 most representative immune-related genes (PSMD11, PPIA, MIF, BMP5, DKK1, PDGFB, ANGPTL4, IL1R2, THRB, LTBR, TNFRSF1, TNFRSF17, IL20RB, and MC1R) with respect to patient prognosis. Then, the prognosis prediction model for lung adenocarcinoma patients (namely, the RiskScore equation) was constructed, and the training set samples were incorporated to evaluate the efficiency of this model to predict and classify patient prognosis. Subsequently, based on functional annotations and KEGG pathway analysis, the 14 immune-related genes were mainly enriched in pathways closely associated with lung adenocarcinoma and its immune microenvironment, such as cytokine-cytokine receptor interaction and human T-cell leukemia virus 1 infection. Furthermore, correlations between the RiskScore and clinical features of the training set samples and signaling pathways (such as p53, cell cycle, and DNA repair) were also demonstrated. Finally, the test set sample data were employed for independent testing and verifying the model. We established a prognostic prediction RiskScore model based on the expression profiles of 14 immune-related genes, which shows high prediction accuracy and stability in identifying immune features. This could provide clinical guidance for the diagnosis and prognosis of different immunophenotypes, and suggest multiple targets for precise advanced lung adenocarcinoma therapy based on subtype-specific immune molecules.

MicroRNA-144 functions as a tumor suppressor in gastric cancer by targeting cyclooxygenase-2.

Gastric cancer (GC) poses a serious public health threat and the 5-year survival rate of patients with GC is low. MicroRNAs (miRNAs/miRs) may serve oncogenic or tumor suppressor functions during tumorigenesis by regulating cell proliferation, apoptosis, migration and invasion and it has been demonstrated that they may be dysregulated in various types of cancer. The present study demonstrated that miR-144 and GATA4 were downregulated in GC tissues and cell lines and suggested that this may be due to hypermethylation. Additionally, miR-144 and GATA4 had synergistic effects on GC cells by repressing cell proliferation and inducing cell cycle arrest and apoptosis. The results of bioinformatics and a luciferase reporter assay indicated that cyclooxygenase-2 (COX-2) is a direct target of miR-144 and that miR-144 negatively regulated the expression of COX-2, which inhibits the viability of GC cells. GATA4 also induced a similar effect on COX-2. Taken together, the results of the present study may improve understanding of the underlying mechanism of miR-144 and GATA4 in GC.