Coronary Artery Disease with Elevated Levels of HDL Cholesterol Is Associated with Distinct Lipid Signatures.

Levels of high-density lipoprotein cholesterol (HDL-C) are inversely associated with the incidence of coronary artery disease (CAD). However, the underlying mechanism of CAD in the context of elevated HDL-C levels is unclear. Our study aimed to explore the lipid signatures in patients with CAD and elevated HDL-C levels and to identify potential diagnostic biomarkers for these conditions. We measured the plasma lipidomes of forty participants with elevated HDL-C levels (men with >50 mg/dL and women with >60 mg/dL), with or without CAD, using liquid chromatography-tandem mass spectrometry. We analyzed four hundred fifty-eight lipid species and identified an altered lipidomic profile in subjects with CAD and high HDL-C levels. In addition, we identified eighteen distinct lipid species, including eight sphingolipids and ten glycerophospholipids; all of these, except sphingosine-1-phosphate (d20:1), were higher in the CAD group. Pathways for sphingolipid and glycerophospholipid metabolism were the most significantly altered. Moreover, our data led to a diagnostic model with an area under the curve of 0.935, in which monosialo-dihexosyl ganglioside (GM3) (d18:1/22:0), GM3 (d18:0/22:0), and phosphatidylserine (38:4) were combined. We found that a characteristic lipidome signature is associated with CAD in individuals with elevated HDL-C levels. Additionally, the disorders of sphingolipid as well as glycerophospholipid metabolism may underlie CAD.

Transcriptome analysis reveals ADAMTS15 is a potential inflammation-related gene in remote ischemic postconditioning.

Background: Remote ischemic postconditioning (RIPostC) induced by brief episodes of the limb ischemia is a potential therapeutic strategy for myocardial ischemia/reperfusion injury, achieved by reducing cardiomyocyte death, inflammation and so on. The actual mechanisms underlying cardioprotection conferred by RIPostC remain unclear. Exploring gene expression profiles in myocardium at transcriptional level is helpful to deepen the understanding on the cardioprotective mechanisms of RIPostC. This study aims to investigate the effect of RIPostC on gene expressions in rat myocardium using transcriptome sequencing. Methods: Rat myocardium samples from the RIPostC group, the control group (myocardial ischemia/reperfusion group) and the sham group were performed transcriptome analysis using RNA sequencing. The levels of cardiac IL-1ß, IL-6, IL-10 and TNFα were analyzed by Elisa. The expression levels of candidate genes were verified by qRT-PCR technique. Infarct size was measured by Evans blue and TTC staining. Apoptosis was assessed by TUNEL assays and caspase-3 levels were detected using western blotting. Results: RIPostC can markedly decrease infarct size and reduce the levels of cardiac IL-1ß, IL-6 and increase the level of cardiac IL-10. This transcriptome analysis showed that 2 genes were up-regulated (Prodh1 and ADAMTS15) and 5 genes (Caspase-6, Claudin-5, Sccpdh, Robo4 and AABR07011951.1) were down-regulated in the RIPostC group. Go annotation analysis showed that Go terms mainly included cellular process, metabolic process, cell part, organelle, catalytic activity and binding. The KEGG annotation analysis of DEGs found only one pathway, amino acid metabolism, was up-regulated. The relative mRNA expression levels of ADAMTS15, Caspase-6, Claudin-5 and Prodh1 were verified by qRT-PCR, which were consistent with the RNA-seq results. In addition, the relative expression of ADAMTS15 was negatively correlated with the level of cardiac IL-1ß (r = -0.748, P = 0.005) and positively correlated with the level of cardiac IL-10 (r = 0.698, P = 0.012). A negative correlation statistical trend was found between the relative expression of ADAMTS15 and the level of cardiac IL-6 (r = -0.545, P = 0.067). Conclusions: ADAMTS15 may be a potential inflammation-related gene in regulation of cardioprotection conferred by remote ischemic postconditioning and a possible therapeutic target for myocardial ischemia reperfusion injury in the future.

CT-guided 125I brachytherapy for hepatocellular carcinoma in high-risk locations after transarterial chemoembolization combined with microwave ablation: a propensity score-matched study.

BACKGROUND: This study aimed to evaluate the safety and efficacy of 125I brachytherapy combined with transarterial chemoembolization (TACE) and microwave ablation (MWA) for unresectable hepatocellular carcinoma (HCC) in high-risk locations. PATIENTS AND METHODS: After 1:2 propensity score matching (PSM), this retrospectively study analyzed 49 patients who underwent TACE +MWA+125I brachytherapy (group A) and 98 patients who only received TACE +MWA (group B). The evaluated outcomes were progression-free survival (PFS), overall survival (OS), and treatment complications. Cox proportional hazards regression analysis survival was used to compare the two groups. RESULTS: The patients in group A showed a longer PFS than group B (7.9 vs. 3.3 months, P = 0.007). No significant differences were observed in median OS between the two groups (P = 0.928). The objective response rate (ORR), disease control rate of tumors in high-risk locations, and the ORR of intrahepatic tumors were 67.3%, 93.9%, and 51.0%, respectively, in group A, and 38.8%, 79.6% and 29.6%, respectively, in group B (P < 0.001, P = 0.025 and P = 0.011, respectively). TACE-MWA-125I (HR = 0.479, P < 0.001) was a significant favorable prognostic factor that affected PFS. The present of portal vein tumor thrombosis was an independent prognostic factor for PFS (HR = 1.625, P = 0.040). The Barcelona clinic liver cancer (BCLC) stage (BCLC C vs. B) was an independent factor affecting OS (HR = 1.941, P = 0.038). The incidence of complications was similar between the two groups, except that the incidence of abdominal pain was reduced in the group A (P = 0.007). CONCLUSIONS: TACE-MWA-125I resulted in longer PFS and better tumor control than did TACE-MWA in patients with unresectable hepatocellular carcinoma in high-risk locations.

Proteomic alterations associated with residual disease in neoadjuvant chemotherapy treated ovarian cancer tissues.

BACKGROUND: Optimal cytoreduction to no residual disease (R0) correlates with improved disease outcome for high-grade serous ovarian cancer (HGSOC) patients. Treatment of HGSOC patients with neoadjuvant chemotherapy, however, may select for tumor cells harboring alterations in hallmark cancer pathways including metastatic potential. This study assessed this hypothesis by performing proteomic analysis of matched, chemotherapy naïve and neoadjuvant chemotherapy (NACT)-treated HGSOC tumors obtained from patients who had suboptimal (R1, n = 6) versus optimal (R0, n = 14) debulking at interval debulking surgery (IDS). METHODS: Tumor epithelium was harvested by laser microdissection from formalin-fixed, paraffin-embedded tissues from matched, pre- and post-NACT treated tumors for twenty HGSOC patients and analyzed by quantitative mass spectrometry-based proteomics. RESULTS: Differential analysis of patient matched pre- and post-NACT treated tumors revealed proteins associated with cell survival and metabolic signaling to be significantly altered in post-NACT treated tumor cells. Comparison of pre-NACT treated tumors from suboptimal (R1) versus optimally (R0) debulked patients identified proteins associated with tumor cell viability and invasion signaling enriched in R1 patients. We identified five proteins altered between R1 and R0 patients in pre- NACT treated tumors that significantly correlated with PFS in an independent cohort of HGSOC patients, including Fermitin family homolog 2 (FERMT2), a protein elevated in R1 that correlated with disease progression in HGSOC patients (multivariate Cox HR = 1.65, Wald p = 0.022) and increased metastatic potential in solid-tumor malignancies. CONCLUSIONS: This study identified distinct proteome profiles in patient matched pre- and post-NACT HGSOC tumors that correlate with NACT resistance and that may predict residual disease status at IDS that collectively warrant further pre-clinical investigation.

Improving Risk Assessment for Metastatic Disease in Endometrioid Endometrial Cancer Patients Using Molecular and Clinical Features: An NRG Oncology/Gynecologic Oncology Group Study.

Objectives: A risk assessment model for metastasis in endometrioid endometrial cancer (EEC) was developed using molecular and clinical features, and prognostic association was examined. Methods: Patients had stage I, IIIC, or IV EEC with tumor-derived RNA-sequencing or microarray-based data. Metastasis-associated transcripts and platform-centric diagnostic algorithms were selected and evaluated using regression modeling and receiver operating characteristic curves. Results: Seven metastasis-associated transcripts were selected from analysis in the training cohorts using 10-fold cross validation and incorporated into an MS7 classifier using platform-specific coefficients. The predictive accuracy of the MS7 classifier in Training-1 was superior to that of other clinical and molecular features, with an area under the curve (95% confidence interval) of 0.89 (0.80-0.98) for MS7 compared with 0.69 (0.59-0.80) and 0.71 (0.58-0.83) for the top evaluated clinical and molecular features, respectively. The performance of MS7 was independently validated in 245 patients using RNA sequencing and in 81 patients using microarray-based data. MS7 + MI (myometrial invasion) was preferrable to individual features and exhibited 100% sensitivity and negative predictive value. The MS7 classifier was associated with lower progression-free and overall survival (p ≤ 0.003). Conclusion: A risk assessment classifier for metastasis and prognosis in EEC patients with primary tumor derived MS7 + MI is available for further development and optimization as a companion clinical support tool.

Cardioprotection of Repeated Remote Ischemic Conditioning in Patients With ST-Segment Elevation Myocardial Infarction.

Background: Repeated remote ischemic conditioning (RIC) after myocardial infarction (MI) has been shown to improve left ventricular (LV) remodeling in the experimental studies, but its cardioprotective effect in patients with ST-segment elevation myocardial infarction (STEMI) is still unknown. Objective: To investigate whether repeated RIC started early after primary percutaneous coronary intervention (PCI) can improve LV function in patients with STEMI. Methods: Patients with STEMI treated by primary PCI were included and randomized to the repeated RIC group (n = 30) or the control group (n = 30). RIC was started within 24 h after PCI and repeated daily for 1 week, using an Auto RIC device. 3D speckle-tracking echocardiography (STE) was used to assessed LV function. The primary study endpoint was the change in LV global longitudinal strain (GLS) from baseline to 1 month after PCI. Results: The repeated RIC group and the control group were well-matched at baseline including mean GLS (-9.8 ± 2.6% vs. -10.1 ± 2.5%, P = 0.62). Despite there was no significant difference in mean GLS at 1 month between the two groups (-11.9 ± 2.1% vs. -10.9 ± 2.7%, P = 0.13), the mean change in GLS from baseline to 1 month was significantly higher in the treatment group than in the control group (-2.1 ± 2.5% vs. -0.8 ± 2.3%, P = 0.04). There were no significant differences in the changes in global circumferential strain (GCS), global area strain (GAS), global radial strain (GRS), LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), and LV end-systolic volume (LVESV) between the two groups. Peak creatine kinase isoenzyme-MB, peak high-sensitivity troponin T, and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at 24 h after PCI did not differ significantly between the two groups, but NT-proBNP levels at 1 week were significantly lower in the treatment group than in the control group [357.5 (184.8-762.8) vs. 465.0 (305.8-1525.8) pg/ml, P = 0.04]. Conclusion: Daily repeated RIC started within 24 h after PCI can improve GLS and reduce plasma NT proBNP levels in patients with STEMI.

TIPS plus sequential systemic therapy of advanced HCC patients with tumour thrombus-related symptomatic portal hypertension.

OBJECTIVES: Portal vein tumour thrombus (PVTT)-related symptomatic portal hypertension (SPH) leads to a poor prognosis in hepatocellular carcinoma (HCC) patients. A transjugular intrahepatic portosystemic shunt (TIPS) can effectively relieve SPH but its effect remains unclear in PVTT-related SPH. This study aimed to evaluate the clinical value of the TIPS procedure combined with sequential systemic therapy in advanced HCC patients with PVTT-related SPH. METHODS: After 1:1 propensity score matching (PSM), this retrospective study analysed 42 patients who underwent TIPS placement plus sequential systemic therapy (group A) and 42 patients who received only symptomatic and supportive treatment (group B). The evaluated outcomes were overall survival (OS) and SPH control rate. Cox proportional hazards regression analysis was used to compare OS in the two groups. RESULTS: In group A, the technical success rate of the TIPS procedure was 95.2%, and no severe complications occurred. The rebleeding rates in group A and group B were 5.0% and 73.7%, respectively (p < 0.001), and the ascites control rates were 92.0% and 28.0%, respectively (p < 0.001). The median OS of group A was significantly better than that of group B (9.6 [95% CI: 7.1, 12.0] vs. 4.9 [95% CI: 3.9, 5.8], months, p < 0.001). Multivariable analysis showed that TIPS plus sequential systemic therapy (hazard ratio [HR] = 5.799; 95% CI: 3.177, 10.585; p < 0.001) was an independent prognostic factor related to OS. Additionally, PVTT degree (I+II) (p = 0.008), AFP ≤ 400 ng/ml (p = 0.003), and Child-Pugh class A (p = 0.046) were significant predictors of OS. CONCLUSION: TIPS plus sequential systemic therapy is safe and feasible for treating advanced HCC with tumour thrombus-related SPH. KEY POINTS: • Portal vein tumour thrombus (PVTT) is common in advanced hepatocellular carcinoma (HCC) and transforms compensated portal hypertension into symptomatic portal hypertension (SPH). • HCC patients with PVTT-related SPH have a very poor prognosis, and there are no effective treatments recommended by the guidelines. • Therefore, a treatment strategy that utilises a transjugular intrahepatic portosystemic shunt (TIPS) to manage SPH combined with sequential systemic therapy in advanced HCC patients is explored in this study for its feasibility and clinical value. This research can fill the gap in current research data to provide clinically meaningful treatment options.

Effect of Al Addition on Grain Refinement and Phase Transformation of the Mg-Gd-Y-Zn-Mn Alloy Containing LPSO Phase.

The effect of 0−1.0 at.% Al additions on grain refinement and phase transformation of the Mg-2.0Gd-1.2Y-0.5Zn-0.2Mn (at.%) alloy containing a long period stacking ordered (LPSO) phase was investigated in this work. The addition of Al promoted the formation of the Al2RE phase in the Mg-2.0Gd-1.2Y-0.5Zn-0.2Mn (at.%) alloy, and the dominant secondary phases in the as-cast Mg-2.0Gd-1.2Y-0.5Zn-0.2Mn-1.0Al (at.%) alloy were the Mg3RE phase, LPSO phase, and Al2RE phase. With increased Al addition, the area fraction of the Al2RE phase increased monotonously, while the area fraction of LPSO phase and Mg3RE phase decreased gradually. The orientation relationship between the Al2RE phase and the α-Mg matrix was determined to be <112>Al2RE//<112¯0>α-Mg, {101}Al2RE//{101¯0}α-Mg, which was not affected by Zn and Mn concentrations in the Al2RE phase. Since the Al2RE particles with a size more than 6 µm located at the center of grains could act as nucleants for α-Mg grains, the average grain size of the as-cast alloys decreased from 276 µm to 49 µm after 1.0% Al addition. The effect of the Al addition on the grain refinement of the Mg-2.0Gd-1.2Y-0.5Zn-0.2Mn alloy was comparable to that of the Zr refined counterpart.

Effects of La Addition on the Microstructure, Thermal Conductivity and Mechanical Properties of Mg-3Al-0.3Mn Alloys.

The effects of La addition on the microstructure, thermal conductivity and mechanical properties of as-cast and as-extruded Mg-3Al-xLa-0.3Mn (x = 1, 3 and 5 wt.%) alloys were studied. The results showed that the thermal conductivity of the alloys increased with the addition of La element, which was due to the formation of the Al11La3 phases by consuming the solute Al and the added La element. The yield strength of the as-cast Mg-3Al-xLa-0.3Mn alloys increased with the increase in La concentration. The thermal conductivity of the as-extruded alloys was lower than that of as-cast counterparts owing to lots of defects generated in the process of hot extrusion deformation, particularly the grain boundaries. The anisotropy of thermal conductivity was discovered in the as-extruded alloys on account of the formation of texture. As the La content increases, the tensile strength and yield strength of the as-extruded alloys decreased gradually. In contrast, the elongation first increased and then decreased, resulting from the combined effect of the texture strengthening and second phase strengthening.

Single-Centre Retrospective Study Using Propensity Score Matching Comparing Left Versus Right Internal Jugular Vein Access for Transjugular Intrahepatic Portosystemic Shunt (TIPS) Creation.

PURPOSE: To compare the safety and efficacy of left versus right internal jugular vein access for portal vein puncture during transjugular intrahepatic portosystemic shunt (TIPS) creation in patients with a small liver and short vertical puncture distance. MATERIALS AND METHODS: The vertical distance from the hepatic vein orifice to the puncture point of the portal vein was measured by CT and DSA. A distance ≤ 30 mm is defined as a short vertical puncture distance. After 1:1 propensity score matching (PSM), 29 patients of left internal jugular vein-TIPS (LIJ-TIPS) and 29 patients of right internal jugular vein-TIPS (RIJ-TIPS) were included. The number of needle punctures, fluoroscopy time, and radiation dose during the puncture process were statistically analyzed. RESULTS: There was no significant difference in the average vertical puncture distances on CT or DSA between LIJ-TIPS and RIJ-TIPS (19.10 ± 0.60 mm vs. 19.30 ± 0.60 mm, P = 0.840; 22.02 ± 0.69 mm vs. 22.23 ± 0.64 mm, P = 0.822, respectively). The average number of needle punctures, fluoroscopy time, and radiation dose in LIJ-TIPS were significantly lower than those in RIJ-TIPS (2.07 ± 0.20 vs. 4.10 ± 0.24, P < 0.001; 78.45 ± 12.80 s vs. 201.16 ± 23.71 s, P < 0.001; 31.55 ± 7.04 mGy vs. 136.69 ± 16.38 mGy, P < 0.001, respectively). Within three punctures, the technical success rate in LIJ-TIPS was significantly higher than that in RIJ-TIPS (86.2 vs. 27.6%, P < 0.001). The incidence of hemoperitoneum in LIJ-TIPS was significantly lower than that in RIJ-TIPS (0% vs. 13.8%, P = 0.038). CONCLUSION: The left internal jugular vein could be used as primary access for TIPS creation in patients with a small liver and short vertical puncture distance.

Transcriptome sequencing-based personalized analysis of hepatocellular carcinoma patients with portal vein tumor thrombus.

BACKGROUND: The mechanism of portal vein tumor thrombus (PVTT) in hepatocellular carcinoma (HCC) has been widely studied, and numerous diagnostic and prognostic biomarkers for HCC with PVTT have been identified. We aimed to evaluate the extent to which these biomarkers may aid the personalized precision therapy of HCC with PVTT. METHODS: Matched tissue specimens [primary HCC tumor (PT), adjacent normal (N) liver, and PVTT tissues] were acquired from 3 Chinese HCC patients who underwent surgery at Sun Yat-sen University Cancer Centre between 2019 and 2020. Ribonucleic acid (RNA) sequencing was performed on the 9 tissue samples. GFOLD (generalized fold change) algorithm was used to analyze the differently expressed genes (DEGs) between the PVTT, PT, and normal tissues from each patient. Genes with a P<0.01 and a |GFOLD value| >1 were identified as having significantly different expression. RESULTS: In total, 3,543, 32,472, and 12,901 tumorigenesis-associated genes, and 2,919, 17,679, and 14,825 metastasis-associated genes, were detected in Patient 1 (P1), Patient 2 (P2), and Patient 3 (P3), respectively. We analyzed the expression levels of genes associated with hypoxia, macrophage recruitment and cancer stem cells (CSCs). The results showed that hypoxia and CSCs may have contributed to tumorigenesis but not to metastasis in P1. We also found the hypoxia microenvironment played an important role in tumorigenesis and metastasis in P2, and CSCs may have contributed to metastasis. Additionally, we found that CSCs played critical roles in metastasis but not in tumorigenesis in P3. The results also showed that the long non-coding RNA (lncRNA) Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) was greatly overexpressed in the PTs and PVTT in all 3 patients, and Heart and Neural Crest Derivatives Expressed 2-antisense RNA 1 (HAND2-AS1) was downregulated in PVTT compared with PTs in all 3 patients. Thus, MALAT1 and HAND2-AS1 may be robust biomarkers for metastasis in HCC patients with PVTT. CONCLUSIONS: Tumor-associated macrophages (TAMs)-targeted immunotherapy is a promising therapy for HCC patients with PVTT. LncRNAs MALAT1, and HAND2-AS1 may be promising targets for HCC therapy.

Acute inferior wall myocardial infarction induced by aortic dissection in a young adult with Marfan syndrome: A case report.

BACKGROUND: Aortic dissection (AD) is an emergent and life-threatening disorder, and its in-hospital mortality was reported to be as high as 24.4%-27.4%. AD can mimic other more common disorders, especially acute myocardial infarction (AMI), in terms of both symptoms and electrocardiogram changes. Reperfusion for patients with AD may result in catastrophic outcomes. Increased awareness of AD can be helpful for early diagnosis, especially among younger patients. CASE SUMMARY: We report a 28-year-old man with acute left side chest pain without cardiovascular risk factors. He was diagnosed with acute inferior ST-segment elevation myocardial infarction (STEMI), which, based on illness history, physical examination, and intraoperative findings, was eventually determined to be type A AD caused by Marfan syndrome. Emergent coronary angiography revealed the anomalous origin of the right coronary artery as well as eccentric stenosis of the proximal segment. Subsequently, computed tomography angiography (CTA) showed intramural thrombosis of the ascending aorta. Finally, the patient was transferred to the cardiovascular surgery department for a Bentall operation. He was discharged 13 d after the operation, and aortic CTA proved a full recovery at the 2-year follow-up. CONCLUSION: It is essential and challenging to differentiate AD from AMI. Type A AD should be the primary consideration in younger STEMI patients without cardiovascular risk factors but with outstanding features of Marfan syndrome.

High mRNA expression of LY6 gene family is associated with overall survival outcome in pancreatic ductal adenocarcinoma.

Pancreatic cancer ranks one of the worst in overall survival outcome with a 5 year survival rate being less than 10%. Pancreatic cancer faces unique challenges in its diagnosis and treatment, such as the lack of clinically validated biomarkers and the immensely immunosuppressive tumor microenvironment. Recently, the LY6 gene family has received increasing attention for its multi-faceted roles in cancer development, stem cell maintenance, immunomodulation, and association with more aggressive and hard-to-treat cancers. A detailed study of mRNA expression of LY6 gene family and its association with overall survival (OS) outcome in pancreatic cancers is lacking. We used publicly available clinical datasets to analyze the mRNA expression of a set of LY6 genes and its effect on OS outcome in the context of the tumor microenvironment and immunomodulation. We used web-based tools Kaplan-Meier Plotter, cBioPortal, Oncomine and R-programming to analyze copy number alterations, mRNA expression and its association with OS outcome in pancreatic cancer. These analyses demonstrated that high expression of LY6 genes is associated with OS and disease free survival (DFS) outcome. High expression of LY6 genes and their association with OS outcome is dependent on the composition of tumor microenvironment. Considering that LY6 proteins are anchored to the outer cell membrane or secreted, making them readily accessible, these findings highlight the potential of LY6 family members in the future of pancreatic cancer diagnosis and treatment.

Neuregulin-1 alleviate oxidative stress and mitigate inflammation by suppressing NOX4 and NLRP3/caspase-1 in myocardial ischaemia-reperfusion injury.

Neuregulin-1 (NRG-1) is reported to be cardioprotective through the extracellular-regulated protein kinase (ERK) 1/2 pathway in myocardial ischaemia-reperfusion injury (MIRI). NOX4-induced ROS activated NLRP3 inflammasome and exacerbates MIRI. This study aims to investigate whether NRG-1 can suppress NOX4 by ERK1/2 and consequently inhibit the NLRP3/caspase-1 signal in MIRI. The myocardial infarct size (IS) was measured by TTC-Evans blue staining. Immunohistochemical staining, real-time quantitative PCR (RT-qPCR) and Western blotting were used for detection of the factors, such as NOX4, ERK1/2, NLRP3, caspase-1 and IL-1ß .The IS in the NRG-1 (3 µg/kg, intravenous) group was lower than that in the IR group. Immunohistochemical analysis revealed NRG-1 decreased 4HNE and NOX4. The RT-qPCR and Western blot analyses revealed that NRG-1 mitigated the IR-induced up-regulation of NOX4 and ROS production. Compared with the IR group, the NRG-1 group exhibited a higher level of P-ERK1/2 and a lower level of NLRP3. In the Langendorff model, PD98059 inhibited ERK1/2 and up-regulated the expression of NOX4, NLRP3, caspase-1 and IL-1ß, which exacerbated oxidative stress and inflammation. In conclusion, NRG-1 can reduce ROS production by inhibiting NOX4 through ERK1/2 and inhibit the NLRP3/caspase-1 pathway to attenuate myocardial oxidative damage and inflammation in MIRI.

Chordoid Glioma: A Neoplasm Found in the Anterior Part of the Third Ventricle.

ABSTRACT: Chordoid glioma is a rare low-grade tumor that originates almost exclusively in the anterior part of the third ventricle. The diagnosis and treatment of the tumor remain controversial. In this article, the authors present a novel case of chordoid glioma of the third ventricle. The patient was treated with less invasive microsurgery followed by low-dose gamma knife radiosurgery. Magnetic resonance imaging revealed a decrease in tumor size and necrosis in the central region of the tumor, without significant complications at follow-up 14 months later. Based on these findings, the authors suggest that less invasive microsurgical resection followed by low-dose gamma knife radiosurgery is safe and effective for the treatment of chordoid glioma of the third ventricle.

Comparative analysis of differentially abundant proteins quantified by LC-MS/MS between flash frozen and laser microdissected OCT-embedded breast tumor samples.

BACKGROUND: Proteomic studies are typically conducted using flash-frozen (FF) samples utilizing tandem mass spectrometry (MS). However, FF specimens are comprised of multiple cell types, making it difficult to ascertain the proteomic profiles of specific cells. Conversely, OCT-embedded (Optimal Cutting Temperature compound) specimens can undergo laser microdissection (LMD) to capture and study specific cell types separately from the cell mixture. In the current study, we compared proteomic data obtained from FF and OCT samples to determine if samples that are stored and processed differently produce comparable results. METHODS: Proteins were extracted from FF and OCT-embedded invasive breast tumors from 5 female patients. FF specimens were lysed via homogenization (FF/HOM) while OCT-embedded specimens underwent LMD to collect only tumor cells (OCT/LMD-T) or both tumor and stromal cells (OCT/LMD-TS) followed by incubation at 37 °C. Proteins were extracted using the illustra triplePrep kit and then trypsin-digested, TMT-labeled, and processed by two-dimensional liquid chromatography-tandem mass spectrometry (2D LC-MS/MS). Proteins were identified and quantified with Proteome Discoverer v1.4 and comparative analyses performed to identify proteins that were significantly differentially expressed amongst the different processing methods. RESULTS: Among the 4,950 proteins consistently quantified across all samples, 216 and 171 proteins were significantly differentially expressed (adjusted p-value < 0.05; |log2 FC|> 1) between FF/HOM vs. OCT/LMD-T and FF/HOM vs. OCT/LMD-TS, respectively, with most proteins being more highly abundant in the FF/HOM samples. PCA and unsupervised hierarchical clustering analysis with these 216 and 171 proteins were able to distinguish FF/HOM from OCT/LMD-T and OCT/LMD-TS samples, respectively. Similar analyses using significantly differentially enriched GO terms also discriminated FF/HOM from OCT/LMD samples. No significantly differentially expressed proteins were detected between the OCT/LMD-T and OCT/LMD-TS samples but trended differences were detected. CONCLUSIONS: The proteomic profiles of the OCT/LMD-TS samples were more similar to those from OCT/LMD-T samples than FF/HOM samples, suggesting a strong influence from the sample processing methods. These results indicate that in LC-MS/MS proteomic studies, FF/HOM samples exhibit different protein expression profiles from OCT/LMD samples and thus, results from these two different methods cannot be directly compared.

Genomic heterogeneity in peritoneal implants: A differential analysis of gene expression using nanostring Human Cancer Reference panel identifies a malignant signature.

OBJECTIVES: Peritoneal implants of ovarian borderline serous tumors are diagnostically challenging. Distinguishing invasive from non-invasive cases is crucial for patient management. This study aims to develop a molecular signature to distinguish invasive implants with malignant potential from those with benign. METHODS: Archival formalin-fixed paraffin embedded tissues were retrieved from 3 institutions, with consensus histologic review. Lesions were classified as a non-invasive implant (n = 10), invasive implant (n = 9) or high grade (HG) peritoneal metastasis from HG serous ovarian carcinoma (n = 4). The nCounter® GX Human Cancer Gene Reference Assay was used to profile expression of 230 cancer genes and 6 control genes. The DEGs in HG peritoneal metastases compared to non-invasive implants were identified using T-tests performed in the NanoString Diff package, then used to cluster cases using the Eisen cluster 3.0 package. Lasso in glmnet package was used to select the subset of genes that most strongly correlate with a malignant potential. RESULTS: 37 genes were downregulated and 16 genes were upregulated in HG peritoneal metastases. Using this 53-gene signature, one of nine of the invasive implants clustered with the HG peritoneal metastasis. Expression of ABCB1, CDC2, CDKN1A, FAT1, MMP9, MSH2, NQO1 and TOP2A were sufficient to indicate malignant potential of implants. The HG peritoneal metastasis and one invasive implant exhibited a high malignant likelihood (>92%) whereas the non-invasive implants and eight invasive implants displayed a low malignant likelihood (≤0.1%). CONCLUSIONS: Invasive implants are heterogenous and often morphologically indistinguishable lesions with transcriptomes that may be classified as malignant or not. Additional research is needed to determine the importance of these genes as drivers and/or surrogates of malignant potential, and their utility for triaging invasive implants.

Jupiter microtubule-associated homolog 1 (JPT1): A predictive and pharmacodynamic biomarker of metformin response in endometrial cancers.

Preoperative use of metformin in obese women with endometrioid endometrial cancer (EEC) reduces tumor proliferation and inhibits the mammalian target of rapamycin pathway, though is only effective in select cases. This study sought to identify a predictive and/or pharmacodynamic proteomic signature of metformin response to tailor its pharmacologic use. Matched pre- and post-metformin-treated tumor tissues from a recently completed preoperative window trial of metformin in EEC patients (ClinicalTrials.gov: NCT01911247) were analyzed by mass spectrometry (MS)-based proteomic and immunohistochemical analyses. Jupiter microtubule-associated homolog 1 (JPT1) was significantly elevated in metformin responders (n = 13) vs nonresponders (n = 7), and found to decrease in abundance in metformin responders following treatment; observations that were verified by immunohistochemical staining for JPT1. Metformin response and loss of JPT1 were assessed in RL95-2 and ACI-181 endometrial cancer (EC) cell lines. We further identified that silencing of JPT1 abundance does not alter cellular response to metformin or basal cell proliferation, but that JPT1 abundance does decrease in response to metformin treatment in RL95-2 and ACI-181 EC cell lines. These data suggest that JPT1 represents a predictive and pharmacodynamic biomarker of metformin response that, if validated in larger patient populations, may enable preoperative EEC patient stratification to metformin treatment and the ability to monitor patient response.

Modification of diatomite with melamine coated zeolitic imidazolate framework-8 as an effective flame retardant to enhance flame retardancy and smoke suppression of rigid polyurethane foam.

In this work, the core-shell structure (ZIF-8@MA) was prepared first with melamine (MA) coated zeolitic imidazolate framework-8 (ZIF-8), and the ternary composite ZMD containing Si-N-Zn was successfully synthesized with the diatomite modified ZIF-8@MA. Subsequently, the prepared ZMD was added into rigid polyurethane foam (RPUF) to investigate its effect on fire safety of RPUF. The results of cone calorimeter and limiting oxygen index (LOI) tests indicated that ZMD effectively reduced the fire hazard of RPUF. This was because of the physical barrier effect of diatomite, the co-catalyzed char formation in the condensed phase of ZnO produced by the decomposition of ZIF-8 and silica produced by the decomposition of diatomite, and the gas phase effect of MA that enabled RPUF to achieve excellent flame retardancy and smoke suppression. The specific mechanism of flame retardancy and smoke suppression of ZMD for RPUF was also discussed in this study.

Biomarker panel for early detection of endometrial cancer in the Prostate, Lung, Colorectal, and Ovarian cancer screening trial.

BACKGROUND: Endometrial cancer is the most common gynecological cancer in the United States. However, no early detection test exists for asymptomatic women at average risk for endometrial cancer. OBJECTIVE: We sought to identify early detection biomarkers for endometrial cancer using prediagnostic serum. STUDY DESIGN: We performed a nested case-control study of postmenopausal women in the Prostate, Lung, Colorectal, and Ovarian cancer screening trial (n = 78,216), including 112 incident endometrial cancer cases and 112 controls. Prediagnostic serum was immunodepleted of high-abundance proteins and digested with sequencing grade porcine trypsin via pressure cycling technology. Quantitative proteomics and phosphoproteomics was performed using high-resolution liquid chromatography-tandem mass spectrometry and highly multiplexed isobaric mass tag combined with basic reversed-phase liquid chromatography. A set of proteins able to predict cancer status was identified with an integrated score assessed by receiver-operator curve analysis. RESULTS: Mean time from blood draw to endometrial cancer diagnosis was 3.5 years (SD, 1.9 years). There were 47 differentially abundant proteins between cases and controls (P < .05). Protein alterations with high predictive potential were selected by regression analysis and compiled into an aggregate score to determine the ability to predict endometrial cancer. An integrated risk score of 6 proteins was directly related to disease incidence in cases with blood draw ≤2 years, >2 years to ≤5 years or >5 years prior to cancer diagnosis. The integrated score distinguished cases from controls with an area under the curve of 0.80 (95% confidence interval, 0.72-0.88). CONCLUSION: An integrated score of 6 proteins using prediagnostic serum from the Prostate, Lung, Colorectal, and Ovarian cancer screening trial distinguishes postmenopausal endometrial cancer cases from controls. Validation is needed to evaluate whether this test can improve prediction or detection of endometrial cancer among postmenopausal women.