A biomechanical analysis of novel endovascular implants for aortic valve replacement and ascending aortic repair.

Advances in medical technology have enabled minimally invasive treatment of type A aortic dissection with accompanying aortic regurgitation. Implants include endovascular stent grafts (ESG) and heart valve substitute (HVS) modules. Traditional implants can be divided into two types based on the assembly relationship between ESG and HVS: separated z-shaped implants (SZ) and separated diamond-shaped implants (SD). This study proposes a novel linked diamond-shaped implant (LD). To evaluate the safety and effectiveness of this new implant, finite element simulation models were created to assess the risks of endoleak, migration, and vascular wall rupture under annulus displacement load. After the SZ, SD, and LD implants were grafted in virtual release method, all the implants can cover tear-entry located in the ascending aorta, but space distance (δ) which exposed to blood was 14.5, 13.1, and 7.4 mm, respectively; the maximum areas of contact gap was 76.5, 51.5 and 6.3 mm2; the maximum migration distance (ΔL1) were 1.27, 1.06, and 0.1 mm; the maximum stress on ascending aorta was 0.19, 0.24, and 0.51 MPa, which were lower than failure stress (0.9 MPa). This study showed that both SZ and SD implants had minimal effects on the ascending aorta; however, higher risks were associated with implant migration and proximal endoleak. In contrast, the LD implant can simplify the surgical procedure, has a lower risk of endoleak and migration, and limited stress stimulation of the aorta. This study validated the feasibility and effectiveness of this novel implant using the finite element method, indicating its potential as a secure and reliable treatment option.

The study of loading mode with in-vitro fatigue testing for mitral annuloplasty ring.

To maintain the physiological dynamics of the mitral annulus, mitral annuloplasty rings (MAR) must be flexible. Enhanced flexibility implies decreased resistance to fatigue and potential for fatigue fracture. This study established new methods to test the flexible fatigue life of MAR in-vitro using numerical analysis; the purpose is that the fatigue test could reflect the real stress distribution in-vivo. Based on the conventional test methods (C1, D1), this paper presents a novel test method (C2, D2). Four testing methods for open-end annuloplasty rings (C1, C2) and closed-end annuloplasty rings (D1, D2) were modelled and their stress distribution calculated by finite element analysis. The mean absolute error (Χ) and the Pearson correlation coefficient (Φ) were used to quantify the difference in stress distribution between the loading modes in-vivo and in-vitro. For closed-end annuloplasty rings, the novel test method (D2) is not obvious better than conventional test methods(D1) in duplicating the stress distribution (ΦD1 = 0.88 vs ΦD2 = 0.92). However, the maximum values of stress in the novel test method are closer to the maximum value of stress under in-vivo loading (ΧD1 = 5.2Mpa vs ΧD2 = 4.4Mpa). For open-end annuloplasty rings, the novel test method(C2) is obviously superior to the conventional test method(C1) in duplicating both the stress distribution and the stress peak values of the in-vivo loading (ΦC1 = 0.22 vs ΦC2 = 0.98; ΧC1 = 59.1Mpa vs ΧC2 = 11.0Mpa). The in-vitro loading methods described in this article more closely approximated in-vivo conditions compared to traditional methods. They are simpler to operate, more efficient and can help manufacturers expedite new product development, assist regulatory agencies with product quality oversight.

Salidroside alleviates LPS-induced liver injury and inflammation through SIRT1- NF-κB pathway and NLRP3 inflammasome.

Objectives: Salidroside (SAL), an active ingredient purified from the medicinal plant Rhodiola rosea, has anti-inflammatory, anti-oxidant, anticancer, and neuroprotective properties. The study aims to examine SAL's protective role in liver damage brought on by lipopolysaccharide (LPS). Materials and Methods: Six to eight-week-old male C57BL/6 wild-type mice were intraperitoneally treated with 10 mg/kg LPS for 24 hr and 50 mg/kg SAL two hours before LPS administration. Mice were categorized into control, LPS, and LPS + SAL groups. To evaluate liver injury, biochemical and TUNNEL staining test studies were performed. The Elisa assay analyzed interleukin- 1ß (IL-1ß), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) pro-inflammatory cytokine expression levels. RT-qPCR and western blotting measured mRNA and protein expression of SIRT1, NF-кB, NLRP3, cleaved caspase-1, and GSDMD, respectively. Results: Analysis of the serum alanine/aspartate aminotransferases (ALT/AST), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) revealed that SAL protected against hepatotoxicity induced by LPS. The pathological evaluation of the liver supported the protection provided by SAL. SAL treatment reversed IL-1ß, TNF-α, and IL-6 pro-inflammatory cytokines after being induced by LPS (all, P<0.001). The western blotting examination results demonstrated that SAL increased the levels of Sirtuin 1 (SIRT1) expression but markedly reduced the phosphorylation of Nuclear Factor Kappa B (NF-B) and the expressions of NLRP3, cleaved caspase-1, and gasdermin D (GSDMD) induced by LPS (all, P<0.001). Conclusion: Our results speculated that by inhibiting the SIRT1- NF-κB pathway and NLRP3 inflammasome, SAL defends against LPS-induced liver injury and inflammation.

Cleaner outdoor air diminishes the overall risk of intracerebral hemorrhage but brings differential benefits to subpopulations: a time-stratified case-crossover study.

BACKGROUND: Short-term air pollution exposure and intracerebral hemorrhage (ICH) risk are related. However, the impact of the pollutant levels decline on this relationship, which attributes to clean air policy implementation and the COVID-19 pandemic lockdown, is unclear. In the present research, we explored the influence of different pollutant levels on ICH risk during eight years in a southwestern China megacity. METHODS: Our research used a time-stratified case-crossover design. We retrospectively analyzed ICH patients in a teaching hospital from January 1, 2014, to December 31, 2021, and divided 1571 eligible cases into two groups (1st group: 2014-2017; 2nd group: 2018-2021). We observed the trend of every pollutant in the entire study period and compared the pollution levels in each group, using air pollutants data (PM2.5, PM10, SO2, NO2, CO, and O3) documented by the local government. We further established a single pollutant model via conditional logistic regression to analyze the association between short-term air pollutants exposure and ICH risk. We also discussed the association of pollution levels and ICH risk in subpopulations according to individual factors and monthly mean temperature. RESULTS: We found that five air pollutants (PM2.5, PM10, SO2, NO2, CO) exhibited a continuous downward trend for the whole duration, and the daily concentration of all six pollutants decreased significantly in 2018-2021 compared with 2014-2017. Overall, the elevation of daily PM2.5, SO2, and CO was associated with increased ICH risk in the first group and was not positively associated with risk escalation in the second group. For patients in subgroups, the changes in the influence of lower pollutant levels on ICH risk were diverse. In the second group, for instance, PM2.5 and PM10 were associated with lower ICH risk in non-hypertension, smoking, and alcohol-drinking participants; however, SO2 had associations with increased ICH risk for smokers, and O3 had associations with raised risk in men, non-drinking, warm month population. CONCLUSIONS: Our study suggests that decreased pollution levels diminish the adverse effects of short-term air pollutants exposure and ICH risk in general. Nevertheless, the influence of lower air pollutants on ICH risk in subgroups is heterogeneous, indicating unequal benefits among subpopulations.

Effect of ureteral stent length and implantation position on migration after implantation.

BACKGROUND: Ureteral obstruction is a urinary system disease that causes urinary retention, renal injury, renal colic, and infection. Ureteral stents are often used for conservative treatment in clinics, and their migration usually results in ureteral stent failure. The migrations include proximal migration to the kidney side and distal migration to the bladder side, but the biomechanism of stent migration is still unknown. METHOD: Finite element models of stents with lengths from 6-30 cm were developed. The stents were implanted into the middle of the ureter to analyze the effect of stent length on its migration, and the effect of stent implantation position on 6-cm-long stent migration was also observed. The stents' maximum axial displacement was used to assess the ease of stent migration. A time-varying pressure was applied to the ureter outer wall to simulate peristalsis. The stent and ureter adopted friction contact conditions. The two ends of the ureter were fixed. The radial displacement of the ureter was used to evaluate the effect of the stent on peristalsis. RESULTS AND DISCUSSION: The maximum migration occurs in the positive direction for a 6-cm-long stent implanted at the proximal ureter (CD and DE), but in the negative direction at the distal ureter (FG and GH). The 6-cm-long stent demonstrated almost no effect on ureteral peristalsis. The 12-cm-long stent diminished the radial displacement of the ureter from 3-5 s. The 18-cm stent diminished the radial displacement of the ureter from 0-8 s, and the radial displacement within 2-6 s was weaker than other time. The 24-cm stent diminished the radial displacement of the ureter from 0-8 s, and the radial displacement within 1-7 s was weaker than other time. CONCLUSION: The biomechanism of stent migration and ureteral peristalsis weakening after stent implantation was explored. Shorter stents were more likely to migrate. The implantation position had less influence on ureteral peristalsis compared with the stent length, which provided a reference for stent design aimed at reducing stent migration. Stent length was the main factor affecting ureteral peristalsis. This study provides a reference for the study of ureteral peristalsis.

Epstein-Barr virus-induced infection-associated hemophagocytic lymphohistiocytosis with acute liver injury: A case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory reaction, which is rare and life-threatening. According to the pathogen, HLH is divided into genetic and acquired. The most common form of acquired HLH is infection-associated HLH, of which Herpes viruses, particularly Epstein-Barr virus (EBV), are the leading infectious triggers. However, it is difficult to distinguish between simple infection with EBV and EBV-induced infection-associated HLH since both can destroy the whole-body system, particularly the liver, thereby increasing the difficulty of diagnosis and treatment. CASE SUMMARY: This paper elaborates a case about EBV-induced infection-associated HLH and acute liver injury, aiming to propose clinical guides for the early detection and treatment of patients with EBV-induced infection-associated HLH. The patient was categorized as acquired hemophagocytic syndrome in adults. After the ganciclovir antiviral treatment combined with meropenem antibacterial therapy and methylprednisolone inhibition to inflammatory response, gamma globulin enhanced immunotherapy, the patient recovered. CONCLUSION: From the diagnosis and treatment of this patient, attention should be paid to routine EBV detection and a further comprehensive understanding of the disease as well as early recognition and early initiation are keys to patients' survival.

Abnormal flow pattern of low wall shear stress and high oscillatory shear index in spontaneous vertebral artery dissection with vertebral artery hypoplasia.

Introduction: Spontaneous vertebral artery dissection (sVAD) might tend to develop in vertebral artery hypoplasia (VAH) with hemodynamic dysfunction and it is crucial to assess hemodynamics in sVAD with VAH to investigate this hypothesis. This retrospective study aimed to quantify hemodynamic parameters in patients with sVAD with VAH. Methods: Patients who had suffered ischemic stroke due to an sVAD of VAH were enrolled in this retrospective study. The geometries of 14 patients (28 vessels) were reconstructed using Mimics and Geomagic Studio software from CT angiography (CTA). ANSYS ICEM and ANSYS FLUENT were utilized for mesh generation, set boundary conditions, solve governing equations, and perform numerical simulations. Slices were obtained at the upstream area, dissection or midstream area and downstream area of each VA. The blood flow patterns were visualized through instantaneous streamline and pressure at peak systole and late diastole. The hemodynamic parameters included pressure, velocity, time-averaged blood flow, time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), endothelial cell action potential (ECAP), relative residence time (RRT) and time-averaged nitric oxide production rate (TARNO). Results: Significant focal increased velocity was present in the dissection area of steno-occlusive sVAD with VAH compared to other nondissected areas (0.910 m/s vs. 0.449 vs. 0.566, p < 0.001), while focal slow flow velocity was observed in the dissection area of aneurysmal dilatative sVAD with VAH according to velocity streamlines. Steno-occlusive sVAD with VAH arteries had a lower time-averaged blood flow (0.499 cm3/s vs. 2.268, p < 0.001), lower TAWSS (1.115 Pa vs. 2.437, p = 0.001), higher OSI (0.248 vs. 0.173, p = 0.006), higher ECAP (0.328 Pa-1 vs. 0.094, p = 0.002), higher RRT (3.519 Pa-1 vs. 1.044, p = 0.001) and deceased TARNO (104.014 nM/s vs. 158.195, p < 0.001) than the contralateral VAs. Conclusion: Steno-occlusive sVAD with VAH patients had abnormal blood flow patterns of focal increased velocity, low time-averaged blood flow, low TAWSS, high OSI, high ECAP, high RRT and decreased TARNO. These results provide a good basis for further investigation of sVAD hemodynamics and support the applicability of the CFD method in testing the hemodynamic hypothesis of sVAD. More detailed hemodynamic conditions with different stages of sVAD are warranted in the future.

Impact of redox-related genes on tumor microenvironment immune characteristics and prognosis of high-grade gliomas.

Introduction: High-grade glioma (HGG) defines a group of brain gliomas characterized by contrast enhancement, high tumor heterogeneity, and poor clinical outcome. Disturbed reduction-oxidation (redox) balance has been frequently associated with the development of tumor cells and their microenvironment (TME). Methods: To study the influence of redox balance on HGGs and their microenvironment, we collected mRNA-sequencing and clinical data of HGG patients from TCGA and CGGA databases and our own cohort. Redox-related genes (ROGs) were defined as genes in the MSigDB pathways with keyword "redox" that were differentially expressed between HGGs and normal brain samples. Unsupervised clustering analysis was used to discover ROG expression clusters. Over-representation analysis (ORA), gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were also employed to understand the biological implication of differentially expressed genes between HGG clusters. CIBERSORTx and ESTIMATE were used to profile the immune TME landscapes of tumors, and TIDE was used to evaluated the potential response to immune checkpoint inhibitors. Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression was used to construct HGG-ROG expression risk signature (GRORS). Results: Seventy-five ROGs were found and consensus clustering using the expression profile of ROGs divided the both IDH-mutant (IDHmut) and IDH-wildtype (IDHwt) HGGs into subclusters with different prognosis. Functional enrichment analysis revealed that the differential aggressiveness between redox subclusters in IDHmut HGGs were significantly associated with cell cycle regulation pathways, while IDHwt HGG redox subclusters showed differentially activated immune-related pathways. In silico TME analysis on immune landscapes in the TME showed that the more aggressive redox subclusters in both IDHmut and IDHwt HGGs may harbor a more diverse composition of tumor-infiltrating immune cells, expressed a higher level of immune checkpoints and were more likely to respond to immune checkpoint blockade. Next, we established a GRORS which showed AUCs of 0.787, 0.884, and 0.917 in predicting 1-3-year survival of HGG patients in the held-out validation datasets, and the C-index of a nomogram combining the GRORS and other prognostic information reached 0.835. Conclusion: Briefly, our results suggest that the expression pattern of ROGs was closely associated with the prognosis as well as the TME immune profile of HGGs, and may serve as a potential indicator for their response to immunotherapies.

Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study.

BACKGROUND: HER2 is an actionable target in metastatic colorectal cancer. We assessed the activity of tucatinib plus trastuzumab in patients with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer. METHODS: MOUNTAINEER is a global, open-label, phase 2 study that enrolled patients aged 18 years and older with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer at 34 sites (clinics and hospitals) in five countries (Belgium, France, Italy, Spain, and the USA). Initially, the study was designed as a single-cohort study, which was expanded following an interim analysis to include more patients. Initially, patients were given tucatinib (300 mg orally twice daily) plus intravenous trastuzumab (8 mg/kg as an initial loading dose, then 6 mg/kg every 21 days; cohort A) for the duration of treatment (until progression), and after expansion, patients were randomly assigned (4:3), using an interactive web response system and stratified by primary tumour location, to either tucatinib plus trastuzumab (cohort B) or tucatinib monotherapy (cohort C). The primary endpoint was confirmed objective response rate per blinded independent central review (BICR) for cohorts A and B combined and was assessed in patients in the full analysis set (ie, patients with HER2-positive disease who received at least one dose of study treatment). Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03043313, and is ongoing. FINDINGS: Between Aug 8, 2017, and Sept 22, 2021, 117 patients were enrolled (45 in cohort A, 41 in cohort B, and 31 in cohort C), of whom 114 patients had locally assessed HER2-positive disease and received treatment (45 in cohort A, 39 in cohort B, and 30 in cohort C; full analysis set), and 116 patients received at least one dose of study treatment (45 in cohort A, 41 in cohort B, and 30 in cohort C; safety population). In the full analysis set, median age was 56·0 years (IQR 47-64), 66 (58%) were male, 48 (42%) were female, 88 (77%) were White, and six (5%) were Black or African American. As of data cutoff (March 28, 2022), in 84 patients from cohorts A and B in the full analysis set, the confirmed objective response rate per BICR was 38·1% (95% CI 27·7-49·3; three patients had a complete response and 29 had a partial response). In cohorts A and B, the most common adverse event was diarrhoea (55 [64%] of 86), the most common grade 3 or worse adverse event was hypertension (six [7%] of 86), and three (3%) patients had tucatinib-related serious adverse events (acute kidney injury, colitis, and fatigue). In cohort C, the most common adverse event was diarrhoea (ten [33%] of 30), the most common grade 3 or worse adverse events were increased alanine aminotransferase and aspartate aminotransferase (both two [7%]), and one (3%) patient had a tucatinib-related serious adverse event (overdose). No deaths were attributed to adverse events. All deaths in treated patients were due to disease progression. INTERPRETATION: Tucatinib plus trastuzumab had clinically meaningful anti-tumour activity and favourable tolerability. This treatment is the first US Food and Drug Administration-approved anti-HER2 regimen for metastatic colorectal cancer and is an important new treatment option for chemotherapy-refractory HER2-positive metastatic colorectal cancer. FUNDING: Seagen and Merck & Co.

A novel score system based on arginine metabolism-related genes to predict prognosis, characterize immune microenvironment, and forecast response to immunotherapy in IDH-wildtype glioblastoma.

Introduction: Glioblastoma is one of the most lethal cancers and leads to more than 200,000 deaths annually. However, despite lots of researchers devoted to exploring novel treatment regime, most of these attempts eventually failed to improve the overall survival of glioblastoma patients in near 20 years. Immunotherapy is an emerging therapy for cancers and have succeeded in many cancers. But most of its application in glioblastoma have been proved with no improvement in overall survival, which may result from the unique immune microenvironment of glioblastoma. Arginine is amino acid and is involved in many physiological processes. Many studies have suggested that arginine and its metabolism can regulate malignancy of multiple cancers and influence the formation of tumor immune microenvironment. However, there is hardly study focusing on the role of arginine metabolism in glioblastoma. Methods: In this research, based on mRNA sequencing data of 560 IDH-wildtype glioblastoma patients from three public cohorts and one our own cohort, we aimed to construct an arginine metabolism-related genes signature (ArMRS) based on four essential arginine metabolism-related genes (ArMGs) that we filtered from all genes with potential relation with arginine metabolism. Subsequently, the glioblastoma patients were classified into ArMRS high-risk and low-risk groups according to calculated optimal cut-off values of ArMRS in these four cohorts. Results: Further validation demonstrated that the ArMRS was an independent prognostic factor and displayed fine efficacy in prediction of glioblastoma patients' prognosis. Moreover, analyses of tumor immune microenvironment revealed that higher ArMRS was correlated with more immune infiltration and relatively "hot" immunological phenotype. We also demonstrated that ArMRS was positively correlated with the expression of multiple immunotherapy targets, including PD1 and B7-H3. Additionally, the glioblastomas in the ArMRS high-risk group would present with more cytotoxic T cells (CTLs) infiltration and better predicted response to immune checkpoint inhibitors (ICIs). Discussion: In conclusion, our study constructed a novel score system based on arginine metabolism, ArMRS, which presented with good efficacy in prognosis prediction and strong potential to predict unique immunological features, resistance to immunotherapy, and guide the application of immunotherapy in IDH-wild type glioblastoma.

Astragaloside IV attenuates lipopolysaccharide induced liver injury by modulating Nrf2-mediated oxidative stress and NLRP3-mediated inflammation.

Aims and objectives: Sepsis-associated liver injury is a common public health problem in intensive care units. Astragaloside IV (AS-IV) is an active component extracted from the Chinese herb Astragalus membranaceus, and has been shown to have anti-oxidation, anti-inflammation, and anti-apoptosis properties. The research aimed to investigate the protective effect of AS-IV in lipopolysaccharide (LPS)-induced liver injury. Methods: Male C57BL/6 wild-type mice (6-8 week-old) were intraperitoneally injected with 10 mg/kg LPS for 24 h and AS-IV (80 mg/kg) 2 h before the LPS injection. Biochemical and histopathological analyses were carried out to assess liver injury. The RT-qPCR analyzed the mRNA expression of IL-1ß, TNF-α, and IL-6. The mRNA and protein expression of SIRT1, nuclear Nrf2, Nrf2, and HO-1 were measured by Western blotting. Results: Serum alanine/aspartate aminotransferases (ALT/AST) analysis, malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) were showed that AS-IV protected against LPS-induced hepatotoxicity. The protection afforded by AS-IV was confirmed by pathological examination of the liver. Pro-inflammatory cytokines, including interleukin- 1ß (IL-1ß), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6), were observed to be reversed by AS-IV after exposure to LPS. Western blot analysis demonstrated that AS-IV enhanced the expression levels of Sirtuin 1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1). Conclusions: AS-IV protects against LPS-induced Liver Injury and Inflammation by modulating Nrf2-mediated oxidative stress and NLRP3-mediated inflammation.

Bovine pericardium leaflet damage during transcatheter aortic valve crimping: a study of the mechanisms.

Leaflet damage has been documented to occur while deploying a transcatheter aortic valve (TAV) due to mechanical loads during the crimping procedures. In this study, the impact of compressive stress on folded leaflets was measured to investigate the mechanism of traumatic leaflet tissue damage. Numerical simulation of TAV crimping procedure was adapted to calculate stress magnitude and distribution of leaflets. A 20 mm balloon expanding short stent TAV with 0.25 mm thickness leaflets was used in the simulation. Then the calculated stresses were applied on leaflet material (bovine pericardium) samples by loading experiments. Mechanical properties evaluation combined with histological and microscopy observation were used to investigate the tissue damage. The elastic modulus and the tensile strength of the tissue began to decrease significantly at 2 MPa stress and 2.5 MPa stress, respectively. No significant differences were observed at 0-1.5 MPa stress. When the TAV was crimped to 14 Fr and 12 Fr, the 2 MPa greater areas on leaflets increased from 18.17% to 76.96%. 2 MPa compressive stress might be the threshold value for leaflet damage. The TAV crimping size should be paid attention to avoid the compressive stress higher than 2 MPa.

Tucatinib vs Placebo, Both in Combination With Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients With Brain Metastases: Updated Exploratory Analysis of the HER2CLIMB Randomized Clinical Trial.

Importance: It is estimated that up to 50% of patients with ERBB2 (HER2)-positive metastatic breast cancer (MBC) will develop brain metastases (BMs), which is associated with poor prognosis. Previous reports of the HER2CLIMB trial have demonstrated that tucatinib in combination with trastuzumab and capecitabine provides survival and intracranial benefits for patients with ERBB2-positive MBC and BMs. Objective: To describe overall survival (OS) and intracranial outcomes from tucatinib in combination with trastuzumab and capecitabine in patients with ERBB2-positive MBC and BMs with an additional 15.6 months of follow-up. Design, Setting, and Participants: HER2CLIMB is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial evaluating tucatinib in combination with trastuzumab and capecitabine. The 612 patients, including those with active or stable BMs, had ERBB2-positive MBC previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. The study was conducted from February 23, 2016, to May 3, 2019. Data from February 23, 2016, to February 8, 2021, were analyzed. Interventions: Patients were randomized 2:1 to receive tucatinib (300 mg orally twice daily) or placebo (orally twice daily), both in combination with trastuzumab (6 mg/kg intravenously or subcutaneously every 3 weeks with an initial loading dose of 8 mg/kg) and capecitabine (1000 mg/m2 orally twice daily on days 1-14 of each 3-week cycle). Main Outcomes and Measures: Evaluations in this exploratory subgroup analysis included OS and intracranial progression-free survival (CNS-PFS) in patients with BMs, confirmed intracranial objective response rate (ORR-IC) and duration of intracranial response (DOR-IC) in patients with measurable intracranial disease at baseline, and new brain lesion-free survival in all patients. Only OS was prespecified before the primary database lock. Results: At baseline, 291 of 612 patients (47.5%) had BMs. Median age was 52 years (range, 22-75 years), and 289 (99.3%) were women. At median follow-up of 29.6 months (range, 0.1-52.9 months), median OS was 9.1 months longer in the tucatinib-combination group (21.6 months; 95% CI, 18.1-28.5) vs the placebo-combination group (12.5 months; 95% CI, 11.2-16.9). The tucatinib-combination group showed greater clinical benefit in CNS-PFS and ORR-IC compared with the placebo-combination group. The DOR-IC was 8.6 months (95% CI, 5.5-10.3 months) in the tucatinib-combination group and 3.0 months (95% CI, 3.0-10.3 months) in the placebo-combination group. Risk of developing new brain lesions as the site of first progression or death was reduced by 45.1% in the tucatinib-combination group vs the placebo-combination group (hazard ratio, 0.55 [95% CI, 0.36-0.85]). Conclusions and Relevance: This subgroup analysis found that tucatinib in combination with trastuzumab and capecitabine improved OS while reducing the risk of developing new brain lesions, further supporting the importance of this treatment option for patients with ERBB2-positive MBC, including those with BMs. Trial Registration: ClinicalTrials.gov Identifier: NCT02614794.

Radiomic study on preoperative multi-modal magnetic resonance images identifies IDH-mutant TERT promoter-mutant gliomas.

OBJECTIVES: Gliomas with comutations of isocitrate dehydrogenase (IDH) genes and telomerase reverse transcriptase (TERT) gene promoter (IDHmut pTERTmut) show distinct biological features and respond to first-line treatment differently in comparison with other gliomas. This study aimed to characterize the IDHmut pTERTmut gliomas in multimodal MRI using the radiomic method and establish a precise diagnostic model identifying this group of gliomas. METHODS: A total of 140 patients with untreated primary gliomas were admitted between 2016 and 2020 to West China Hospital as a discovery cohort, including 22 IDHmut pTERTmut patients. Thirty-four additional cases from a different hospital were included in the study as an independent validation cohort. A total of 3654 radiomic features were extracted from the preoperative multimodal MRI images (T1c, FLAIR, and ADC maps) and filtered in a data-driven approach. The discovery cohort was split into training and test sets by a 4:1 ratio. A diagnostic model (multilayer perceptron classifier) for detecting the IDHmut pTERTmut gliomas was trained using an automatic machine-learning algorithm named tree-based pipeline optimization tool (TPOT). The most critical radiomic features in the model were identified and visualized. RESULTS: The model achieved an area under the receiver-operating curve (AUROC) of 0.971 (95% CI, 0.902-1.000), the sensitivity of 0.833 (95% CI, 0.333-1.000), and the specificity of 0.966 (95% CI, 0.931-1.000) in the test set. The area under the precision-recall curve (AUCPR) was 0.754 (95% CI, 0.572-0.833) and the F1 score was 0.833 (95% CI, 0.500-1.000). In the independent validation set, the model reached 0.952 AUROC, 0.714 sensitivity, 0.963 specificity, 0.841 AUCPR, and 0.769 F1 score. MR radiomic features of the IDHmut pTERTmut gliomas represented homogenous low-complexity texture in three modalities. CONCLUSIONS: An accurate diagnostic model was constructed for detecting IDHmut pTERTmut gliomas using multimodal radiomic features. The most important features were associated with the homogenous simple texture of IDHmut pTERTmut gliomas in MRI images transformed using Laplacian of Gaussian and wavelet filters.

The Regulatory Effect of Braided Silk Fiber Skeletons with Differential Porosities on In Vivo Vascular Tissue Regeneration and Long-Term Patency.

The development of small-diameter vascular grafts that can meet the long-term patency required for implementation in clinical practice presents a key challenge to the research field. Although techniques such as the braiding of scaffolds can offer a tunable platform for fabricating vascular grafts, the effects of braided silk fiber skeletons on the porosity, remodeling, and patency in vivo have not been thoroughly investigated. Here, we used finite element analysis of simulated deformation and compliance to design vascular grafts comprised of braided silk fiber skeletons with three different degrees of porosity. Following the synthesis of low-, medium-, and high-porosity silk fiber skeletons, we coated them with hemocompatible sulfated silk fibroin sponges and then evaluated the mechanical and biological functions of the resultant silk tubes with different porosities. Our data showed that high-porosity grafts exhibited higher elastic moduli and compliance but lower suture retention strength, which contrasted with low-porosity grafts. Medium-porosity grafts offered a favorable balance of mechanical properties. Short-term in vivo implantation in rats indicated that porosity served as an effective means to regulate blood leakage, cell infiltration, and neointima formation. High-porosity grafts were susceptible to blood leakage, while low-porosity grafts hindered graft cellularization and tended to induce intimal hyperplasia. Medium-porosity grafts closely mimicked the biomechanical behaviors of native blood vessels and facilitated vascular smooth muscle layer regeneration and polarization of infiltrated macrophages to the M2 phenotype. Due to their superior performance and lack of occlusion, the medium-porosity vascular grafts were evaluated in long-term (24-months) in vivo implantation. The medium-porosity grafts regenerated the vascular smooth muscle cell layers and collagen extracellular matrix, which were circumferentially aligned and resembled the native artery. Furthermore, the formed neoarteries pulsed synchronously with the adjacent native artery and demonstrated contractile function. Overall, our study underscores the importance of braided silk fiber skeleton porosity on long-term vascular graft performance and will help to guide the design of next-generation vascular grafts.

Serine and glycine metabolism-related gene expression signature stratifies immune profiles of brain gliomas, and predicts prognosis and responses to immunotherapy.

Glioma is one of the most lethal cancers and causes more than 200,000 deaths every year. Immunotherapy was an inspiring therapy for multiple cancers but failed in glioma treatment. The importance of serine and glycine and their metabolism has been well-recognized in the physiology of immune cells and microenvironment in multiple cancers. However, their correlation with prognosis, immune cells, and immune microenvironment of glioma remains unclear. In this study, we investigated the relationships between the expression pattern of serine and glycine metabolism-related genes (SGMGs) and clinicopathological features, prognosis, and tumor microenvironment in glioma based on comprehensive analyses of multiple public datasets and our cohort. According to the expression of SGMGs, we conducted the consensus clustering analysis to stratify all patients into four clusters with remarkably distinctive clinicopathological features, prognosis, immune cell infiltration, and immune microenvironment. Subsequently, a serine and glycine metabolism-related genes signature (SGMRS) was constructed based on five critical SGMGs in glioma to stratify patients into SGMRS high- and low-risk groups and tested for its prognostic value. Higher SGMRS expressed genes associated with the synthesis of serine and glycine at higher levels and manifested poorer prognosis. Besides, we confirmed that SGMRS was an independent prognostic factor and constructed nomograms with satisfactory prognosis prediction performance based on SGMRS and other factors. Analyzing the relationship between SGMRS and immune landscape, we found that higher SGMRS correlated with 'hotter' immunological phenotype and more immune cell infiltration. Furthermore, the expression levels of multiple immunotherapy-related targets, including PD-1, PD-L1, and B7-H3, were positively correlated with SGMRS, which was validated by the better predicted response to immune checkpoint inhibitors. In conclusion, our study explored the relationships between the expression pattern of SGMGs and tumor features and created novel models to predict the prognosis of glioma patients. The correlation of SGMRS with immune cells and microenvironment in gliomas suggested an essential role of serine and glycine metabolism in reforming immune cells and microenvironment. Finally, the results of our study endorsed the potential application of SGMRS to guide the selection of immunotherapy for gliomas.

Prognosis prediction and tumor immune microenvironment characterization based on tryptophan metabolism-related genes signature in brain glioma.

Glioma is the most common malignant tumor in the central nervous system with no significant therapeutic breakthrough in recent years. Most attempts to apply immunotherapy in glioma have failed. Tryptophan and its metabolism can regulate malignant features of cancers and reshape immune microenvironment of tumors. However, the role of tryptophan metabolism in glioma remains unclear. In current study, we explored the relationships between the expression pattern of tryptophan metabolism-related genes (TrMGs) and tumor characteristics, including prognosis and tumor microenvironment of gliomas through analyzing 1,523 patients' samples from multiple public databases and our own cohort. Based on expression of TrMGs, K-means clustering analysis stratified all glioma patients into two clusters with significantly different TrMG expression patterns, clinicopathological features and immune microenvironment. Furthermore, we constructed a tryptophan metabolism-related genes signature (TrMRS) based on seven essential TrMGs to classify the patients into TrMRS low- and high-risk groups and validated the prognostic value of the TrMRS in multiple cohorts. Higher TrMRS represented for potentially more active tryptophan catabolism, which could subsequently lead to less tryptophan in tumor. The TrMRS high-risk group presented with shorter overall survival, and further analysis confirmed TrMRS as an independent prognostic factor in gliomas. The nomograms uniting TrMRS with other prognostic factors manifested with satisfactory efficacy in predicting the prognosis of glioma patients. Additionally, analyses of tumor immune landscapes demonstrated that higher TrMRS was correlated with more immune cell infiltration and "hot" immunological phenotype. TrMRS was also demonstrated to be positively correlated with the expression of multiple immunotherapy targets, including PD1 and PD-L1. Finally, the TrMRS high-risk group manifested better predicted response to immune checkpoint inhibitors. In conclusion, our study illustrated the relationships between expression pattern of TrMGs and characteristics of gliomas, and presented a novel model based on TrMRS for prognosis prediction in glioma patients. The association between TrMRS and tumor immune microenvironment of gliomas indicated an important role of tryptophan and its metabolism in reshaping immune landscape and the potential ability to guide the application of immunotherapy for gliomas.

Purine metabolism-related gene expression signature predicts survival outcome and indicates immune microenvironment profile of gliomas.

Glioma is the most common malignant tumor in the central nervous system. The impact of metabolism on cancer development and the immune microenvironment landscape has recently gained broad attention. Purines are involved in multiple metabolic pathways. It has been proved that purine metabolism could regulate malignant biological behaviors and response to immune checkpoint inhibitors in multiple cancers. However, the relationship of purine metabolism with clinicopathological features and the immune landscape of glioma remains unclear. In this study, we explored the relationships between the expression of purine metabolism-related genes (PuMGs) and tumor features, including prognosis and microenvironment of glioma, based on analyses of 1,523 tumors from 4 public databases and our cohort. Consensus clustering based on 136 PuMGs classified the glioma patients into two clusters with significantly distinguished prognosis and immune microenvironment landscapes. Increased immune infiltration was associated with more aggressive gliomas. The prognostic Purine Metabolism-Related Genes Risk Signature (PuMRS), based on 11 critical PuMGs, stratified the patients into PuMRS low- and high-risk groups in the training set and was validated by validation sets from multiple cohorts. The high-risk group presented with significantly shorter overall survival, and further survival analysis demonstrated that the PuMRS was an independent prognostic factor in glioma. The nomogram combining PuMRS and other clinicopathological factors showed satisfactory accuracy in predicting glioma patients' prognosis. Furthermore, analyses of the tumor immune microenvironment suggested that higher PuMRS was correlated with increased immune cell infiltration and gene expression signatures of "hotË® tumors. Gliomas in the PuMRS high-risk group presented a higher expression level of multiple immune checkpoints, including PD-1 and PD-L1, and a better-predicted therapy response to immune checkpoint inhibitors. In conclusion, our study elucidated the relationship between the expression level of PuMGs and the aggressiveness of gliomas. Our study also endorsed the application of PuMRS to construct a new robust model for the prognosis evaluation of glioma patients. The correlations between the profiles of PuMGs expression and tumor immune microenvironment potentially provided guidance for immunotherapy in glioma.

Prognostic value of lactate metabolism-related gene expression signature in adult primary gliomas and its impact on the tumor immune microenvironment.

Glioma is one of the most malignant intracerebral tumors, whose treatment means was limited, and prognosis was unsatisfactory. Lactate metabolism patterns have been shown to be highly heterogenous among different tumors and produce diverse impact on the tumor microenvironment. To understand the characteristics and implications of lactate metabolism gene expression, we developed a lactate metabolism-related gene expression signature of gliomas based on RNA-sequencing data of a total of 965 patient samples from TCGA, CGGA, and our own glioma cohort. Sixty-three lactate metabolism-related genes (LMGs) were differentially expressed between glioma and normal brain tissue, and consensus clustering analysis identified two clusters distinct LMG expression patterns. The consensus clusters differed in prognosis, molecular characteristics and estimated immune microenvironment landscape involving immune checkpoint proteins, T cell dysfunction and exclusion, as well as tumor purity. Univariate Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) Cox hazard regression was applied in determining of prognosis-related lactate metabolism genes (PRLMGs), on which prognostic lactate metabolism risk score (PLMRS) was constructed. The high PLMRS group was associated with significantly poorer patient outcome. A nomogram containing PLMRS and other independent prognostic variables was established with remarkable predictive performance on patient survival. Exploration on the somatic mutations and copy number variations of the high- and low-PLMRS groups demonstrated their distinct genetic background. Together, our results indicated that the expression signature of LMG was associated with the prognosis of glioma patients and influenced the activity of immune cells in the tumor microenvironment, which may serve as a potential biomarker for predicting response of gliomas to immunotherapy.

Prognostic value of cuproptosis-related genes signature and its impact on the reshaped immune microenvironment of glioma.

Glioma is the most prevalent malignancy in the central nervous system. The impact of ion-induced cell death on malignant tumors' development and immune microenvironment has attracted broad attention in recent years. Cuproptosis is a novel copper-dependent mechanism that could potentially regulate tumor cell death by targeting mitochondria respiration. However, the role of cuproptosis in gliomas remains unclear. In the present study, we investigated the relationships between the expression of cuproptosis-related genes (CRGs) and tumor characteristics, including prognosis and microenvironment of glioma, by analyzing multiple public databases and our cohort. Consensus clustering based on the expression of twelve CRGs stratified the glioma patients into three subgroups with significantly different prognosis and immune microenvironment landscapes. Reduced immune infiltration was associated with the less aggressive CRG cluster. A prognostic CRGs risk signature (CRGRS), based on eight critical CRGs, classified the patients into low- and high-risk groups in the training set and was endorsed by validation sets from multiple cohorts. The high-risk group manifested a shorter overall survival, and further survival analysis demonstrated that the CRGRS was an independent prognostic factor. The nomogram combining CRGRS and other clinicopathological factors exhibited good accuracy in predicting the prognosis of glioma patients. Moreover, analyses of tumor immune microenvironment indicated that higher CRGRS was correlated with increased immune cell infiltration but diminished immune function. Gliomas in the high-risk group exhibited higher expression of multiple immune checkpoints, including PD-1 and PD-L1, and a better predicted therapy response to immune checkpoint inhibitors. In conclusion, our study elucidated the connections between CRGs expression and the aggressiveness of gliomas, and the application of CRGRS derived a new robust model for prognosis evaluation of glioma patients. The correlations between the profiles of CRGs expression and immune tumor microenvironment illuminated prospects and potential indications of immunotherapy for glioma.