Introduction: The prognosis of acute lymphoblastic leukemia (ALL) in adolescents and adults is poor, and recurrence is an important cause of their death. Changes of genetic information play a vital role in the pathogenesis and recurrence of ALL; however, the impact of molecular genetic mutations on disease diagnosis and prognosis remains unexplored. This study aimed to explore the frequency spectrum of gene mutations and their prognostic significance, along with the minimal residual disease (MRD) level and hematopoietic stem cell transplantation (HSCT), in adolescent and adult patients aged ≥15 years with ALL. Methods: The basic characteristics, cytogenetics, molecular genetics, MRD level, treatment regimen and survival outcome of patients with untreated ALL (≥15 years) were collected, and the correlation and survival analysis were performed using the SPSS 25.0 and R software. Results: This study included 404 patients, of which 147 were selected for next-generation sequencing (NGS). NGS results revealed that 91.2 % of the patients had at least one mutation, and 67.35% had multiple (≥ 2) mutations. NOTCH1, PHF6, RUNX1, PTEN, JAK3, TET2, and JAK1 were the most common mutations in T-ALL, whereas FAT1, TET2, NARS, KMT2D, FLT3, and RELN were the most common mutations in B-ALL. Correlation analysis revealed the mutation patterns, which were significantly different between T-ALL and B-ALL. In the prognostic analysis of 107 patients with B-ALL, multivariate analysis showed that the number of mutations ≥5 was an independent risk factor for overall survival and the RELN mutation was an independent poor prognostic factor for event-free survival. Discussion: The distribution of gene mutations and the co-occurrence and repulsion of mutant genes in patients with ALL were closely related to the immunophenotype of the patients. The number of mutations ≥5 and the RELN mutation were significantly associated with poor prognosis in adolescent and adult patients with ALL.
High-temperature requirement A1 (HtrA1) has been identified as a disease-susceptibility gene for age-related macular degeneration (AMD) including polypoidal choroidal neovasculopathy (PCV). We characterized the underlying phenotypic changes of transgenic (Tg) mice expressing ubiquitous CAG promoter (CAG-HtrA1 Tg). In vivo imaging modalities and histopathology were performed to investigate the possible neovascularization, drusen formation, and infiltration of macrophages. Subretinal white material deposition and scattered white-yellowish retinal foci were detected on CFP [(Tg—33% (20/60) and wild-type (WT)—7% (1/15), p < 0.05]. In 40% (4/10) of the CAG-HtrA1 Tg retina, ICGA showed punctate hyperfluorescent spots. There was no leakage on FFA and OCTA failed to confirm vascular flow signals from the subretinal materials. Increased macrophages and RPE cell migrations were noted from histopathological sections. Monocyte subpopulations were increased in peripheral blood in the CAG-HtrA1 Tg mice (p < 0.05). Laser induced CNV in the CAG-HtrA1 Tg mice and showed increased leakage from CNV compared to WT mice (p < 0.05). Finally, choroidal explants of the old CAG-HtrA1 Tg mice demonstrated an increased area of sprouting (p < 0.05). Signs of subclinical inflammation was observed in CAG-HtrA1 Tg mice. Such subclinical inflammation may have resulted in increased RPE cell activation and angiogenic potential.
Recent studies have shown that Notch pathway plays a key role in the pathogenesis of diabetic nephropathy (DN), however, the exact mechanisms remain elusive. Here we demonstrated that high glucose (HG) upregulated Notch pathway in podocytes accompanied with the alteration of Bcl-2 and p53 pathways, subsequently leading to podocytes apoptosis. Inhibition of Notch pathway by chemical inhibitor or specific short hairpin RNA (shRNA) vector in podocytes prevented Bcl-2- and p53-dependent cell apoptosis. These findings suggest that Notch pathway mediates HG-induced podocytes apoptosis via Bcl-2 and p53 pathways.
Peroxisome proliferator-activated receptor (PPAR)β/δ is a member of the nuclear receptor superfamily of transcription factors, which plays fundamental roles in cell proliferation and differentiation, inflammation, adipogenesis, and energy homeostasis. Previous studies demonstrated a reduced choroidal neovascularization (CNV) in Pparβ/δ-deficient mice. However, PPARβ/δ’s role in physiological blood vessel formation and vessel remodeling in the retina has yet to be established. Our study showed that PPARβ/δ is specifically required for disordered blood vessel formation in the retina. We further demonstrated an increased arteriovenous crossover and wider venous caliber in Pparβ/δ-haplodeficient mice. In summary, these results indicated a critical role of PPARβ/δ in pathological angiogenesis and blood vessel remodeling in the retina.
<p>S1. Post-slippage cells arrest at G1 as tetraploid multinucleated cells. S2. Correlation of multinucleation and senescence post-slippage in response to various anti-mitotic drugs. S3. In vivo association of senescence and anti-mitotic drug treatment. S4. Post-slippage cells increase expression of factors associated with senescence and SASP. S5. SASP factors from post-slippage cells do not affect proliferation of neighbouring cells. S6. Autophagy mediates senescence. S7. Autophagy does not modulate cell fate during prolonged mitotic arrest. S8. Autophagy-dependent IL-1β and IL-8 expression mediate cell invasiveness in a paracrine manner. S9. Silencing of p53 increases post-slippage cell death. S10. p53 status determines synergistic effect of microtubule poisons and autophagy inhibition. Table S1. List of differentially regulated proteins after 48 h Noc treatment detected by SILAC mass spectrometry. Table S2. List of antibodies. Table S3. List of chemicals. Table S4. List of primers. Table S5. Quantitative H scoring method</p>
The purpose of this study was to evaluate and compare knee kinematics and stability following either triangular or anatomical reconstruction of the superficial medial collateral ligament (sMCL) and posterior oblique ligament (POL). In a cadaveric model (12 knees), the stability and kinematics following two experimental sMCL and POL reconstructions were compared in sMCL- and POL-deficient knees versus normal knees. The first reconstruction was a triangular reconstruction of the sMCL and POL, while the second involved an anatomical reconstruction of the sMCL and POL. All knees were tested through four different states. The changes in valgus angles, external rotation, and internal rotation were measured in the normal and sMCL- and POL-deficient knees, as well as in the knees that had undergone the two different forms (triangular and anatomical) of reconstruction. After initial sectioning of the sMCL and POL, we observed significantly increased valgus rotation, external rotation, and internal rotation at all knee flexion angles (0°, 20°, 30°, 60°, 90°). Additionally, passive stability testing demonstrated a significant increase in tibial internal rotation following triangular reconstruction compared with anatomical reconstruction at knee flexion angles of 20° and 30°. A significant increase in internal rotation was present following triangular reconstruction compared with anatomical reconstruction at 20° (mean difference = 2.77) (P = 0.008) and 30° (mean difference = 0.99) (P < 0.001) of knee flexion. This study suggests that anatomical sMCL and POL reconstruction produces slightly better biomechanical stability than triangular reconstruction. However, triangular reconstruction may restore a near-normal knee joint is both less invasive and more practical.
Introduction: Previous research has demonstrated that an isocaloric diet rich in trans fatty acid (TFA), saturated fatty acid (SFA), and cholesterol (Chol) promoted steatosis-derived hepatic tumorigenesis in hepatitis C virus core gene transgenic (HCVcpTg) mice in different manners. Growth factor signaling and ensuing angiogenesis/lymphangiogenesis are key factors in hepatic tumorigenesis that have become recent therapeutic targets for hepatocellular carcinoma. However, the influence of dietary fat composition on these factors remains unclear. This study investigated whether the type of dietary fat would have a specific impact on hepatic angiogenesis/lymphangiogenesis in HCVcpTg mice. Methods: Male HCVcpTg mice were treated with a control diet, an isocaloric diet containing 1.5% cholesterol (Chol diet), or a diet replacing soybean oil with hydrogenated coconut oil (SFA diet) for a period of 15 months, or with shortening (TFA diet) for 5 months. The degree of angiogenesis/lymphangiogenesis and the expression of growth factors, including fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF), were evaluated in non-tumorous liver tissues using quantitative mRNA measurement, immunoblot analysis, and immunohistochemistry. Results: Long-term feeding of SFA and TFA diets to HCVcpTg mice increased the expressions of vascular endothelial cell indicators, such as CD31 and TEK tyrosine kinase, in addition to lymphatic vessel endothelial hyaluronan receptor 1, indicating that angiogenesis/lymphangiogenesis were up-regulated only by these fatty acid-enriched diets. This promoting effect correlated with elevated VEGF-C and FGF receptor 2 and 3 levels in the liver. c-Jun N-terminal kinase (JNK) and hypoxia-inducible factor (HIF) 1α, both key regulators of VEGF-C expression, were enhanced in the SFA- and TFA-rich diet groups as well. The Chol diet significantly increased the expressions of such growth factors as FGF2 and PDGF subunit B (PDGF-B), without any detectable impact on angiogenesis/lymphangiogenesis. Conclusion: This study revealed that diets rich in SFA and TFA, but not Chol, might stimulate hepatic angiogenesis/lymphangiogenesis mainly through the JNK-HIF1α-VEGF-C axis. Our observations indicate an importance of dietary fat species for preventing hepatic tumorigenesis.
Background The contribution of Cutibacterium acnes ( C . acnes ) infection to intervertebral disc degeneration (IDD) and the antibiotic therapy has evoked several controversies in recent years. While some microbiology studies report bacterial disc infection within IDD patients, others attribute the positive results to contamination during prolonged cultures. In addition to the clinical controversy, little was known about the mechanism of C . acnes -caused Modic changes (MCs) if C . acnes was the pathogenic factor. Objectives This study aimed to investigate the inflammatory mechanism of MCs induced by different phylotypes of C . acnes in patients with IDD. Methods Specimens from sixty patients undergoing microdiscectomy for disc herniation were included, C . acnes were identified by anaerobic culture, followed by biochemical and PCR-based methods. The identified species of C . acnes were respectively inoculated into the intervertebral discs of rabbits. MRI and histological change were observed. Additionally, we detected MMP expression in the rabbit model using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results Of the 60 cases, 18 (30%) specimens were positive for C . acnes , and we identified 4 of 6 defined phylogroups: IA, IB, II and III. The rabbits that received Type IB or II strains of C . acnes showed significantly decreased T1WI and higher T2WI at eighth weeks, while strain III C . acnes resulted in hypointense signals on both T1WI and T2WI. Histological examination results showed that all of the three types of C . acnes could cause disc degeneration and endplates rupture. Moreover, endplate degeneration induced by type IB or II strains of C . acnes is related with MMP13 expression. Meanwhile, strain III C . acnes might upregulated the level of MMP3. Conclusion This study suggested that C . acnes is widespread in herniated disc tissues. Different types of C . acnes could induce different MCs by increasing MMP expression.
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