Expression of the tumor suppressor gene TUSC2 is reduced or absent in most lung cancers and is associated with worse overall survival. In this study, we restored TUSC2 gene expression in several wild ...type EGFR non-small cell lung cancer (NSCLC) cell lines resistant to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib and analyzed their sensitivity to erlotinib in vitro and in vivo. A significant inhibition of cell growth and colony formation was observed with TUSC2 transient and stable expression. TUSC2-erlotinib cooperativity in vitro could be reproduced in vivo in subcutaneous tumor growth and lung metastasis formation lung cancer xenograft mouse models. Combination treatment with intravenous TUSC2 nanovesicles and erlotinib synergistically inhibited tumor growth and metastasis, and increased apoptotic activity. High-throughput qRT-PCR array analysis enabling multi-parallel expression profile analysis of eighty six receptor and non-receptor tyrosine kinase genes revealed a significant decrease of FGFR2 expression level, suggesting a potential role of FGFR2 in TUSC2-enhanced sensitivity to erlotinib. Western blots showed inhibition of FGFR2 by TUSC2 transient transfection, and marked increase of PARP, an apoptotic marker, cleavage level after TUSC2-erlotinb combined treatment. Suppression of FGFR2 by AZD4547 or gene knockdown enhanced sensitivity to erlotinib in some but not all tested cell lines. TUSC2 inhibits mTOR activation and the latter cell lines were responsive to the mTOR inhibitor rapamycin combined with erlotinib. These results suggest that TUSC2 restoration in wild type EGFR NSCLC may overcome erlotinib resistance, and identify FGFR2 and mTOR as critical regulators of this activity in varying cellular contexts. The therapeutic activity of TUSC2 could extend the use of erlotinib to lung cancer patients with wildtype EGFR.
Cellular senescence contributes to inflammatory kidney disease via the secretion of inflammatory and profibrotic factors. Protease-activating receptor 2 (PAR2) is a key regulator of inflammation in ...kidney diseases. However, the relationship between PAR2 and cellular senescence in kidney disease has not yet been described. In this study, we found that PAR2-mediated metabolic changes in renal tubular epithelial cells induced cellular senescence and increased inflammatory responses. Using an aging and renal injury model, PAR2 expression was shown to be associated with cellular senescence. Under in vitro conditions in NRK52E cells, PAR2 activation induces tubular epithelial cell senescence and senescent cells showed defective fatty acid oxidation (FAO). Cpt1α inhibition showed similar senescent phenotype in the cells, implicating the important role of defective FAO in senescence. Finally, we subjected mice lacking PAR2 to aging and renal injury. PAR2-deficient kidneys are protected from adenine- and cisplatin-induced renal fibrosis and injury, respectively, by reducing senescence and inflammation. Moreover, kidneys lacking PAR2 exhibited reduced numbers of senescent cells and inflammation during aging. These findings offer fresh insights into the mechanisms underlying renal senescence and indicate that targeting PAR2 or FAO may be a promising therapeutic approach for managing kidney injury.
Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and ranges from isolated steatosis to NASH. To determine whether circulating fatty acids could serve as diagnostic ...markers of NAFLD severity and whether specific fatty acids could contribute to the pathogenesis of NASH, we analyzed two independent NAFLD patient cohorts and used the methionine- and choline-deficient diet (MCD) NASH mouse model. We identified six fatty acids that could serve as non-invasive markers of NASH in patients with NAFLD. Serum levels of 15:0, 17:0 and 16:1n7t negatively correlated with NAFLD activity scores and hepatocyte ballooning scores, while 18:1n7c serum levels strongly correlated with fibrosis stage and liver inflammation. Serum levels of 15:0 and 17:0 also negatively correlated with fasting glucose and AST, while 16:1n7c and 18:1n7c levels positively correlated with AST and ferritin, respectively. Inclusion of demographic and clinical parameters improved the performance of the fatty acid panels in detecting NASH in NAFLD patients. The panel 15:0, 16:1n7t, 18:1n7c, 22:5n3, age, ferritin and APRI predicted intermediate or advanced fibrosis in NAFLD patients, with 82% sensitivity at 90% specificity AUROC = 0.92. 15:0 and 18:1n7c were further selected for functional studies in vivo. Mice treated with 15:0-supplemented MCD diet showed reduced AST levels and hepatic infiltration of ceroid-laden macrophages compared to MCD-treated mice, suggesting that 15:0 deficiency contributes to liver injury in NASH. In contrast, 18:1n7c-supplemented MCD diet didn't affect liver pathology. In conclusion, 15:0 may serve as a promising biomarker or therapeutic target in NASH, opening avenues for the integration of diagnosis and treatment.
Mesenchymal stromal cells (MSC) support acute myeloid leukemia (AML) cell survival in the bone marrow (BM) microenvironment. Protein expression profiles of AML-derived MSC are unknown. Reverse phase ...protein array analysis was performed to compare expression of 151 proteins from AML-MSC (n=106) with MSC from healthy donors (n=71). Protein expression differed significantly between the two groups with 19 proteins over-expressed in leukemia stromal cells and 9 over-expressed in normal stromal cells. Unbiased hierarchical clustering analysis of the samples using these 28 proteins revealed three protein constellations whose variation in expression defined four MSC protein expression signatures: Class 1, Class 2, Class 3, and Class 4. These cell populations appear to have clinical relevance. Specifically, patients with Class 3 cells have longer survival and remission duration compared to other groups. Comparison of leukemia MSC at first diagnosis with those obtained at salvage (i.e. relapse/refractory) showed differential expression of 9 proteins reflecting a shift toward osteogenic differentiation. Leukemia MSC are more senescent compared to their normal counterparts, possibly due to the overexpressed p53/p21 axis as confirmed by high β-galactosidase staining. In addition, overexpression of BCL-X
in leukemia MSC might give survival advantage under conditions of senescence or stress and overexpressed galectin-3 exerts profound immunosuppression. Together, our findings suggest that the identification of specific populations of MSC in AML patients may be an important determinant of therapeutic response.
The front cover illustrates the streamlined synthesis of representative non‐alternant polycyclic aromatic hydrocarbons through Lewis acid‐catalyzed Prins‐type cycloaromatization (on the earth). ...Notable features of the catalytic reaction encompass air tolerance, high productivity, remarkably short reaction times, and scalability. The plausible mechanism suggests that Prins‐type benzannulation competes with oxonium‐ene cyclization. The robustness and high productivity of the key reaction allowed the application towards total synthesis of natural benzojfluoranthene, viridistratin A (on the moon). Details can be found in the Communication by Hwayoung Yun and co‐workers (M. Jeong, M. Yoon, L. H. Nguyen, S. Kim, J. Han, C. S. Tran, J. Kim, J. Jo, Y.‐S. Jung, J.‐W. Yoo, H. Yun, Adv. Synth. Catal. 2024, 366, 390–395, DOI: 10.1002/adsc.202300600).
Oceanographic conditions in the Southern Ocean are closely related to the oceanic frontal system. Glacial-interglacial changes in cryosphere influence variations in oceanic fronts in the Southern ...Ocean and vice versa, causing changes in surface water productivity, nutrient utilization, bottom water chemistry, and/or bottom current intensity. Here, we documented geochemical, nitrogen isotope, and grain size records over the last 600 kyrs from the Drake Passage with previously published data to compare between glacial and interglacial oceanic conditions from surface to bottom. Biogenic opal (diatom) and export productions were high during interglacial periods and low during glacial periods. Surface water production was dominated by open ocean species during both glacial and interglacial periods without a clear glacial-interglacial change in sea ice species. After Marine Isotope Stage (MIS) 9, interglacial biogenic opal and diatom abundance increased distinctively with decreased terrestrial influence. Nutrient utilization increased (decreased) during interglacial (glacial) periods with increased (decreased) surface water production, particularly after MIS 9. This indicates that surface water production was regulated by light availability in association with sea ice duration/extent. According to good correlation between sortable silt mean grain size (SS MGS) and %sortable silt, SS MGS can be used for bottom current intensity indicator in this study; increased (decreased) bottom current during glacial (interglacial) periods. Increased glacial bottom current is likely related to southwestward flowing bottom current. Interglacial bottom current intensity became also significantly weakened after MIS 9. However, outstanding interglacial warmth in the Drake Passage occurred from MIS 9, not following the global trend to occur after MIS 11. This implies that more studies from the Southern Ocean in response to the Mid-Brunhes Event are required in the future.
•Surface and bottom oceanic conditions showed clear glacial-interglacial variations.•More open ocean condition prevailed during interglacial periods after MIS 9.•Nitrate utilization is related to light availability; high/low during interglacials/glacials.•Sortable silt mean grain size in GC05-DP02 can be used for bottom current intensity.•Influence of southwestward flowing bottom current increased during glacial periods.
The outer Ross Sea continental shelf has experienced large variations in ice sheet extent over the Pleistocene that are theorized to be largely driven by changes in the westward-flowing Antarctic ...Slope Current (ASC) at the continental shelf break. This current regulates southward incursions of warm modified Circumpolar Water, and it is thought to have triggered past marine ice sheet retreat. Additionally, expansions of grounded ice sheets on the continental shelf have fundamentally altered the Ross Sea water mass formation processes, influencing surface water salinity, sea ice cover, nutrient utilization, deep-water ventilation, and primary productivity. Here, we report the geochemical, physical properties, grain size, bulk δ15N, and diatom records during the late Pleistocene from two sediment cores from the Iselin Bank on the outermost continental shelf in the Ross Sea. These core sites were not overridden by grounded ice sheets during the late Pleistocene glacial-interglacial cycles, allowing for a continuous archive of glacimarine environments that were influenced by the ASC. Interglacial periods are typically characterized by high surface water productivity and nutrient utilization, with Chaetoceros resting spores indicating nutrient limitation under open ocean conditions, and glacial periods are typically characterized by low surface water productivity and nutrient utilization, with sea ice diatoms and planktonic foraminifers indicating light limitation under extensive sea ice/ice margin proximal conditions. A grain size analysis indicates coarse-skewed distributions and winnowing in the Iselin Bank region during cold periods. The winnowing may be related to enhanced ASC flow instead of density driven shelf water outflow.
Although adefovir dipivoxil (ADV) has a unique profile of delayed and infrequent resistance in treatment‐naïve chronic hepatitis B patients, the association of ADV resistance with previous lamivudine ...(LAM) resistance is not well understood. We compared the emergence of the ADV‐resistant mutations rtA181V/T and rtN236T between LAM‐resistant patients and treatment‐naïve patients at 48 weeks of ADV monotherapy. Fifty‐seven LAM‐resistant patients and 38 treatment‐naïve patients were treated with 10 mg/d ADV for more than 48 weeks. Both baseline and 48‐week blood samples were analyzed for ADV‐resistant mutations via restriction fragment mass polymorphism analysis. Antiviral responses were evaluated according to changes in serum HBV DNA (measured via real‐time polymerase chain reaction) and alanine aminotransferase (ALT) levels and loss of hepatitis B e antigen (HBeAg). After 48 weeks, 10 (18%) of the 57 LAM‐resistant patients were found to have developed ADV‐resistant mutations, whereas none of the 38 treatment‐naïve patients developed such mutations (P < .01). Among LAM‐resistant patients, the reduction in serum HBV DNA levels was significantly lower in patients with ADV‐resistant mutations than in those without such mutations (−1.04 vs. −2.63 log10 copies/mL) (P = .01). However, the rates of serum ALT normalization (60% vs. 55%) and HBeAg loss (14% vs. 21%) were not significantly different between the 2 groups (P > .05). In conclusion, the emergence of the rtA181V/T and rtN236T mutations was more common in LAM‐resistant patients than in treatment‐naïve patients after 48 weeks of ADV therapy and was associated with reduced antiviral efficacy to drug treatment. (HEPATOLOGY 2006;43:1385–1391.)
Severe fever with thrombocytopenia syndrome virus was first discovered in 2009 as the causative agent of severe fever with thrombocytopenia syndrome. Despite its potential threat to public health, no ...prophylactic vaccine is yet available. This study developed a heterologous prime-boost strategy comprising priming with recombinant replication-deficient human adenovirus type 5 (rAd5) expressing the surface glycoprotein, Gn, and boosting with Gn protein. This vaccination regimen induced balanced Th1/Th2 immune responses and resulted in potent humoral and T cell-mediated responses in mice. It elicited high neutralizing antibody titers in both mice and non-human primates. Transcriptome analysis revealed that rAd5 and Gn proteins induced adaptive and innate immune pathways, respectively. This study provides immunological and mechanistic insight into this heterologous regimen and paves the way for future strategies against emerging infectious diseases.
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