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In this review, we will discuss the potential link between Sestrins, stem cells, and ageing.Hematopoietic stem cells (HSCs) are characterized by two key features Self-renewal ability and multilineage differentiation potential (multipotentiality). With aging, these key features gradually change. This is thought to be related to hematological diseases. However, clonal in vivo analysis assessing the potential of HSCs to differentiate along erythroid and platelet lineages ("five-lineage tracing") has not been performed in the aged bone marrow. By contrast, in young HSCs clonal in vivo analysis combined with five-lineage tracing has provided us with novel insights into HSC biology. Understanding HSC aging at the clonal level will help us to elucidate aging mechanisms and disease progression. We review recent progress towards understanding HSC aging at the clonal cell level in the transplantation setting.Nine new limonoids, named thaixylomolins S-Z (1-8) and 2-O-acetylthaixylomolin Z (9), were isolated from seeds of the mangrove, Xylocarpus moluccensis, collected in the mangrove swamp of Trang Province, Thailand. Thaixylomolin S (1) is the fourth member of the khayalactone class of limonoids containing a hexahydro-2H-2,5- propanocyclopenta[b]furan motif. Thaixylomolins T-Y (2-7) are structurally diverse mexicanolides; whereas thaixylomolin Z (8) and 2-O-acetylthaixylomolin Z (9) are phragmalin 8,9,30-orthoesters. The structures of these compounds were established by HRESIMS and extensive 1D and 2D NMR investigations. The absolute configurations of thaixylomolins S (1), U (3), and Z (8) were unambiguously established by single-crystal X-ray diffraction analyses, conducted with Cu Kα radiation; whereas that of 2-O-acetylthaixylomolin Z (9) was determined to be the same as that of thaixylomolin Z (8) by the accurate fit of their experimental electronic circular dichroism spectra. Thaixylomolin S (1), featuring the presence of a 30-(2'-methyl)butyryloxy group, is the first limonoid of the khayalactone class, whose constitution and absolute configuration are unequivocally determined by X-ray crystallography. The inhibitory activities of all the compounds, except for the epimers 4, were assayed against human carboxylesterase 2. All the tested compounds exhibited inhibition rates in the range of 16-65% at the concentration of 100.0 μM.
Isolation space must be expanded during pandemics involving airborne transmission. Little to no work has been done to establish optimal design strategies and implementation plans to ease surge capacity and expand isolation capacity over long periods in congregate living facilities. The COVID-19 pandemic has an airborne transmission component and requires isolation, which is difficult to accomplish in skilled nursing facilities.
In this study we designed, implemented, and validated an isolation space at a skilled nursing facility in Lancaster, PA. The overall goal was to minimize disease transmission between residents and staff within the facility. We created an isolation space by modifying an existing HVAC system of the SNF. learn more We measured pressure on-site and performed computational fluid dynamics and Lagrangian particle-based modeling to test containment and possible transmission extent given the isolation space is considered negative rather than individual rooms.
Pressure data shows the isolation space maintained an average (standard deviation) hourly value of -2.3 Pa (0.12 Pa) pressure differential between it and the external hallway connected to the rest of the facility. No transmission of SARS-CoV-2 between residents isolated to the space occurred, nor did any transmission to the staff or other residents occur. The isolation space was successfully implemented and, as of writing, continues to be operational through the pandemic.
Skilled nursing facilities can be retrofitted to provide negative pressure isolation space in a reasonable time frame and a cost effective manner to minimize airborne disease transmission within that space.
Skilled nursing facilities can be retrofitted to provide negative pressure isolation space in a reasonable time frame and a cost effective manner to minimize airborne disease transmission within that space.Tumor-associated macrophages (TAM) constitute up to 50-80% of stromal cells in breast cancer (BC), and are correlated with poor prognosis. As epidermal growth factor receptor (EGFR) is overexpressed in 60-80% of patients with triple negative breast cancer (TNBC), photoimmunotherapy (PIT) with cetuximab-targeted gold nanorods (CTX-AuNR) is an attractive therapeutic strategy for TNBC. The 3D cell culture model can mimic drug resistance conferred by the tumor microenvironment and its 3D organization; therefore, TAM and non-TAM embedded TNBC spheroids were constructed to evaluate the therapeutic efficacy of CTX-AuNR plus near infrared (NIR) irradiation. Cytotoxicity, reactive oxygen species (ROS) generation, and protein expression were compared in TNBC (± TAM) spheroids. The IC50 values of doxorubicin (DOX) in TAM-embedded TNBC spheroids were significantly higher than those in TNBC spheroids, demonstrating drug resistance, which could be explained by activation of IL-10/IL-10 receptor/STAT3/Bcl-2 signaling. However, 3D in vitro and in vivo results demonstrated that the efficacy of CTX-AuNR plus NIR irradiation was not significantly different in (± TAM) embedded TNBC cells. By enhancing ROS generation, CTX-AuNR plus NIR irradiation reprogrammed TAM polarization to the M1 anti-tumor phenotype, as indicated by macrophage mannose receptor (MMR) downregulation. Thus, CTX-AuNR plus NIR can serve as a potent PIT strategy for treating EGFR-overexpressing TNBC cells.The development of targeted nanomedicines for cancer therapy has been an utmost focus of research across different fields including materials science, nanotechnology, biotechnology, pharmaceutics, and clinical medicine. Vehicle-mediated, enhanced and tumor-selective delivery is deemed as a powerful tool to boost the efficacy and meanwhile minimize the off-target effect of potent chemo drugs, and to potentiate biopharmaceuticals such as nucleic acids (DNA, siRNA, miRNA, mRNA, CRISPR/Cas9, etc.), proteins and peptides that poorly penetrate the cell membrane on their own while having explicit effects intracellularly. The targeted nanomedicines may further provide imminent treatments for intractable brain tumors by transporting drugs across the blood-brain barriers, multi-drug resistant (MDR) tumors by evading the MDR pathways, metastatic tumors by inhibiting migratory tumor cells, and relapsed tumors by eliminating the cancer stem cells. The preclinical and clinical investigations demonstrate the clear benefits of targeted nanomedicines in treating advanced solid and hematological malignancies.
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