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ABSTRACT Background Aim Methods Results Conclusions The dermal extracellular matrix (ECM) is a dynamic scaffold composed mainly of proteins, with collagen as the key structural component providing resilience and support to the skin. Post‐menopause, declining estrogen levels lead to a significant reduction in skin health, notably a 30% decrease in collagen types I and III within 5 years.To discover natural extracts that stimulate collagen production.We utilized PathwayStudio to analyze protein–protein interactions and identify regulators of essential collagen types. Our study assessed Glycyrrhiza uralensis extract's ability to boost collagen production and enhance dermal density both in vitro and in vivo.PathwayStudio analysis highlighted phytoestrogens including glycyrrhizin, isoliquiritigenin, liquiritigenin, liquiritin, and glabrol, as potential candidates. Liquorice rhizome (G. uralensis), used in traditional Chinese medicine, is rich in phytoestrogens like liquiritigenin. The G. uralensis extract increased collagen I and III gene expression and pro‐collagen I protein levels in human dermal fibroblasts and inhibited UVB and pollution‐induced matrix metalloproteinase‐1 (MMP1) production. In an in vivo study, a topical formulation containing the extract significantly improved dermal density after 56 days, measured by the DUB SkinScanner.These findings suggest G. uralensis extract as a promising agent for enhancing collagen production and skin health, particularly in postmenopausal women. Further research is needed to explore its mechanisms and long‐term effects. [ABSTRACT FROM AUTHOR]

Spectrally resolved fluorescence lifetime imaging (FLIM) with high spatial precision offers comprehensive information on species localization and behavior. It is challenging to resolve weak fluorescence signals in multiple dimensions (spatial, spectral, and temporal) at high frame rates, especially in dynamic live cell processes, as photobleaching and phototoxicity limit acceptable photon count rates. We developed a multiplexed confocal FLIM technique, which uses a prism-based imaging spectrometer to separate a 10 × 10 array of confocal foci into their spectral components. This allows the sampling of the spectra by a time-resolved image sensor to produce a multispectral time-resolved data set used for generating multispectral lifetime images. This system captures 300 × 300 pixel FLIM containing 12 unique spectral bands covering a 450–700 nm spectral range in 1.8 s of exposure. Its performance was demonstrated in fixed stained samples and in multispectral imaging of FLIM-FRET in live cells.

Anti-apoptotic proteins such as BCL-XL promote cell survival by sequestering pro-apoptotic BCL-2 family members, an activity that frequently contributes to tumorigenesis. Thus, the development of small-molecule inhibitors for anti-apoptotic proteins, termed BH3-mimetics, is revolutionizing how we treat cancer. BH3 mimetics kill cells by displacing sequestered pro-apoptotic proteins to initiate tumor-cell death. Recent evidence has demonstrated that in live cells the BH3-only proteins PUMA and BIM resist displacement by BH3-mimetics, while others like tBID do not. Analysis of the molecular mechanism by which PUMA resists BH3-mimetic mediated displacement from full-length anti-apoptotic proteins (BCL-XL, BCL-2, BCL-W, and MCL-1) reveals that both the BH3-motif and a novel binding site within the carboxyl-terminal sequence (CTS) of PUMA contribute to binding. Together these sequences bind to anti-apoptotic proteins, which effectively ‘double-bolt locks’ the proteins to resist BH3-mimetic displacement. The pro-apoptotic protein BIM has also been shown to double-bolt lock to anti-apoptotic proteins however, the novel binding sequence in PUMA is unrelated to that in the CTS of BIM and functions independent of PUMA binding to membranes. Moreover, contrary to previous reports, we find that when exogenously expressed, the CTS of PUMA directs the protein primarily to the endoplasmic reticulum (ER) rather than mitochondria and that residues I175 and P180 within the CTS are required for both ER localization and BH3-mimetic resistance. Understanding how PUMA resists BH3-mimetic displacement will be useful in designing more efficacious small-molecule inhibitors of anti-apoptotic BCL-2 proteins.

AimThis study aimed to determine the prevalence of malnutrition in a head and neck cancer (HNC) population according to the Global Leadership Initiative on Malnutrition (GLIM) criteria and to assess its relation to survival. The secondary aim was to compare GLIM criteria to Patient–Generated Subjective Global Assessment (PG–SGA) and Nutritional Risk Screening 2002 (NRS 2002) methods.MethodsThe assessment was performed in a series of 65 curative patients with newly diagnosed HNC in a nutrition intervention study. Malnutrition was defined as PG-SGA classes BC and nutritional risk as NRS 2002 score ≥3 and was retrospectively diagnosed with GLIM criteria in prospectively collected data at diagnosis. Sensitivity, specificity, and kappa (κ) were analyzed. Predictive accuracy was assessed by calculating the area under curve (AUC) b y receiver operating characteristic (ROC) analysis. Kaplan–Meier and Cox regression analyses were used to evaluate association between malnutrition and overall survival (OS), and disease-free survival (DFS).ResultsGLIM-defined malnutrition was present in 37% (24/65) of patients. The GLIM showed 77% sensitivity and 84% specificity with agreement of κ = 0.60 and accuracy of AUC = 0.80 (p < 0.001) with PG-SGA and slightly higher sensitivity (83%) with NRS 2002 (κ = 0.58). Patients with GLIM-defined malnutrition had shorter OS (56 vs. 72 months, HR 2.26, 95% CI 1.07–4.77, p = 0.034) and DFS (37 vs. 66 months, HR 2.01, 95% CI 0.99–4.09, p = 0.054), than well-nourished patients. The adjusted HR was 2.53 (95% CI 1.14–5.47, p = 0.023) for OS and 2.10 (95% CI 0.98–4.48, p = 0.056) for DFS in patients with GLIM-defined malnutrition.ConclusionA substantial proportion of HNC patients were diagnosed with malnutrition according to the GLIM criteria and this showed a moderate agreement with NRS 2002- and PG–SGA-defined malnutrition. Even though the GLIM criteria had strong association with OS, its diagnostic value was poor. Therefore, the GLIM criteria seem potential for malnutrition diagnostics and outcome prediction in the HNC patient population. Furthermore, NRS 2002 score ≥3 indicates high nutritional risk in this patient group.

BackgroundKRAS mutations, present in over 40% of metastatic colorectal cancer (mCRC), are negative predictive factors for anti-EGFR therapy. Mutations in KRAS-G12C have a cysteine residue for which drugs have been developed. Published data on this specific mutation are conflicting; thus, we studied the frequency and clinical characteristics in a real-world and population-based setting.MethodsPatients from three Nordic population-based cohorts and the real-life RAXO-study were combined. RAS and BRAF tests were performed in routine healthcare, except for one cohort. The dataset consisted of 2,559 patients, of which 1,871 could be accurately classified as KRAS, NRAS, and BRAF-V600E. Demographics, treatments, and outcomes were compared using logistic regression. Overall survival (OS) was estimated with Kaplan–Meier, and differences were compared using Cox regression, adjusted for baseline factors.ResultsThe KRAS-G12C frequency was 2%–4% of all tested in the seven cohorts (mean 3%) and 4%–8% of KRAS mutated tumors in the cohorts (mean 7%). Metastasectomies and ablations were performed more often (38% vs. 28%, p = 0.040), and bevacizumab was added more often (any line 74% vs. 59%, p = 0.007) for patients with KRAS-G12C- vs. other KRAS-mutated tumors, whereas chemotherapy was given to similar proportions. OS did not differ according to KRAS mutation, neither overall (adjusted hazard ratio (HR) 1.03; 95% CI 0.74–1.42, reference KRAS-G12C) nor within treatment groups defined as “systemic chemotherapy, alone or with biologics”, “metastasectomy and/or ablations”, or “best supportive care”, RAS and BRAF wild-type tumors (n = 548) differed similarly to KRAS-G12C, as to other KRAS- or NRAS-mutated (n = 66) tumors.ConclusionsIn these real-life and population-based cohorts, there were no significant differences in patient characteristics and outcomes between patients with KRAS-G12C tumors and those with other KRAS mutations. This contrasts with the results of most previous studies claiming differences in many aspects, often with worse outcomes for those with a KRAS-G12C mutation, although not consistent. When specific drugs are developed, as for this mutation, differences in outcome will hopefully emerge.