Luteolin is a natural flavonoid with strong anti–oxidative properties that is reported to have an anti–cancer effect in several malignancies other than bladder cancer. In this study, we describe the ...effect of luteolin on a human bladder cancer cell line, T24, in the context of the regulation of p21, thioredoxin‐1 (TRX1) and the mechanistic target of rapamycin (mTOR) pathway. Luteolin inhibited cell survival and induced G2/M cell‐cycle arrest, p21 upregulation and downregulation of phospho(p)‐S6, which is downstream of mTOR signaling. Luteolin also upregulated TRX1 and reduced intracellular reactive oxygen species production. In a subcutaneous xenograft mouse model using the rat bladder cancer cell line, BC31, tumor volumes were significantly decreased in mice orally administered luteolin compared to control. Immunohistochemical analysis revealed that increased p21 and decreased p‐S6 expression were induced in the luteolin treatment group. Moreover, in another in vivo N‐butyl‐N‐(4‐hydroxybutyl) nitrosamine (BBN)‐induced rat bladder cancer model, the oral administration of luteolin led to a trend of decreased bladder tumor dimension and significantly decreased the Ki67‐labeling index and p‐S6 expression. Furthermore, the major findings on the metabolism of luteolin suggest that both plasma and urine luteolin‐3ʹ‐O‐glucuronide concentrations are strongly associated with the inhibition of cell proliferation and mTOR signaling. Moreover, a significant decrease in the squamous differentiation of bladder cancer is attributed to plasma luteolin‐3ʹ‐glucuronide concentration. In conclusion, luteolin, and in particular its metabolized product, may represent another natural product‐derived therapeutic agent that acts against bladder cancer by upregulating p21 and inhibiting mTOR signaling.
Luteolin suppresses cell proliferation through downregulation of mTOR signaling and upregulation of p21 in bladder cancers both in vitro and in vivo. mTOR activity is correlated with invasive ability in human bladder cancer cases. A metabolite of luteolin decreases cell viability and squamous differentiation in in vivo rat bladder cancer models.
In Vivo Gold Complex Catalysis within Live Mice Tsubokura, Kazuki; Vong, Kenward K. H.; Pradipta, Ambara R. ...
Angewandte Chemie International Edition,
March 20, 2017, Letnik:
56, Številka:
13
Journal Article
Recenzirano
Metal complex catalysis within biological systems is largely limited to cell and bacterial systems. In this work, a glycoalbumin–AuIII complex was designed and developed that enables organ‐specific, ...localized propargyl ester amidation with nearby proteins within live mice. The targeted reactivity can be imaged through the use of Cy7.5‐ and TAMRA‐linked propargyl ester based fluorescent probes. This targeting system could enable the exploitation of other metal catalysis strategies for biomedical and clinical applications.
The first metal‐catalyzed reaction that proceeds within live mice is based on a targeting approach with glycans. Glycoalbumin–AuIII complexes can be accumulated in specific organs where they catalyze amide bond formation between a propargyl ester probe and amine groups on nearby proteins. The selective targeting was confirmed by whole body fluorescence imaging and analysis of dissected tissues.
Several limitations of
FFDG have been reported, such as nonspecific uptake of inflammation foci. Moreover,
CMET has been found to accumulate in normal and inflammatory tissues as well as tumors. To ...increase specificity to tumor tissues, PET probes with tumor-specific molecular targets have been actively developed.
FFIMP was found to be highly accumulated in LAT1-positive tumors but not in inflamed tissue. The aim of this study was to explore whether
FFIMP can be used for the early-phase evaluation of radiotherapy accompanied by inflammation, and compare its effectiveness with those of
CMET and
FFDG. Tumor uptake of
FFIMP decreased at day 1 after irradiation, and remained low until day 14. Comparatively, that of
FFDG initially decreased at day 3 but was transiently elevated at day 7 and then decreased again at day 10. Decreased tumor uptake of
CMET was observed at day 10. In line with the uptake of
FFIMP, the ratio of Ki-67 immuno-positive cells in tumor tissues significantly decreased at day 1, 7, and 10 as compared with that in the control. These findings suggest that
FFIMP may be a PET probe involved in the early detection and prediction of radiotherapy efficacy, although further clarification is needed.
We demonstrate directed differentiation of telencephalic precursors from mouse embryonic stem (ES) cells using optimized serum-free suspension culture (SFEB culture). Treatment with Wnt and Nodal ...antagonists (Dkk1 and LeftyA) during the first 5 d of SFEB culture causes nearly selective neural differentiation in ES cells ( approximately 90%). In the presence of Dkk1, with or without LeftyA, SFEB induces efficient generation ( approximately 35%) of cells expressing telencephalic marker Bf1. Wnt3a treatment during the late culture period increases the pallial telencephalic population (Pax6(+) cells yield up to 75% of Bf1(+) cells), whereas Shh promotes basal telencephalic differentiation (into Nkx2.1(+) and/or Islet1/2(+) cells) at the cost of pallial telencephalic differentiation. Thus, in the absence of caudalizing signals, floating aggregates of ES cells generate naive telencephalic precursors that acquire subregional identities by responding to extracellular patterning signals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Positron emission tomography (PET) imaging can assist in the early-phase diagnostic and therapeutic evaluation of tumors. Here, we report the radiosynthesis, small animal PET imaging, and ...biological evaluation of a L-type amino acid transporter 1 (LAT1)-specific PET probe,
18
F-FIMP. This probe demonstrates increased tumor specificity, compared to existing tumor-specific PET probes (
18
F-FET,
11
C-MET, and
18
F-FDG). Evaluation of probes by
in vivo
PET imaging,
18
F-FIMP showed intense accumulation in LAT1-positive tumor tissues, but not in inflamed lesions, whereas intense accumulation of
18
F-FDG was observed in both tumor tissues and in inflamed lesions. Metabolite analysis showed that
18
F-FIMP was stable in liver microsomes, and mice tissues (plasma, urine, liver, pancreas, and tumor). Investigation of the protein incorporation of
18
F-FIMP showed that it was not incorporated into protein. Furthermore, the expected mean absorbed dose of
18
F-FIMP in humans was comparable or slightly higher than that of
18
F-FDG and indicated that
18
F-FIMP may be a safe PET probe for use in humans.
18
F-FIMP may provide improved specificity for tumor diagnosis, compared to
18
F-FDG,
18
F-FET, and
11
C-MET. This probe may be suitable for PET imaging for glioblastoma and the early-phase monitoring of cancer therapy outcomes.
Background
After first-line chemotherapy failure, metastatic urothelial carcinoma (mUC) patients undergo pembrolizumab (PEM) or gemcitabine and docetaxel (GD) therapy. We retrospectively investigated ...outcomes of second-line GD or PEM for mUC patients.
Methods
A total of 198 mUC patients from Nagoya City University and affiliated hospitals who received second-line treatment were grouped according to immune check point inhibitor (ICI) availability: Groups A (pre-ICI:
n
= 104) and B (post-ICI:
n
= 94). We compared clinical outcomes using Kaplan–Meier curves. Univariate and multivariate Cox regression analyses assessed potential prognostic factors for overall survival (OS).
Results
Median OS was significantly longer for Group B median 13.6 months, 95% confidence interval (CI): 7.6–17.6 than A (7.6 months, 5.3–8.8). By sub-group analysis, patients received no additional treatment (Naïve,
n
= 70), or PEM or GD (Salvage,
n
= 24) in Group B, with median OS of Naïve and A groups similar. Compared to the Salvage group, significant differences in OS were observed (median 7.6 months, 95% CI 5.3–8.8; Group A, 7.6 months, 4.7–13.8; Naïve, 25.7 months, 14.0–31.0;
p
< 0.01). For the Salvage group, OS for sequential treatment of GD–salvage PEM and PEM–salvage GD patients was similar (
p
= 0.10). Multivariate analysis showed a low neutrophil-to-lymphocyte ratio (NLR) and high geriatric nutritional risk index (GNRI) as significant prognostic factors affecting long OS 95% CI 1.12–3.45, hazard ratio (HR): 1.97; 95% CI 0.24–0.71, 0.41, respectively.
Conclusion
Second-line GD or PEM therapy for mUC patients showed equivalent survival benefits. GNRI and NLR are prognostic biomarkers for survival outcome.
The aim of this study was to evaluate whether frailty was associated with 6-month mortality in older adults who were admitted to the intensive care unit (ICU) with an illness requiring emergency ...care. The investigation was a prospective, multi-center, observational study conducted among the ICUs of 17 participating hospitals. Patients ≥ 65 years of age who were admitted to the ICU directly from an emergency department visit were assessed to determine their baseline Clinical Frailty Scale (CFS) scores before the illness and were surveyed 6 months after admission. Among 650 patients included in the study, the median age was 79 years old, and overall mortality at 6 months was as low as 21%, ranging from 6.2% in patients with CFS 1 to 42.9% in patients with CFS ≥ 7. When adjusted for potential confounders, CFS score was an independent prognostic factor for mortality (one-point increase in CFS, adjusted risk ratio with 95% confidence interval 1.19 1.09-1.30). Quality of life 6 months after admission worsened as baseline CFS score increased. However, there was no association between total hospitalization cost and baseline CFS. CFS is an important predictor of long-term outcomes among critically ill older patients requiring emergent admission.
This work represents the first broad study of testing diverse heterogenous glycoconjugates (7 different glycoalbumins) for their differential in vivo binding (11 different cancer cell types) in both ...cell- and animal-based studies. As a result, various changes in biodistribution, excretion, and even tumor adhesion were observed.
Background
The sperm retrieval rate of microdissection testicular sperm extraction varies from 25% to 60%. Therefore, it is necessary to establish objective selection criteria for identifying ...seminiferous tubules with spermatozoa.
Objectives
Our aim was to develop a method for identifying spermatogenesis without sectioning testicular tissues.
Materials and methods
Testicular tissues of 10‐week‐old normal rats were fixed with 4% paraformaldehyde. Fluorescent labeling of seminiferous tubule nuclei and F‐actin was performed, and the specimens were observed without sectioning using a multiphoton microscope. Cryptorchid rats were used as a model lacking elongated spermatids. Multiphoton images were compared with images of normal seminiferous tubules. In addition, seminiferous tubules of 10‐week‐old normal rats were labeled by testicular interstitial injection of fluorescent probes and observed by a multiphoton microscope without fixation. Terminal deoxynucleotidyl transferase dUTP nick end labeling‐stained images of normal and probe‐injected testes were compared.
Results
In fixed seminiferous tubules, elongated spermatids were identified. In addition, F‐actin of apical ectoplasmic specialization was observed around elongated spermatids. Furthermore, spermatogenic stages were identified by an array of nuclei or F‐actin. In cryptorchid testes, elongated spermatids and F‐actin of the apical ectoplasmic specialization were not observed. In testes injected with fluorescent probes, F‐actin of the apical ectoplasmic specialization was observed, and spermatogenic stages were identified without fixation. There was no significant difference in the number of terminal deoxynucleotidyl transferase dUTP nick end labeling‐positive cells per seminiferous tubule between normal and probe‐injected testes.
Conclusions
Seminiferous epithelium could be observed without sectioning of tissues by fluorescent probes and a multiphoton microscope. Active spermatogenesis was observed by labeling F‐actin with and without fixation. Moreover, the toxicity of fluorescent probes was limited. Our method has a potential for live imaging of testicular tissue.
We elucidated the efficacy of gut microbiome-altering drugs on pembrolizumab efficacy in patients with metastatic urothelial carcinoma (mUC). Clinical data were analyzed retrospectively from 133 ...patients with mUC who received second-line pembrolizumab therapy between January 2018 and January 2021, following failed platinum-based chemotherapy. We evaluated the effects of gut microbiome-altering drugs (proton pump inhibitors PPI/potassium-competitive acid blockers P-CAB, H2 blockers, antibiotics, non-steroidal anti-inflammatory drugs NSAIDs, metformin, antipsychotics, steroids, and opioids), taken by patients within 30 days before/after pembrolizumab treatment, on progression-free survival (PFS) and overall survival (OS). Fifty-one patients received PPI/P-CAB (37/14, respectively); H2 blockers, 7; antibiotics, 35; NSAIDs, 22; antipsychotics, 8; metformin, 3; steroids, 11; and opioids, 29. Kaplan-Meier curves revealed PPI or P-CAB users showed shorter PFS than non-PPI-P-CAB users (p = 0.001, p = 0.005, respectively). Multivariate analysis highlighted PPI/P-CAB use as the only independent prognostic factor for disease progression (hazards ratio: 1.71, 95% confidence interval: 1.14-2.07, p = 0.010) but not death (p = 0.177). Proton pump inhibitors/potassium-competitive acid blockers may decrease the efficacy of pembrolizumab therapy for mUC, possibly via gut microbiome modulation.
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![Comparison of [ 18 F]FIMP, ...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/2045-2322/small "Comparison of [ 18 F]FIMP, [ 11 C]MET, and [ 18 F]FDG PET for early-phase assessment of radiotherapy response")
