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Most nanomedicines require efficient in vivo delivery to elicit meaningful diagnostic and therapeutic effects. However, en route to their intended tissues, systemically administered nanoparticles often encounter delivery barriers. To describe these barriers, the term "nanoparticle blood removal pathways" (NBRP) is proposed, which summarizes the interactions between nanoparticles and the body's various cell‐dependent and cell‐independent blood clearance mechanisms. Nanoparticle design and biological modulation strategies are reviewed to mitigate nanoparticle‐NBRP interactions. As these interactions affect nanoparticle delivery, the preclinical literature from 2011–2021 is studied, and the nanoparticle blood circulation and organ biodistribution data are analyzed. The findings reveal that nanoparticle surface chemistry affects the in vivo behavior more than other nanoparticle design parameters. Combinatory biological‐PEG surface modification improves the blood area under the curve by ≈418%, with a decrease in liver accumulation of up to 47%. A greater understanding of nanoparticle‐NBRP interactions and associated delivery trends will provide new nanoparticle design and biological modulation strategies for safer, more effective, and more efficient nanomedicines. [ABSTRACT FROM AUTHOR]

Current ovarian cancer maintenance therapy is limited by toxicity and no proven impact on overall survival. To study a maintenance strategy targeted at missense mutant p53, we hypothesized that the release of mutant p53 from mortalin inhibition by the SHetA2 drug combined with reactivation of mutant p53 with the PRIMA‐1MET drug inhibits growth and tumor establishment synergistically in a mutant‐p53 dependent manner. The Cancer Genome Atlas (TCGA) data and serous ovarian tumors were evaluated for TP53 and HSPA9/mortalin status. SHetA2 and PRIMA‐1MET were tested in ovarian cancer cell lines and fallopian tube secretory epithelial cells using isobolograms, fluorescent cytometry, Western blots and ELISAs. Drugs were administered to mice after peritoneal injection of MESOV mutant p53 ovarian cancer cells and prior to tumor establishment, which was evaluated by logistic regression. Fifty‐eight percent of TP53 mutations were missense and there were no mortalin mutations in TCGA high‐grade serous ovarian cancers. Mortalin levels were sequentially increased in serous benign, borderline and carcinoma tumors. SHetA2 caused p53 nuclear and mitochondrial accumulation in cancer, but not in healthy, cells. Endogenous or exogenous mutant p53 increased SHetA2 resistance. PRIMA‐1MET decreased this resistance and interacted synergistically with SHetA2 in mutant and wild type p53‐expressing cell lines in association with elevated reactive oxygen species/ATP ratios. Tumor‐free rates in animals were 0% (controls), 25% (PRIMA1MET), 42% (SHetA2) and 67% (combination). SHetA2 (p = 0.004) and PRIMA1MET (p = 0.048) functioned additively in preventing tumor development with no observed toxicity. These results justify the development of SHetA2 and PRIMA‐1MET alone and in combination for ovarian cancer maintenance therapy. What's new? Ovarian cancer patients need an effective maintenance therapy with minimal toxicity to prevent deadly recurrence of the disease. In this paper, the authors focused on reactivating missense mutant p53. Most high grade serous ovarian cancer contains mutations in p53, which can confer resistance to therapy. The authors tested SHetA2, a drug that frees p53 from sequestration by the protein mortalin, combined with a p53 activating drug, PRIMA‐1MET. The two drugs combined achieved a 67% tumor‐free rate in mice, higher than either alone. This success fuels further testing of the two agents as combination therapy for ovarian cancer. [ABSTRACT FROM AUTHOR]

Background This study aims to compare dosimetrically and radiobiologically 3 D conformal, intensity modulated radiation therapy ( IMRT), RapidArc ( RA) volumetric modulated arc therapy and proton therapy techniques for early-stage glottic cancer. Methods Ten patients were retrospectively selected. Photon treatment planning was performed using Eclipse External Beam Planning, and proton planning was performed using CMS Xio. The minimum, mean and maximum dose values for planning target volume ( PTV), mean and maximum dose values for organ at risk, % of volume of PTV receiving at least 95% of the prescription dose, and D20, D50 and D90 of carotid arteries were compared. Biological response models of tumour control probabilities and normal tissue complication probabilities were calculated. Results IMRT, RA and proton plans versus three-dimensional conformal radiotherapy (3 D-CRT) plans consistently provided superior PTV coverage and decreased mean dose to the thyroid and carotid arteries. Conclusion All these three modalities showed superiority with less variation among themselves compared with 3 D-CRT plans. Clinical investigation is warranted to determine if these treatment approaches will translate into a reduction in radiation therapy-induced toxicities. [ABSTRACT FROM AUTHOR]

Proton T2 relaxation times of metabolites in the human brain were measured using point resolved spectroscopy at 3T in vivo. Four echo times (54, 112, 246 and 374 ms) were selected from numerical and phantom analyses for effective detection of the glutamate multiplet at ~ 2.35 ppm. In vivo data were obtained from medial and left occipital cortices of five healthy volunteers. The cortices contained predominantly gray and white matter, respectively. Spectra were analyzed with LCModel software using volume-localized calculated spectra of brain metabolites. The estimate of the signal strength vs. TE was fitted to a monoexponential function for estimation of apparent T2 (T2†). T2† was estimated to be similar between the brain regions for creatine, choline, glutamate and myo-inositol, but significantly different for N-acetylaspartate singlet and multiplet. T2†s of glutamate and myo-inositol were measured as 181 ± 16 and 197 ± 14 ms (mean ± SD, N = 5) for medial occipital cortices, and 180 ± 12 and 196 ± 17 ms for left occipital cortices, respectively. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

OBJECTIVE To assess the maintenance of efficacy of duloxetine beyond 3 months, using data from several long-term, open-label studies, as the efficacy of duloxetine 40-mg twice daily for treating women with stress urinary incontinence (SUI) for up to 3 months has been established in several randomized, placebo-controlled clinical trials. PATIENTS AND METHODS Data from 1424 patients (Cohort A) enrolled in three 12-week, placebo-controlled clinical trials and their uncontrolled, open-label extensions, and in one uncontrolled, open-label study, were used to assess long-term continuation rates and continued efficacy based on responses to the validated Patient Global Impression of Improvement (PGI-I) scale for up to 30 months. Data from another 2758 patients (Cohort B) enrolled in an additional placebo-controlled study and its open-label extension were used to assess PGI-I ratings, reductions in incontinence episode frequency (IEF) recorded on urinary diaries, and the relationship between PGI-I ratings and reductions in IEF for up to 72 weeks. RESULTS In Cohort A, the duloxetine continuation rate at 1 year was 42.5%. At 12, 24 and 30 months, most (83%, 83% and 88%, respectively) patients in Cohort A who continued treatment rated their incontinence in one of the three ‘better since starting treatment’ PGI-I categories. Both the median IEF reductions (50–77%) and the PGI-I ‘better’ ratings (70–88% of patients) remained fairly consistent over 72 weeks in Cohort B. Finally, IEF reductions increased with increasing PGI-I ratings (≈46% for ‘a little better’, 75% for ‘much better’ and 95% for ‘very much better’) over the first year of treatment. CONCLUSION The benefits of duloxetine were maintained in patients who continued treatment for up to 30 months. However, these favourable results need to be interpreted cautiously, as many patients discontinued treatment and those with better responses are more likely to continue taking medication. [ABSTRACT FROM AUTHOR]

In this paper we study sample size calculation methods for the asymptotic Wilcoxon-Mann-Whitney test for data with or without ties. The existing methods are applicable either to data with ties or to data without ties but not to both cases. While the existing methods developed for data without ties perform well, the methods developed for data with ties have limitations in that they are either applicable to proportional odds alternatives or have computational difficulties. We propose a new method which has a closed-form formula and therefore is very easy to calculate. In addition, the new method can be applied to both data with or without ties. Simulations have demonstrated that the new sample size formula performs very well as the corresponding actual powers are close to the nominal powers. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The van Elteren test is a type of stratified Wilcoxon-Mann-Whitney test for comparing two treatments accounting for strata. In this paper, we study sample size estimation methods for the asymptotic version of the van Elteren test, assuming that the stratum fractions (ratios of each stratum size to the total sample size) and the treatment fractions (ratios of each treatment size to the stratum size) are known in the study design. In particular, we develop three large-sample sample size estimation methods and present a real data example to illustrate the necessary information in the study design phase in order to apply the methods. Simulation studies are conducted to compare the performance of the methods and recommendations are made for method choice. Finally, sample size estimation for the van Elteren test when the stratum fractions are unknown is also discussed. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]