A highly tumor-targeted nanoparticle of podophyllotoxin penetrated tumor core and regressed multidrug resistant tumors

Podophyllotoxin (PPT) exhibited significant activity against P-glycoprotein mediated multidrug resistant (MDR) tumor cell lines; however, due to its poor solubility and high toxicity, PPT cannot be dosed systemically, preventing its clinical use for MDR cancer. We developed a nanoparticle dosage form of PPT by covalently conjugating PPT and polyethylene glycol (PEG) with acetylated carboxymethyl cellulose (CMC-Ac) using one-pot esterification chemistry. The polymer conjugates self-assembled into nanoparticles (NPs) of variable sizes (20–120 nm) depending on the PPT-to-PEG molar ratio (2–20). The conjugate with a low PPT/PEG molar ratio of 2 yielded NPs with a mean diameter of 20 nm and released PPT at ∼5%/day in serum, while conjugates with increased PPT/PEG ratios (5 and 20) produced bigger particles (30 nm and 120 nm respectively) that displayed slower drug release (∼2.5%/day and ∼1%/day respectively). The 20 nm particles exhibited 2- to 5-fold enhanced cell killing potency and 5- to 20-fold increased tumor delivery compared to the larger NPs. The biodistribution of the 20 nm PPT-NPs was highly selective to the tumor with 8-fold higher accumulation than all other examined tissues, while the larger PPT-NPs (30 and 120 nm) exhibited increased liver uptake. Within the tumor, >90% of the 20 nm PPT-NPs penetrated to the hypovascular core, while the larger particles were largely restricted in the hypervascular periphery. The 20 nm PPT-NPs displayed significantly improved efficacy against MDR tumors in mice compared to the larger PPT-NPs, native PPT and the standard taxane chemotherapies, with minimal toxicity.     

The impact of California's staffing mandate and the economic recession on registered nurse staffing levels: A longitudinal analysis

BackgroundDespite the importance of adequate hospital nurse staffing, California is the only state with minimum nurse-to-patient ratio mandates. The health care workforce is historically “countercyclical”—exhibiting growth during economic recessions when employment in other sectors is shrinking.PurposeThis study was to examine how staffing mandates impact hospital nurse staffing during economic recessions.MethodWe compared hospital nurse staffing in California and in other states over 20 years to examine differences before and after the California mandate and, within the postmandate period, before, during, and after the Great Recession of 2008.FindingsStaffing differences increased during the postmandate period due to faster growth in California staffing compared to other states, except during the Great Recession, when staffing remained stable in California but declined in other states.DiscussionState legislators deliberating staffing mandates should consider the protective factor such policies provide during economic recessions and the implications for the quality and safety of care.     

Women heroin users: Exploring the limitations of the structural violence approach

This paper reports on the lives of women heroin users resident in a Kenyan coastal resort town. Data on the everyday lives of 24 women were collected using ethnographic field methods. Eighteen women also completed questionnaires about their reproductive health. Using these data, we analyse the extent to which the women are victims of ‘structural violence’, and how their disadvantaged social status and poverty make them particularly vulnerable to poor health, injury and death. The problems these women face are similar to women heroin users in other parts of the world. These Kenyan women live in a country where the majority of people are victims of ‘structural violence’, but as drug users and sex workers they face particular disadvantage. The limitations of using individual case studies that detail the lives of ‘victims’ of structural violence are discussed.     

Fine particulate matter exposure during pregnancy and infancy and incident asthma

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Vulvodynia management

Vulval pain is a common problem encountered in many clinical settings involving women’s health. Many women with vulval pain will have no apparent cause and a diagnosis of vulvodynia should be considered. Vulvodynia is defined as vulval discomfort, most often described as burning pain occurring in the absence of relevant visible findings, or a specific, clinically identifiable neurologic disorder. Before vulvodynia is diagnosed patients presenting with vulval pain need a careful history and clinical examination to avoid missing subtle relevant dermatological conditions of the vulva. Women with vulvodynia form a diverse group with different levels of symptoms, experiences and expectations of treatment. Clinicians not familiar with assessment and management with vulvodynia should refer onto secondary level care or specialist clinics. When making a diagnosis of vulvodynia clinicians should identify subtypes of vulvodynia and explore the key treatment needs of each patient. Based on current evidence, the prognosis for many women with vulvodynia is hopeful if an early diagnosis can be made and correct, individualized treatment given.     

Selective inhibition of IDO1, D-1-methyl-tryptophan (D-1MT), effectively increased EpCAM/CD3-bispecific BiTE antibody MT110 efficacy against IDO1hibreast cancer via enhancing immune cells activity

MuS110 and MT110 are BiTE antibodies bispecific for CD3 and EpCAM, which is the most frequently and highly expressed tumor-associated antigen on breast cancer. And pronounced expression of IDO1 has also been reported in breast cancer. Our study aimed to investigate whether IDO1 inhibitor D-1MT combing with MuS110/MT110 had synergistic antitumor effects on IDO expressing EpCAM-positive breast cancer cells in vitro and in vivo. Data suggested that the expression of IDO1 on Epcam-positive breast cancer 4T1 and MCF-7 decreased MuS110/MT110 antitumor efficacy by the suppression of T cells activation in vitro. Combining D-1MT with MT110 in IDO⁺ MCF-7 cells, or with MuS110 in IDO⁺ 4T1 cells, significantly improved the antitumor efficacy of BiTE antibodies via increasing T cell cytotoxicity and contributing to cytokines releasing. In vivo assay, combination of D-1MT with MT110 in NOD/SCID mice bearing IDO^hi MCF-7 xenografts or MuS110 in immune competent BALB/c mice bearing IDO^hi 4T1 xenografts suggested the similar synergistic effect. Together, IDO inhibition could reverse the suppression of T cells due to IDO expressing on breast cancer, and improve the antitumor efficacy of EpCAM/CD3-bispecific BiTE antibody.     

Testing for Equivalence: An Intersection-Union Permutation Solution

The notion of testing for equivalence of two treatments is widely used in clinical trials, pharmaceutical experiments, bioequivalence, and quality control. It is essentially approached within the intersection-union (IU) principle. According to this principle, the null hypothesis is stated as the set of effects lying outside a suitably established interval and the alternative as the set of effects lying inside that interval. The solutions provided in the literature are mostly based on likelihood techniques, which in turn are rather difficult to handle, except for cases lying within the regular exponential family and the invariance principle. The main goal of the present article is to go beyond most of the limitations of likelihood-based methods, that is, to work in a nonparametric setting within the permutation frame. To obtain practical solutions, a new IU permutation test is presented and discussed. A simple simulation study for evaluating its main properties, and three application examples are also presented.     

An exploration of the structure of mentors' behavior in nursing education using exploratory factor analysis and Mokken scale analysis

BackgroundTo understand nursing students' expectation from their mentors and assess mentors' performance, a scale of mentors' behavior was developed based on literature review and focus group in China.ObjectivesThis study aims to explore the structure of mentors' behavior.DesignA cross-sectional survey.SettingData were collected from nursing students in three hospitals in southwest China in 2014.ParticipantA total of 669 pre-registered nursing students in their final year clinical learning participated in this study.MethodsExploratory factor analysis and Mokken scale analysis was employed to explore the structure and hierarchical property of mentors' behavior.ResultsThree dimensions (professional development, facilitating learning and psychosocial support) were identified by factor analysis and confirmed by Mokken scaling analysis. The three sub-scales showed internal consistency reliability from 87% to 91%, and moderate to strong precision in ordering students' expectation about mentors' behavior and a small Mokken scale showing hierarchy was identified.ConclusionSome insight into the structure of mentoring in nursing education has been obtained and a scale which could be used in the study of mentoring and in the preparation of mentors has been developed.