Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists

PURPOSE: The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT(3) receptor antagonists to assess its translational validity. METHODS: A systematic review identified available evidence and was used to perform meta-analyses. RESULTS: Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n = 53) used a 10 mg kg(−1) dose to induce acute emesis, which peaked after 2 h. More recent studies (n = 11) also used 5 mg kg(−1), which induced a biphasic response peaking at 12 h and 48 h. Overall, 5-HT(3) receptor antagonists reduced cisplatin (5 mg kg(−1)) emesis by 68% (45–91%) during the acute phase (day 1) and by 67% (48–86%) and 53% (38–68%, all P < 0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin. CONCLUSION: Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT(3) receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret

The potential contribution of disruptive low-carbon innovations to 1.5 °C climate mitigation

This paper investigates the potential for consumer-facing innovations to contribute emission reductions for limiting warming to 1.5 °C. First, we show that global integrated assessment models which characterise transformation pathways consistent with 1.5 °C mitigation are limited in their ability to analyse the emergence of novelty in energy end-use. Second, we introduce concepts of disruptive innovation which can be usefully applied to the challenge of 1.5 °C mitigation. Disruptive low-carbon innovations offer novel value propositions to consumers and can transform markets for energy-related goods and services while reducing emissions. Third, we identify 99 potentially disruptive low-carbon innovations relating to mobility, food, buildings and cities, and energy supply and distribution. Examples at the fringes of current markets include car clubs, mobility-as-a-service, prefabricated high-efficiency retrofits, internet of things, and urban farming. Each of these offers an alternative to mainstream consumer practices. Fourth, we assess the potential emission reductions from subsets of these disruptive low-carbon innovations using two methods: a survey eliciting experts’ perceptions and a quantitative scaling-up of evidence from early-adopting niches to matched segments of the UK population. We conclude that disruptive low-carbon innovations which appeal to consumers can help efforts to limit warming to 1.5 °C

An assessment of American Indian women's mammography experiences

<p>Abstract</p> <p>Background</p> <p>Mortality from breast cancer has increased among American Indian/Alaskan Native (AI/AN) women. Despite this alarming reality, AI/AN women have some of the lowest breast cancer screening rates. Only 37% of eligible AI/AN women report a mammogram within the last year and 52% report a mammogram within the last two years compared to 57% and 72% for White women. The experiences and satisfaction surrounding mammography for AI/AN women likely are different from that of women of other racial/ethnic groups, due to cultural differences and limited access to Indian Health Service sponsored mammography units. The overall goals of this study are to identify and understand the mammography experiences and experiential elements that relate to satisfaction or dissatisfaction with mammography services in an AI/AN population and to develop a culturally-tailored AI/AN mammography satisfaction survey.</p> <p>Methods and Design</p> <p>The three project aims that will be used to guide this work are: 1) To compare the mammography experiences and satisfaction with mammography services of Native American/Alaska Native women with that of Non-Hispanic White, Hispanic, and Black women, 2) To develop and validate the psychometric properties of an American Indian Mammography Survey, and 3) To assess variation among AI/AN women's assessments of their mammography experiences and mammography service satisfaction. Evaluations of racial/ethnic differences in mammography patient satisfaction have received little study, particularly among AI/AN women. As such, qualitative study is uniquely suited for an initial examination of their experiences because it will allow for a rich and in-depth identification and exploration of satisfaction elements.</p> <p>Discussion</p> <p>This formative research is an essential step in the development of a validated and culturally tailored AI/AN mammography satisfaction assessment. Results from this project will provide a springboard from which a maximally effective breast cancer screening program to benefit AI/AN population will be developed and tested in an effort to alter the current breast cancer-related morbidity and mortality trajectory among AI/AN women.</p

Kışladağ露天金矿(土耳其乌萨克省)疏干排水量计算及采后矿坑湖预测

The KA +/- AYladag gold mine (UAYak, Turkey) has operated since 2006 and is projected to close by 2030, leaving a large open pit. We quantified dewatering requirements during the operational period, predicted pit lake formation during the post-closure period, and assessed the likely impacts on groundwater resources. Groundwater inflow into the pit during 17 years of mining was calculated using analytical and numerical models. The analytical model yielded lower inflow rates because it does not account for groundwater that will be released from storage. Post-closure, pit lake water balance calculations show that the system will reach equilibrium 585 years after dewatering ceases and that lake levels will stabilize at 816 m above sea level (masl). Further analysis indicated that 830 masl is a critical level, below which the pit will behave as a sink; above that, it will be a flowthrough system that could possibly affect downgradient groundwater quality

Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia

Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683)