ATR inhibition facilitates targeting of leukemia dependence on convergent nucleotide biosynthetic pathways.

Leukemia cells rely on two nucleotide biosynthetic pathways, de novo and salvage, to produce dNTPs for DNA replication. Here, using metabolomic, proteomic, and phosphoproteomic approaches, we show that inhibition of the replication stress sensing kinase ataxia telangiectasia and Rad3-related protein (ATR) reduces the output of both de novo and salvage pathways by regulating the activity of their respective rate-limiting enzymes, ribonucleotide reductase (RNR) and deoxycytidine kinase (dCK), via distinct molecular mechanisms. Quantification of nucleotide biosynthesis in ATR-inhibited acute lymphoblastic leukemia (ALL) cells reveals substantial remaining de novo and salvage activities, and could not eliminate the disease in vivo. However, targeting these remaining activities with RNR and dCK inhibitors triggers lethal replication stress in vitro and long-term disease-free survival in mice with B-ALL, without detectable toxicity. Thus the functional interplay between alternative nucleotide biosynthetic routes and ATR provides therapeutic opportunities in leukemia and potentially other cancers.Leukemic cells depend on the nucleotide synthesis pathway to proliferate. Here the authors use metabolomics and proteomics to show that inhibition of ATR reduced the activity of these pathways thus providing a valuable therapeutic target in leukemia

Chemical composition and apparent digestibility of a panel of dried microalgae and cyanobacteria biomasses in rainbow trout (Oncorhynchus mykiss)

Despite a growing interest in microalgae and cyanobacteria as potential sources of nutrients in aquafeeds, little information is presently available on their nutritive value for carnivorous fish species. The aim of this study was to evaluate chemical composition and nutrient digestibility of a panel of microalgae and cyanobacteria dried biomasses (MACB), using rainbow trout (Oncorhynchus mykiss W.) as a fish model. Nine test diets were obtained by mixing 80 parts of a reference diet, added with 20 g/kg of acid insoluble ash as an indigestible marker, to 20 parts of each of the following dried whole-cell biomass: Arthrospira platensis, Nostoc sphaeroides, two strains of Chlorella sorokiniana, Nannochloropsis oceanica, Tisochrysis lutea, Phaeodactylum tricornutum, Porphyridium purpureum and Tetraselmis suecica. The digestibility measurements were conducted with rainbow trout (52.4 \ub1 1.5 g) kept in six tank units each including three 60-L vessels singularly stocked with 12 fish and fitted with a settling column for faecal recovery. Per each diet, faeces were collected over three independent 10-day periods. Apparent digestibility coefficients (ADCs) of dry matter, crude protein (CP), organic matter and gross energy (GE) of single MACB were calculated by difference relative to those of the reference diet. The MACBs had heterogeneous chemical composition (CP, from 20 to 69%; Lipid, 5\u201327%; GE, 12.5-\u201322.6 MJ/kg dry matter basis) reflecting their overall biodiversity. Most of them can be considered as virtually good sources of minerals and trace elements and exhibit an essential amino acid profile comparable or even better than that of soybean meal commonly used in fish feeds with P. purpureum showing the best protein profile. The digestibility results obtained with rainbow trout allowed ranking the MACBs into two major groups. A first one, including C. sorokiniana, N. oceanica and T. suecica, resulted in markedly lower (P < 0.05) crude protein and energy ADC (64\u201373%; 51\u201359%, respectively) compared to a second group including P. purpureum, T. lutea and cyanobacteria (CP-ADC, 83\u201388%; GE-ADC, 74\u201390%) while P. tricornutum resulted in intermediate values. Overall, the present study confirms the consistently reported role of cell-wall structure/composition in affecting accessibility of nutrients to digestive enzyme. Based on the overall outcomes, only T. lutea and cyanobacteria actually meet the requirements for being used as protein sources in aquafeeds provided their mass production becomes more feasible and costeffective, hence attractive for the feed-mill industry in the near future

Combining carfilzomib and panobinostat to treat relapsed/refractory multiple myeloma: results of a Multiple Myeloma Research Consortium Phase I Study

Key points CarPan is a highly active, steroid-sparing regimen, effective in both bortezomib-sensitive and refractory patients.The safety profile of CarPan, particularly thrombocytopenia and gastrointestinal adverse events, compares favorably with that of panobinostat and bortezomib

Estimating internationally imported cases during the early COVID-19 pandemic

Early in the COVID-19 pandemic, predictions of international outbreaks were largely based on imported cases from Wuhan, China, potentially missing imports from other cities. We provide a method, combining daily COVID-19 prevalence and flight passenger volume, to estimate importations from 18 Chinese cities to 43 international destinations, including 26 in Africa. Global case importations from China in early January came primarily from Wuhan, but the inferred source shifted to other cities in mid-February, especially for importations to African destinations. We estimate that 10.4 (6.2 - 27.1) COVID-19 cases were imported to these African destinations, which exhibited marked variation in their magnitude and main sources of importation. We estimate that 90% of imported cases arrived between 17 January and 7 February, prior to the first case detections. Our results highlight the dynamic role of source locations, which can help focus surveillance and response efforts

Validity of recalled versus recorded birth weight: a systematic review and meta-analysis

Low birth weight is associated with adverse health outcomes. If birth weight records are not available, studies may use recalled birth weight. It is unclear whether this is reliable. We performed a systematic review and meta-analysis of studies comparing recalled with recorded birth weights. We followed the Meta-Analyses of Observational Studies in Epidemiology (MOOSE) statement and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched MEDLINE, EMBASE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) to May 2015. We included studies that reported recalled birth weight and recorded birth weight. We excluded studies investigating a clinical population. Two reviewers independently reviewed citations, extracted data, assessed risk of bias. Data were pooled in a random effects meta-analysis for correlation and mean difference. In total, 40 studies were eligible for qualitative synthesis (n=78,997 births from 78,196 parents). Agreement between recalled and recorded birth weight was high: pooled estimate of correlation in 23 samples from 19 studies (n=7406) was 0.90 [95% confidence interval (CI) 0.87–0.93]. The difference between recalled and recorded birth weight in 29 samples from 26 studies (n=29,293) was small [range −86–129 g; random effects estimate 1.4 g (95% CI −4.0–6.9 g)]. Studies were heterogeneous, with no evidence for an effect of time since birth, person reporting, recall bias, or birth order. In post-hoc subgroup analysis, recall was higher than recorded birth weight by 80 g (95% CI 57–103 g) in low and middle income countries. In conclusion, there is high agreement between recalled and recorded birth weight. If birth weight is recalled, it is suitable for use in epidemiological studies, at least in high income countries

Orientifolds and the Refined Topological String

We study refined topological string theory in the presence of orientifolds by counting second-quantized BPS states in M-theory. This leads us to propose a new integrality condition for both refined and unrefined topological strings when orientifolds are present. We define the SO(2N) refined Chern-Simons theory which computes refined open string amplitudes for branes wrapping Seifert three-manifolds. We use the SO(2N) refined Chern-Simons theory to compute new invariants of torus knots that generalize the Kauffman polynomials. At large N, the SO(2N) refined Chern-Simons theory on the three-sphere is dual to refined topological strings on an orientifold of the resolved conifold, generalizing the Gopakumar-Sinha-Vafa duality. Finally, we use the (2,0) theory to define and solve refined Chern-Simons theory for all ADE gauge groups