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The treatment landscape of acute myeloid leukemia (AML) is evolving, with promising therapies entering clinical translation, yet patient responses remain heterogeneous, and biomarkers for tailoring treatment are lacking. To understand how disease heterogeneity links with therapy response, we determined the leukemia cell hierarchy makeup from bulk transcriptomes of more than 1,000 patients through deconvolution using single-cell reference profiles of leukemia stem, progenitor and mature cell types. Leukemia hierarchy composition was associated with functional, genomic and clinical properties and converged into four overall classes, spanning Primitive, Mature, GMP and Intermediate. Critically, variation in hierarchy composition along the Primitive versus GMP or Primitive versus Mature axes were associated with response to chemotherapy or drug sensitivity profiles of targeted therapies, respectively. A seven-gene biomarker derived from the Primitive versus Mature axis was associated with response to 105 investigational drugs. Cellular hierarchy composition constitutes a novel framework for understanding disease biology and advancing precision medicine in AML.
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Fresh-harvested Gambel oak (Quercus gambelii) browse was mixed with chopped alfalfa hay to formulate six diets , varying in oak content at two phenological stages. Diets included juvenile oak (65 ,80,95%), mature oak (40,80%), and an alfalfa control. Diets we re evaluated for goats using a series of total-collection digestion balance trials. Dry matter intake was highest for animal s on mature oak diets, and lowest on diets containing a high percentage of juvenile oak, possibly due to differences in diet dry matter content . Apparent digestibility of dry matter and cell wall components was lowest for mature oak diets, and highest for diets high in juvenile oak. Nitrogen and energy balances were positive in all cases , and all diets provided nitrogen and energy in excess of maintenance requirements. This was reflected by weight gains for all animals in every trial. Fecal and urinary nitrogen losses did not appear to be related to tannin content of the diets, because high-percentage juvenile oak diets resulted in reduced nitrogen outputs, presumably due to reduced nitrogen intakes for these diets. In comparison with previous data using pelleted formulations, the fresh-fed material was consistently higher in digestibility of the various fractions, and associated with lower dry matter intakes.
Tierra Curry, a Knott County native who is now a scientist with the Center for Biological Diversity, said there have been conservative estimates that 2,000 stream miles in Appalachia have been buried under hollow fills and valley fills. Mining also removes mature forests from large areas, she said.
Examination of numerous specimens of S. rivulatus from those inhabiting the coast of Yanbu (200 km north of the mangrove swamps) revealed that they were not naturally infected with any intestinal helminth parasite. Therefore, 70 specimens of nearly equal lengths (12-16 cm) were marked and transferred alive in June of 2010 to the lagoon to allow their infection with G. volubilis to be followed after ten weeks. To prevent fishes from escaping from the lagoon, a plastic net with narrow mesh size was used as a barrier at the lagoon mouth; the lagoon can therefore be considered as a natural aquarium. Through one week, 42 specimens (five-seven specimens/ day) of the marked fishes were caught from the lagoon by hand net. To avoid parasite postmortem or other migration along the gastrointestinal tract, each fish was killed and measured immediately after capture by a blow to the head and examined at a field laboratory (within 30-45 min after capture). Then the entire alimentary canal of each fish was immediately removed and, to record the exact position of individual parasites, the intestine was cut into ten equal sections; tied before cutting. Each section was opened and its contents examined under a dissecting stereomicroscope; individual parasites were examined to determine if they were alive or not, carefully teased out, re-examined alive in a saline solution, and the opened section was then shaken vigorously in a jar of saline to dislodge further worms and to remove mucus. Trematodes were placed in whirling hot water before fixation in hot 5% formalin under a slight coverslip pressure. This procedure gives specimens a uniform size and shape. The infrapopulation collected from each fish host was carefully counted, and its distribution in the intestine was recorded. Wholemounts were stained in alum carmine, cleared in terpineol and mounted in Canada balsam. All trematodes recovered were identified and their body lengths, round testes, round ovaries and oval eggs were measured (in micrometres) using a compound microscope with an eyepiece micrometer. The different stages of the parasite were classified according to Al-Jahdali & Hassanine (2012b); worms were categorized as newly excysted juveniles if they were closely similar to metacercariae, as immature if the sexual organs were little or moderately developed and the uterus contained no eggs, and as mature if the sexual organs were fully developed and the uterus contained eggs.
G. volubilis infrapopulations consisted of newly excysted juveniles (coming from new infections with metacercariae), immature and mature worms. These stages were only found in the anterior four segments (40 %) of the intestine of S. rivulatus, i.e. in a welldefined fundamental niche along the intestine of this fish. In all infrapopulations, immature and mature worms were found alive, while newly excysted juveniles were found alive or dead. In small infrapopulations (I-IX, slight densities), all newly excysted juveniles were alive. In larger infrapopulations (X-XXX, higher densities), the number of dead newly excysted juveniles gradually increased with infrapopulation size to include all juveniles in the largest infrapopulations (Table I). Dead juveniles (not included in infrapopulation size) were mostly found in second segment of the intestine and some were scattered along the posterior intestine (possibly carried out by the intestinal peristaltic to this region); their body walls seemed less transparent, their internal fluids exhibited no movement and their bodies were completely immobile. The relationship between number of dead newly excysted juveniles and infrapopulation size was strongly positive (R2 = 0.829, slope = 3.574, P
The distribution of newly excysted juveniles, immature and mature worms of Gyliauchen volubilis (in 30 infrapopulations; each represented by a bar) along the anterior four segments of the intestine of Siganus rivulatus (see also Table II).
In G. volubilis infrapopulations, the proportions of newly excysted juveniles, immature and mature worms showed a clear ascending order in each infrapopulation. This seemed to be normal, and was more probably due to the continuing accumulation of infections and the duration of each stage. In small infrapopulations (slight density), all stages of G. volubilis were found alive. In larger infrapopulations (high intensity), a differential mortality was only, and consistently, observed among the newly excysted juveniles, and significantly increased with infrapopulation size. Thus, newly excysted juveniles seemed to be adversely affected or more sensitive to crowding stress than immature and mature worms. This result strongly suggests density-dependent effects and intraspecific competition among juvenile worms and probably between them and immature and mature worms. Such a competition, which leads to individual mortality in high-density infrapopulations, may contribute to regulating the size of infrapopulations (Uznanski & Nickol 1982; Brown 1986; Kennedy 2006; Poulin 2007). However, failure of newly excysted juveniles to survive in high-density infrapopulations greatly supports the experimental finding of Uznanski & Nickol (1982) and Brown (1986) that parasite activation (excystment) is a density-independent process, but establishment and survival are apparently density dependent. 041b061a72