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يتحدث الكتاب عن جون فيتزجيرالد \"جاك\" كينيدي منذ ولادته والتحاقة بالجامعة ومن ثم ألتحاقة في منصب أعضاء الكونجرس عضو في الحزب الديمقراطي ؛ وإختصارا للكتاب ولد كينيدي في بروكلين 29 مايو 1917، بماساتشوستس وهو ابن جوزيف كينيدي الأب وروز كينيدي. وهو سليل عائلة كينيدي التي هاجرت من مقاطعة وكسفورد في أيرلندا، ويشار إليه عادة بأحرفه الأولى JFK، هو سياسي أمريكي، كينيدي هو عضو في الحزب الديمقراطي، ومثل ولاية ماساتشوستس في مجلس النواب ومجلس الشيوخ قبل أن يصبح رئيسا. تولى منصب الرئيس الخامس والثلاثين للولايات المتحدة من 20 يناير 1961 خدم كينيدي كرئيس في ذروة الحرب الباردة، وركز في جل فترة رئاسته على إدارة العلاقات مع الاتحاد السوفيتي. حتى اغتياله في 22 نوفمبر 1963.

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. A novel gene expression classifier of AML heterogeneity captures patient-specific variation in leukemia cell composition and predicts clinical responses to treatment.

Highbush blueberry (Vaccinium corymbosum) fruits contain substantial quantities of flavonoids, which are implicated in a wide range of health benefits. Although the flavonoid constituents of ripe blueberries are known, the molecular genetics underlying their biosynthesis, localization, and changes that occur during development have not been investigated. Two expressed sequence tag libraries from ripening blueberry fruit were constructed as a resource for gene identification and quantitative realtime reverse transcription-polymerase chain reaction primer design. Gene expression profiling by quantitative real-time reverse transcription-polymerase chain reaction showed that flavonoid biosynthetic transcript abundance followed a tightly regulated biphasic pattern, and transcript profiles were consistent with the abundance of the three major classes of flavonoids.Proanthocyanidins (PAs) and corresponding biosynthetic transcripts encoding anthocyanidin reducíase and leucoanthocyanidin reducíase were most concentrated in young fruit and localized predominantly to the inner fruit tissue containing the seeds and placentae. Mean PA polymer length was seven to 8.5 subunits, linked predominantly via B-type linkages, and was relatively constant throughout development. Flavonol accumulation and localization patterns were similar to those of the PAs, and the B-ring hydroxylation pattern of both was correlated with flavonoid-3'-hydroxylase transcript abundance. By contrast, anthocyanins accumulated late in maturation, which coincided with a peak in flavonoid-3-O-glycosyltransferase and flavonoid-3' 5'-hydroxylase transcripts. Transcripts of VcMYBPAl, which likely encodes an R2R3-MYB transcriptional regulator of PA synthesis, were prominent in both phases of development. Furthermore, the initiation of ripening was accompanied by a substantial rise in abscisic acid, a growth regulator that may be an important component of the ripening process and contribute to the regulation of blueberry flavonoid biosynthesis.

Little is known about the impact of temperature on proanthocyanidin (PA) accumulation in grape skins, despite its significance in berry composition and wine quality. Field-grown grapes (cv. Merlot) were cooled during the day or heated at night by +/−8 °C, from fruit set to véraison in three seasons, to determine the effect of temperature on PA accumulation. Total PA content per berry varied only in one year, when PA content was highest in heated berries (1.46 mg berry−1) and lowest in cooled berries (0.97 mg berry−1). In two years, cooling berries resulted in a significant increase in the proportion of (−)-epigallocatechin as an extension subunit. In the third year, rates of berry development, PA accumulation, and the expression levels of several genes involved in flavonoid biosynthesis were assessed. Heating and cooling berries altered the initial rates of PA accumulation, which was correlated strongly with the expression of core genes in the flavonoid pathway. Both heating and cooling altered the rate of berry growth and coloration, and the expression of several structural genes within the flavonoid pathway.

Our understanding of leukemia development and progression has been hampered by the lack of in vivo models in which disease is initiated from primary human hematopoietic cells. We showed that upon transplantation into immunodeficient mice, primitive human hematopoietic cells expressing a mixed-lineage leukemia (MLL) fusion gene generated myeloid or lymphoid acute leukemias, with features that recapitulated human diseases. Analysis of serially transplanted mice revealed that the disease is sustained by leukemia-initiating cells (L-ICs) that have evolved over time from a primitive cell type with a germline immunoglobulin heavy chain (IgH) gene configuration to a cell type containing rearranged IgH genes. The L-ICs retained both myeloid and lymphoid lineage potential and remained responsive to microenvironmental cues. The properties of these cells provide a biological basis for several clinical hallmarks of MLL leukemias.

Grape seed procyanidins (PC) are flavan-3-ol oligomers and polymers known for their biological activity in the gut. Grape seed extract (GSE) have been reported to reduce intestinal injury in a rat model of mucositis. We sought to investigate effects of purified PC fractions differing in mean degree of polymerization (mDP) combined with 5-Fluorouracil (5-FU) chemotherapy on the viability of colon cancer cells (Caco-2). SixPC fractions (F1-F6) were isolated from Cabernet Sauvignon seeds at two ripeness stages: pre-veraison unripe (immature) and ripe (mature), utilizing step gradient, low-pressure chromatography on a Sephadex LH-20 resin. Fractions were tested on Caco-2 cells, alone and in combination with 5-FU. Eluted fractions were characterized by phloroglucinolysis and gel permeation chromatography. Cell viability was determined by the 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide) (MTT) assay. All isolated fractions significantly reduced Caco-2 cell viability compared to the control (P<0.05), but F2 and F3 (mDP 2-6) were the most active fractions (immature F2 = 32% mDP 2.4, F3 = 35% mDP 5.8 and mature F2 = 13% mDP 3.6 and F3 = 17% mDP 5.9; percentage of viable cells remaining) on Caco-2 cells. When combined with 5-FU, immature fractions F1-F3 enhanced the cell toxicity effects of 5-FU by 27-73% (P<0.05). Mature seed PC fractions (F1-F4) significantly enhanced the toxicity of 5-FU by 60-83% against Caco-2 cells (P<0.05). Moreover, some fractions alone were more potent at decreasing viability in Caco-2 cells (P<0.05; immature fractions = 65-68% and mature fractions = 83-87%) compared to 5-FU alone (37%). PCs of mDP 2-6 (immature F1-F3 and mature F1 and F4)not only enhanced the impact of 5-FU in killing Caco-2 cells, but also surpassed standard 5-FU chemotherapy as an anti-cancer agent.The bioactivity of PC is therefore attributed primarily to lower molecular weight PCs.

In cool-climate viticulture, the short growing season can influence grape seed maturation by reducing the apparent oxidation of flavan-3-ol monomers and associated increase in seed browning. A reduction in seed maturation increases the potential extraction of flavan-3-ol monomers into wine during maceration operations, heightening bitterness. Here, we carried out a 2 × 2 factorial experiment to test the ability of freezing and heating treatments to advance maturation (decrease flavan-3-ol, improve browning) of ( Vitis vinifera L.) Pinot noir and Cabernet Sauvignon seeds over a 24-h incubation period. Only freezing significantly increased seed browning in both cultivars. Subsequent correlations with seed flavan-3-ol monomer concentrations suggest that freezing enhanced the oxidation of these compounds. Interestingly, natural ripening and freezing reduced galloylated flavan-3-ol monomers to a greater extent than non-galloylated ones. This study provides new information regarding the susceptibility of flavan-3-ol monomers to freezing and heating, and also suggests that freezing can advance the maturation the seeds of under-ripe red vinifera grapes.

Grapevine productivity, and berry and wine flavonoid concentration, depend on the interactions of cultivar, environment, and applied cultural practices. We characterized the effects that mechanical leaf removal and irrigation treatments had on the flavonoid concentration of ‘Merlot’ (Vitis vinifera, L.) grape berries and wines in a hot climate over two growing seasons with contrasting precipitation patterns. Leaves were removed by machine, either at prebloom (PBLR), or at post-fruit-set (PFLR), or not removed (control) and irrigation was either applied as sustained deficit irrigation (SDI) at 0.8 of crop evapotranspiration (ETc) from budbreak to fruit set, or regulated deficit irrigation (RDI) at 0.8 ETc from bud break to fruit set, 0.5 ETc from fruit set to veraison, and 0.8 ETc from veraison to harvest, of ETc In 2014, PFLR reduced the leaf area index (LAI) compared to control. The RDI decreased season-long leaf water potential (ΨInt) compared to SDI. However, in 2015, none of the treatments affected LAI or ΨInt. In 2014, berry flavonoid concentrations were reduced by PBLR as well as SDI. SDI increased the flavonoid concentrations in wine, and PFLR increased some wine flavonols in one season. No factor affected the concentrations of wine proanthocyanidins or mean degree of polymerization. Thus, mechanical PFLR and RDI may increase berry flavonoid accumulation without yield reduction, in red wine grapes cultivars grown in hot climates when precipitation after bud break is lacking. However, spring precipitation may influence the effectiveness of these practices as evidenced by this work in a changing climate.

Background Osteoporosis and osteopenia are conditions characterised by reduced bone mineral density (BMD). There is concern that bone with reduced BMD may not provide sufficient fixation for cementless components which primarily rely on the quality of surrounding bone. The aim of our study was to report the midterm clinical outcomes of patients with reduced BMD undergoing cementless unicompartmental knee replacements (UKR). Our hypothesis was that there would be no difference in outcome between patients with normal bone and those with reduced BMD. Methods From a prospective cohort of 70 patients undergoing cementless UKR surgery, patients were categorised into normal ( n  = 20), osteopenic ( n  = 38) and osteoporotic groups ( n  = 12) based on their central dual-energy X-ray absorptiometry (DEXA) scans according to the World Health Organization criteria. Patients were followed up by independent research physiotherapists and outcome scores; Oxford Knee Score (OKS), Tegner score, American Knee Society Score Functional (AKSS-F) and Objective (AKSS-O) were recorded preoperatively and at a mean of 4 years postoperatively. The prevalence of reoperations, revisions and mortality was also recorded at a mean of 5 years postoperatively. Results There were no significant differences in the midterm postoperative OKS ( P  = 0.83), Tegner score ( P  = 0.17) and AKSS-O ( P  = 0.67). However, the AKSS-F was significantly higher ( P  = 0.04) in normal (90, IQR 37.5) compared to osteoporotic (65, IQR 35) groups. There were no significant differences ( P  = 0.82) between normal and osteopenic bone (80, IQR 35). The revision prevalence was 5%, 2.6% and 0% in the normal, osteopenic and osteoporotic groups respectively. The reoperation prevalence was 5%, 7.9% and 0% respectively. There were no deaths in any group related to the implant. Conclusions We found that patients with reduced BMD could safely undergo cementless UKR surgery and have similar clinical outcomes to those with normal BMD. However, larger studies with longer follow-up are needed to confirm our findings and ensure that cementless fixation is safe in patients with reduced BMD.

A rapid gene signature test (LSC17) that captures stem cell expression programs in acute myeloid leukaemia patients at diagnosis is associated with therapy response and survival, facilitating initial treatment stratification. LSC17 score evaluated in acute leukaemia The prevalence of stem cell features can influence the prognosis of acute myeloid leukaemia. In this report, the authors identify and validate a 17-gene leukemia stem cell (LSC) signature score, termed the LSC17 score, that captures the prevalence of stem cell expression programs in patients and their influence on clinical outcome. Further testing will determine if the signature can be incorporated into risk assessment algorithms to better define prognosis of patient subsets in acute myeloid leukaemia. Refractoriness to induction chemotherapy and relapse after achievement of remission are the main obstacles to cure in acute myeloid leukaemia (AML) 1 . After standard induction chemotherapy, patients are assigned to different post-remission strategies on the basis of cytogenetic and molecular abnormalities that broadly define adverse, intermediate and favourable risk categories 2 , 3 . However, some patients do not respond to induction therapy and another subset will eventually relapse despite the lack of adverse risk factors 4 . There is an urgent need for better biomarkers to identify these high-risk patients before starting induction chemotherapy, to enable testing of alternative induction strategies in clinical trials 5 . The high rate of relapse in AML has been attributed to the persistence of leukaemia stem cells (LSCs), which possess a number of stem cell properties, including quiescence, that are linked to therapy resistance 6 , 7 , 8 , 9 , 10 . Here, to develop predictive and/or prognostic biomarkers related to stemness, we generated a list of genes that are differentially expressed between 138 LSC + and 89 LSC − cell fractions from 78 AML patients validated by xenotransplantation. To extract the core transcriptional components of stemness relevant to clinical outcomes, we performed sparse regression analysis of LSC gene expression against survival in a large training cohort, generating a 17-gene LSC score (LSC17). The LSC17 score was highly prognostic in five independent cohorts comprising patients of diverse AML subtypes ( n  = 908) and contributed greatly to accurate prediction of initial therapy resistance. Patients with high LSC17 scores had poor outcomes with current treatments including allogeneic stem cell transplantation. The LSC17 score provides clinicians with a rapid and powerful tool to identify AML patients who do not benefit from standard therapy and who should be enrolled in trials evaluating novel upfront or post-remission strategies.