Drug‐microenvironment perturbations reveal resistance mechanisms and prognostic subgroups in CLL

The tumour microenvironment and genetic alterations collectively influence drug efficacy in cancer, but current evidence is limited and systematic analyses are lacking. Using chronic lymphocytic leukaemia (CLL) as a model disease, we investigated the influence of 17 microenvironmental stimuli on 12 drugs in 192 genetically characterised patient samples. Based on microenvironmental response, we identified four subgroups with distinct clinical outcomes beyond known prognostic markers. Response to multiple microenvironmental stimuli was amplified in trisomy 12 samples. Trisomy 12 was associated with a distinct epigenetic signature. Bromodomain inhibition reversed this epigenetic profile and could be used to target microenvironmental signalling in trisomy 12 CLL. We quantified the impact of microenvironmental stimuli on drug response and their dependence on genetic alterations, identifying interleukin 4 (IL4) and Toll‐like receptor (TLR) stimulation as the strongest actuators of drug resistance. IL4 and TLR signalling activity was increased in CLL‐infiltrated lymph nodes compared with healthy samples. High IL4 activity correlated with faster disease progression. The publicly available dataset can facilitate the investigation of cell‐extrinsic mechanisms of drug resistance and disease progression.     

T1 relaxation times in vivo of human normal pelvic tissues and gynecologic malignancies

The spin-lattice relaxation time (T1) of the water protons of intrapelvic tissues was determined in vivo in women using an NMR imager. T1's of squamous cell carcinoma of the cervix are significantly longer than those of the normal cervix. A similar trend occurs in carcinomas of the endometrium and ovary. The results suggest that direct determination of T1 in vivo may be useful in the diagnosis and management of gynecologic malignancies.     

Muscle fiber structure in an aging long-lived seabird,the black-legged kittiwake (Rissa tridactyla)

Many long-lived animals do not appear to show classic signs of aging, perhaps because they show negligible senescence until dying from “catastrophic” mortality. Muscle senescence is seldom examined in wild animals, yet decline in muscle function is one of the first signs of aging in many lab animals and humans. Seabirds are an excellent study system for physiological implications of aging because they are long-lived animals that actively forage and reproduce in the wild. Here, we examined linkages between pectoralis muscle fiber structure and age in black-legged kittiwakes (Rissa tridactyla). Pectoralis muscle is the largest organ complex in birds, and responsible for flight and shivering. We obtained and fixed biopsies from wild black-legged kittiwakes of known age. We then measured muscle fiber diameter, myonuclear domain and capillaries per fiber area among birds of differing ages. All muscle parameters were independent of age. Number of nuclei per mm of fiber showed a positive correlation with muscle fiber cross-sectional area, and myonuclear domain increased with muscle fiber diameter. Thus, as muscle fibers increased in size, they may not have recruited satellite cells, increasing the protein turnover load per nuclei. We conclude that senescence in a long-lived bird with an active lifestyle, does not entail mammalian-like changes in muscle structure.     

RANK links senescence to stemness in the mammary epithelia,delaying tumor onset but increasing tumor aggressiveness

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Genetic control of synapsis and recombination in Lolium amphidiploids

Homologous bivalent formation in amphidiploids of Lolium is promoted during meiosis by diploidising genes carried by A-chromosomes and by supernumerary B-chromosomes. The site and mode of action of these diploidising factors were investigated by comparing the relative frequencies of pairing configurations at meiotic prophase and metaphase I in several different hybrid genotypes. The results indicate that diploidising genes act predominatly by increasing the stringency of synapsis at early stages of meiotic prophase. By contrast, B-chromosomes appear to promote bivalent formation by ensuring that homoeologously paired chromosome segments within multivalents do not crossover. The results show that the additive effects of diploidising genes and B-chromosomes are to a certain extent separable in terms of their mode of action and timing during meiosis.     

The Horyzons project: a randomized controlled trial of a novel online social therapy to maintain treatment effects from specialist first‐episode psychosis services

This study aimed to determine whether, following two years of specialized support for first‐episode psychosis, the addition of a new digital intervention (Horyzons) to treatment as usual (TAU) for 18 months was more effective than 18 months of TAU alone. We conducted a single‐blind randomized controlled trial. Participants were people with first‐episode psychosis (N=170), aged 16‐27 years, in clinical remission and nearing discharge from a specialized service. They were randomly assigned (1:1) to receive Horyzons plus TAU (N=86) or TAU alone (N=84) between October 2013 and January 2017. Horyzons is a novel, comprehensive digital platform merging: peer‐to‐peer social networking; theory‐driven and evidence‐informed therapeutic interventions targeting social functioning, vocational recovery and relapse prevention; expert clinician and vocational support; and peer support and moderation. TAU involved transfer to primary or tertiary community mental health services. The primary outcome was social functioning at 18 months as measured by the Personal and Social Performance Scale (PSP). Forty‐seven participants (55.5%) in the Horyzons plus TAU group logged on for at least 6 months, and 40 (47.0%) for at least 9 months. Social functioning remained high and stable in both groups from baseline to 18‐month follow‐up, with no evidence of significant between‐group differences (PSP mean difference: –0.29, 95% CI: –4.20 to 3.63, p=0.77). Participants in the Horyzons group had a 5.5 times greater increase in their odds to find employment or enroll in education compared with those in TAU (odds ratio, OR=5.55, 95% CI: 1.09‐28.23, p=0.04), with evidence of a dose‐response effect. Moreover, participants in TAU were twice as likely to visit emergency services compared to those in the Horyzons group (39% vs. 19%; OR=0.31, 95% CI: 0.11‐0.86, p=0.03, number needed to treat, NNT=5). There was a non‐significant trend for lower hospitalizations due to psychosis in the Horyzons group vs. TAU (13% vs. 27%; OR=0.36, 95% CI: 0.11‐1.08, p=0.07, NNT=7). So, although we did not find a significant effect of Horyzons on social functioning compared with TAU, the intervention was effective in improving vocational or educational attainment, a core component of social recovery, and in reducing usage of hospital emergency services, a key aim of specialized first‐episode psychosis services. Horyzons holds significant promise as an engaging and sustainable intervention to provide effective vocational and relapse prevention support for young people with first‐episode psychosis beyond specialist services.