Membrane-Bound IL-21 Promotes Sustained Ex Vivo Proliferation of Human Natural Killer Cells

NK cells have therapeutic potential for a wide variety of human malignancies. However, because NK cells expand poorly in vitro, have limited life spans in vivo, and represent a small fraction of peripheral white blood cells, obtaining sufficient cell numbers is the major obstacle for NK-cell immunotherapy. Genetically-engineered artificial antigen-presenting cells (aAPCs) expressing membrane-bound IL-15 (mbIL15) have been used to propagate clinical-grade NK cells for human trials of adoptive immunotherapy, but ex vivo proliferation has been limited by telomere shortening. We developed K562-based aAPCs with membrane-bound IL-21 (mbIL21) and assessed their ability to support human NK-cell proliferation. In contrast to mbIL15, mbIL21-expressing aAPCs promoted log-phase NK cell expansion without evidence of senescence for up to 6 weeks of culture. By day 21, parallel expansion of NK cells from 22 donors demonstrated a mean 47,967-fold expansion (median 31,747) when co-cultured with aAPCs expressing mbIL21 compared to 825-fold expansion (median 325) with mbIL15. Despite the significant increase in proliferation, mbIL21-expanded NK cells also showed a significant increase in telomere length compared to freshly obtained NK cells, suggesting a possible mechanism for their sustained proliferation. NK cells expanded with mbIL21 were similar in phenotype and cytotoxicity to those expanded with mbIL15, with retained donor KIR repertoires and high expression of NCRs, CD16, and NKG2D, but had superior cytokine secretion. The mbIL21-expanded NK cells showed increased transcription of the activating receptor CD160, but otherwise had remarkably similar mRNA expression profiles of the 96 genes assessed. mbIL21-expanded NK cells had significant cytotoxicity against all tumor cell lines tested, retained responsiveness to inhibitory KIR ligands, and demonstrated enhanced killing via antibody-dependent cell cytotoxicity. Thus, aAPCs expressing mbIL21 promote improved proliferation of human NK cells with longer telomeres and less senescence, supporting their clinical use in propagating NK cells for adoptive immunotherapy

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Memory and religious experience in the Greco-Roman world

The concepts of memory and experience have stimulated interest in a wide range of recent cultural studies. In the history of scholarship on religion in Mediterranean antiquity, scholars have focused on the emotional dimension of both terms by employing the concepts of \u201aChristianity\u2018 and its derivative, \u201aoriental religion\u2018. Only recently analyses in this field started focusing on interaction and individual experience. Research initiatives at Palermo and Erfurt have taken up this lead and brought together a group of scholars testing such approaches for new perspectives on the history of religion in the Greek and Roman world. This volume reviews the cognitive and emotional dimensions of such experiences in their diverse local, social, and ritual contexts. Memory likewise opens a window onto the interaction of individual and society. Contributions address the individual processes of memorialization and remembrance. They analyse the collective evocation of memories and their shaping of individual memory

The influence of women's fear, attitudes and beliefs of childbirth on mode and experience of birth

Background: Women's fears and attitudes to childbirth may influence the maternity care they receive and the outcomes of birth. This study aimed to develop profiles of women according to their attitudes regarding birth and their levels of childbirth related fear. The association of these profiles with mode and outcomes of birth was explored. Methods: Prospective longitudinal cohort design with self report questionnaires containing a set of attitudinal statements regarding birth (Birth Attitudes Profile Scale) and a fear of birth scale (FOBS). Pregnant women responded at 18-20 weeks gestation and two months after birth from a regional area of Sweden (n = 386) and a regional area of Australia (n = 123). Cluster analysis was used to identify a set of profiles. Odds ratios (95% CI) were calculated, comparing cluster membership for country of care, pregnancy characteristics, birth experience and outcomes. Results: Three clusters were identified - 'Self determiners' (clear attitudes about birth including seeing it as a natural process and no childbirth fear), 'Take it as it comes' (no fear of birth and low levels of agreement with any of the attitude statements) and 'Fearful' (afraid of birth, with concerns for the personal impact of birth including pain and control, safety concerns and low levels of agreement with attitudes relating to women's freedom of choice or birth as a natural process). At 18 - 20 weeks gestation, when compared to the 'Self determiners', women in the 'Fearful' cluster were more likely to: prefer a caesarean (OR = 3.3 CI: 1.6-6.8), hold less than positive feelings about being pregnant (OR = 3.6 CI: 1.4-9.0), report less than positive feelings about the approaching birth (OR = 7.2 CI: 4.4-12.0) and less than positive feelings about the first weeks with a newborn (OR = 2.0 CI 1.2-3.6). At two months post partum the 'Fearful' cluster had a greater likelihood of having had an elective caesarean (OR = 5.4 CI 2.1-14.2); they were more likely to have had an epidural if they laboured (OR = 1.9 CI 1.1-3.2) and to experience their labour pain as more intense than women in the other clusters. The 'Fearful' cluster were more likely to report a negative experience of birth (OR = 1.7 CI 1.02-2.9). The 'Take it as it comes' cluster had a higher likelihood of an elective caesarean (OR 3.0 CI 1.1-8.0). Conclusions: In this study three clusters of women were identified. Belonging to the 'Fearful' cluster had a negative effect on women's emotional health during pregnancy and increased the likelihood of a negative birth experience. Both women in the 'Take it as it comes' and the 'Fearful' cluster had higher odds of having an elective caesarean compared to women in the 'Self determiners'. Understanding women's attitudes and level of fear may help midwives and doctors to tailor their interactions with women