Recombinant interleukin-21 plus sorafenib for metastatic renal cell carcinoma: a phase 1/2 study

Abstract Background Despite the positive impact of targeted therapies on metastatic renal cell carcinoma (mRCC), durable responses are infrequent and an unmet need exists for novel therapies with distinct mechanisms of action. We investigated the combination of recombinant Interleukin 21 (IL-21), a cytokine with unique immunostimulatory properties, plus sorafenib, a VEGFR tyrosine kinase inhibitor. Methods In this phase 1/2 study, 52 mRCC patients received outpatient treatment with oral sorafenib 400 mg twice daily plus intravenous IL-21 (10–50 mcg/kg) on days 1–5 and 15–19 of each 7-week treatment course. The safety, antitumor activity, pharmacokinetic and pharmacodynamic effects of the combination were evaluated. Results In phase 1 (n = 19), the maximum tolerated dose for IL-21 with the standard dose of sorafenib was determined to be 30 mcg/kg/day; grade 3 skin rash was the only dose-limiting toxicity. In phase 2, 33 previously-treated patients tolerated the combination therapy well with appropriate dose reductions; toxicities were mostly grade 1 or 2. The objective response rate was 21% and disease control rate was 82%. Two patients have durable responses that are ongoing, despite cessation of both IL-21 and sorafenib, at 41+ and 30+ months, respectively. The median progression-free survival in phase 2 was 5.6 months. The pharmacokinetic and pharmacodynamic properties of IL-21 appeared to be preserved in the presence of sorafenib. Conclusion IL-21 plus sorafenib has antitumor activity and acceptable safety in previously treated mRCC patients. IL-21 may represent a suitable immunotherapy in further exploration of combination strategies in mRCC. Trial registration ClinicalTrials.gov Identifier: NCT0038928

Response of Submerged Macrophyte Communities to External and Internal Restoration Measures in North Temperate Shallow Lakes

Submerged macrophytes play a key role in north temperate shallow lakes by stabilising clear-water conditions. Eutrophication has resulted in macrophyte loss and shifts to turbid conditions in many lakes. Considerable efforts have been devoted to shallow lake restoration in many countries, but long-term success depends on a stable recovery of submerged macrophytes. However, recovery patterns vary widely and remain to be fully understood. We hypothesize that reduced external nutrient loading leads to an intermediate recovery state with clear spring and turbid summer conditions similar to the pattern described for eutrophication. In contrast, lake internal restoration measures can result in transient clear-water conditions both in spring and summer and reversals to turbid conditions. Furthermore, we hypothesize that these contrasting restoration measures result in different macrophyte species composition, with added implications for seasonal dynamics due to differences in plant traits. To test these hypotheses, we analysed data on water quality and submerged macrophytes from 49 north temperate shallow lakes that were in a turbid state and subjected to restoration measures. To study the dynamics of macrophytes during nutrient load reduction, we adapted the ecosystem model PCLake. Our survey and model simulations revealed the existence of an intermediate recovery state upon reduced external nutrient loading, characterised by spring clear-water phases and turbid summers, whereas internal lake restoration measures often resulted in clear-water conditions in spring and summer with returns to turbid conditions after some years. External and internal lake restoration measures resulted in different macrophyte communities. The intermediate recovery state following reduced nutrient loading is characterised by a few macrophyte species (mainly pondweeds) that can resist wave action allowing survival in shallow areas, germinate early in spring, have energy-rich vegetative propagules facilitating rapid initial growth and that can complete their life cycle by early summer. Later in the growing season these plants are, according to our simulations, outcompeted by periphyton, leading to late-summer phytoplankton blooms. Internal lake restoration measures often coincide with a rapid but transient colonisation by hornworts, waterweeds or charophytes. Stable clear-water conditions and a diverse macrophyte flora only occurred decades after external nutrient load reduction or when measures were combined.Additional co-authors: Wolf M. Mooij, Ruurd Noordhuis, Geoff Phillips, Jacqueline Rücker, Hans-Heinrich Schuster, Martin Søndergaard, Sven Teurlincx, Klaus van de Weyer, Ellen van Donk, Arno Waterstraat and Carl D. Saye

Inflation and Dark Energy from spectroscopy at z > 2

The expansion of the Universe is understood to have accelerated during two epochs: in its very first moments during a period of Inflation and much more recently, at z < 1, when Dark Energy is hypothesized to drive cosmic acceleration. The undiscovered mechanisms behind these two epochs represent some of the most important open problems in fundamental physics. The large cosmological volume at 2 < z < 5, together with the ability to efficiently target high-$z$ galaxies with known techniques, enables large gains in the study of Inflation and Dark Energy. A future spectroscopic survey can test the Gaussianity of the initial conditions up to a factor of ~50 better than our current bounds, crossing the crucial theoretical threshold of $\sigma(f_{NL}^{\rm local})$ of order unity that separates single field and multi-field models. Simultaneously, it can measure the fraction of Dark Energy at the percent level up to $z = 5$, thus serving as an unprecedented test of the standard model and opening up a tremendous discovery space

Actionable, Pathogenic Incidental Findings in 1,000 Participants’ Exomes

The incorporation of genomics into medicine is stimulating interest on the return of incidental findings (IFs) from exome and genome sequencing. However, no large-scale study has yet estimated the number of expected actionable findings per individual; therefore, we classified actionable pathogenic single-nucleotide variants in 500 European- and 500 African-descent participants randomly selected from the National Heart, Lung, and Blood Institute Exome Sequencing Project. The 1,000 individuals were screened for variants in 114 genes selected by an expert panel for their association with medically actionable genetic conditions possibly undiagnosed in adults. Among the 1,000 participants, 585 instances of 239 unique variants were identified as disease causing in the Human Gene Mutation Database (HGMD). The primary literature supporting the variants’ pathogenicity was reviewed. Of the identified IFs, only 16 unique autosomal-dominant variants in 17 individuals were assessed to be pathogenic or likely pathogenic, and one participant had two pathogenic variants for an autosomal-recessive disease. Furthermore, one pathogenic and four likely pathogenic variants not listed as disease causing in HGMD were identified. These data can provide an estimate of the frequency (∼3.4% for European descent and ∼1.2% for African descent) of the high-penetrance actionable pathogenic or likely pathogenic variants in adults. The 23 participants with pathogenic or likely pathogenic variants were disproportionately of European (17) versus African (6) descent. The process of classifying these variants underscores the need for a more comprehensive and diverse centralized resource to provide curated information on pathogenicity for clinical use to minimize health disparities in genomic medicine

The combined effects of obesity, abdominal obesity and major depression/anxiety on health-related quality of life: The lifelines cohort study

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Differential Gene Expression Patterns of EBV Infected EBNA-3A Positive and Negative Human B Lymphocytes

The genome of Epstein-Barr virus (EBV) encodes 86 proteins, but only a limited set is expressed in EBV–growth transformed B cells, termed lymphoblastoid cell lines (LCLs). These cells proliferate via the concerted action of EBV nuclear antigens (EBNAs) and latent membrane proteins (LMPs), some of which are rate limiting to establish a stable homeostasis of growth promoting and anti-apoptotic activities. We show here that EBV mutants, which lack the EBNA-3A gene, are impaired but can still initiate cell cycle entry and proliferation of primary human B cells in contrast to an EBNA-2 deficient mutant virus. Surprisingly, and in contrast to previous reports, these viral mutants are attenuated in growth transformation assays but give rise to permanently growing EBNA-3A negative B cell lines which exhibit reduced proliferation rates and elevated levels of apoptosis. Expression profiles of EBNA-3A deficient LCLs are characterized by 129 down-regulated and 167 up-regulated genes, which are significantly enriched for genes involved in apoptotic processes or cell cycle progression like the tumor suppressor gene p16/INK4A, or might contribute to essential steps of the viral life cycle in the infected host. In addition, EBNA-3A cellular target genes remarkably overlap with previously identified targets of EBNA-2. This study comprises the first genome wide expression profiles of EBNA-3A target genes generated within the complex network of viral proteins of the growth transformed B cell and permits a more detailed understanding of EBNA-3A's function and contribution to viral pathogenesis

Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukemia

Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2DBCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered.This work was supported in part by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital; by a Stand Up to Cancer Innovative Research Grant and St. Baldrick’s Foundation Scholar Award (to C.G.M.); by a St. Baldrick’s Consortium Award (S.P.H.), by a Leukemia and Lymphoma Society Specialized Center of Research grant (S.P.H. and C.G.M.), by a Lady Tata Memorial Trust Award (I.I.), by a Leukemia and Lymphoma Society Special Fellow Award and Alex’s Lemonade Stand Foundation Young Investigator Awards (K.R.), by an Alex’s Lemonade Stand Foundation Award (M.L.) and by National Cancer Institute Grants CA21765 (St Jude Cancer Center Support Grant), U01 CA157937 (C.L.W. and S.P.H.), U24 CA114737 (to Dr Gastier-Foster), NCI Contract HHSN261200800001E (to Dr Gastier-Foster), U10 CA180820 (ECOG-ACRIN Operations) and CA180827 (E.P.); U10 CA180861 (C.D.B. and G.M.); U24 CA196171 (The Alliance NCTN Biorepository and Biospecimen Resource); CA145707 (C.L.W. and C.G.M.); and grants to the COG: U10 CA98543 (Chair’s grant and supplement to support the COG ALL TARGET project), U10 CA98413 (Statistical Center) and U24 CA114766 (Specimen Banking). This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract Number HHSN261200800001E

Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3

Evolving treatments, disease phenotypes, and biology, together with a changing drug development environment, have created the need to revise castration-resistant prostate cancer (CRPC) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups

Responses to an acellular pertussis booster vaccination in children, adolescents, and young and older adults: A collaborative study in Finland, the Netherlands, and the United Kingdom

Background: Pertussis can lead to serious disease and even death in infants. Older adults are more vulnerable to complications as well. In high-income countries, acellular pertussis vaccines are used for priming vaccination. In the administration of booster vaccinations to different age groups and target populations there is a substantial between-country variation. We investigated the effect of age on the response to acellular pertussis booster vaccination in three European countries.Methods: This phase IV longitudinal intervention study performed in Finland, the Netherlands and the United Kingdom between October 2017 and January 2019 compared the vaccine responses between healthy participants of four age groups: children (7-10y), adolescents (11-15y), young adults (20-34y), and older adults (60-70y). All participants received a three-component acellular pertussis vaccine. Serum IgG and IgA antibody concentrations to pertussis antigens at day 0, 28, and 1 year were measured with a multiplex immunoassay, using pertussis toxin concentrations at day 28 as primary outcome. This trial is registered with ClinicalTrialsRegister.eu (2016-003,678-42).Findings: Children (n = 109), adolescents (n = 121), young adults (n = 74), and older adults (n = 75) showed high IgG antibody concentrations to pertussis toxin at day 28 with GMCs of 147 (95% CI 120-181), 161 (95% CI 132-196), 103 (95% CI 80-133), and 121 IU/ml (95% CI 94-155), respectively. A significant increase in GMCs for vaccine antigens in all age groups by 28 days was found which had decreased by 1 year. Differences in patterns of IgG GMCs at 28 days and 1 year post-vaccination did not have a consistent relationship to age. In contrast, IgA antibodies for all antigens increased with age at all timepoints.Interpretation: Acellular pertussis booster vaccination induces significant serum IgG responses to pertussis antigens across the age range which are not uniformly less in older adults. Acellular boosters could be considered for older adults to reduce the health and economic burden of pertussis.</p

On the notion of home and the goals of palliative care

The notion of home is well known from our everyday experience, and plays a crucial role in all kinds of narratives about human life, but is hardly ever systematically dealt with in the philosophy of medicine and health care. This paper is based upon the intuitively positive connotation of the term “home.” By metaphorically describing the goal of palliative care as “the patient’s coming home,” it wants to contribute to a medical humanities approach of medicine. It is argued that this metaphor can enrich our understanding of the goals of palliative care and its proper objectives. Four interpretations of “home” and “coming home” are explored: (1) one’s own house or homelike environment, (2) one’s own body, (3) the psychosocial environment, and (4) the spiritual dimension, in particular, the origin of human existence. Thinking in terms of coming home implies a normative point of view. It represents central human values and refers not only to the medical-technical and care aspects of health care, but also to the moral context