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Immune cell-driven anti-cancer activity is paramount for effective responses to checkpoint inhibitors (ICB). However, the contribution of the different immune cell subsets in the circulation and within the tumour is poorly understood.To elucidate the role of the different cell subsets in anti-tumour responses elicited by ICB, we performed single-cell analysis of the transcriptome and surface proteome of paired pre- and early on-treatment metastatic melanoma tumour biopsies and matched peripheral blood mononuclear cell samples. We next compared the survival of metastatic melanoma patients treated with ICB according to the abundance of pre-treatment tumour-infiltrating B cell clonotypes.We identified cell clusters associated with disease control or progression, defined differential expression of biological pathways likely involved in the immune awakening against the tumour and examined how cell-cell communication patterns between the tumour cell subsets change during treatment. Furthermore, we discovered that B cells (immunoglobulin expression and abundance of B cell clonotypes) discriminate the clinical response after ICB and propose that B cells likely contribute to anti-tumour immunity by antigen presentation through major histocompatibility complex molecules. Finally, we demonstrated that the abundance of tumour-infiltrating B cell clonotypes at baseline identifies two distinct risk groups, a finding that we confirmed in an independent cohort.Our exploratory translational study provides new insights on the mechanistic role of B cells in anti-melanoma immunity during treatment with ICB. Additionally, we support pre-treatment B cell tumour infiltration as a promising prognostic biomarker to be further validated as a tool for clinical risk stratification.

The maintenance of intestinal homeostasis is a fundamental process critical for organismal integrity. Sitting at the interface of the gut microbiome and mucosal immunity, adaptive and innate lymphoid populations regulate the balance between commensal micro-organisms and pathogens. Checkpoint inhibitors (CPI), particularly those targeting the CTLA-4 pathway, disrupt this fine balance and can lead to inflammatory bowel disease (IBD) and immune checkpoint colitis (CPI-C). Here, we show that CTLA-4 is expressed by innate lymphoid cells (ILC) and that its expression is regulated by ILC subset-specific cytokine cues in a microbiota-dependent manner. Genetic deletion or antibody blockade of CTLA-4 demonstrates that this pathway plays a key role in intestinal homeostasis and is conserved in human IBD and CPI-induced colitis (CPI-C). We propose that this population of CTLA-4-positive ILC may serve as an important target for the treatment of idiopathic and iatrogenic intestinal inflammation.

BackgroundPost-transplant glomerulonephritis (PTGN) has been associated with inferior long-term allograft survival, and its incidence varies widely in the literature.MethodsThis is a cohort study of 7,623 patients transplanted between 2005 and 2016 at four major transplant UK centres. The diagnosis of glomerulonephritis (GN) in the allograft was extracted from histology reports aided by the use of text-mining software. The incidence of the four most common GN post-transplantation was calculated, and the risk factors for disease and allograft outcomes were analyzed.ResultsIn total, 214 patients (2.8%) presented with PTGN. IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and membranoproliferative/mesangiocapillary GN (MPGN/MCGN) were the four most common forms of post-transplant GN. Living donation, HLA DR match, mixed race, and other ethnic minority groups were associated with an increased risk of developing a PTGN. Patients with PTGN showed a similar allograft survival to those without in the first 8 years of post-transplantation, but the results suggest that they do less well after that timepoint. IgAN was associated with the best allograft survival and FSGS with the worst allograft survival.ConclusionsPTGN has an important impact on long-term allograft survival. Significant challenges can be encountered when attempting to analyze large-scale data involving unstructured or complex data points, and the use of computational analysis can assist.

Immune checkpoint inhibitors (CPIs) have revolutionised cancer treatment, with previously untreatable disease now amenable to potential cure. Combination regimens of anti-CTLA-4 and anti-PD-1 show enhanced efficacy but are prone to off-target immune-mediated tissue injury, particularly at the barrier surfaces. CPI-induced colitis is a common and serious complication. To probe the impact of immune checkpoints on intestinal homeostasis, mice were challenged with combination anti-CTLA-4/anti-PD-1 immunotherapy and manipulation of the intestinal microbiota. Colonic immune responses were profiled using bulk and single-cell RNA-sequencing and flow cytometry. CPI-colitis was dependent on the composition of the intestinal microbiota and was characterized by remodelling of mucosal lymphocytes with induction of polyfunctional lymphocyte responses characterized by increased expression of interferon-γ (IFNγ), other pro-inflammatory cytokines/chemokines (Il22, Il17a Ccl3, Ccl4 and Ccl9), cytotoxicity molecules (Gzmb, Gzma, Prf1, Nkg7) and the chemokine receptor Cxcr6. In comparison with mucosal lymphocytes in the steady state, polyfunctional lymphocytes from both CD4+ and CD8+ lineages upregulated costimulatory molecules and checkpoint molecules in CPI-colitis, indicating that these cells are tightly regulated. CPI-colitis was attenuated following depletion of effector lymphocytes or following blockade of the IL23/IFNγ axis. This study provides new mechanistic insights into CPI-colitis, identifying polyfunctional, cytotoxic lymphocytes as key mediators of disease. Therapeutic targeting of their effector response or regulatory networks, including the IL23/IFNγ axis likely holds the key to preventing and reversing CPI-colitis.

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P = 3.01 x 10(-7)) in SOX2OT and rs17030795 (P = 5.84 x 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P = 5.76 x 10(-6)) between CUL3 and FAM124B and rs1886797 (P = 8.05 x 10(-6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P= 4x10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

"In this paper, we use simulation models to demonstrate the complexity of the relationship between the marriage selection process and the resulting RMRs [relative mortality ratios]. In particular, we show that marriage selection alone can produce a relative mortality ratio which remains large and relatively constant at ages far beyond the marriage span....Our general objective...is to determine the range of age patterns of relative mortality which could, in theory, result from marriage selection on the basis of health characteristics. We also evaluate the effects of variations in the marriage selection mechanisms on the resulting mortality patterns.... We develop and apply several simple mathematical models of the marriage selection process. In order to distinguish the potential consequences of marriage selection from marriage protection, we consider hypothetical populations in which causal effects are absent.... We begin by considering an extremely simple marriage selection process and subsequently explore a more realistic selection model based on recent death and marriage rates for Japan."

If m = σ ( n ) − n − 1 m = \sigma (n) - n - 1 and n = σ ( m ) − m − 1 n = \sigma (m) - m - 1 , the integers m and n are said to be quasi-amicable numbers. This paper is devoted to a study of such numbers.

The mathematical derivations described in this paper offer a new look at the entropy of the life table, denoted by H. Contrary to previous claims, it is theoretically possible, and has been observed empirically, for life tables to have entropy values greater than unity. A re-expression of H as a weighted average of life expectancy at different ages relative to life expectancy at birth demonstrates clearly the conditions under which reductions in mortality by a fixed amount at all ages can result in even greater gains in life expectancy.

Life table calculations from survey data are frequently based on events for which exact dates are not available. When these dates are coded in monthly form (e.g., century months), estimates should take into account the fact that the first duration interval—the interval which captures events occurring in the first month of exposure—is half the length of all remaining intervals. Although failure to do so has a trivial effect on many demographic calculations, estimates which are based on events which occur with high frequency in the first few months of exposure can be substantially biased. Estimates offecundability for four countries in the World Fertility Survey are used to illustrate this bias.

Using formulas which measure life cycle characteristics of widowhood as a function of life table survivorship and age at marriage, we illustrate changes in patterns of widowhood and widowerhood since 1950, as well as differences by race, by age of bride and of groom, and by age differences between spouses. Although the current inequality in the risks of widowhood and widowerhood for the average couple is mostly due to sex differences in mortality, a one year age difference between spouses has about the same impact as does a one year difference in life expectancy. Calculations based on current distributions of age of groom by age of bride indicate that the older the age of groom, the greater the age difference between spouses and the higher the likelihood of a woman outliving her husband: the typical groom who marries in his fifties faces a 4 to 1 chance that he will be outlived by his spouse.

Derivations by Mitre were made on the approximation of H in quantifying the alteration in life expectancy due to a sudden mortality change as employed by Keyfitz in a short note on the Taeuber paradox. The author replies to these formulations and takes a new look at entropy and the life table and discusses some implications. The example is given that Mitre set up values for H which exceeded unity in the Coale and Demeny West Life Tables; this was done after previously published work identified that H was bounded by 1. The position in this paper is that H cannot exceed 1. An alternative approximation of mortality changes on the expectation of life is provided. This new formula gives the average number of years a person can expect to live given a 2nd chance on life relative to the expected life span. Mitre used a similar formula but only in his development of the approximation of H. The finiteness of H is deduced solely from the property that life expectancy tends to zero as "a" approaches the oldest age of life "w" which is finite. The author defines H according to McClean which is different from the subsequent work of Demetrius. Demetrius implies that H is less than 1 if "a" the mean age of the stationary population is less than the expectation of life at birth. The limit behavior is insufficient by itself to force the boundness of H if "w" is taken to equal infinity. It is necessary that life expectancy tend to zero as "a" approaches infinity for the convergence of the integral in the numerator. The authors characterization of life tables exhibiting an H value larger than 1 is based on 2 families of curves for modeling all or part of the survival function. The 1st family of curves claims that the limit behavior does not mimic a human life table but that it is possible to have H larger than 1 for a specific value of "k" which is less than or equal to 1. The 2nd family of curves also provides the simplicity of the functional form of the family which clarifies the relationship of life at "x" to its derivative functions and to H.