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Combining authoritative, exciting text and bold images, The World War I Book explores the historical background of the war, its causes, all of the key events across the major theatres of conflict, and its aftermath. Using the original, graphic-led approach of the series, entries profile more than 90 of the key events during and surrounding the conflict -- from the growing tensions between Europe's major powers to the assassination of Archduke Franz Ferdinand, the German invasion of Belgium, the endless slaughter in the trenches, the American entry into the war, the Russian Revolution, the Armistice, and the creation of the League of Nations.

In advanced cancers, transforming growth factor-beta (TGFβ) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma. In this multi-center phase I trial, cohorts of patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at 0.1, 0.3, 1, 3, 10, or 15 mg/kg on days 0, 28, 42, and 56. Patients achieving at least stable disease were eligible to receive Extended Treatment consisting of 4 doses of GC1008 every 2 weeks for up to 2 additional courses. Pharmacokinetic and exploratory biomarker assessments were performed. Twenty-nine patients, 28 with malignant melanoma and 1 with renal cell carcinoma, were enrolled and treated, 22 in the dose-escalation part and 7 in a safety cohort expansion. No dose-limiting toxicity was observed, and the maximum dose, 15 mg/kg, was determined to be safe. The development of reversible cutaneous keratoacanthomas/squamous-cell carcinomas (4 patients) and hyperkeratosis was the major adverse event observed. One malignant melanoma patient achieved a partial response, and six had stable disease with a median progression-free survival of 24 weeks for these 7 patients (range, 16.4-44.4 weeks). GC1008 had no dose-limiting toxicity up to 15 mg/kg. In patients with advanced malignant melanoma and renal cell carcinoma, multiple doses of GC1008 demonstrated acceptable safety and preliminary evidence of antitumor activity, warranting further studies of single agent and combination treatments. Clinicaltrials.gov NCT00356460.

Set in a future where the Capitol selects a boy and girl from the twelve districts to fight to the death on live television. Katniss Everdeen volunteers to take her younger sister's place for the latest match.

Clinical and correlative biomarker results from a phase 1 clinical trial in patients with different solid tumours are presented; the findings indicate that PD-L1 expression on tumour-infiltrating immune cells is associated with clinical response to MPDL3280A (anti-PD-L1). Predicting patient response to anti-PD-L1 anti-cancer therapy The transmembrane protein PD-L1 (programmed death-ligand 1) is upregulated in many different types of cancer and protocols targeting its interactions have shown promise in pre-clinical studies. Here Roy Herbst et al . present clinical and correlative biomarker results from a phase I clinical trial in patients with solid tumours of various types treated with the engineered anti-PD-L1 antibody MPDL3280A. The findings indicate that PD-L1 expression on tumour-infiltrating immune cells is associated with clinical response to MPDL3280A. The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system 1 , 2 , 3 , 4 . However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment 5 . Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the ‘cancer immunity cycle’ by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing 6 , 7 , 8 , 9 , 10 . The PD-L1–PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections 11 . Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (T H 1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment.

Streptococcus pneumoniae is a leading cause of pneumonia and a significant economic burden. Antibiotic-resistant S. pneumoniae has become more prevalent in recent years and many pneumonia cases are caused by S. pneumoniae that is resistant to at least one antibiotic. The ubiquitin ligase natural killer lytic-associated molecule (NKLAM/RNF19b) plays a role in innate immunity and studies using NKLAM-knockout (NKLAM-KO) macrophages have demonstrated that NKLAM positively affects the transcriptional activity of STAT1. Using an inhalation infection model, we found that NKLAM-KO mice had a significantly higher lung bacterial load than WT mice but had less lung inflammation. Coincidently, NKLAM-KO mice had fewer neutrophils and NK cells in their lungs. NKLAM-KO mice also expressed less iNOS in their lungs as well as less MCP-1, MIP1α, TNFα, IL-12, and IFNγ. Both neutrophils and macrophages from NKLAM-KO mice were defective in killing S. pneumoniae as compared to wild type cells (WT). The phosphorylation of STAT1 and STAT3 in NKLAM-KO lungs was lower than in WT lungs at 24 hours post-infection. NKLAM-KO mice were afforded some protection against a lethal dose of S. pneumoniae compared to WT mice. In summary, our novel data demonstrate a role for E3 ubiquitin ligase NKLAM in modulating innate immunity via the positive regulation of inflammatory cytokine expression and bactericidal activity.

Concurrent administration of the immune checkpoint inhibitors nivolumab and ipilimumab has shown greater efficacy than either agent alone in patients with advanced melanoma, albeit with more high-grade adverse events. We assessed whether sequential administration of nivolumab followed by ipilimumab, or the reverse sequence, could improve safety without compromising efficacy. We did this randomised, open-label, phase 2 study at nine academic medical centres in the USA. Eligible patients (aged ≥18 years) with unresectable stage III or IV melanoma (treatment-naive or who had progressed after no more than one previous systemic therapy, with an Eastern Cooperative Oncology Group performance status of 0 or 1) were randomly assigned (1:1) to induction with intravenous nivolumab 3 mg/kg every 2 weeks for six doses followed by a planned switch to intravenous ipilimumab 3 mg/kg every 3 weeks for four doses, or the reverse sequence. Randomisation was done by an independent interactive voice response system with a permuted block schedule (block size four) without stratification factors. After induction, both groups received intravenous nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary endpoint was treatment-related grade 3–5 adverse events until the end of the induction period (week 25), analysed in the as-treated population. Secondary endpoints were the proportion of patients who achieved a response at week 25 and disease progression at weeks 13 and 25. Overall survival was a prespecified exploratory endpoint. This study is registered with ClinicalTrials.gov, number NCT01783938, and is ongoing but no longer enrolling patients. Between April 30, 2013, and July 21, 2014, 140 patients were enrolled and randomly assigned to nivolumab followed by ipilimumab (n=70) or to the reverse sequence of ipilimumab followed by nivolumab (n=70), of whom 68 and 70 patients, respectively, received at least one dose of study drug and were included in the analyses. The frequencies of treatment-related grade 3–5 adverse events up to week 25 were similar in the nivolumab followed by ipilimumab group (34 [50%; 95% CI 37·6–62·4] of 68 patients) and in the ipilimumab followed by nivolumab group (30 [43%; 31·1–55·3] of 70 patients). The most common treatment-related grade 3–4 adverse events during the whole study period were colitis (ten [15%]) in the nivolumab followed by ipilimumab group vs 14 [20%] in the reverse sequence group), increased lipase (ten [15%] vs 12 [17%]), and diarrhoea (eight [12%] vs five [7%]). No treatment-related deaths occurred. The proportion of patients with a response at week 25 was higher with nivolumab followed by ipilimumab than with the reverse sequence (28 [41%; 95% CI 29·4–53·8] vs 14 [20%; 11·4–31·3]). Progression was reported in 26 (38%; 95% CI 26·7–50·8) patients in the nivolumab followed by ipilimumab group and 43 (61%; 49·0–72·8) patients in the reverse sequence group at week 13 and in 26 (38%; 26·7–50·8) and 42 (60%; 47·6–71·5) patients at week 25, respectively. After a median follow-up of 19·8 months (IQR 12·8–25·7), median overall survival was not reached in the nivolumab followed by ipilimumab group (95% CI 23·7–not reached), whereas over a median follow-up of 14·7 months (IQR 5·6–23·9) in the ipilimumab followed by nivolumab group, median overall survival was 16·9 months (95% CI 9·2–26·5; HR 0·48 [95% CI 0·29–0·80]). A higher proportion of patients in the nivolumab followed by ipilimumab group achieved 12-month overall survival than in the ipilimumab followed by nivolumab group (76%; 95% CI 64–85 vs 54%; 42–65). Nivolumab followed by ipilimumab appears to be a more clinically beneficial option compared with the reverse sequence, albeit with a higher frequency of adverse events. Bristol-Myers Squibb.

Recent studies have begun to elucidate a role for E3 ubiquitin ligases as important mediators of the innate immune response. Our previous work defined a role for the ubiquitin ligase natural killer lytic-associated molecule (NKLAM/RNF19b) in mouse and human innate immunity. Here, we present novel data describing a role for NKLAM in regulating the immune response to Sendai virus (SeV), a murine model of paramyxoviral pneumonia. NKLAM expression was significantly upregulated by SeV infection. SeV-infected mice that are deficient in NKLAM demonstrated significantly less weight loss than wild type mice. In vivo, Sendai virus replication was attenuated in NKLAM-/- mice. Autophagic flux and the expression of autophagy markers LC3 and p62/SQSTM1 were also less in NKLAM-/- mice. Using flow cytometry, we observed less neutrophils and macrophages in the lungs of NKLAM-/- mice during SeV infection. Additionally, phosphorylation of STAT1 and NFκB p65 was lower in NKLAM-/- than wild type mice. The dysregulated phosphorylation profile of STAT1 and NFκB in NKLAM-/- mice correlated with decreased expression of numerous proinflammatory cytokines that are regulated by STAT1 and/or NFκB. The lack of NKLAM and the resulting attenuated immune response is favorable to NKLAM-/- mice receiving a low dose of SeV; however, at a high dose of virus, NKLAM-/- mice succumbed to the infection faster than wild type mice. In conclusion, our novel results indicate that NKLAM plays a role in regulating the production of pro-inflammatory cytokines during viral infection.

Arctic permafrost coasts are sensitive to changing climate. The lengthening open water season and the increasing open water area are likely to induce greater erosion and threaten community and industry infrastructure as well as dramatically change nutrient pathways in the near-shore zone. The shallow, mediterranean Arctic Ocean is likely to be strongly affected by changes in currently poorly observed arctic coastal dynamics. We present a geomorphological classification scheme for the arctic coast, with 101,447 km of coastline in 1,315 segments. The average rate of erosion for the arctic coast is 0.5 m year⁻¹ with high local and regional variability. Highest rates are observed in the Laptev, East Siberian, and Beaufort Seas. Strong spatial variability in associated database bluff height, ground carbon and ice content, and coastline movement highlights the need to estimate the relative importance of shifting coastal fluxes to the Arctic Ocean at multiple spatial scales.

A subset of patients with metastatic melanoma have sustained remissions following treatment with immune checkpoint inhibitors. However, analyses of pretreatment tumor biopsies for markers predictive of response, including PD-1 ligand (PD-L1) expression and mutational burden, are insufficiently precise to guide treatment selection, and clinical radiographic evidence of response on therapy may be delayed, leading to some patients receiving potentially ineffective but toxic therapy. Here, we developed a molecular signature of melanoma circulating tumor cells (CTCs) to quantify early tumor response using blood-based monitoring. A quantitative 19-gene digital RNA signature (CTC score) applied to microfluidically enriched CTCs robustly distinguishes melanoma cells, within a background of blood cells in reconstituted and in patient-derived (n = 42) blood specimens. In a prospective cohort of 49 patients treated with immune checkpoint inhibitors, a decrease in CTC score within 7 weeks of therapy correlates with marked improvement in progression-free survival [hazard ratio (HR), 0.17; P = 0.008] and overall survival (HR, 0.12; P = 0.04). Thus, digital quantitation of melanoma CTC-derived transcripts enables serial noninvasive monitoring of tumor burden, supporting the rational application of immune checkpoint inhibition therapies.

Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin ( B2M ), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1. Resistance to immune-checkpoint blockade often occurs in treated patients. Here, the authors demonstrate that B2M loss is a mechanism of primary and acquired resistance to therapies targeting CTLA4 or PD-1 in melanoma patients.