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Clinical trial data can provide a wealth of information about how drugs work. Yet such information often belongs to pharmaceutical companies and is rarely accessible to the scientific community at large. Cristescu et al. provide exploratory analysis of a cancer genomics dataset, collected from four separate clinical trials of Merck's PD-1 immunotherapy drug, pembrolizumab. This informative public resource examines more than 300 patient samples representing 22 different tumor types. Two widely used signatures that currently predict immunotherapy response are tumor mutational burden and a “hot” T cell–inflamed microenvironment. The study analyzed these two proposed biomarkers in combination to see what predictive clinical utility they may hold. Science , this issue p. eaar3593 Genomic biomarkers will help to elucidate which cancer patients will benefit from PD-1 blockade immunotherapy. Programmed cell death protein–1 (PD-1) and programmed cell death ligand–1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell–inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti–PD-1 monotherapy and combination immunotherapy regimens.

A bstract In contrast to massless spinning particles, scalars are not heavily constrained by unitarity and locality. Off-shell, no gauge symmetries are required to write down manifestly local theories, while on-shell consistent factorisation is trivial. Instead a useful classification scheme for scalars is based on the symmetries they can non-linearly realise. Motivated by the breaking of Lorentz boosts in cosmology, in this paper we classify the possible symmetries of a shift-symmetric scalar that is assumed to non-linearly realise Lorentz boosts as, for example, in the EFT of inflation. Our classification method is algebraic; guided by the coset construction and inverse Higgs constraints. We rediscover some known phonon theories within the superfluid and galileid classes, and discover a new galileid theory which we call the extended galileid . Generic galileids correspond to the broken phase of galileon scalar EFTs and our extended galileids correspond to special subsets where each galileon coupling is fixed by an additional symmetry. We discuss the broken phase of theories that also admit a perturbation theory around Poincaré invariant vacua and we show that the so-called exceptional EFTs, the DBI scalar and special galileon, do not admit such a broken phase. Concentrating on DBI we provide a detailed account of this showing that the scattering amplitudes are secretly Poincaré invariant when the theory is expanded around the superfluid background used in the EFT of inflation. We point out that DBI is an exception to the common lore that the residue of the total energy pole of cosmological correlators is proportional to the amplitude. We also discuss the inevitability of poles in 2 → 2 scattering amplitudes when boost are spontaneously broken meaning that such theories do not admit Adler zeros and generalisations even in the presence of a shift symmetry.

Surface structuring provides a broad range of water-repellent materials known for their ability to reflect millimetre-sized raindrops. Dispelling water at the considerably reduced scale of fog or dew, however, constitutes a significant challenge, owing to the comparable size of droplets and structures. Nonetheless, a surface comprising nanocones was recently reported to exhibit strong anti-fogging behaviour, unlike pillars of the same size. To elucidate the origin of these differences, we systematically compare families of nanotexture that transition from pillars to sharp cones. Through environmental electron microscopy and modelling, we show that microdroplets condensing on sharp cones adopt a highly non-adhesive state, even at radii as low as 1.5 µm, contrasting with the behaviour on pillars where pinning results in impedance of droplet ejection. We establish the antifogging abilities to be universal over the range of our cone geometries, which speaks to the unique character of the nanocone geometry to repel dew. Truncated cones are finally shown to provide both pinning and a high degree of hydrophobicity, opposing characteristics that lead to a different, yet efficient, mechanism of dew ejection that relies on multiple coalescences. Spontaneous jumping of condensing droplets holds promise for antifogging, but is generally inhibited for microdroplets. Lecointre et al. show that antifogging ability of cone structures at nanoscales is universal over a large range of cone sizes, shapes, apex angles and even truncation.

Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-γ is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti-PD-1 therapies, including pembrolizumab. However, whether quantifying T cell-inflamed microenvironment is a useful pan-tumor determinant of PD-1-directed therapy response has not been rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA from baseline tumor samples of pembrolizumab-treated patients. We identified immune-related signatures correlating with clinical benefit using a learn-and-confirm paradigm based on data from different clinical studies of pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually defining a pan-tumor T cell-inflamed GEP in 220 patients with 9 cancers. Predictive value was independently confirmed and compared with that of PD-L1 immunohistochemistry in 96 patients with head and neck squamous cell carcinoma. The T cell-inflamed GEP contained IFN-γ-responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance, and these features were necessary, but not always sufficient, for clinical benefit. The T cell-inflamed GEP has been developed into a clinical-grade assay that is currently being evaluated in ongoing pembrolizumab trials.

To investigate the responses of a natural microbial plankton community of coastal Mediterranean waters to warming, which are still poorly known, an in situ mesocosm experiment was carried out in Thau Lagoon during autumn 2018. Several microorganisms, including virio-, bacterio-, and phytoplankton < 10 µm in size, were monitored daily and analysed using flow cytometry for 19 consecutive days in six mesocosms. Three mesocosms (control) had the same natural water temperature as the lagoon, and the other three were warmed by + 3 °C in relation to the control temperature. The cytometric analyses revealed an unexpected community dominated by picophytoplanktonic cells, including Prochlorococcus-like and Picochlorum-like cells, which had not previously been found in Thau Lagoon. The experimental warming treatment increased the abundances of nanophytoplankton, cyanobacteria, bacteria and viruses during the experiment and triggered earlier blooms of cyanobacteria and picoeukaryotes. Only the abundance of Picochlorum-like cells was significantly reduced under warmer conditions. The growth and grazing rates of phytoplankton and bacterioplankton estimated on days 2 and 8 showed that warming enhanced the growth rates of most phytoplankton groups, while it reduced those of bacteria. Surprisingly, warming decreased grazing on phytoplankton and bacteria at the beginning of the experiment, while during the middle of the experiment it decreased the grazing on prokaryote only but increased it for eukaryotes. These results reveal that warming affected the Thau Lagoon plankton community from viruses to nanophytoplankton in fall, inducing changes in both dynamics and metabolic rates.

The SEIS (Seismic Experiment for Interior Structures) instrument on board the InSight mission to Mars is the critical instrument for determining the interior structure of Mars, the current level of tectonic activity and the meteorite flux. Meeting the performance requirements of the SEIS instrument is vital to successfully achieve these mission objectives. The InSight noise model is a key tool for the InSight mission and SEIS instrument requirement setup. It will also be used for future operation planning. This paper presents the analyses made to build a model of the Martian seismic noise as measured by the SEIS seismometer, around the seismic bandwidth of the instrument (from 0.01 Hz to 1 Hz). It includes the instrument self-noise, but also the environment parameters that impact the measurements. We present the general approach for the model determination, the environment assumptions, and we analyze the major and minor contributors to the noise model.

Chromosome breakage is a major threat to genome integrity. The most accurate way to repair DNA double strand breaks (DSB) is homologous recombination (HR) with an intact copy of the broken locus. Mobility of the broken DNA has been seen to increase during the search for a donor copy. Observing chromosome dynamics during the earlier steps of HR, mainly the resection from DSB ends that generates recombinogenic single strands, requires a visualization system that does not interfere with the process, and is small relative to the few kilobases of DNA that undergo processing. Current visualization tools, based on binding of fluorescent repressor proteins to arrays of specific binding sites, have the major drawback that highly-repeated DNA and lengthy stretches of strongly bound protein can obstruct chromatin function. We have developed a new, non-intrusive method which uses protein oligomerization rather than operator multiplicity to form visible foci. By applying it to HO cleavage of the MAT locus on Saccharomyces cerevisiae chromosome III, we provide the first real-time analysis of resection in single living cells. Monitoring the dynamics of a chromatin locus next to a DSB revealed transient confinement of the damaged chromatin region during the very early steps of resection, consistent with the need to keep DNA ends in contact. Resection in a yku70 mutant began ∼ 10 min earlier than in wild type, defining this as the period of commitment to homology-dependent repair. Beyond the insights into the dynamics and mechanism of resection, our new DNA-labelling and -targeting method will be widely applicable to fine-scale analysis of genome organization, dynamics and function in normal and pathological contexts.

In fetal alcohol spectrum disorders (FASD), brain growth deficiency is a hallmark of subjects both with fetal alcohol syndrome (FAS) and with non‐syndromic FASD (NS‐FASD, i.e., those without specific diagnostic features). However, although the cerebellum was suggested to be more severely undersized than the rest of the brain, it has not yet been given a specific place in the FASD diagnostic criteria where neuroanatomical features still count for little if anything in diagnostic specificity. We applied a combination of cerebellar segmentation tools on a 1.5 T 3DT1 brain MRI dataset from a monocentric population of 89 FASD (52 FAS, 37 NS‐FASD) and 126 typically developing controls (6–20 years old), providing 8 volumes: cerebellum, vermis and 3 lobes (anterior, posterior, inferior), plus total brain volume. After adjustment of confounders, the allometric scaling relationship between these cerebellar volumes (Vi) and the total brain or cerebellum volume (Vt) was fitted (Vi = bVta), and the effect of group (FAS, control) on allometric scaling was evaluated. We then estimated for each cerebellar volume in the FAS population the deviation from the typical scaling (vDTS) learned in the controls. Lastly, we trained and tested two classifiers to discriminate FAS from controls, one based on the total cerebellum vDTS only, the other based on all the cerebellar vDTS, comparing their performance both in the FAS and the NS‐FASD group. Allometric scaling was significantly different between FAS and control group for all the cerebellar volumes (p < .001). We confirmed the excess of total cerebellum volume deficit (vDTS = −10.6%) and revealed an antero‐inferior‐posterior gradient of volumetric undersizing in the hemispheres (−12.4%, 1.1%, 2.0%, respectively) and the vermis (−16.7%, −9.2%, −8.6%, repectively). The classifier based on the intracerebellar gradient of vDTS performed more efficiently than the one based on total cerebellum vDTS only (AUC = 92% vs. 82%, p = .001). Setting a high probability threshold for >95% specificity of the classifiers, the gradient‐based classifier identified 35% of the NS‐FASD to have a FAS cerebellar phenotype, compared to 11% with the cerebellum‐only classifier (pFISHER = 0.027). In a large series of FASD, this study details the volumetric undersizing within the cerebellum at the lobar and vermian level using allometric scaling, revealing an anterior‐inferior‐posterior gradient of vulnerability to prenatal alcohol exposure. It also strongly suggests that this intracerebellar gradient of volumetric undersizing may be a reliable neuroanatomical signature of FAS that could be used to improve the specificity of the diagnosis of NS‐FASD. In fetal alcohol syndrome (FAS), the cerebellum is smaller than expected for brain size, and within the cerebellum follows an anterior‐posterior‐inferior gradient of severity. A classifier including this cerebellar gradient efficiently discriminating FAS from controls categorizes one third of the non syndromic fetal alcohol spectrum disorder subjects with a FAS‐like cerebellar pattern.

Advanced-stage cutaneous T-cell lymphomas (CTCLs) are rare, usually refractory, and fatal diseases. Case series have suggested that allogeneic haematopoietic stem cell transplantation (HSCT) might improve the prognosis of advanced-stage CTCLs. The objective of this study was to investigate the effect of allogeneic HSCT compared with non-HSCT therapy on the outcome of individuals with advanced-stage CTCLs. In this prospective, multicentre, matched controlled trial, conducted at 30 hospitals, participants with advanced CTCLs were allocated treatment: if they had an available compatible related donor they were assigned to allogeneic HSCT, or if not they were allocated to non-allogeneic HSCT therapy. Key inclusion criteria were participants aged 18–70 years, with advanced stage mycosis fungoides or Sézary syndrome, and at least one poor prognostic criteria. Participants were excluded if they were not in complete or partial remission of the disease. Propensity score 1:1 matching with replacement (ie, that each participant treated with HSCT was matched to the participant with the closest propensity score treated with non-HSCT therapy, even if they had already been matched) was used to handle confounding factors, with the balance of covariate distribution between HSCT and non-HSCT groups assessed using standardised mean differences. The primary endpoint was progression-free survival in the matched intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02520908), and is currently active but not recruiting. From June 1, 2016, to March 3, 2022, total of 99 participants were enrolled at 17 centres in France. Participants with a sibling or matched unrelated donor were assigned to allogeneic HSCT (HSCT group, n=55 [56%]) and participants without a donor were assigned to non-allogeneic HSCT treatment (non-HSCT group, n=44 [44%]). The median follow-up among survivors was 12·6 months (IQR 11·0–35·2). In the HSCT group, 51 participants (93%) were 1:1 matched to participants from the non-HSCT group. In the intention-to-treat analysis, median progression-free survival was significantly longer in the HSCT group (9·0 months [95% CI 6·6–30·5]) than in the non-HSCT group (3·0 months [2·0–6·3]), with a hazard ratio of 0·38 (95% CI 0·21–0·69; p<0·0001). In the per-protocol population, 40 participants (78%) in the HSCT group had 101 serious events and 29 participants (67%) in the non-HSCT group had 70 serious adverse events. The most common serious adverse event other than graft-versus-host disease in both groups was infections, occurring in 30 participants (59%) in the HSCT group and in 19 participants (44%) in the non-HSCT group. Allogeneic HSCT was associated with significantly longer progression-free survival in participants with advanced-stage CTCLs. These results indicate that allogeneic HSCT treatment should be made available to individuals with high-risk, advanced-stage mycosis fungoides or Sézary syndrome who achieve pre-transplant disease remission. French Ministry of Health, National Cancer Institute, Programme Hospitalier de Recherche Clinique en Cancérologie.