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Supplementary Table from Adenosine-Deaminase-Acting-on-RNA-1 Facilitates T-cell Migration toward Human Melanoma Cells

The effect of tumor/T-cell interactions on subsequent immune infiltration is undefined. Here, we report that preexposure of melanoma cells to cognate T cells enhanced the chemotaxis of new T cells in vitro. The effect was HLA class I–restricted and IFNγ-dependent, as it was abolished by β2M-knockdown, MHC-blocking antibodies, JAK1 inhibitors, JAK1-silencing and IFNgR1-blocking antibodies. RNA sequencing (RNA-seq) of 73 melanoma metastases showed a significant correlation between the interferon-inducible p150 isoform of adenosine-deaminase-acting-on-RNA-1 (ADAR1) enzyme and immune infiltration. Consistent with this, cocultures of cognate melanoma/T-cell pairs led to IFNγ-dependent induction of ADAR1-p150 in the melanoma cells, as visualized in situ using dynamic cell blocks, in ovo using fertilized chick eggs, and in vitro with Western blots. ADAR1 staining and RNA-seq in patient-derived biopsies following immunotherapy showed a rise in ADAR1-p150 expression concurrently with CD8+ cell infiltration and clinical response. Silencing ADAR1-p150 abolished the IFNγ-driven enhanced T-cell migration, confirming its mechanistic role. Silencing and overexpression of the constitutive isoform of ADAR1, ADAR1-p110, decreased and increased T-cell migration, respectively. Chemokine arrays showed that ADAR1 controls the secretion of multiple chemokines from melanoma cells, probably through microRNA-mediated regulation. Chemokine receptor blockade eliminated the IFNγ-driven T-cell chemotaxis. We propose that the constitutive ADAR1 downregulation observed in melanoma contributes to immune exclusion, whereas antigen-specific T cells induce ADAR1-p150 by releasing IFNγ, which can drive T-cell infiltration.

Supplementary Figure from Adenosine-Deaminase-Acting-on-RNA-1 Facilitates T-cell Migration toward Human Melanoma Cells

Corrugated metal pipes (CMPs) deployed across North America are in various states of deteriorations with diminishing structural health that can cause road failure and pose serious threat to public safety. This paper presents an extensive experimental study conducted on deteriorated and retrofitted CMPs, and compares the results with available analytic approach — Modified Iowa equation. Simulated deterioration was performed on the new CMPs using mechanical approach and later, those CMP specimens were retrofitted using four different non-invasive methods. The specimens were tested under five different overburden pressures. Responses of the soil-pipe systems for deteriorated and rehabilitated specimens in terms of surrounding soil pressure and deformations at crown, spring-line, and invert were recorded and compared. It was found that the soil envelops and the CMPs experienced considerable change in pressure and deflections, respectively due to deterioration. However, rehabilitation using all the invasive approaches helped to regain soil pressures and deflections close to the original state, indicating their viability. The measured deflections from experimental studies were also compared with the predicted values obtained from the Modified Iowa equation. Such comparison is of immense importance to establish design guidelines for rehabilitated liner-CMP culvert systems.

Several landmark preclinical studies have shown an association between the gut microbiota and the effectiveness of immunotherapy for cancer. These studies have sparked clinical trials aimed at modulating the gut microbiota in order to improve clinical response rates to immunotherapy. Despite this, the mechanisms through which the gut microbiota influences the effectiveness of immunotherapy are still incompletely characterized. Preclinical and preliminary clinical findings from numerous types of gut microbiota modulation studies, including fecal transplantation, probiotics, consortia, and diet, demonstrate that favorable microbiota modulation is associated with increased intratumoral infiltration of CD8+ effector T cells. This CD8+ T-cell infiltration is often associated with enhanced intratumoral activity of T-helper type 1 cells and dendritic cells and a lower density of immunosuppressive cells. Herein, we discuss how gut microbiota may affect the activity of immune cells by at least three interlacing mechanisms: activation of pattern recognition receptors, molecular mimicry, and impact of metabolites. We also discuss the therapeutic potential and limitations of the different gut microbiota modulation techniques and their putative mechanisms of immune activation.

New fecal microbiota for cancer patients The composition of the gut microbiome influences the response of cancer patients to immunotherapies. Baruch et al. and Davar et al. report first-in-human clinical trials to test whether fecal microbiota transplantation (FMT) can affect how metastatic melanoma patients respond to anti–PD-1 immunotherapy (see the Perspective by Woelk and Snyder). Both studies observed evidence of clinical benefit in a subset of treated patients. This included increased abundance of taxa previously shown to be associated with response to anti–PD-1, increased CD8 + T cell activation, and decreased frequency of interleukin-8–expressing myeloid cells, which are involved in immunosuppression. These studies provide proof-of-concept evidence for the ability of FMT to affect immunotherapy response in cancer patients. Science , this issue p. 602 , p. 595 ; see also p. 573

Background The prognostic performance of the recently updated American Joint Committee on Cancer lymph node classification of cutaneous head and neck squamous cell carcinoma (HNSCC) has not been validated. The objective of this study was to assess the prognostic role of extranodal extension (ENE) in cutaneous HNSCC. Methods This was a retrospective analysis of 1258 patients with cutaneous HNSCC who underwent surgery with or without adjuvant therapy between 1995 and 2019 at The University of Texas MD Anderson Cancer Center. The primary outcome was disease-specific survival (DSS). Local, regional, and distant metastases-free survival were secondary outcomes. Recursive partitioning analysis (RPA) and a Cox proportional hazards regression model were used to assess the fitness of staging models. Results No significant differences in 5-year DSS were observed between patients with pathologic lymph node-negative (pN0) disease (67.4%) and those with pN-positive/ENE-negative disease (68.2%; hazard ratio, 1.02; 95% CI, 0.61-1.79) or between patients with pN-positive/ENE-negative disease and those with pN-positive/ENE-positive disease (52.7%; hazard ratio, 0.57; 95% CI, 0.31-1.01). The RPA-derived model achieved better stratification between high-risk patients (category III, ENE-positive with >2 positive lymph nodes) and low-risk patients (category I, pN0; category II, ENE-positive/pN1 and ENE-negative with >2 positive lymph nodes). The performance of the RPA-derived model was better than that of the pathologic TNM classification (Akaike information criterion score, 1167 compared with 1176; Bayesian information criterion score, 1175 compared with 1195). Conclusions The number of metastatic lymph nodes and the presence of ENE are independent prognostic factors for DSS in cutaneous HNSCC, and incorporation of these factors in staging systems improves the performance of the American Joint Committee on Cancer lymph node classification.

We optimised the shapes of the sub-apertures both in aperture masking and for segmented telescopes, by improving their MTF, and allowing for easier alignment. With ellipses or ovoids, our lab model also showed better convergence.

To circumvent Heisenberg’s uncertainty principle, we multiplied the number of white light photons using a dye. With larger wave-packets, the resolution is improved, as if with a larger aperture, but longer integration times are necessary.

Another benefit of dietary fiber The gut microbiome can modulate the immune system and influence the therapeutic response of cancer patients, yet the mechanisms underlying the effects of microbiota are presently unclear. Spencer et al . add to our understanding of how dietary habits affect microbiota and clinical outcomes to immunotherapy. In an observational study, the researchers found that melanoma patients reporting high fiber (prebiotic) consumption had a better response to checkpoint inhibitor immunotherapy compared with those patients reporting a low-fiber diet. The most marked benefit was observed for those patients reporting a combination of high fiber consumption and no use of over-the-counter probiotic supplements. These findings provide early insights as to how diet-related factors may influence the immune response. —PNK

International audience; Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.

Immunotherapy with checkpoint inhibitors revolutionized melanoma treatment in both the adjuvant and metastatic setting, yet not all metastatic patients respond, and metastatic disease still often recurs among immunotherapy-treated patients with locally advanced disease. TNFSF4 is a co-stimulatory checkpoint protein expressed by several types of immune and non-immune cells, and was shown in the past to enhance the anti-neoplastic activity of T cells. Here, we assessed its expression in melanoma and its association with outcome in locally advanced and metastatic disease. We used publicly available data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), and RNA sequencing data from anti-PD1-treated patients at Sheba medical center. TNFSF4 mRNA is expressed in melanoma cell lines and melanoma samples, including those with low lymphocytic infiltrates, and is not associated with the ulceration status of the primary tumor. Low expression of TNFSF4 mRNA is associated with worse prognosis in all melanoma patients and in the cohorts of stage III and stage IIIc-IV patients. Low expression of TNFSF4 mRNAs is also associated with worse prognosis in the subgroup of patients with low lymphocytic infiltrates, suggesting that tumoral TNFSF4 is associated with outcome. TNFSF4 expression was not correlated with the expression of other known checkpoint mRNAs. Last, metastatic patients with TNFSF4 mRNA expression within the lowest quartile have significantly worse outcome on anti-PD1 treatment, and a significantly lower response rate to these agents. Our current work points to TNFSF4 expression in melanoma as a potential determinant of prognosis, and warrants further translational and clinical research.

We designed and built a novel model of a deployed space telescope which can reliably align its segments to achieve the finest possible resolution. An asymmetric design of both the segment shapes and their pupil locations were tested in simulation and experiment. We optimised the sparse aperture for better spatial frequency coverage and for smoother images with less artifacts. The unique segment shapes allow for an easier identification and alignment, and the feedback is based only upon the focal image. The autonomous alignment and fine tuning are governed by mechanical simplicity and reliability.

Background The survival benefit of elective neck dissection (END) for patients with cutaneous squamous cell carcinoma (cSCC) of the head and neck and no evidence of regional metastasis (cN0) has never been reported. The aim of this study was to determine the effect of END on patient survival. Methods The authors included patients with head and neck cSCC who had undergone primary surgery from 1995 to 2017. The primary end point was survival, and the secondary end points were the incidence of occult regional disease and regional disease control. To assess the impact of END on survival, the authors used multivariable Cox proportional hazards models with propensity score and matching techniques for internal validation. Results A total of 1111 patients presented with no evidence of nodal disease; 173 had END, and 938 were observed. Adjuvant radiotherapy to the neck was administered to 101 patients (9%). END resulted in a 5-year overall survival rate of 52%, whereas the rate was 63% in the observation group (P = .003 [log-rank]). The 5-year disease-free survival rate for patients undergoing END was similar to that for the observation group (73% vs 75%; P = .429). A multivariate regression model showed that the performance of END was not associated with improved rates of overall, disease-specific, or disease-free survival; similarly, among patients with advanced disease (T3-4), those who underwent END did not have improved survival rates. Conclusions Among patients with cSCC of the head and neck, observation of the neck nodes resulted in noninferior survival rates in comparison with END at the time of primary surgery. Further studies are required to elucidate the role of END in patients with advanced disease.

Heisenberg's uncertainty principle tells us that it is impossible to determine simultaneously the position of a photon crossing a telescope's aperture and its momentum. Super-resolution imaging techniques rely on modification of the observed sample, or on entangling photons. In astronomy we have no access to the object, but resolution may be improved by optical amplification. Unfortunately, spontaneous emission contributes noise and negates the possible gain from stimulated emissions. We show that it is possible to increase the weight of the stimulated photons by considering photon statistics, and observe an improvement in resolution. Most importantly, we demonstrate a method which can apply for all imaging purposes., Accepted for publications in the Journal of the Optical Society of America B Special Issue on Astrophotonics

Heisenberg's uncertainty principle tells us that it’s impossible to determine simultaneously the position of a photon crossing a telescope's aperture as well as the angle of its momentum. A new technique suggests to overcome the diffraction limit via optical amplification. A number of entangled photons, created by amplification of a single photon, behaves as a single quantum system with respect to the uncertainty principle. Unfortunately, spontaneous emission contributes noise and negates the possible gain from this stimulated emission. The spontaneous photons guarantee the uncertainty principle. Thus the problem of low resolution is replaced by the problem of low SNR. The detection of spontaneous photons follows the same Poisson statistics in time and space. However, the stimulated photons are spatially and temporally coherent with the incoming photons. A pixel with additional hidden thermal signal will slightly modify the Poisson statistics, and only within the diffraction pattern of the photon packets. We characterise the average number of spontaneous photons in all pixels, and subtract it from the stimulated photons. This algorithm is applied on simulated detection events of an amplified signal. The reconstructed image is resolved beyond the limit of the same optical system in the absence of amplification. We produced a number of samples of a wide-band solid-state dye (DCM within PMMA), because the expected number of (stellar) photons is small, and a solid-state dye is easier to handle compared to a dye solution. Initial results with a white light source and a laser pump depict the parameters of the method.

We propose to vary the shape of the sub-apertures both in cases of aperture masking and for segmented space telescopes. Most sub-apertures assume the shape of circles, rectangles and hexagons, but it is possible to use other shapes such as ellipses. Compared to polygons, ellipses reduce diffraction spokes in the PSF. They can have different axis ratios, and more importantly be placed at different rotation angles. This allows their easier identification in the focal plane for tip-tilt measurement. In the pupil auto-correlation (uv) plane it also allows the unique separation of sub-aperture pairs for piston measurements. Optimisation of separation angles lead to rough values of 67, 84, 113 and 96 degrees, for a range of ellipticity values.

We develop an interferometer for measurement of narrow atmospheric spectral lines, mainly in the infra-red. The bias and background are dominant, but irrelevant for the measurement. Hence we employ an optical band-pass filter tuned to the expected width of the spectral lines: Instead of scanning the full path delay with a single detector, we image the fringes on a two-dimensional camera. Applications are for search for life on exoplanets, and for our own atmosphere

We designed and built a laboratory model of a sparse space telescope. The purpose of the model is to test various algorithmic, optical, and mechanical issues with such a telescope: how to achieve alignment after deployment that yields diffraction limited optical performance. Our model uses four non-redundant sparse sectors. Each segment has three degrees of freedom, with supplementary coarse focusing, so the search volume for a perfect image is quite large, ~1051. We tried stochastic searches, optimizing the point spread to its minimum, and are now testing different directed search algorithms, of volume order 1019 or less. This will cut the search time from one day to about one hour, with much less chance of actuator failure.

While immune checkpoint inhibitor (ICI) therapy has improved melanoma patient outcomes, it has also resulted in the rise of unique immune-related adverse events (irAEs). Here, we review and synthesize irAE management recommendations from several oncological societies into a streamlined format to aid in diagnosis and management. We also include clinical pearls highlighting several recent research studies in this field. Knowledge of immunotherapy toxicity has continually evolved, and several major oncologic societies have recently released new or updated guidelines. Keeping up with the evolving field of immunotherapy and related toxicities is crucial, because ICI use, in combination with other agents, will only continue to increase and likely result in new and different patterns of irAEs. Providing clear and concise references for clinicians will help ensure proper irAE evaluation and management going forward. We present one such reference here, covering management of common and/or serious irAEs.

Omics analyses often result in dozens to hundreds of potential targets, requiring validation for their biological relevance. Current high-throughput functional investigation methods are frequently labor-intensive, expensive, and display low reproducibility. The Immune Co-Culture Cell Microarray (ICCM) is a formalin-fixed paraffin-embedded cell block microarray based on co-cultures of patient-derived tumor-infiltrating lymphocytes and their autologous melanoma cells. Each ICCM slide represents the same experiment and can be stained using standard immunohistochemistry and immunofluorescence techniques. Functional dynamics assessment of both proteins and microRNAs using ICCM stained slides demonstrated similar findings to flow cytometry assays and to previously published patient-derived biopsy reports.