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Introduction: Postoperative complications following major surgery have been shown to be associated with reduced health-related quality of life (HRQL), and severe complications may have profound negative effects. This study aimed to examine whether long-term HRQL differs with the occurrence and severity of complications in a European multicenter prospective dataset of patients following esophagectomy for cancer. Methods: Disease-free patients following esophagectomy for cancer between 2010 and 2016 from the LASER study were included. Patients completed the LASER, EORTC QLQ-C30 and EORTC QLQ-OG25 questionnaires >1 year following treatment. Long-term HRQL was compared between patients with and without postoperative complications, subgroup analysis was performed for severity of complications (no, minor [Clavien-Dindo I-II], severe [Clavien-Dindo ≥ III]), using univariable and multivariable regression. Results: 645 patients were included: 283 patients with no, 207 with minor and 155 with severe complications. Significantly more dyspnea (QLQ-C30) was reported by patients with compared to patients without complications (differenceinmeans 6.3). In subgroup analysis, patients with severe complications reported more dyspnea (difference in means 8.3) than patients with no complications. None of the differences were clinically relevant (difference in means ≥ 10 points). LASER-based low mood (OR2.3) was statistically different for minor versus severe complications. Conclusion: Comparable HRQL was found in patients with and without postoperative complications following esophagectomy for cancer, after a mean follow-up of 4.4 years. Furthermore, patients with different levels of severity of complications had comparable HRQL. The level of HRQL in esophageal cancer patients are more likely explained by the impact of the complex procedure of the esophagectomy itself.

MotivationCells contain dozens of major organelles and thousands of other structures, many of which vary extensively in their number, size, shape and spatial distribution. This complexity and variation dramatically complicates the use of both traditional and deep learning methods to build accurate models of cell organization. Most cellular organelles are distinct objects with defined boundaries that do not overlap, while the pixel resolution of most imaging methods is not sufficient to resolve these boundaries. Thus while cell organization is conceptually object-based, most current methods are pixel-based. Using extensive image collections in which particular organelles were fluorescently-labeled, deep learning methods can be used to build conditional autoencoder models for particular organelles. A major advance occurred with the use of a U-net approach to make multiple models all conditional upon a common reference, unlabeled image, allowing the relationships between different organelles to be at least partially inferred.ResultsWe have developed improved GAN-based approaches for learning these models and have also developed novel criteria for evaluating how well synthetic cell images reflect the properties of real images. The first set of criteria measure how well models preserve the expected property that organelles do not overlap. We also developed a modified loss function that allows retraining of the models to minimize that overlap. The second set of criteria uses object-based modeling to compare object shape and spatial distribution between synthetic and real images. Our work provides the first demonstration that, at least for some organelles, deep learning models can capture object-level properties of cell images.AvailabilityA Reproducible Research Archive containing all source code, generated images and analysis results will be made available at http://murphylab.cbd.cmu.edu/Software upon publication.Contactmurphy@cmu.eduSupplementary informationSupplementary data are available at Bioinformatics online.

TABLE OF CONTENTS GENERAL INFORMATION TITLE AUTHORS AND BEST CONTACT LICENSES USEFUL LINKS DATE OF DATA COLLECTION FILE ORGANIZATION FUNDING ---- Release Notes:This is a pre-publication placeholder for primary data release for the publication listed below. In common with GEO, PRIDE, and other data repositories, this will be populated with final data following peer review. ---- GENERAL INFORMATION Publication Title:Immune Profiling of Dermatologic Adverse Events from Checkpoint Blockade using Tissue Cyclic Immunofluorescence Authors:Zoltan Maliga, Daniel Y. Kim, Ai-Tram N. Bui, Jia-Ren Lin, Anna K. Dewan, George G. Murphy, Ajit J. Nirmal, Christine G. Lian, Peter K. Sorger, Nicole R. LeBoeuf Contact Information Nicole LeBoeuf, MD, MPH Vice Chair of Dermatology,Dana-FarberCancer Institute,; Chief, Division of Oncodermatology, Brigham and Women's Hospital; Clinical Director, Center for Cutaneous Oncology, Dana-Farber/Brigham Cancer Center, HarvardMedical School nleboeuf@partners.org Publications that cite or use the data:** Maliga, M, Kim, DY, Tram, B, Lin, JR, Dewan, AK, Jadeja, S, Murphy, G, Nirmal, AJ, Lian, C, Sorger, PK, LeBoeuf, NR. Immune Profiling of Dermatologic Adverse Events from Checkpoint Blockade using Tissue Cyclic Immunofluorescence.https://doi.org/10.1101/2023.04.03.535435 Licenses/restrictions placed on the data:CC BYhttps://creativecommons.org/licenses/by/4.0/ ---- FILE ORGANIZATION FILE TYPES/SUMMARY:Each folder corresponds to a patient sample (N). The following files are available for each patient and are located on [Synapse/AWS/Etc]. File Type Description Location N.ome.tif Stitched multiplex CyCIF image pyramid in ome.tif format AWS N_IHC.ome.tiff Immunohistochemistry stained image of serial FFPE tissue section in .ome.tiff format AWS N_HE.ome.tiff Hematoxylin and eosin stained image of FFPE tissue section in .ome.tiff format AWS markers.csv List of all markers in ome.tif image Synapse N_Quantification.csv Single-cell feature table, including intensity data for all channels Synapse segmentation/ Folder of segmentation maps for tissue image in .tif format AWS Synapse Library:Edit this to link directly to your public Synapse Library Free account registration is required to download files from Synapse. Images and metadata are available in the bucket at the following AWS location:[ADD BUCKET DETAILS] To browse and download the data use either a graphical file transfer application that supports S3 such asCyberDuck, or theAWS CLI tools. A graphical tool may be more convenient but the CLI tools will likely offer higher download speeds. FILE LIST N.ome.tif LSP Slide ID File Name File Size LSP10925 LSP10925_CyCIF_Image.ome.tif 9.3 GB LSP10929 LSP10929_CyCIF_Image.ome.tif 6.0 GB LSP10931 LSP10931_CyCIF_Image.ome.tif 8.7 GB LSP10933 LSP10933_CyCIF_Image.ome.tif 6.7 GB LSP10951 LSP10951_CyCIF_Image.ome.tif 11 GB LSP10980 LSP10980_CyCIF_Image.ome.tif 9.3 GB 51 GB markers.csv File name File Size Synapse ID markers.csv 0.7 KB N_Quantification.csv LSP Slide ID File Name File Size Synapse ID LSP10925 LSP10925_CyCIF_Quantification.csv 20 MB LSP10929 LSP10929_CyCIF_Quantification.csv 12 MB LSP10931 LSP10931_CyCIF_Quantification.csv 5.9 MB LSP10933 LSP10933_CyCIF_Quantification.csv 7.5 MB LSP10951 LSP10951_CyCIF_Quantification.csv 8.3 MB LSP10980 LSP10980_CyCIF_Quantification.csv 12 MB segmentation/ LSP Slide ID File Name File Size LSP10925 LSP10925_cellRingMask.tif 20 MB LSP10929 LSP10929_cellRingMask.tif 12 MB LSP10931 LSP10931_cellRingMask.tif 5.9 MB LSP10933 LSP10933_cellRingMask.tif 7.5 MB LSP10951 LSP10951_cellRingMask.tif 8.3 MB LSP10980 LSP10980_cellRingMask.tif 12 MB 66 MB N_IHC.ome.tiff LSP Slide ID Description File name File Size LSP16237 CD103 Image LSP16237_IHC_CD103.ome.tiff 2.8 GB LSP16240 PD1 Image LSP16240_IHC_PD1.ome.tiff 3.1 GB LSP16241 MART1 Image LSP16241_IHC_MART1.ome.tiff 2.9 GB LSP16242 FOXP3 Image LSP16242_IHC_FOXP3.ome.tiff 3.5 GB LSP16243 CD3 Image LSP16243_IHC_CD3.ome.tiff 2.9 GB LSP16244 CD4 Image LSP16244_IHC_CD4.ome.tiff 3.2 GB LSP16245 CD8 Image LSP16245_IHC_CD8.ome.tiff 3.2 GB LSP16246 CD20 Image LSP16246_IHC_CD20.ome.tiff 3.2 GB LSP16247 CD19 Image LSP16247_IHC_CD19.ome.tiff 3.7 GB LSP16248 CD163 Image LSP16248_IHC_CD163.ome.tiff 4.0 GB LSP16249 PDL1 Image LSP16249_IHC_PDL1.ome.tiff 3.7 GB LSP16250 CD69 Image LSP16250_IHC_CD69.ome.tiff 3.2 GB 39 GB N_HE.ome.tiff LSP Slide ID Description File name File Size LSP16237 H&E Image LSP16234_HE.ome.tiff 14 GB 14 GB ---- FUNDING R50-CA252138, U2C-CA233262 and Ludwig Cancer Research

The human microbiome has emerged as an intriguing field of scientific research. Its role in human physiology impacts both health and disease, contributing to the enhancement or impairment of metabolic and immune functions. Sometimes referred to as our body’s “second genome”, the alteration of the microbiome’s bacterial ecology (dysbiosis), is linked to increasing numbers of illnesses, including cancer. The tumor microenvironment (TME) is the environment in which tumors grow and modulate the tumorigenic process depending on a myriad of distinct factors, including cell types, vascular system, and cytokines. Given the emerging relationship between the microbiome and the TME, this perspective aims to distill some of the key factors regulating the crosstalk between the microbiome and the TME. It also outlines why manipulating the microbiome may be a feasible strategy for anti-cancer therapy.

Information about patterns of healthcare utilization for people living with spinal cord injury (SCI) is currently limited, and this is needed to understand independent community living after SCI. This study investigates self-reported healthcare utilization among community-living people with SCI and assesses disparities across demographic, socioeconomic, and injury-related subgroups.Secondary analysis of cross-sectional survey data administered via telephone interview.6 SCI Model Systems centers in the United States (California, Colorado, New Jersey, New York, Ohio, and Pennsylvania).Adults with chronic, traumatic SCI who were community-living for at least one year after the completion of an inpatient rehabilitation program (N = 617).Not applicable.Utilization of a usual source of 4 types of health care in the past 12 months: primary, SCI, dental, and optical.84% of participants reported utilizing primary care in the past year. More than half reported utilizing SCI (54%) and dental (57%) care, and 36% reported utilizing optical care. There were no significant differences across key subgroups in the utilization of primary care. Participants who had been injured for 5 years or less and participants with greater educational attainment were more likely to report utilizing SCI care. Participants with higher household income levels were more likely to report using dental care. Female participants and older age groups were more likely to report using optical care.Rates of healthcare utilization among people with SCI are below recommended rates and vary across demographic, socioeconomic, and injury-related subgroups. This information can inform future research to target barriers to using healthcare services among community-living people with SCI.

Cutaneous melanoma is a highly immunogenic malignancy that is surgically curable at early stages but life-threatening when metastatic. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially resolved microregion transcriptomics to study immune evasion and immunoediting in primary melanoma. We find that recurrent cellular neighborhoods involving tumor, immune, and stromal cells change significantly along a progression axis involving precursor states, melanoma in situ, and invasive tumor. Hallmarks of immunosuppression are already detectable in precursor regions. When tumors become locally invasive, a consolidated and spatially restricted suppressive environment forms along the tumor–stromal boundary. This environment is established by cytokine gradients that promote expression of MHC-II and IDO1, and by PD1–PDL1-mediated cell contacts involving macrophages, dendritic cells, and T cells. A few millimeters away, cytotoxic T cells synapse with melanoma cells in fields of tumor regression. Thus, invasion and immunoediting can coexist within a few millimeters of each other in a single specimen.Significance:The reorganization of the tumor ecosystem in primary melanoma is an excellent setting in which to study immunoediting and immune evasion. Guided by classic histopathology, spatial profiling of proteins and mRNA reveals recurrent morphologic and molecular features of tumor evolution that involve localized paracrine cytokine signaling and direct cell–cell contact.This article is highlighted in the In This Issue feature, p. 1397

An automated image analysis pipeline to map cell geometry and basal body organization in the ciliate Tetrahymena thermophila is described. Generative modeling was used to computationally reconstruct cell cycle progression from images of cells at single time points. The results reveal novel aspects of basal body distribution and replication.

Nontypeable Haemophilus influenzae (NTHi) persists in the lower airways of adults with chronic obstructive pulmonary disease (COPD) for months to years, increasing airway inflammation that accelerates the progressive loss of lung function. Understanding the mechanisms of persistence in human airways by NTHi is critical in developing novel interventions.

As alien invasive species are a key driver of biodiversity loss, understanding patterns of rapidly changing global species compositions depends upon knowledge of invasive species population dynamics and trends at large scales. Within this context, the Ponto-Caspian region is among the most notable donor regions for aquatic invasive species in Europe. Using macroinvertebrate time series collected over 52 years (1968–2020) at 265 sites across 11 central and western European countries, we examined the occurrences, invasion rates, and abundances of freshwater Ponto-Caspian fauna. We examined whether: (i) successive Ponto-Caspian invasions follow a consistent pattern of composition pioneered by the same species, and (ii) Ponto-Caspian invasion accelerates subsequent invasion rates. In our dataset, Ponto-Caspian macroinvertebrates increased from two species in 1972 to 29 species in 2012. This trend was parallelled by a non-significant increasing trend in the abundances of Ponto-Caspian taxa. Trends in Ponto-Caspian invader richness increased significantly over time. We found a relatively uniform distribution of Ponto-Caspian macroinvertebrates across Europe without any relation to the distance to their native region. The Ponto-Caspian species that arrived first were often bivalves (46.5% of cases), particularly Dreissena polymorpha, followed secondarily by amphipods (83.8%; primarily Chelicorophium curvispinum and Dikerogammarus villosus). The time between consecutive invasions decreased significantly at our coarse regional scale, suggesting that previous alien establishments may facilitate invasions of subsequent taxa. Should alien species continue to translocate from the Ponto-Caspian region, our results suggest a high potential for their future invasion success highly connected central and western European waters. However, each species’ population may decline after an initial ‘boom’ phase or after the arrival of new invasive species, resulting in different alien species dominating over time., This study was supported by the Grant Agency of the University of South Bohemia, project number 065/2022/Z. R.N.C. acknowledges funding from the Leverhulme Trust Early Career Fellowship (ECF-2021-001). We also acknowledge Flanders Environment Agency for providing the publicy available data. P.H. and P.J.H. received funding from the EU Horizon 2020 project eLTER PLUS (Grant Agreement No. 871128). NB and MC were supported by the Serra-Hunter programme (Generalitat de Catalunya). MC was also supported by a Ramón y Cajal contract funded by the Spanish Ministry of Science and Innovation (RYC2020-029829-I). NB was also supported by the H2020 European Research and Innovation action Grant Agreement no. 869226 (DRYvER). The FEHM (Freshwater Ecology, Hydrology and Management) research group (to which NB and MC belong) was funded by the “Agència de Gestió d’Ajuts Universitaris i de Recerca” (AGAUR) at the "Generalitat de Catalunya” (2017SGR1643). BG was funded through the 2017–2018 Belmont Forum and BIODIVERSA joint call for research proposals, under the BiodivScen ERANet COFUND programme, funded through the Spanish State Research Agency (MCI/AEI/FEDER, UE, PCI2018-092986).

In this study, we demonstrate the utility of whole-slide CyCIF (tissue-based cyclic immunofluorescence) imaging for characterizing immune cell infiltrates in immune checkpoint inhibitor (ICI)-induced dermatologic adverse events (dAEs). We analyzed six cases of ICI-induced dAEs, including lichenoid, bullous pemphigoid, psoriasis, and eczematous eruptions, comparing immune profiling results obtained using both standard immunohistochemistry (IHC) and CyCIF. Our findings indicate that CyCIF provides more detailed and precise single-cell characterization of immune cell infiltrates than IHC, which relies on semi-quantitative scoring by pathologists. This pilot study highlights the potential of CyCIF to advance our understanding of the immune environment in dAEs by revealing tissue-level spatial patterns of immune cell infiltrates, allowing for more precise phenotypic distinctions and deeper exploration of disease mechanisms. By demonstrating that CyCIF can be performed on friable tissues, such as bullous pemphigoid, we provide a foundation for future studies to examine the drivers of specific dAEs using larger cohorts of phenotyped toxicity and suggest a broader role for highly multiplexed tissue imaging in phenotyping the immune mediated disease that they resemble.

Supplementary Table from The Spatial Landscape of Progression and Immunoediting in Primary Melanoma at Single-Cell Resolution

Supplementary Figure from The Spatial Landscape of Progression and Immunoediting in Primary Melanoma at Single-Cell Resolution

Cutaneous melanoma is a highly immunogenic malignancy that is surgically curable at early stages but life-threatening when metastatic. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially resolved microregion transcriptomics to study immune evasion and immunoediting in primary melanoma. We find that recurrent cellular neighborhoods involving tumor, immune, and stromal cells change significantly along a progression axis involving precursor states, melanoma in situ, and invasive tumor. Hallmarks of immunosuppression are already detectable in precursor regions. When tumors become locally invasive, a consolidated and spatially restricted suppressive environment forms along the tumor–stromal boundary. This environment is established by cytokine gradients that promote expression of MHC-II and IDO1, and by PD1–PDL1-mediated cell contacts involving macrophages, dendritic cells, and T cells. A few millimeters away, cytotoxic T cells synapse with melanoma cells in fields of tumor regression. Thus, invasion and immunoediting can coexist within a few millimeters of each other in a single specimen.Significance:The reorganization of the tumor ecosystem in primary melanoma is an excellent setting in which to study immunoediting and immune evasion. Guided by classic histopathology, spatial profiling of proteins and mRNA reveals recurrent morphologic and molecular features of tumor evolution that involve localized paracrine cytokine signaling and direct cell–cell contact.This article is highlighted in the In This Issue feature, p. 1397

Supplementary Data from The Spatial Landscape of Progression and Immunoediting in Primary Melanoma at Single-Cell Resolution

Effects on DTIC-treated melanoma cell lines.

PDF file 135KB, Non-specific negative effect of DMSO on the GVT activity of T-cells

PDF file - 82K, Response kinetics in treated patients. Baseline tumor measurements are standardized to zero. A. Entire treatment population (cohorts 1-4). B. Cohort 2 patients (MTD). Horizontal line PD = progressive disease representing 20% increase. Horizontal line PR represents 30% decrease from baseline. Filled in circle depicts radiographic development of new sites of disease.

PDF file - 68K, A. Axial CT section of the chest at baseline demonstrates two nodules in the right lung, the dominant one in the lower lobe (white arrows). B. Follow-up CT 3 months after start of treatment demonstrates resolution of one of the nodules and no change in the other nodule. C. Axial CT section 8 months after start of treatment demonstrates complete resolution of the dominant lung nodule.

PDF file - 74K, High-power H&E and CD31 stained post treatment biopsy of intratumoral vessels. The endothelial cells appear morphologically columnar. CD31 staining is concentrated at the interendothelial junctions (arrows).

Supplementary Data PDF file - 189K, supplementary data showing: a. Primers used for RT-PCR analysis of human prostate tissue and cell lines b. Primer pairs used for detection of human EP3 isoforms c. RT-PCR analysis of human EP3 isoforms present in malignant and benign human prostate cell lines

PDF file 96K, Pre-treatment of donor T-cells with a c-Rel antagonist promotes IL-2 secretion in vivo

PDF file - 59K

PDF file - 64K, Illustrations of the variation in pathologic responses to treatment. Examples of intermediate and no response.

DTIC and anti-Nodal antibody combination treatment promotes cell death in SK-MEL-28 cells.

PDF file - 76K, CONSORT Diagram.

PGE2 has been implicated in prostate cancer tumorigenesis. We hypothesized that abnormal prostaglandin receptor (EPR) expression may contribute to prostate cancer growth. Twenty-six archived radical prostatectomy specimens were evaluated by immunohistochemistry (IHC) and Western blotting for the expression of EP1, EP2, EP3, and EP4. As a corollary, EPR expression in one normal (PZ-HPV7) and four prostate cancer cell lines (CA-HPV10, LNCaP, PC3, and Du145) were assessed by Western blotting. Prostate cancer and normal cell growth were compared in vitro after EPR blockade, siRNA EPR knockdown, or overexpression. EP1, EP2, EP3, and EP4 receptors were detected by IHC in all areas of benign tissue within the clinical prostate cancer specimens. In areas of prostate cancer, EP4 and EP2 were overexpressed in 85% (22 of 26) and 75% (18 of 24) and EP3 expression was reduced in all (26 of 26, 100%) specimens (P < 0.05 vs. benign tissue). EP1 showed no specific differential expression pattern. Increased EP4 and reduced EP3 was confirmed by Western blotting in fresh clinical specimens and in prostate cancer cell lines (CA-HPV10, LNCaP, PC3, and Du145) compared with the normal prostate cell line (PZ-HPV7). EP2 and EP4 siRNA knockdown resulted in reduced in vitro growth and metastasis-related gene expression (MMP9 and Runx2) of prostate cancer lines, and in vitro migration was inhibited by EP4 antagonists. As a corollary, EP3-overexpressing PC3 cells displayed impaired growth in vitro. Human prostate cancer is associated with EP4 and EP2 overexpression and reduced EP3 expression. These data suggest that targeting specific EPR may represent a novel therapeutic approach for prostate cancer. Mol Cancer Res; 11(4); 427–39. ©2013 AACR.

Effects of anti-Nodal antibody treatment on SK-MEL-28 cells.

PDF file - 125K, Individual response of CCR7+CD45RO+ and CCD7-CD45RO+ of CD4+ and CD8+ T cells in melanoma patients treated with ipilimumab (3mg/kg), ipilimumab (3mg/kg) plus bevacizumab, or ipilimumab (10mg/kg) plus bevacizumab.

Nodal in SK-MEL-28 cells surviving treatment with the B-RAF inhibitor, RG7204.

PDF file - 39K, Summary of grade 3 and grade 4 events incidence at each dose level for all events and those events possibly, probably, or definitively related.

PDF file - 111K, Patient Demographics.

PDF file - 59K, Kaplan-Meier estimates for time-to-progression in the entire treated population (A) and by treatment cohort (B). Kaplan-Meier estimates for overall survival in the entire treated population (C) and by treatment cohort (D).

PDF file 128KB, Treg depletion from c-Rel deficient donor T-cells results in exacerbated GVHD

Nodal expression in DTIC-treated melanoma cell lines.

PDF file 92K, Table 1. Characteristics of c-Rel inhibitor compounds; Table 2. Roles of c-Rel in T-cell responses and transplantation immunology