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Checkpoint inhibition (CPI) therapy and adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL-based ACT) are the two most effective immunotherapies for the treatment of metastatic melanoma. While CPI has been the dominating therapy in the past decade, TIL-based ACT is beneficial for individuals even after progression on previous immunotherapies. Given that notable differences in response have been made when used as a subsequent treatment, we investigated how the qualities of TILs changed when the ex vivo microenvironment of intact tumor fragments were modulated with checkpoint inhibitors targeting programmed death receptor 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Initially, we show that unmodified TILs from CPI-resistant individuals can be produced, are overwhelmingly terminally differentiated, and are capable of responding to tumor. We then investigate these properties in ex vivo checkpoint modulated TILs finding that that they retain these qualities. Lastly, we confirmed the specificity of the TILs to the highest responding tumor antigens, and identified this reactivity resides largely in CD39 + CD69 + terminally differentiated populations. Overall, we found that anti-PD-1 will alter the proliferative capacity while anti-CTLA4 will influence breadth of antigen specificity., Competing Interests: IMS has lectured for or had advisory board relationships with MSD, Sanofi Aventis, BMS, Pierre Fabre, Novartis, TILT Biotherapeutics, IO Biotech, and Novo Nordisk. IS has received research grants from Lytix biopharma, IO Biotech, BMS, Adaptimmune, and TILT Biotherapeutics. IS is a co-founder and shareholder for the company IO Biotech. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor NO declared a shared parent affiliation with the authors TH, CF, JG, TB, MP, MD, MA, IMS and OM at the time of review., (Copyright © 2023 Hulen, Friese, Kristensen, Granhøj, Borch, Peeters, Donia, Andersen, Hadrup, Svane and Met.)

Background: To reduce the risk of invasive aspergillosis (IA), air purification by high-efficiency particulate air filtration and laminar air flow (HEPA/LAF) is standard of care in allogeneic blood stem cell transplantation. Its use in non-transplant haematological patients is inconsistent., Objectives: We sought to assess the incidence and outcome of pulmonary IA in non-transplant patients with life-threatening neutropenia by comparing an ambient air hospitalisation period (2008-2011) with a subsequent HEPA/LAF hospitalisation period (2012-2014)., Patients and Methods: We compared 204 consecutive patients with acute myeloid leukaemia, acute lymphoblastic leukaemia or aplastic anaemia completing 534 neutropenia-related hospitalisations under ambient air conditions with 126 such patients completing 437 neutropenia-related hospitalisations under HEPA/LAF conditions. IA was defined using the 2008 EORTC/MSG criteria., Results: Within a 7-year study period, we observed one 'proven', three 'probable' and 73 'possible' IAs, most often during acute leukaemia remission induction. Their frequency rose with increasing duration of life-threatening neutropenia (1-10 days, 1.8%; >40 days, 35.2%) and concomitant severe anaemia (0 days, 3.2%; >20 days, 31.0%). Multiple logistic regression revealed a strong correlation between IA incidence and hospitalisation under HEPA/LAF conditions (odds ratio [OR], 0.368 [95% confidence interval, 0.207-0.654]; p < .001) and duration of neutropenia (OR, 1.043 [1.023-1.062] per day; p < .001) and anaemia (OR, 1.044 [1.008-1.081] per day; p = .016). IA-associated fatal outcomes were non-significantly reduced under HEPA/LAF (OR, 0.077 [0.005-1.151]; p = .063). The protective effect of HEPA/LAF was not seen under posaconazole prophylaxis (OR, 0.856 [0.376-1.950]; p = .711)., Conclusions: Implementation of HEPA/LAF was associated with a significant reduction in neutropenia-related IA in non-transplant haematological patients., (© 2023 The Authors. Mycoses published by Wiley-VCH GmbH.)

Objective: Oral anticancer agents (OAAs) are associated with side effects that interfere with medication adherence, despite patient education regarding side effect management. Video reflexive ethnography (VRE) captures care processes on video that allow participants to learn from videos. The purpose of this pilot study was to assess the usefulness and impact of VRE on improving OAA education., Methods: This qualitative study was conducted in a pharmacist-managed OAA clinic: two pharmacists and four patients participated. We filmed each pharmacist providing education to two patients. We conducted patient interviews and one reflexivity session with both pharmacists to learn participants' perspectives. We used thematic content analysis to analyze data., Results: Two themes emerged: what patients liked/helped, and things that were unclear. Patients liked instructions on temperature taking, directions to safely handle and store OAAs. Unclear areas included knowing the timing of the worst side effects.During the reflexivity session, pharmacists found patients' comments useful to improve their practice., Conclusion: VRE was acceptable to pharmacists and patients. Pharmacists recognized VRE as a helpful technique to improve patient education on OAAs., Innovation: The use of video enables participants to scrutinize and reshape their practices, making VRE a powerful innovation and adjunct to quality improvement initiatives., Competing Interests: The authors have no completing interests to declare., (© 2023 The Authors.)

This paper investigates the 'cynical scientist' as a figure in British animal science discourse that developed in relation to the nineteenth-century emergence of the 'sceptical scientist'. Here, efforts by scientists to demarcate their profession's territory led to religious backlash against an alleged 'divorce' of British science from Christian morality. Animal experimentation became embroiled in this controversy through antivivisectionists' conviction that animal research was symptomatic of scientific scepticism and Continental atheism's malign influence. Accusations of cynicism ultimately forced British scientists to accept legal regulation following the 1875 Royal Commission on Vivisection. British scientists were, however, able to utilise their political leverage and credibility as experts to favourably influence licensing and inspection. We suggest that efforts to silence public claims of scientific cynicism may have enabled 'cynical scientists' to remain invisible and that this was marked by privilege and power, not marginality. Nevertheless, we argue that regulation and reforms have also worked to internalise within British animal science the notion that scientific cynicism must be combatted through proper governance and internal discipline., Competing Interests: Conflict of interestThe authors do not have any competing interests—intellectual or financial—in the research detailed in the manuscript., (© The Author(s) 2023.)

Background: Vaccination is an important preventive health measure to protect against symptomatic and severe COVID-19. Impaired immunity secondary to an underlying malignancy or recent receipt of antineoplastic systemic therapies can result in less robust antibody titers following vaccination and possible risk of breakthrough infection. As clinical trials evaluating COVID-19 vaccines largely excluded patients with a history of cancer and those on active immunosuppression (including chemotherapy), limited evidence is available to inform the clinical efficacy of COVID-19 vaccination across the spectrum of patients with cancer., Patients and Methods: We describe the clinical features of patients with cancer who developed symptomatic COVID-19 following vaccination and compare weighted outcomes with those of contemporary unvaccinated patients, after adjustment for confounders, using data from the multi-institutional COVID-19 and Cancer Consortium (CCC19)., Results: Patients with cancer who develop COVID-19 following vaccination have substantial comorbidities and can present with severe and even lethal infection. Patients harboring hematologic malignancies are over-represented among vaccinated patients with cancer who develop symptomatic COVID-19., Conclusions: Vaccination against COVID-19 remains an essential strategy in protecting vulnerable populations, including patients with cancer. Patients with cancer who develop breakthrough infection despite full vaccination, however, remain at risk of severe outcomes. A multilayered public health mitigation approach that includes vaccination of close contacts, boosters, social distancing, and mask-wearing should be continued for the foreseeable future., Competing Interests: Disclosure ALS reports non-financial support from Astellas, non-financial support from Pfizer, outside the submitted work. CL reports research support from Genentech/imCORE, outside the submitted work. ZB reports non-financial support from Bristol Myers Squibb, grants from Genentech/imCORE, personal fees from UpToDate, outside the submitted work. CYH reports personal fees from NashBio, outside the submitted work. SAB reports personal fees from Exelixis, personal fees from Seattle Genetics, personal fees from Pfizer, personal fees from Bristol Myers Squibb, outside the submitted work. CRF reports research grants from the Merck Foundation and National Comprehensive Cancer Network (NCCN)/Pfizer, outside the submitted work. EAG reports personal fees and other from Alexion Pharmaceuticals, personal fees and non-financial support from Novartis Pharmaceuticals, personal fees, non-financial support and other from Astex/Otsuka Pharmaceuticals, other from Apellis Pharmaceuticals, personal fees, non-financial support, and other from Celgene/Bristol Myers Squibb, grants and personal fees from AbbVie/Genentech, other from Celldex Therapeutics, personal fees from Boston Biomedical, outside the submitted work. JEH reports research funding paid to her institution from Dendreon Pharmaceuticals LLC, research funding paid to her institution from Regeneron Pharmaceuticals, personal fees from Genzyme, personal fees from Seagen, outside the submitted work. RRM reports grants and personal fees from Bayer, grants from Pfizer, grants from Tempus, personal fees from AVEO, personal fees from Caris, personal fees from Bristol Myers Squib, personal fees from Exelixis, personal fees from Janssen, personal fees from Novartis, personal fees from Pfizer, personal fees from Sanofi, personal fees from Tempus, personal fees from Dendreon, personal fees from Vividion, personal fees from AstraZeneca, personal fees from Calithera, personal fees from Merck, outside the submitted work. OAP reports personal fees from International Consulting Associates, Inc., outside the submitted work. EMW-B reports personal fees from Astellas, personal fees from AVEO Oncology, personal fees from Bristol Myers Squibb, other from Exelixis, grants from Pfizer Global Medical Grants, other from Nektar, other from Immunomedics, outside the submitted work. SM reports personal fees from National Geographic, outside the submitted work. DF reports a grant from Merck to study COVID-19 in immunocompromised patients, outside of the submitted work. YS reports personal fees from Novartis, personal fees from Roche, personal fees from Pfizer, personal fees from Janssen, personal fees from Eisai, personal fees from AstraZeneca, outside of the submitted work. JLW reports personal fees from Westat, personal fees from Roche, personal fees from Melax Tech, personal fees from Flatiron Health, other from HemOnc.org LLC (ownership), outside the submitted work. TKC reports institutional and personal, paid and unpaid support for research, advisory boards, consultancy, and honoraria from AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVIA, Ipsen, Kanaph, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, Takeda, Tempest, UpToDate, CME events (Peerview, OncLive and others), outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Galectin-3 (Gal3) can be expressed by many cells in the tumor microenvironment (TME), including cancer cells, cancer-associated fibroblasts, tumor-associated macrophages, and regulatory T cells (Tregs). In addition to immunosuppression, Gal3 expression has been connected to malignant cell transformation, tumor progression, and metastasis. In the present study, we found spontaneous T-cell responses against Gal3-derived peptides in PBMCs from both healthy donors and cancer patients. We isolated and expanded these Gal3-specific T cells in vitro and showed that they could directly recognize target cells that expressed Gal3. Finally, therapeutic vaccination with a long Gal3-derived peptide epitope, which induced the expansion of Gal3-specific CD8 + T cells in vivo , showed a significant tumor-growth delay in mice inoculated with EO771.LMB metastatic mammary tumor cells. This was associated with a significantly lower percentage of both Tregs and tumor-infiltrating Gal3 + cells in the non-myeloid CD45 + CD11b - compartment and with an alteration of the T-cell memory populations in the spleens of Gal3-vaccinated mice. These results suggest that by activating Gal3-specific T cells by an immune-modulatory vaccination, we can target Gal3-producing cells in the TME, and thereby induce a more immune permissive TME. This indicates that Gal3 could be a novel target for therapeutic cancer vaccines., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background: Patients with cancer may be at high risk of adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We analyzed a cohort of patients with cancer and coronavirus 2019 (COVID-19) reported to the COVID-19 and Cancer Consortium (CCC19) to identify prognostic clinical factors, including laboratory measurements and anticancer therapies., Patients and Methods: Patients with active or historical cancer and a laboratory-confirmed SARS-CoV-2 diagnosis recorded between 17 March and 18 November 2020 were included. The primary outcome was COVID-19 severity measured on an ordinal scale (uncomplicated, hospitalized, admitted to intensive care unit, mechanically ventilated, died within 30 days). Multivariable regression models included demographics, cancer status, anticancer therapy and timing, COVID-19-directed therapies, and laboratory measurements (among hospitalized patients)., Results: A total of 4966 patients were included (median age 66 years, 51% female, 50% non-Hispanic white); 2872 (58%) were hospitalized and 695 (14%) died; 61% had cancer that was present, diagnosed, or treated within the year prior to COVID-19 diagnosis. Older age, male sex, obesity, cardiovascular and pulmonary comorbidities, renal disease, diabetes mellitus, non-Hispanic black race, Hispanic ethnicity, worse Eastern Cooperative Oncology Group performance status, recent cytotoxic chemotherapy, and hematologic malignancy were associated with higher COVID-19 severity. Among hospitalized patients, low or high absolute lymphocyte count; high absolute neutrophil count; low platelet count; abnormal creatinine; troponin; lactate dehydrogenase; and C-reactive protein were associated with higher COVID-19 severity. Patients diagnosed early in the COVID-19 pandemic (January-April 2020) had worse outcomes than those diagnosed later. Specific anticancer therapies (e.g. R-CHOP, platinum combined with etoposide, and DNA methyltransferase inhibitors) were associated with high 30-day all-cause mortality., Conclusions: Clinical factors (e.g. older age, hematological malignancy, recent chemotherapy) and laboratory measurements were associated with poor outcomes among patients with cancer and COVID-19. Although further studies are needed, caution may be required in utilizing particular anticancer therapies., Clinical Trial Identifier: NCT04354701., Competing Interests: Disclosure JDA reports research funding to the institution from Tesaro, outside the submitted work. ZB reports nonfinancial support from Bristol Myers Squibb and grants from Genentech/imCORE, outside the submitted work. BB reports research funding to the institution from Boehringer Ingelheim, Bicycle Therapeutics, Syros Pharmaceuticals, and Ikena Oncology, all outside the submitted work. TB-S reports research funding to the institution from Agios, Arys, Boston Biomedical, Bayer, Amgen, Merck, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Array Biopharma, Genentech, Novartis, Mirati, Merus, AbGenomics, Incyte, Pfizer, BMS; consulting (to institution) for Ipsen, Array Biopharma, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, and Merck; consulting (to self) for AbbVie, Boehringer Ingelheim, Janssen, Eisai, Daiichi Sankyo, Natera, Treos Bio, Celularity, Exact Science, Sobi, BeiGene, Xilis, Astra Zeneca, and Foundation Medicine; serving on Independent Data Monitoring Committee/Data and Safety Monitoring Board (to self) for AstraZeneca, Exelixis, Lilly, PanCAN, and 1Globe; positions on Scientific Advisory Board for Imugene, Immuneering, and Sun Biopharma; and inventions/patents (WO/2018/183488 and WO/2019/055687), all outside the submitted work. SB reports being on advisory boards for Bristol Meyers Squibb and Seattle Genetics. MAB reports personal fees from Exelixis, Bristol-Myers Squibb, Bayer, Eisai, Pfizer, AstraZeneca, Janssen, Genomic Health, Nektar, and Sanofi; grants from Xencor, Bayer, Bristol-Myers Squibb, Genentech/Roche, Seattle Genetics, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peloton Therapeutics, and Pfizer, outside the submitted work. NB reports honoraria from Novartis, Pfizer, Roche, and Lilly, outside the submitted work. DWB reports research funding to the institution from Exelixis, Ayala, Merck, and Elevar, all outside the submitted work. DDC declares consulting or advisory role with Exelixis, outside the submitted work. TKC reports institutional and personal research support from Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Calithera, Cerulean, Corvus, Eisai, Exelixis, F. Hoffmann-La Roche, Foundation Medicine Inc., Genentech, GlaxoSmithKline, Ipsen, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Roche, Roche Products Limited, Sanofi/Aventis, Takeda, Tracon; consulting/honoraria or advisory role with Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Corvus, Eisai, EMD Serono, Exelixis, Foundation Medicine Inc., Genentech, GlaxoSmithKline, Heron Therapeutics, Infinity Pharma, Ipsen, Jansen Oncology, IQVIA, Lilly, Merck, NCCN, Novartis, Peloton, Pfizer, Pionyr, Prometheus Labs, Roche, Sanofi/Aventis, Surface Oncology, Tempest, Up-to-Date; CME-related events (e.g. OncLive, PVI, MJH Life Sciences); stock ownership in Pionyr, Tempest; patents filed, royalties, or other intellectual properties related to biomarkers of immune checkpoint blockers; fees for travel, accommodations, expenses, medical writing in relation to consulting, advisory roles, or honoraria; and no speaker's bureau; also supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI. DBD reports consulting for Ipsen, Boehringer Ingelheim; ASCO Young Investigator Award from Conquer Cancer Foundation, outside the submitted work. AE reports grant support from AstraZeneca, outside the submitted work. DF reports research funding to the institution from Viracor-Eurofins and Astellas, all outside the submitted work. LAF reports clinical trial funding to the institution from BMS, EMD Serono, Pfizer, Merck KGaA, Array, Kartos, Merck, and Incyte, ECOG-ACRIN study funding from Array; and personal fees from Elsevier and Via Oncology, outside the submitted work. DBF reports honoraria from Castle Biosciences. SMG reports Honoraria from AstraZeneca, Merck, Genentech/Roche; consulting or advisory role with Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Takeda, Xcovery, Boehringer Ingelheim, Novocure, Daiichi Sankyo, Novartis, Jazz Pharmaceuticals, Blueprint Medicines, Eli Lilly, Pfizer, Janssen Oncology; research funding (to self) from Merck, AstraZeneca; research funding (to institution) from Genentech/Roche, Merck, Blueprint Medicines, ARIAD/Takeda, Astellas Pharma, Lycera, Daiichi Sankyo, IMAB, Nektar, AstraZeneca, Pfizer, Amgen; travel, accommodations, expenses from Genentech/Roche, Merck; and other relationship from AstraZeneca, all outside the submitted work. MDG reports personal fees from Genentech, Pfizer, Astra Zeneca, Merck, Bristol Myers Squib, Dragonfly, Dracen, Seattle Genetics, and Astellas, outside the submitted work. PG reports consulting fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis Oncology, Dyania Health, Driver, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, Genzyme, GlaxoSmithKline, Heron Therapeutics, Immunomedics, Infinity Pharmaceuticals, Janssen, Merck, Mirati Therapeutics, Pfizer, Seattle Genetics, QED Therapeutics; research funding to institution from Merck, Mirati Therapeutics, Pfizer, Clovis Oncology, Bavarian Nordic, Immunomedics, Debiopharm, Bristol-Myers Squibb, QED Therapeutics, GlaxoSmithKline, and Kure It Cancer Research, all outside the submitted work. SG reports research funding to the institution from AstraZeneca and consulting/advisory role with Puma Biotechnology. SG reports consultancy fees from BMS, Merck, AstraZeneca, Seattle Genetics, Pfizer; and speaker fees from Seattle Genetics and Janssen, all outside the submitted work. TRH reports consulting or advisory role with Curium, ScioScientific, TERUMO, Lexicon, Ipsen, Advanced Accelerator; research funding from Ipsen, ArQule, Agios, Thermo Fisher Scientific, Basilea. BH reports research funding to the institution from Amgen, AbbVie, BI, Mirati, Merck, Eli-Lilly, AstraZeneca, BMS, Novartis, GSK, Pfizer, Advaxis, and Guardant Health; consulting/advisory role with Merck, BMS, Genentech, AstraZeneca, Amgen, Novartis, TPT, VI, Guardant Health; and honoraria from PER and OncLive, all outside the submitted work. JEH reports research funding from Regeneron and Dendreon; and travel, accommodations, and expenses from Genzyme. CH reports funding from the Henry Ford Cancer Institute supporting the current work; research funding to institution from Merck, Exelixis, Bayer, AstraZeneca, Genentech, Dendreon and Bausch; personal fees from Sanofi/Genzyme, Dendreon, Exelixis, Bristol Myers Squibb, Astellas, Medivation, Bayer, and Janssen Scientific, all outside the submitted work; and stock ownership by an immediate family member in Johnson and Johnson. DBJ reports advisory board participation for Array Biopharma, BMS, Catalyst Biopharma, Iovance, Jansen, Merck, Novartis, and OncoSec, and receives research funding from BMS and Incyte, all outside the submitted work. AK reports support to his institution from TESARO, Halozyme, Geistlich Pharma, Astellas Pharma, and Rafael Pharmaceuticals; and honoraria from OncLive, outside the submitted work. ARK (or an immediate family member) has currently or during the past 2 years owned stock or held an ownership interest in Merck, Sanofi, and BMS. VSK reports personal fees from Pfizer, Janssen, Dendreon, AstraZeneca, Seattle Genetics, and Clovis; grants (for institution) from Nektar, Novartis/Endocyte, Janssen, Clovis, and Prostate Cancer Foundation, all outside the submitted work. NMK reports personal fees from G1 Therapeutics, Invitae, Beyond Spring, Spectrum, BMS, Janssen, and Total Health, all outside the submitted work. PEL reports consulting/advisory role with Pfizer, Merck, Teva, BI, and Astra Zeneca, all outside the submitted work. AL-B reports personal fees from PSI CRO, Bayer, Blueprint, Astra-Zeneca, Medidata, Taiho, QED, Cardinal Health, BrightInsight, The Lynx Group, Boston Biomedical, Amgen, Bayer, Guardant, Natera, Eisai, Ipsen, and Merck; and stock options from Massive Bio, outside the submitted work. GdLL reports honoraria from Boehringer Ingelheim; consulting or advisory role for Pfizer and AstraZeneca; research funding from AstraZeneca; funding to his institution from Merck Sharp & Dohme, EMD Serono, AstraZeneca, Blueprint Medicines, Tesaro, Bavarian Nordic, NOVARTIS, G1 Therapeutics, Adaptimmune, BMS, GSK, AbbVie, Rgenix, Pfizer, Roche, Genentech, Lilly, and Janssen; travel, accommodations, and expenses from Boehringer Ingelheim, Pfizer, E.R. Squibb Sons, LLC, Janssen. GHL reports grants from AMGEN (institution); personal fees from G1 Therapeutics, TEVA, Samsung Bioepis, Beyond Spring, and Merck, outside the submitted work. RRM reports research funding from Bayer, Pfizer, Tempus; serves on Advisory Board for AstraZeneca, Bayer, Bristol Myers Squibb, Calithera, Exelixis, Janssen, Merck, Novartis, Pfizer, Sanofi, Tempus; is a consultant for Dendreon, Vividion; and serves on the molecular tumor board at Caris. RAM grants from Incyte, CTI, AbbVie, and Celgene; personal fees from Novartis, Genentech, Sierra Oncology, La Jolla, and Samus, outside the submitted work. VM has currently or during the past 2 years employment and stock or other ownership interest with Johnson & Johnson, all outside the submitted work. GN reports research funding to the institution from Novartis, all outside the submitted work. JN reports personal fees from AstraZeneca, Clovis Oncology; all outside the submitted work. CAP (or an immediate family member) has currently or during the past 2 years owned stock or held an ownership interest in Pfizer, Epizyme, Inovio, OPKO Health Inc, Roche. JMP reports grant from Dana-Farber/Harvard Cancer Center Breast SPORE Program, outside the submitted work. PP reports receiving payment for speakers' bureau from Novartis, Daichi Sankyo, Genentech, Seattle Genetics, and Pfizer, all outside the submitted work. NAP reports personal fees from Eli Lilly, Merck, BMS, Genentech, AstraZeneca, Inivata, and Regeneron, outside the submitted work. SP reports personal fees from AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics and Takeda, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp and Dohme, Novartis, Pfizer, and Takeda; nonfinancial support from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Meyers Squibb, Clovis, F. Hoffmann-La Roche, Illumina, Merck Sharp and Dohme, Merck Serono, Novartis, Pfizer, and Sanofi; and personal fees from BioInvent (all fees to institution), outside the submitted work. DYR reports consulting/advisory role with and coverage of travel/accommodation expenses by Castle Biosciences, all outside the submitted work. BIR reports grants, personal fees, and nonfinancial support from Merck; grants and personal fees from BMS, Pfizer, Aveo, and Genentech; grants from Astra Zeneca; personal fees from Synthorx, 3D Medicines, Aravive, Surface Oncology, and Arrowhead Therapeutics; and other from PTC Therapeutics, outside the submitted work. RPR reports research grants to her institution from BMS and Janssen and has worked as a consultant/advisor and received honoraria from BMS and Janssen, all of which are outside the scope of submitted work. ALS reports travel support provided by Pfizer and Astellas. GKS reports personal fees from Apexigen, Array, Epizyme, GenCirq, Daiichi Sankyo, Fortress, Iovance Biotherapeutics, Bayer Pharmaceuticals, Pfizer Oncology, Array Advisory Board, Oncogenuity, Puretech, PTC Therapeutics, Ellipses Pharma, Concarlo; advisory board for Bionaut; grants from Astex; stock ownership in Pfizer, all outside the submitted work. SS reports stock and other ownership interests in Grand Rounds, Janssen, and Natera. YS reports honoraria from Boehringer Ingelheim, AstraZeneca, Novartis, and Eisai; consulting or advisory role with Pfizer, AstraZeneca, Novartis, Roche, Genentech, and Janssen, all outside the submitted work. MAT reports travel support from Syapse, Royalties from UpToDate, Connect MDS/AML Registry in Celgene (now owned by BMS), Myeloma Registry in Takeda; stock ownership in Doximity; personal fees from VIA Oncology (now owned by Elsevier ClinicalPath), Adaptive Advisory Board, and GSK; he is the local PI for Clinical Trials in AbbVie, BMS, CRAB CTC, Denovo, Research Network, Eli Lilly, LynxBio, Strata Oncology, and TG Therapeutics, all outside the submitted work. AKV reports research funding to the institution from BMS, MedPacto, Prelude, iOnctura, and Janssen; honoraria from Acceleron and Novartis; consulting/advisory role with Stelexis and Janssen; stock or other ownership in Stelexis; and an immediate family member with employment/leadership with CereXis, all outside the submitted work. DCV reports honoraria and speakers' bureau fees from CSL Behring, Merck Canada, Novartis Canada, Takeda, and UCB Biosciences GmbH, and travel accommodations from CSL Behring, and Avir Pharma, all outside the submitted work. He is supported by the Fonds de la recherche en santé du Québec (FRQS) Clinician-Scientist Junior 2 program. JLW reports grants from the National Cancer Institute during the conduct of the study; personal fees from Westat and IBM Watson Health; and other from HemOnc.org LLC, outside the submitted work. TMW-D reports stock and other ownership interests in High Enroll; honoraria from Physicians' Education Resource; consulting or advisory roles with Shattuck Labs, Rakuten Medical, Exicure; research funding from Merck, AstraZeneca/MedImmune, Bristol-Myers Squibb, GlaxoSmithKline, Caris Life Sciences, GlaxoSmithKline; travel, accommodations, expenses from Merck, Bristol-Myers Squibb, Bexion, AstraZeneca/MedImmune, Caris Life Sciences, Lilly, and Tesaro, all outside the submitted work. EW-B reports work in a consultant/advisor role for Astellas and BMS; funding support from Pfizer Global Medical Grants; other for Exelixis; and an immediate family member with stock ownership in Immunomedics and Nektar, all outside the submitted work. TZ reports research funding (to Duke) from Pfizer, Janssen, Acerta, AbbVie, Novartis, Merrimack, OmniSeq, PGDx, Merck, Mirati, Astellas, and Regeneron; consulting/speaking role with Genentech Roche, Exelixis, Genomic Health, and Sanofi Aventis; and serves on the consulting/advisory board for AstraZeneca, Bayer, Pfizer, Foundation Medicine, Janssen, Amgen, BMS, Calithera, Dendreon, and MJH Associates; stock ownership/employment (spouse) from Capio Biosciences, Archimmune Therapeutics, and Nanorobotics. AYZ has currently or during the past 2 years owned stock or held an ownership interest in Gilead Sciences. LZ reports personal fees from MERCK, outside the submitted work. All others have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Novel approaches to address the most vexing problems facing patients and vulnerable populations are needed. The purpose of this project was to establish an innovative research Center based on the principles of transformational organizations., Methods: A new Center formed included faculty members with expertise in cancer, serious illness, and population health. Applying Sinek's "why, how, and what" framework, members developed and refined a purpose statement and strategic objectives. The Center now includes members representing diverse disciplines. Year 1 accomplishments included a refined mission and vision statement, two funded research proposals, one submitted training grant, one administrative hire, and active recruitment of two-research faculty to support Center activities., Conclusions: The newly-formed Center for Improving Patient and Population Health has enabled scholars within a research-intensive school of nursing to forge new partnerships to compete successfully for larger, complicated grant proposals on shorter deadlines. Opportunities exist to integrate students and research staff more fully into Center operations., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Communication between scientists and animal technicians is considered important for creating a 'culture of care' in facilities that use animals in scientific research. For example, the Brown report, which investigated alleged failures of animal care at Imperial College London, noted the physical and social separation between animal technicians and scientists as a problem that delimited a culture of care. This paper seeks to better understand the communicative relationships between scientists and animal technicians in this context. We conducted a survey of scientists working in the UK who use animals in their research (n = 230), asking who they spoke with about various aspects related to using animals in research. We found that scientists communicated with technicians about operational issues, while they spoke with other scientists about experimental design as well as moral questions and concerns. We probe the meaning of these communicative relationships using narrative analysis of semi-structured, qualitative interviews conducted with consenting survey respondents (n = 14). Analytically, this paper seeks to bridge social network analysis with geographies of care through a shared concern with relations of power., Competing Interests: No potential conflict of interest was reported by the authors., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Purpose: To identify modifiable and non-modifiable risk factors for peripheral intravenous catheter (PIV) failure among patients requiring intravenous treatment for oncology and haematology conditions., Methods: A single-centre prospective cohort study was conducted between October 2017 and February 2019. Adult in-patients requiring a PIV for therapy were prospectively recruited from two cancer units at a tertiary hospital in Queensland, Australia. The primary outcome was a composite of complications leading to PIV failure (local and bloodstream infection; occlusion; infiltration/extravasation; leakage; dislodgement; and/or phlebitis). Secondary outcomes were (i) PIV dwell time; (ii) insertion and (iii) failure of a CVAD; (iv) adverse events; (v) length of hospital stay. Outcomes were investigated using Bayesian multivariable linear regression modelling and survival analysis., Results: Of 200 participants, 396 PIVs were included. PIV failure incidence was 34.9%; the most common failure type was occlusion/infiltration (n = 74, 18.7%), then dislodgement (n = 33, 8.3%), and phlebitis (n = 30, 7.6%). While several patient and treatment risk factors were significant in univariable modelling, in the final multivariable model, only the use of non-sterile tape (external to the primary dressing) was significantly associated with decreased PIV dislodgement (hazard ratio 0.06, 95% confidence interval 0.01, 0.48; p = 0.008)., Conclusion: PIV failure rates among patients receiving cancer treatment are high, the sequelae of which may include delayed treatment and infection. Larger studies on risk factors and interventions to prevent PIV failure in this population are needed; however, the use of secondary securements (such as non-sterile tape) to provide further securement to the primary PIV dressing is particularly important., Trial Registration: Study methods were registered prospectively with the Australian New Zealand Clinical Trials Registry on the 27 th March 2017 (ACTRN12617000438358); https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372191&isReview=true.

This paper explores how, at the 1875 Royal Commission on Vivisection, the anaesthetised animal was construed as a boundary object around which "cooperation without consensus" (Star, in: Esterbrook (ed) Computer supported cooperative work: cooperation or conflict? Springer, London, 1993) could form, serving the interests of both scientists and animals. Advocates of anaesthesia presented it as benevolently intervening between the scientific agent and animal patient. Such articulations of 'ethical' vivisection through anaesthesia were then mandated in the 1876 Cruelty to Animals Act, and thus have had significant downstream effects on the regulation of laboratory animals in Britain and beyond. Constructing this 'consensus' around the anaesthetised animal, however, required first excluding abolitionists and inhumane scientists, and secondly limiting the interests of experimental animals to the avoidance of pain through anaesthesia and euthanasia, thereby circumventing the issue of their possible interest in future life. This consensus also served to secure the interests of vivisecting scientists and to limit the influence of public opinion in the laboratory to administrative procedure and scheduled inspection. The focus on anaesthesia was connected with discussions of what supporting infrastructures were required to ensure proper ethical procedure was carried out by scientists. In contrast to the much studied polarisation in British society between pro- and antivivisectionists after 1876, we understand the 1875 Commission as a conflict amongst scientists themselves, while also being an intra-class conflict amongst the ruling class (French in Antivivisection and medical science in Victorian society, Princeton University Press, Princeton, 1975).

Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) can induce durable complete tumor regression in patients with advanced melanoma. Efforts are currently underway to expand this treatment modality to other cancer types. In the microenvironment of ovarian cancer, the engagement of co-inhibitory immune checkpoint molecules such as CTLA-4 can lead to the inactivation of TILs. Thus, approaches that directly manipulate co-inhibitory pathways within the tumor microenvironment might improve the expansion of tumor-reactive TILs. The initial expansion of TILs for ACT from tumor fragments provides a window of opportunity to manipulate an intact tumor microenvironment and improve CD8 + T-cell output and TIL tumor reactivity. To exploit this, we used a CTLA-4-blocking antibody, added during the initial TIL culture, and found that the blockade of CTLA-4 favored the propagation of CD8 + TILs from ovarian tumor fragments. Interestingly, adding the CTLA-4 blocking antibody in the initial phase of the TIL culture resulted in more potent anti-tumor TILs in comparison to standard TIL cultures. This phenotype was preserved during the rapid expansion phase. Thus, targeting CTLA-4 within the intact tumor microenvironment of tumor fragments enriches tumor-reactive TILs and may improve clinical outcome of TIL-based ACT in ovarian cancer.

PURPOSE We aimed to evaluate the influence of irreversible image compression at varying levels on image post-processing algorithms (3D volume rendering of angiographs, computer-assisted detection of lung nodules, segmentation and volumetry of liver lesions, and automated evaluation of functional cardiac imaging) in computed tomography (CT). METHODS Uncompressed CT image data (30 angiographs of the lower limbs, 38 lung exams, 20 liver exams and 30 cardiac exams) were anonymized and subsequently compressed using the JPEG2000 algorithm with compression ratios of 8:1, 10:1, and 15:1. Volume renderings of CT angiographies obtained from compressed and uncompressed data were compared using objective and subjective measures. Computer-assisted detection of lung nodules was performed on compressed and uncompressed image data and compared with respect to diagnostic performance. Segmentation and volumetry of liver lesions as well as measurement of ejection fraction on cardiac studies was performed on compressed and uncompressed datasets; differences in measurements were analyzed. RESULTS No differences could be detected for the 3D volume renderings and no statistically significant differences in performance were found for the computer-assisted detection algorithm. Measurements in volumetry of liver lesions and functional cardiac imaging showed good to excellent reliability. CONCLUSION Irreversible image compression within the limits proposed by the European Society of Radiology has no significant influence on commonly used image post-processing algorithms in CT.

It is becoming increasingly common to hear life scientists say that high quality life science research relies upon high quality laboratory animal care. However, the idea that animal care is a crucial part of scientific knowledge production is at odds with previous social science and historical scholarship regarding laboratory animals. How are we to understand this discrepancy? To begin to address this question, this paper seeks to disentangle the values of scientists in identifying animal care as important to the production of high quality scientific research. To do this, we conducted a survey of scientists working in the United Kingdom who use animals in their research. The survey found that being British is associated with thinking that animal care is a crucial part of conducting high quality science. To understand this finding, we draw upon the concept of 'civic epistemologies' (Jasanoff 2005; Prainsack 2006) and argue that 'animals' and 'care' in Britain may converge in taken-for-granted assumptions about what constitutes good scientific knowledge. These ideas travel through things like state regulations or the editorial policies of science journals, but do not necessarily carry the embodied civic epistemology of 'animals' and 'science' from which such modes of regulating laboratory animal welfare comes., (© 2019 The Authors. The British Journal of Sociology published by John Wiley & Sons Ltd on behalf of London School of Economics and Political Science.)

PD-L1-specific T cells are a natural part of the T-cell repertoire in humans. Hence, we have previously described spontaneous CD8 + and CD4 + T-cell reactivity against PD-L1 in the peripheral blood of patients with various cancers as well as in healthy donors. It is well described that the expression of the PD-L1 protein is introduced in cells by pro-inflammatory cytokines, e.g. IFN-γ. In the current study, we were able to directly link inflammation with PD-L1-specific T cells by showing that inflammatory mediators such as IFN-γ generate measurable numbers of PD-L1-specific T cells in human PBMCs as well as in in vivo models. These PD-L1-specific T cells can vigorously modulate the cell compartments of the local environment. PD-L1-specific T cells may be important for immune homeostasis by sustaining the ongoing inflammatory response by the suppression of regulatory cell function both directly and indirectly., Competing Interests: Conflict of interest: Mads Hald Andersen has filed several patent applications based on the use of PD-L1 for vaccination. The rights of the patent applications have been transferred to Copenhagen University Hospital, Herlev, according to the Danish Law of Public Inventions at Public Research Institutions. The capital region has licensed these patents to the company IO Biotech ApS. MHA is a shareholder and board member of the IO Biotech ApS. The other authors declare “no conflict of interest”., (Copyright: © 2019 Munir et al.)

Drawing on collaborative ethnographic fieldwork, this article explores how human health becomes entangled with that of model organisms in day-to-day biomedical science. Social science scholarship on modeling has explored either how specific models impact and shape our knowledge of human disease or how animal technicians and scientists affect laboratory animals. This article extends this relational approach by asking how embodied and institutional care practices for model organisms affect the health and well-being of animal technicians and scientists. We focus on two interspecies bodily experiences: pathogenic exchange and stress. We then explore enrichment as a strategy for producing health and well-being across species. We suggest that relations of care form a crucial part of biomedical knowledge production. Not only does care figure in the shaping of model organisms; care for technicians and scientists also plays a role in bioscientific knowledge production. We conclude by proposing an interspecies approach to occupational health., (© 2019 The Authors. Medical Anthropology Quarterly published by Wiley Periodicals, Inc. on behalf of American Anthropological Association.)

Background: Solid malignancies are frequently infiltrated with T cells. The success of adoptive cell transfer (ACT) with expanded tumour-infiltrating lymphocytes (TILs) in melanoma warrants its testing in other cancer types. In this preclinical study, we investigated whether clinical-grade TILs could be manufactured from ovarian cancer (OC) tumour specimens., Methods: Thirty-four tumour specimens were obtained from 33 individual patients with OC. TILs were analysed for phenotype, antigen specificity and functionality., Results: Minimally expanded TILs (Young TILs) were successfully established from all patients. Young TILs contained a high frequency of CD3 + cells with a variable CD4/CD8 ratio. TILs could be expanded to clinical numbers. Importantly, recognition of autologous tumour cells was demonstrated in TILs in >50% of the patients. We confirmed with mass spectrometry the presentation of multiple tumour antigens, including peptides derived from the cancer-testis antigen GAGE, which could be recognised by antigen-specific TILs. Antigen-specific TILs could be isolated and further expanded in vitro., Conclusion: These findings support the hypothesis that patients with OC can benefit from ACT with TILs and led to the initiation of a pilot clinical trial at our institution ., Trial Registration: clinicaltrials.gov: NCT02482090.

Deficient expression of SATB1 hampers thymocyte development and results in inept T-cell lineages. Recent data implicate dysregulated SATB1 expression in the pathogenesis of mycosis fungoides, the most frequent variant of cutaneous T-cell lymphoma. Here, we report on a disease stage-associated decrease of SATB1 expression and an inverse expression of STAT5 and SATB1 in situ. STAT5 inhibited SATB1 expression through induction of microRNA-155. Decreased SATB1 expression triggered enhanced expression of IL-5 and IL-9 (but not IL-6 and IL-32), whereas increased SATB1 expression had the opposite effect, indicating that the microRNA-155 target SATB1 is a repressor of IL-5 and IL-9 in malignant T cells. In accordance, inhibition of STAT5 and its upstream activator JAK3 triggered increased SATB1 expression and a concomitant suppression of IL-5 and IL-9 expression in malignant T cells. In conclusion, we provide a mechanistic link between the proto-oncogenic JAK3/STAT5/microRNA-155 pathway, SATB1, and cytokines linked to CTCL severity and progression, indicating that SATB1 dysregulation is involved in cutaneous T-cell lymphoma pathogenesis., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The calreticulin (CALR) exon 9 mutations are found in ∼30% of patients with essential thrombocythemia and primary myelofibrosis. Recently, we reported spontaneous immune responses against the CALR mutations. Here, we describe that CALR-mutant (CALRmut)-specific T cells are able to specifically recognize CALRmut cells. First, we established a T-cell culture specific for a CALRmut epitope. These specific T cells were able to recognize several epitopes in the CALRmut C terminus. Next, we established a CALRmut-specific CD4 + T-cell clone by limiting dilution. These CD4 + T cells recognized autologous CALRmut monocytes and hematopoietic stem cells, and T-cell recognition of target cells was dependent on the presence of CALR. Furthermore, we showed that the CALRmut response was human leukocyte antigen (HLA)-DR restricted. Finally, we demonstrated that the CALRmut-specific CD4 + T cells, despite their phenotype, were cytotoxic to autologous CALRmut cells, and that the cytotoxicity was mediated by degranulation of the T cells. In conclusion, the CALR exon 9 mutations are targets for specific T cells and thus are promising targets for cancer immune therapy such as peptide vaccination in patients harboring CALR exon 9 mutations.

The relative contribution of the effector molecules produced by T cells to tumour rejection is unclear, but interferon-γ (IFNγ) is critical in most of the analysed models. Although IFNγ can impede tumour growth by acting directly on cancer cells, it must also act on the tumour stroma for effective rejection of large, established tumours. However, which stroma cells respond to IFNγ and by which mechanism IFNγ contributes to tumour rejection through stromal targeting have remained unknown. Here we use a model of IFNγ induction and an IFNγ-GFP fusion protein in large, vascularized tumours growing in mice that express the IFNγ receptor exclusively in defined cell types. Responsiveness to IFNγ by myeloid cells and other haematopoietic cells, including T cells or fibroblasts, was not sufficient for IFNγ-induced tumour regression, whereas responsiveness of endothelial cells to IFNγ was necessary and sufficient. Intravital microscopy revealed IFNγ-induced regression of the tumour vasculature, resulting in arrest of blood flow and subsequent collapse of tumours, similar to non-haemorrhagic necrosis in ischaemia and unlike haemorrhagic necrosis induced by tumour necrosis factor. The early events of IFNγ-induced tumour ischaemia resemble non-apoptotic blood vessel regression during development, wound healing or IFNγ-mediated, pregnancy-induced remodelling of uterine arteries. A better mechanistic understanding of how solid tumours are rejected may aid the design of more effective protocols for adoptive T-cell therapy.

Improving laboratory animal science and welfare requires both new scientific research and insights from research in the humanities and social sciences. Whilst scientific research provides evidence to replace, reduce and refine procedures involving laboratory animals (the '3Rs'), work in the humanities and social sciences can help understand the social, economic and cultural processes that enhance or impede humane ways of knowing and working with laboratory animals. However, communication across these disciplinary perspectives is currently limited, and they design research programmes, generate results, engage users, and seek to influence policy in different ways. To facilitate dialogue and future research at this interface, we convened an interdisciplinary group of 45 life scientists, social scientists, humanities scholars, non-governmental organisations and policy-makers to generate a collaborative research agenda. This drew on methods employed by other agenda-setting exercises in science policy, using a collaborative and deliberative approach for the identification of research priorities. Participants were recruited from across the community, invited to submit research questions and vote on their priorities. They then met at an interactive workshop in the UK, discussed all 136 questions submitted, and collectively defined the 30 most important issues for the group. The output is a collaborative future agenda for research in the humanities and social sciences on laboratory animal science and welfare. The questions indicate a demand for new research in the humanities and social sciences to inform emerging discussions and priorities on the governance and practice of laboratory animal research, including on issues around: international harmonisation, openness and public engagement, 'cultures of care', harm-benefit analysis and the future of the 3Rs. The process outlined below underlines the value of interdisciplinary exchange for improving communication across different research cultures and identifies ways of enhancing the effectiveness of future research at the interface between the humanities, social sciences, science and science policy.

Purpose/objectives: To examine differences in healthcare service utilization among patients with advanced cancer participating in a nurse-led psychoeducational intervention., Design: Secondary analysis of trial data., Setting: Four Michigan cancer centers., Sample: 484 patients with advanced cancer., Methods: Patients were randomized to three groups., Main Research Variables: Study arm (brief, extensive, or control), ED visitation (one or more times versus none), inpatient hospitalizations (one or more times versus none), and covariates., Findings: No significant differences in ED visits or inpatient hospitalizations were observed among study arms. ED visits were more frequent for patients with lung or colorectal cancer, more comorbidities, and lower baseline QOL. Baseline QOL was associated with inpatient hospitalizations in the adjusted analysis., Conclusions: The psychoeducational intervention, either in brief or extensive format, is unlikely to increase healthcare service utilization., Implications for Nursing: Efficacious nurse-led psychoeducational interventions to improve QOL do not place undue burdens on the healthcare system and may improve care.

Background: Abundance of commensals constituting the intestinal microbiota (IM) affects the immune system and predisposes to a variety of diseases, including intestinal infections, cancer, inflammatory and metabolic disorders. Housing conditions determine the IM and can hence influence the immune system. We analyzed how both variables affect the IM of four immune-compromized mouse lines kept under different housing conditions., Methodology/principal Findings: We investigated the IM composition in mice by quantitative 16S rRNA RT-PCR analysis of the main fecal bacterial groups (Enterobacteriaceae, enterococci, lactobacilli, bifidobacteria, Bacteroides/Prevotella (BP) spp., Clostridium leptum and coccoides groups). Mice were homozygous (HO) or heterozygous (HE) for a targeted inactivating mutation of either the IFN-γ Receptor (R), IFN-γ, Rag1 or IL-4 genes. Overall, differences in IM composition were subtle. However, in the SPF-barrier, total eubacterial loads were higher in Rag1 HE versus Rag1 HO mice as well as in IFN-γR HE versus IFN-γR HO and WT animals. Although absent in WT mice, bifidobacterial loads were higher in HO and HE IFN-γ and Rag1 as well as IL-4 HO mice. Furthermore, BP was slightly lower in HO and HE IFN-γR and IFN-γ mice as well as in IL-4 HO mice as compared to WT controls. Interestingly, IM compositions were comparable in WT mice when kept in individual ventilated cages (IVC) or open cages (OC). IFN-γ HO and HE mice, however, had higher enterobacteria and BP loads, but lacked bifidobacteria when kept in OC versus IVC, as was the case in HO and HE Rag1 mice. In addition, Rag1 HO mice harbored higher clostridial loads when housed in OC as compared to IVC. Unexpectedly, lactobacilli levels were higher in IFN-γR mice when kept in OC versus IVC., Conclusion/significance: Housing-dependent and immune-deficiency mediated changes in intestinal microbiota composition were rather subtle but may nevertheless impact immunopathology in experimental models.

Competing Interests: The authors have declared that no competing interests exist.

High-quality nursing care is not delivered consistently to the millions of Americans treated for invasive cancer in the United States. As part of its quality initiative, the Oncology Nursing Society (ONS) developed and tested nursing-sensitive quality measures for breast cancer care. Findings from the pilot testing suggested significant knowledge and practice gaps that could be addressed through member education.

Due to increasing amounts of data in radiology methods for image compression appear both economically and technically interesting. Irreversible image compression allows markedly higher reduction of data volume in comparison with reversible compression algorithms but is, however, accompanied by a certain amount of mathematical and visual loss of information. Various national and international radiological societies have published recommendations for the use of irreversible image compression. The degree of acceptable compression varies across modalities and regions of interest.The DICOM standard supports JPEG, which achieves compression through tiling, DCT/DWT and quantization. Although mathematical loss due to rounding up errors and reduction of high frequency information occurs this results in relatively low visual degradation.It is still unclear where to implement irreversible compression in the radiological workflow as only few studies analyzed the impact of irreversible compression on specialized image postprocessing. As long as this is within the limits recommended by the German Radiological Society irreversible image compression could be implemented directly at the imaging modality as it would comply with § 28 of the roentgen act (RöV).

To enhance protection from pathogens, housing conditions have been improved constantly. We wanted to test whether various environmental conditions and caging systems affect serum cytokine levels of immunodeficient mice differently than they affect immunocompetent control animals. We compared serum cytokine levels of immunodeficient and immunocompetent mice kept in three different environments: a specific pathogen free (SPF) breeding barrier with open cages. An SPF experimental unit with individually ventilated cages. An experimental semi-barrier with open cages. Serum from Rag1(-/-), μMT(-/-), IFN-γR(-/-), IFN-γ(-/-), IL-4(-/-), the heterozygous controls and wild type C57BL/6 or BALB/c mice was analyzed for the presence of 10 cytokines (IL-1α, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, IFN-γ, TNF-α and GM-CSF). No major changes in cytokine levels were detected in mice exposed to different housing conditions. However, irrespective of immunodeficiency at 4 weeks of age a number of mice from the breeding colonies with a targeted mutation (TM), both -/- and +/- mice, showed a statistically significant elevation of some cytokines (primarily IL-1α, IL-5) when compared to wild type BALB/c and C57BL/6 mice. We conclude that under SPF conditions, immunodeficient mice can be kept either in open caging or IVC systems without affecting serum cytokine levels. The more important conclusion, however, stems from the observation that there is a significant difference in serum cytokine levels between wild type and mice carrying either one or two alleles of a targeted mutation (either -/- and +/- mice). This suggests an altered base-line inflammatory responsiveness in the TM-breeding colonies., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

To study mechanisms of T cell-mediated rejection of B cell lymphomas, we developed a murine lymphoma model wherein three potential rejection antigens, human c-MYC, chicken ovalbumin (OVA), and GFP are expressed. After transfer into wild-type mice 60-70% of systemically growing lymphomas expressing all three antigens were rejected; lymphomas expressing only human c-MYC protein were not rejected. OVA expressing lymphomas were infiltrated by T cells, showed MHC class I and II upregulation, and lost antigen expression, indicating immune escape. In contrast to wild-type recipients, 80-100% of STAT1-, IFN-γ-, or IFN-γ receptor-deficient recipients died of lymphoma, indicating that host IFN-γ signaling is critical for rejection. Lymphomas arising in IFN-γ- and IFN-γ-receptor-deficient mice had invariably lost antigen expression, suggesting that poor overall survival of these recipients was due to inefficient elimination of antigen-negative lymphoma variants. Antigen-dependent eradication of lymphoma cells in wild-type animals was dependent on cross-presentation of antigen by cells of the tumor stroma. These findings provide first evidence for an important role of the tumor stroma in T cell-mediated control of hematologic neoplasias and highlight the importance of incorporating stroma-targeting strategies into future immunotherapeutic approaches.

Disrupted sleep is considered a patient outcome sensitive to oncology nursing care and can lead to a variety of physical and psychologic dysfunctions, such as insomnia, chronic pain, respiratory distress, obesity, stress, and anxiety. Although sleep disturbances have been studied in recipients of hematopoietic stem cell transplantations (HSCTs), these studies have not examined the acute phase of transplantation. The current study aimed to identify the level of sleep disturbance in this patient population, identify factors contributing to decreased ability to sleep for hospitalized recipients of HSCT, and compare the differences in sleep disturbance between age, gender, type of transplantation, and initial stem cell transplantation versus readmission for transplantation-associated complications. Among the 69 patients studied, 26% reported clinical insomnia, as measured by the Insomnia Severity Index, and 74% had some degree of insomnia. Patient characteristics were not significantly associated with insomnia scores. Patients reported bathroom use as the most frequent reason for sleep disruption (85%). These findings suggest that sleep disturbances are common in hospitalized patients undergoing HSCT, and strategies to reduce disruptions are needed to improve patient outcomes.

Transcriptional signatures are an indispensible source of correlative information on disease-related molecular alterations on a genome-wide level. Numerous candidate genes involved in disease and in factors of predictive, as well as of prognostic, value have been deduced from such molecular portraits, e.g. in cancer. However, mechanistic insights into the regulatory principles governing global transcriptional changes are lagging behind extensive compilations of deregulated genes. To identify regulators of transcriptome alterations, we used an integrated approach combining transcriptional profiling of colorectal cancer cell lines treated with inhibitors targeting the receptor tyrosine kinase (RTK)/RAS/mitogen-activated protein kinase pathway, computational prediction of regulatory elements in promoters of co-regulated genes, chromatin-based and functional cellular assays. We identified commonly co-regulated, proliferation-associated target genes that respond to the MAPK pathway. We recognized E2F and NFY transcription factor binding sites as prevalent motifs in those pathway-responsive genes and confirmed the predicted regulatory role of Y-box binding protein 1 (YBX1) by reporter gene, gel shift, and chromatin immunoprecipitation assays. We also validated the MAPK-dependent gene signature in colorectal cancers and provided evidence for the association of YBX1 with poor prognosis in colorectal cancer patients. This suggests that MEK/ERK-dependent, YBX1-regulated target genes are involved in executing malignant properties., Competing Interests: The authors have declared that no competing interests exist.

Data submitted by transplant programs to the Organ Procurement and Transplantation Network (OPTN) are used by the Scientific Registry of Transplant Recipients (SRTR) for policy development, performance evaluation and research. This study compared OPTN/SRTR data with data extracted from medical records by research coordinators from the nine-center A2ALL study. A2ALL data were collected independently of OPTN data submission (48 data elements among 785 liver transplant candidates/recipients; 12 data elements among 386 donors). At least 90% agreement occurred between OPTN/SRTR and A2ALL for 11/29 baseline recipient elements, 4/19 recipient transplant or follow-up elements and 6/12 donor elements. For the remaining recipient and donor elements, >10% of values were missing in OPTN/SRTR but present in A2ALL, confirming that missing data were largely avoidable. Other than variables required for allocation, the percentage missing varied widely by center. These findings support an expanded focus on data quality control by OPTN/SRTR for a broader variable set than those used for allocation. Center-specific monitoring of missing values could substantially improve the data.

The allelopathic potential of the Eurasian invasive plant Alliaria petiolata has been well documented, with the bulk of the effects believed to be mediated by arbuscular mycorrhizal fungi (AMF). We exposed the herbaceous annual Impatiens pallida, which is native to North America, to fractionated A. petiolata extracts at four developmental stages (germination, presymbiosis growth, symbiosis formation, and symbiosis growth) by using exposure levels expected to be similar to field levels. Surprisingly, we found strong direct effects on I. pallida germination and growth, but no indirect effects on I. pallida growth mediated by AMF. We also observed strong synergistic effects with a complete A. petiolata extract that inhibited I. pallida germination and presymbiosis root growth more than either a glucosinolate or flavonoid enriched fraction alone. In fact, the flavonoid enriched fraction tended to stimulate germination and presymbiosis root growth. In contrast to these strong direct effects, I. pallida plant growth during both the symbiosis formation and symbiosis growth phases was unaffected by A. petiolata extracts. We also found no inhibition of AMF colonization of roots or soils by A. petiolata extracts. We show that AMF can actually ameliorate allelopathic effects of an invasive plant, and suggest that previously observed allelopathic effects of A. petiolata may be due to direct inhibition of plant and fungal growth before symbiosis formation.

Chemotherapy-induced neutropenia (CIN) is a common and serious toxicity of cancer chemotherapy. It can lead to febrile neutropenia (FN), which often requires patients to be hospitalised for intravenous antibiotic therapy. Chemotherapy dose reductions or delays, which can compromise clinical outcomes, may also result from CIN and FN. Prophylactic use of colony-stimulating factors (CSFs) reduces the incidence, duration, and severity of FN, and there is evidence that it helps maintain scheduled chemotherapy dose delivery. In 2006, three organisations published new or updated guidelines for the use of CSFs in cancer treatment. Each recommends that FN risk be determined individually for each patient, taking into account patient- and disease-specific risk factors, the chemotherapy regimen, and treatment intent. Particular consideration should be given to patients who are > or =65 years old, receiving chemotherapy regimens associated with > or =20% risk of FN, receiving dose-dense chemotherapy, and receiving treatment that is adjuvant, potentially curative, or intended to prolong survival. Accordingly, oncology nurses can play an important role in assessing and identifying patients at risk for FN before every chemotherapy cycle. There is evidence that, regardless of practice type or size, implementing guidelines for CSF use within a multidisciplinary team improves patient outcomes.

Midlife, once a focus of particular interest to gerontologists because of its implications for later life, has recently received little attention. But as new reproductive technologies have expanded in the United States, motherhood is occurring at older ages. While older motherhood is not a new social practice, what is unique is that an increasing number of women are becoming pregnant through technological means, often for the first time, at the end of their reproductive cycle. These women can be understood as part of a new middle age, engaging in new life course possibilities that respond to changing social, cultural, physical, and economic realities, and potentially extending much later in the life course. Drawing on interviews with 79 couples, we utilize symbolic interactionist conceptualizations of identity and stigma to consider how women negotiate the shifting social identities associated with older motherhood. We conclude that older motherhood will be one phenomenon contributing to an enduring change in views of what constitutes old age, and that it will be seen as occurring much later in the life course.

Over the past generation, aging and female reproduction have been lodged within the gendered and gendering debates regarding women's involvement in the workforce and demographic shifts toward delayed parenting that culminate in discourses on the "biological clock". Technological solutions to the biological clock, specifically in vitro fertilization, have led to clinical attempts to assess "ovarian reserve", or qualitative and quantitative changes in the ovary that correlate with aging and with successful infertility treatment. Rupturing the longstanding historical connections between menstruation and female reproductive capacity by specifically focusing on the aging of a woman's eggs, the clinical designation of "diminished ovarian reserve" has come to imply that a woman has "old eggs". This is associated in practitioners' and patients' minds with the eclipse of a woman's reproductive potential and with hidden harbingers of menopause. In an ethnographic interview study of 79 couples in the US who conceived after using donor oocytes, we found that women voiced two different narratives that described their experience and attitudes when confronted with an apparent age-related decline in their fertility. The "eleventh-hour mom" narrative was voiced by women who initially tried to become pregnant with their own eggs and turned to donated oocytes as a second-choice option, whereas the "miracle mom" narrative was expressed by women who were generally older, some of whom had entered infertility treatment hoping to conceive with their own eggs, but some who knew from the outset that it was not going to be possible. Through their narratives women not only embodied and made meaningful "diminished ovarian reserve" in varying ways that connect with cultural, social, structural/organizational, symbolic and physical aspects of aging, they reproduced the socio-biological project of the biological clock, but rooted this social project in the metaphor of "old eggs" rather than menopause.

Objective: To ascertain what couples think about their embryos and how they approach making a decision about disposition in light of the fact that the disposition of unused frozen embryos has significant implications for medical research and embryo donation., Design: Ethnographic qualitative interview study., Setting: Academic research environment., Patient(s): Fifty-eight couples who had conceived using a donor oocyte and had at least one frozen embryo in storage., Main Outcome Measure(s): Tape-recorded interviews with 58 wives and 37 husbands were transcribed and analyzed for emergent themes., Result(s): With an average of 7.1 embryos per couple, after an average of 4.2 years of storage, 72% of couples with frozen embryos had not reached a disposition decision. Most couples had not anticipated or appreciated the consequences of having surplus embryos. Parents variously conceptualized frozen embryos as biologic tissue, living entities, "virtual" children having interests that must be considered and protected, siblings of their living children, genetic or psychological "insurance policies," and symbolic reminders of their past infertility., Conclusion(s): The disposition decision is not only a significant and frequently unresolved issue for couples with stored frozen embryos, but their deeply personal conceptualizations of their embryos contributes to their ambivalence, uncertainty, and difficulty in reaching a decision.

A nursing council modeled after the traditional five nursing roles--manager, educator, practitioner, evaluator and researcher--improves patient outcomes and enhances nurse work satisfaction. The council provides a participative forum to address nursing and patient-care issues within a decentralized matrix organization.

Renal transplantation using infant donors is associated with significantly less graft survival (GS) and increased morbidity, especially from very young and small donors. We report our results using specific strategies to determine which age and size donor require en bloc renal transplant reconstruction and associated immunologic protocols for optimization of subsequent GS. Forty cadaveric pediatric en bloc renal transplants were performed. Mean donor age was 23.6+/-18.4 months with subgroups: 2-12 months, n=14; 13-24 months, n=19; and 25-60 months, n=7. Mean donor weight was 14.4+/-4.5 kg. All kidneys were placed in primary, nonsensitized (peak PRA = 7.9+/-5.6%) adult (41.6+/-16 years) recipients. Low weight was preferred (62.4+/-12.8 kg). Mean cold ischemia time was 26.9+/-8.6 hr. Immunosuppression consisted of quadruple immunosuppression (QI) with OKT3 induction. All patients had ureteral stents placed intraoperatively. Mean follow-up was 16.9 months. Actuarial GS at 12, 24, and 33 months were 100% (n=13), 85% (n=20), and 71% (n=7), respectively. Total GS was 35/40=88%. All grafts functioned immediately and there were no technical losses. Biopsy proven rejections occurred in 12 (30%) patients, developing at 16-167 days postoperatively (mean = 50.3 days). Mean serum creatinine at one week and 1, 6, 12, and 18 months were 2.1+/-2.0, 1.5+/-0.8, 1.3+/-0.5, 1.1+/-0.4, and 0.9+/-0.4 mg/dl, respectively. Functional isotopic renography, as well as sonographic monitoring reflected rapid initial and continued growth in these kidneys. Mean BP at 12 and 24 months postoperatively were 145/83+/-18/13 and 122/76+/-20/10 mmHg, respectively, with no significant proteinuria noted. Excellent results with minimal complications utilizing very small and young infant donors can be achieved with QI immunosuppression, and selection of low immune reactive and noncomplicated adult recipients. Additionally, maximal renal dosing by minimizing recipient weight may prevent future hyperfiltration damage.

As of March 1992, 83 percent of America's more than 2.2 million licensed registered nurses (RNs) were actively employed in nursing. RNs are the largest group of U.S. health care professionals and constitute a major part of the infrastructure necessary to any health care reform agenda. Therefore, it is critical to assess the extent to which the current nurse workforce is adequately prepared for its future role in a reformed health care system. Two central trends in the composition of the nurse workforce are noteworthy. First, while the number of RNs is large and continues to grow, cyclical, demand-driven shortages have occurred nationally since World War II. Further, hospital cost containment strategies periodically depress nurses' relative wages, contributing to the substitution of RNs for other workers. Second, there is concern in nursing, as in medicine, that the RN workforce is not optimally trained to meet future needs. While two-year associate degree programs now produce a majority of nursing graduates, the greatest need is for advanced practice nurses. Demand for such nurses is high and is expected to increase as more of the population gains access to health care services. The incentives put forth in the health care reform debate--expanded health insurance coverage, integrated health care delivery systems, and cost-effective practice--create the potential for expanded roles and increased job opportunities for nurses. Realizing this potential will depend largely on the profession's responsiveness to the changes confronting it under health care reform.

Cryphonectria parasitica is a unique fungus which can serve as a model for understanding transfer of genes between eukaryotic microorganisms. We studied transfer of double-stranded RNA (dsRNA) between compatible and incompatible strains of C. parasitica to determine whether hyphal types or temperature could restrict that exchange. Hyphal connections between incompatible strains occurred at about 30% of the frequency of connections between compatible strains and differed morphologically. Gel electrophoresis and in situ hybridization confirmed that dsRNA was transferred through substrate hyphae but not through aerial hyphae. Freezing temperatures resulted in the loss of dsRNA from the new mycelium of the donor colony and stimulated the production of virulent pycnidiospores. These temperature and structural restrictions may help to explain the lack of spread of the dsRNA despite its presence in the field.

Successful clinical double-lung transplantation after 5 1/2 hours of pulmonary ischemia is reported. Static hypothermic preservation with a high-volume, high flow rate-modified Collin's solution pulmonary artery flush was used. Excellent early and late pulmonary function demonstrates the efficacy of the technique that is described in detail. Lung transplantation remains limited by the lack of reliable methods of long-term storage of donor organs, but refinement of current techniques may soon allow its wider application.