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Background: Marijuana smoke contains some of the same toxicants present in tobacco smoke. Marijuana smoking is prevalent among HIV+ individuals, but few studies have characterized smoke-related toxicants or associated health outcomes in exclusive marijuana users. Methods: This longitudinal study included 245 participants over age 40 (76% HIV+). 33 plasma and 28 urine metabolites of nicotine, ∆-9-trans-tetrahydrocannabinol, polycyclic aromatic hydrocarbons, and volatile organic compounds were assayed by liquid or gas chromatography/mass spectrometry. Exposures and health outcomes were assessed from surveys and medical records. Findings: At baseline, 18% of participants were marijuana-only smokers, 20% tobacco-only smokers, and 24% dual marijuana-tobacco smokers (median (IQR) age 53 (47–60) years, 78% male, 54% white race). Marijuana smoking was independently associated with elevated plasma naphthalenes, 2-hydroxyfluorene sulfate, 4-vinylphenol sulfate, and o-cresol sulfate (p

Backgound: The potential of a single progenitor cell to establish and maintain long-term protective T-cell immunity in humans is unknown. For genetic disorders disabling T-cell immunity, somatic reversion was shown to support limited T-cell development attenuating the clinical phenotype. However, the cases reported so far deteriorated over time leaving unanswered the important question of long-term activity of revertant precursors and the robustness of the resulting T-cell system. Methods: We applied TCRβ-CDR3 sequencing and mass cytometry on serial samples of a now 18 year-old SCIDX1 patient with somatic reversion to analyse the longitudinal diversification and stability of a T-cell system emerging from somatic gene rescue. Findings: We detected close to 105 individual CDR3β sequences in the patient. Blood samples of equal size contained about 10-fold fewer unique CDR3β sequences compared to healthy donors, indicating a surprisingly broad repertoire. Despite dramatic expansions and contractions of individual clonotypes representing up to 30% of the repertoire, stable diversity indices revealed that these transient clonal distortions did not cause long-term repertoire imbalance. Phenotypically, the T-cell system did not show evidence for progressive exhaustion. Combined with immunoglobulin substitution, the limited T-cell system in this patient supported an unremarkable clinical course over 18 years. Interpretation: Genetic correction in the appropriate cell type, in our patient most likely in a T-cell biased self-renewing hematopoietic progenitor, can yield a diverse T-cell system that provides long-term repertoire stability, does not show evidence for progressive exhaustion and is capable of providing protective and regulated T-cell immunity for at least two decades. Funding: DFG EH 145/9-1, DFG SCHW 432/4-1 and the German Research Foundation under Germany's Excellence Strategy–EXC-2189–Project ID: 390939984.

Summary: Background: Lung disease is a common comorbidity in people with HIV/AIDS, independent of smoking status. The effects of marijuana smoking on risk of lung disease in HIV-infected individuals are unclear. Methods: In this prospective cohort study, we quantified lung disease risk among men enrolled in the Multicenter AIDS Cohort Study (MACS), a long-term observational cohort of HIV-infected and uninfected men who have sex with men. Eligible participants were aged ≥30 years with self-reported marijuana and tobacco smoking data from biannual study visits between 1996 and 2014. Pulmonary diagnoses were obtained from self-report and medical records. Analyses were performed using Cox models and Generalized Estimating Equations adjusted for tobacco smoking, CD4 T cell count, and other risk factors. Findings: 1630 incident pulmonary diagnoses were reported among 1352 HIV-seropositive and 1352 HIV-seronegative eligible participants matched for race and baseline age (53,794 total person-visits, median follow-up 10.5 years). 27% of HIV-infected participants reported daily or weekly marijuana smoking for one or more years in follow-up, compared to 18% of uninfected participants (median 4·0 and 4·5 years daily/weekly use, respectively). HIV-infected participants had an increased likelihood of infectious or non-infectious pulmonary diagnoses compared to uninfected participants (33·2% vs. 21·5%, and 20·6% vs. 17·2%, respectively). Among HIV-infected participants, recent marijuana smoking was associated with increased risk of infectious pulmonary diagnoses and chronic bronchitis independent of tobacco smoking and other risk factors for lung disease (hazard ratio [95% confidence interval] 1·43 [1·09–1·86], and 1·54 [1·11–2·13], respectively); these risks were additive in participants smoking both substances. There was no association between marijuana smoking and pulmonary diagnoses in HIV-uninfected participants. Interpretation: In this longitudinal study, long-term marijuana smoking was associated with lung disease independent of tobacco smoking and other risk factors in HIV-infected individuals. These findings could be used to reduce modifiable risks of lung disease in high-risk populations. Funding: U.S. National Institutes of Health.

Insects are widely disliked by the public, despite the fact that they provide valuable ecosystem services and are vital components of ecosystems. Public support toward wildlife conservation is influenced by attitudes toward different taxa, thus, the widespread negativity toward insects shown by the general public almost certainly detracts from conservation efforts for them. Negative attitudes toward insects and other invertebrates take many forms, one of which is the feeling of disgust. Disgust has been widely researched and is typically divided into distinct domains (e.g., moral disgust). In order to determine whether insect-specific disgust is unique from other domains of disgust, we conducted a survey of 704 incoming freshmen at a major Midwestern university with questions pertaining to Moral, Pathogen, and Insect-specific Disgust. Factor analyses indicate that Insect Disgust and Pathogen Disgust are part of the same construct, unique from Moral Disgust. Our results suggest that survey respondents perceived insects in the same way as they would pathogens, at least in regard to disgust. This research provides insight into how the public views insects, and will facilitate educational interventions aimed at challenging negative attitudes toward insects. The Insect Disgust Scale will be a useful measure of insect-related disgust in future studies. Keywords: Insects, Disgust, Survey, Invertebrate conservation

Background: Oral cancer medications offer advantages but also pose challenges for therapy management and adherence. An eHealth-based platform such as CANKADO can help to support therapy management by probing the patient's quality of life (QoL) continuously throughout the course of treatment., Material and Methods: AGO-B WSG PreCycle (NCT03220178) is a multicenter, randomized phase IV intergroup trial evaluating the impact of eHealth-based Patient-Reported Outcome (ePRO) assessment on QoL in patients with hormone receptor-positive (HR + )/HER2-negative (HER2-) advanced breast cancer treated with palbociclib and endocrine therapy. Patients were randomized (2:1) to CANKADO-active arm (supported by CANKADO PRO-React) or CANKADO-inform arm (drug intake documentation only) This exploratory analysis reports the impact of CANKADO PRO-React on safety. Time to first serious adverse event (SAE) was estimated taking competing risks into account., Results: While distributions of adverse events (AEs) were similar by arm overall, patients in the CANKADO-active arm had a favorable hazard ratio of 0.67 (95%CI 0.46-0.97; p = 0.04) for time to first SAE and were significantly less likely overall to suffer an SAE than patients in the inform arm. At 24 months, 22.9% [17.9%-27.8%] of patients in CANKADO-active had suffered an SAE vs. 30.3% [22.6%-38.0%] in CANKADO-inform. AE-related dose reductions affected approximately 20% of patients (CANKADO-active: 18.2%, CANKADO-inform: 21.1%)., Conclusion: Exploratory safety analysis of PreCycle demonstrates for the first time in a randomized prospective trial that interactive autonomous eHealth-based support has a substantial favorable impact on the risk of SAEs and mitigates their severity for patients with advanced HR+/HER2- breast cancer on oral tumor therapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [NH reported support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.) from palleos healthcare; consulting fees from Gilead, Pfizer, Sanofi, Sandoz, Roche, Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, EPG Communication, Lilly, MSD, Pierre Fabre, Roche, Seagen, Viatris, Daiichi Sankyo, Gilead, MEDSCAPE, Novartis, Pfizer, Sanofi, Springer, Zuelligpharma; and co-director position at WSG – West German Study Group. REK reported consulting fees to an immediate family member from Roche/Genentech, Novartis, BMS, Pfizer, Lilly, Sandoz, Daiichi Sankyo, Agendia, AstraZeneca, Merck Sharp & Dohne, Ondonate Therapeutics, Sattle Genetics, and palleos healthcare; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events to an immediate family member from Roche, Novartis, BMS, Amgen, Pfizer, Genomic Health, and NanoString Technologies. TS reported stock or stock options from CANKADO GmbH; other financial or non-financial interests from CANKADO GmbH. RW reported consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events as well as support for attending meetings and/or travel from Agendia, Aristo, BMS, Daiichi Sankyo, Exact Sciences, Glaxo Smith Kline, Lilly, MSD, Mylan, Novartis, Paxman, Pfizer, PINK, Sandoz/Hexal, Riemser, Seattle Genetics/Seagen, Tesaro Bio, Veracyte, Amgen, AstraZeneca, Clovis Oncology, Eisai, Gilead, Hexal, Medstrom Medical, Mundipharma, Nanostring, Ondonate, palleos healthcare, Perre Fabre, PumyBiotechnology, Roche, Sanofi Genzyme, Stemline, Teva, Viatris; other financial or non-financial interests from FOMF, Pomme Med, MCI, Aurikamed, medconcept and Breast Center, Department of Obstetrics and Gynecology and Comprehensive Center (CCC) Munich, LMU University Hospital, Munich Germany. DL reported consulting fees from AstraZeneca, Novartis, Daiichi Sankyo, Amgen, Loreal, High5md, Eli Lilly, Pfizer, Gilead, GSK, Onkowissen; honoraria from Astra Zeneca, Novartis, Daiichi Sankyo, Amgen, Loreal, High5md, Eli Lilly, Pfizer, Gilead, GSK, Onkowissen; payment for expert testimony from AstraZeneca, Novartis, Daiichi Sankyo, Amgen, Loreal, High5md, Eli Lilly, Pfizer, Gilead, GSK, Onkowissen; support for attending meetings and/or travel from AstraZeneca, Novartis, Daiichi Sankyo, Amgen, Loreal, High5md, Eli Lilly, Pfizer, Gilead, GSK, Onkowissen; Board or Advisory Board from AstraZeneca, Novartis, Daiichi Sankyo, Amgen, Loreal, High5md, Eli Lilly, Pfizer, Gilead, GSK, Onkowissen; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Deutsche Stiftung für junge Erwachsene mit Krebs. OH reported consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events as well as support for attending meetings and/or travel, and participation on a Data Safety Monitoring Board or Advisory Board from Roche, MSD, Gilead, Novartis, Lilly, Pfizer, AstraZeneca, Daiichi Sankyo, Seagen, Amgen, Eisai; from Roche, MSD, Gilead, Novartis, Lilly, Pfizer, AstraZeneca, Daiichi Sankyo, Seagen, Amgen, Eisai. TDecker reported personal fees from Adboards, Novartis and iOMEDICO. MR reported consulting fees from Roche, Daiichi Sankyo, Somatex; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, AstraZeneca, Novartis, Daiichi Sankyo, Gilead, Somatex, Pfizer, Lilly; support for attending meetings and/or travel from Novartis, Pfizer, Gilead and Astra Zeneca. PS reported honoraria from Abbvie, Amgen, AstraZeneca, BMS, MSD Oncology, Pfizer, Merck Serono, Roche, Novartis; consulting or advisory role from Abbvie, Amgen, AstraZeneca, BMS; speakers' bureau from Abbvie, Amgen, AstraZeneca, BMS, Roche, Pfizer; research funding from Abbvie, BMS, Novartis, Roche; travel, accommodations, expenses from Abbvie, AstraZeneca; other from Abbvie, Amgen, BMS, Eisai, Incyte, Ipsen, Gilead Sciences, AstraZeneca, Janssen Oncology, Lilly Medical, Merck Serono, MSD Oncology, Pfizer, Roche, Novartis, Takeda. OG reported consulting fees from Daiichi Sankyo, BMS, Genomic Health/Exact Sciences, Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Pierre Fabre, Gilead, Molecular Health; honoraria from Genomic Health/Exact Sciences, Eisai, Roche, BMS, Pfizer, Novartis, NanoString Technologies, Agendia, AstraZeneca; travel support from Roche, Daiichi Sankyo, all outside of the submitted work; co-director position at West German Study Group (WSG). PAF reported personal fees for advisory board from Agendia, AstraZeneca, Daiichi Sankyo, Eisai, Hexal, Lilly, Merck, Sharp&Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi Aventis, Seagen; personal fees for invited speaker from AstraZeneca, Daiichi Sankyo, Eisai, Gilead, Lilly, Merck, Sharp&Dohme, Novartis, Seagen; personal fees for medical writing support from Roche; non-financial support to the Institution from BioNTech, Cepheid; non-financial interests: member for Arbeitsgemeinschaft für Gynäkologische Onkologie, ASCO, Deutsche Gesellschaft für Senologie, Translational Research in Oncology. MS reported grants or contracts paid to the Institution from from AstraZeneca, BioNTech, Eisai, German Breast Group, Genentech, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche; consulting fees from AstraZeneca, BioNTech, Eisai, Daiichi Sankyo, Lilly, MSD, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche, Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Novartis, Pfizer, Roche, Seagen; support for attending meetings and/or travel from Pfizer, Roche; patents planned, issued or pending EP 2951317 B1, EP 2390370 B1; participation on a Data Safety Monitoring Board or Advisory Board from AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, Lilly, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche and Seagen. All other authors have declared no conflicts of interest.]., (Copyright © 2023. Published by Elsevier Ltd.)

Purpose: This phase II study evaluated the impact of adding ribociclib to maintenance endocrine therapy (ET) treatment of physicians' choice following the first palliative chemotherapy in pre- and post-menopausal women with hormone receptor positive (HR+)/human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (mBC)., Patients and Methods: The initial randomized study design was later amended into a single-arm study, and all subsequent patients received ribociclib and ET. The primary end point was locally assessed progression-free survival (PFS). Secondary end points included overall survival (OS), clinical benefit rate (CBR), safety, compliance, and quality of life (QoL)., Results: A total of 43 patients received ribociclib + ET and 10 patients received ET only. Median PFS was 12.4 months [95% CI 8.7-24.4] for patients who received ribociclib + ET and 4.75 months [95% CI 1.0-10.3] for those who received ET only. Median OS was not reached for patients who received ribociclib + ET, and 28 (65.1%) patients experienced clinical benefit [95% CI 49.1-79.0]. For patients who received ribociclib + ET, grade 3-4 hematological adverse events (AEs) occurred in 25 (58.1%) patients, and grade 3-4 non-hematological AEs occurred in 17 (39.5%) patients. During the study, 15 patients died - 14 of whom due to tumor-related reasons, and one patient due to pneumonia, which was not treatment-related., Conclusion: The results of the AMICA study show a promising efficacy and safety of maintenance treatment with ribociclib added to ET after at least stable disease following the first metastatic chemotherapy in patients with HR+/HER2-mBC., Trial Registration: Anti-hormonal Therapy With Ribociclib in HR-positive/HER2- Negative Metastatic Breast Cancer (AMICA), NCT03555877, https://clinicaltrials.gov/ct2/show/NCT03555877., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. T. Decker reports ad boards from Lilly, Novartis, and IOMEDICO. K. Luedtke-Heckenkamp reports personal fees from AstraZeneca, Gilead, Novartis, and Pfizer. She is on the advisory board of Daiichi Sankyo, Lilly, and Roche. K. Lübbe is on the advisory board of Genomic Health, Roche, Daiichy Sankyo, Lilly, MSD, EISAI, Seagen, and Novartis, and has received lecture fees from Novartis, AstraZeneca, Genomic Health, Roche, and Lilly. M. Schmidt reports personal fees from AstraZeneca, personal fees from BioNTech, personal fees from Daiichi Sankyo, personal fees from Eisai, personal fees from Lilly, personal fees from MSD, personal fees from Novartis, personal fees from Pfizer, personal fees from Pierre-Fabre, personal fees from Roche, and personal fees from SeaGen outside the submitted work; in addition, M. Schmidt has a patent for EP 2390370 B1: A method for predicting the response of a tumor in a patient suffering from or at risk of developing recurrent gynecologic cancer towards a chemotherapeutic agent issued and a patent for EP 2951317 B1: A method for predicting the benefit from inclusion of a taxane in a chemotherapy regimen in patients with breast cancer issued. C. Denkert reports grants from European Commission H2020, grants from German Cancer Aid Translational Oncology, grants from German Breast Group; personal fees from Novartis, Roche, MSD Oncology, Daiichi Sankyo, AstraZeneca, Lilly, Molecular Health, Merck, grants from Myriad to his institution, other from Sividon diagnostics (cofounder and former shareholder until 2016); In addition, C. Denkert has a patent VMScope digital pathology software with royalties paid, a patent WO2020109570A1 - cancer immunotherapy pending, and a patent WO2015114146A1 and WO2010076322A1- therapy response issued. V. Müller received speaker honoraria from Amgen, Astra Zeneca, Daiichi-Sankyo, Eisai, GSK, Pfizer, MSD, Medac, Novartis, Roche, Teva, Seagen, Onkowissen, high5 Oncology, Medscape, Gilead, and Pierre Fabre; consultancy honoraria from Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Sanofi, Seagen, and Gilead; institutional research support from Novartis, Roche, Seagen, and Genentech; and travel grants from Roche, Pfizer, Daiichi Sankyo, and Gilead. M. Thill is on the advisory boards of Agendia, Amgen, AstraZeneca, Aurikamed, Becton/Dickinson, Biom‘Up, ClearCut, Clovis, Daiichi Sankyo, Eisai, Exact Sciences, Gilead Science, Grünenthal, GSK, Lilly, MSD, Norgine, Neodynamics, Novartis, Onkowissen, Organon, Pfizer, pfm Medical, Pierre-Fabre, Roche, RTI Surgical, Seagen, Sirius Pintuition, and Sysmex. He has received support from Amgen, AstraZeneca, Celgene, ClearCut, Clovis, Daiichi Sanyko, Hexal, Neodynamics, Novartis, Pfizer, pfm medical, Roche, Servier, and Sirius Medical. He reports travels expenses from Amgen, Art Tempi, AstraZeneca, Clearcut, Clovis, Connect Medica, Daiichi Sankyo, Eisai, Exact Sciences, Hexal, I-Med-Institute, Lilly, MCI, Medtronic, MSD, Neodynamics, Norgine, Novartis, Pfizer, pfm Medical, Roche, RTI Surgical, and Seagen. He has received honoraria and funding from Amgen, Art Tempi, AstraZeneca, Biom’Up, Celgene, Clearcut, Clovis, Connect Medica, Eisai, Endomag, Exact Sciences, Gedeon Richter, Gilead Science, GSK, Hexal, I-Med-Institute, Jörg Eickeler, Laborarztpraxis Walther et al., Lilly, MCI, Medscape, MSD, Medtronic, Neodynamics, Novartis, Onkowissen, Pfizer, pfm medical, Roche, RTI Surgical, Seagen, StreamedUp, Sysmex, Vifor, and Viatris. N. Hirmas and N. Filmann declare to be GBG Forschungs GmbH employees. GBG Forschungs GmbH received funding for research grants from Abbvie, AstraZeneca, BMS, Daiichi-Sankyo, Gilead, Novartis, Pfizer, and Roche (paid to the institution); other (non-financial/medical writing) from Daiichi-Sankyo, Gilead, Novartis, Pfizer, Roche and Seagen (paid to the institution). GBG Forschungs GmbH has following royalties/patents: EP14153692.0, EP21152186.9, EP15702464.7, EP19808852.8 and VM Scope GmbH. S. Loibl reports grants or contracts paid to institute from Abbvie, AstraZeneca, DSI, Celgene, Gilead, Novartis, Pfizer, Roche, Molecular H; in addition, S. Loibl has royalties or licenses for Digital Ki67 Evaluator from VM Scope GmbH that were paid to institute; in addition, S. Loibl receives honorary for lectures paid to the institute from AstraZeneca, DSI, Gilead, Novartis, Pfizer, and Roche; non-financial for Medical Writing from DSI, Gilead, Novartis, Pfizer, Roche, and Seagen; in addition, S. Loibl has patent for EP14153692.0, EP21152186.9, EP15702464.7 and EP19808852.8, all patents via institute; in addition, S. Loibl declares participation on a Data Safety Monitoring Board or Advisory Board from Abbvie, Amgen, AstraZeneca, BMS, Celgene, DSI, Eirgenix, Eisai Europe, GSK, Gilead, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Relay Therapeutics, Roche, Sanofi, and Seagen, all paid to institute., (Copyright © 2023. Published by Elsevier Ltd.)

Background: The multicenter, randomized, phase IV, intergroup AGO-B WSG PreCycle trial (NCT03220178) evaluated the impact of CANKADO-based electronic patient-reported outcome (ePRO) assessment on quality of life (QoL) in hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer (MBC) patients receiving palbociclib and an aromatase inhibitor or palbociclib + fulvestrant. CANKADO PRO-React, a European Union-registered medical device, is an interactive autonomous application reacting to patient self-reported observations., Patients and Methods: Between 2017 and 2021, 499 patients (median age 59 years) from 71 centers were randomized (2 : 1, stratified by therapy line) between an active version of CANKADO PRO-React (CANKADO-active arm) and a version with limited functionality (CANKADO-inform arm). A total of 412 patients (271 CANKADO-active; 141 CANKADO-inform) were available for analysis of the primary endpoint, time to deterioration (TTD) of QoL [10-point drop on the Functional Assessment of Cancer Therapy-General (FACT-G) score], using an Aalen-Johansen estimator for cumulative incidence function of TTD DQoL (QoL deterioration) with 95% pointwise confidence intervals (CIs). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and DQoL., Results: In all patients [intention-to-treat (ITT)-ePRO], cumulative incidence of DQoL was significantly more favorable (lower) in the CANKADO-active arm (hazard ratio 0.698, 95% CI 0.506-0.963). Among first-line patients (n = 295), the corresponding hazard ratio was 0.716 (0.484-1.060; P = 0.09), and in second-line patients (n = 117) it was 0.661 (0.374-1.168; P = 0.2). Absolute patient numbers declined in later visits; FACT-G completion rates were 80% and higher until about visit 30. Mean FACT-G scores showed a steady decline from baseline and an offset in favor of CANKADO-active. No significant differences in clinical outcome were observed between arms: median PFS (ITT population) was 21.4 (95% CI 19.4-23.7) (CANKADO-active) and 18.7 (15.1-23.5) months (CANKADO-inform); median OS was not reached (CANKADO-active) and 42.6 months (CANKADO-inform)., Conclusions: PreCycle is the first multicenter randomized eHealth trial demonstrating a significant benefit for MBC patients receiving oral tumor therapy when using an interactive autonomous patient empowerment application., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Obesity and the presence of circulating tumor cells (CTCs) before and/or after chemotherapy are associated with poor outcome in breast cancer (BC) patients. The activation of oncogenic pathways in fatty tissue leads to cell proliferation, suggesting a possible link between obesity and CTCs., Materials and Methods: In the phase III SUCCESS A trial, 3754 patients with early BC were randomized to 3 cycles of fluorouracil, epirubicin and cyclophosphamide followed by 3 cycles of docetaxel with or without gemcitabine. Data of 1088 patients with CTC assessments (CellSearch-System; Menarini Silicon Biosystems, Italy) and body mass index (BMI) measurements both before and after chemotherapy were available. Patients were classified according to the WHO's international definitions as underweight, normal weight, overweight, or obese, and according to their weight-change during chemotherapy into a weight-loss group (> 5% decrease), stable-weight group (≤ 5% weight-change) or weight-gain group (>5% increase). Associations between CTC positivity and, BMI or weight-change group were analyzed using frequency-table methods., Results: At study entry, 47.4% patients were underweight or normal weight, 33.6% were overweight and 18.9% were obese. Before and after chemotherapy, CTCs were detected in 20.1% and 22.6% of patients, respectively. There was no association between CTC positivity and BMI before (P = 0.104) or after (P = 0.051) chemotherapy. Furthermore, there was no association between weight-change group and CTC status before/after chemotherapy (P = 0.332)., Conclusions: According to our analysis, the risk factors obesity and prevalence of CTCs are not associated and may represent independent prognostic factors., Competing Interests: Disclosure TWP: Personal fees from Lilly and Novartis. FS: Grants from AstraZeneca, Roche and Karyopharm. Personal fees from Roche, Pfizer, Novartis, AstraZeneca, GSK, MSD, Clovis and Eisai. TF: Personal fees from Medconcept, Onkowissen. KP: Grants from: EU/IMI CANCER-ID EFPIA, Personal fees from: BMS, Agena, Menarini, Novartis, Sanofi, Illumina, Abcam, MSD, Boehringer Ingelheim, Eppendorf and Hummingbird. AS: Grants from Celgene, Roche and AbbVie. Personal fees from Celgene, Roche, Pfizer, AstraZeneca, Novartis, MSD, Tesaro, Lilly, Seagen, Gilead, GSK, Bayer, Amgen and Pierre Fabre. HT: Personal fees from Novartis, Roche, GSK, Seagan, Pfizer, Lilly, Astra Zeneca, Daiichi, Exact Science, Vifor and Seagan. Shares/stocks from CHOP GmbH, VISION MED GmbH, Care and Coach GmbH, Onco Medical Consult GmbH. VA-F: Honoraria from Novartis. PF: Grants from Pfizer, Cepheid and Biontech. Personal fees from Novartis Daiichi-Sankyo, Pfizer Astra Zeneca, Eisai, Merck Sharp & Dohme, Lilly, Pierre Fabre, SeaGen, Roche, Agendia, Sanofi Aventis, Gilead, Mylan and Menarini., WJ: honoraria from Sanofi-Aventis, Novartis and Pfizer. BR: honoraria from AstraZeneca, Chugai, Lilly, Novartis, Sanofi-Aventis, and Jannssen-Cilag. All other authors have no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Recent self-report and behavioral studies have demonstrated that pubertal testosterone is related to an increase in risky and impulsive behavior. Yet, the mechanisms underlying such a relationship are poorly understood. Findings from both human and rodent studies point towards distinct striatal pathways including the ventral and dorsal striatum as key target regions for pubertal hormones. In this study we investigated task-related impatience of boys between 10 and 15 years of age (N = 75), using an intertemporal choice task combined with measures of functional magnetic resonance imaging and hormonal assessment. Increased levels of testosterone were associated with a greater response bias towards choosing the smaller sooner option. Furthermore, our results show that testosterone specifically modulates the dorsal, not ventral, striatal pathway. These results provide novel insights into our understanding of adolescent impulsive and risky behaviors and how pubertal hormones are related to neural processes., Competing Interests: Declaration of Competing Interest We declare no conflicts of interest., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Selecting optimal stimulation parameters from numerous possibilities is a major obstacle for assessing the efficacy of non-invasive brain stimulation., Objective: We demonstrate that Bayesian optimization can rapidly search through large parameter spaces and identify subject-level stimulation parameters in real-time., Methods: To validate the method, Bayesian optimization was employed using participants' binary judgements about the intensity of phosphenes elicited through tACS., Results: We demonstrate the efficiency of Bayesian optimization in identifying parameters that maximize phosphene intensity in a short timeframe (5 min for >190 possibilities). Our results replicate frequency-dependent effects across three montages and show phase-dependent effects of phosphene perception. Computational modelling explains that these phase effects result from constructive/destructive interference of the current reaching the retinas. Simulation analyses demonstrate the method's versatility for complex response functions, even when accounting for noisy observations., Conclusion: Alongside subjective ratings, this method can be used to optimize tACS parameters based on behavioral and neural measures and has the potential to be used for tailoring stimulation protocols to individuals., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro., Methods: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs., Results: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001)., Conclusion: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.

Background: Trastuzumab improves the outcome of women with HER2 positive breast cancer. We aimed to assess whether trastuzumab decreases the detection rate of circulating tumor cells (CTCs) in women with high risk, HER2 nonamplified, early breast cancer., Patients and Methods: The EORTC 90091-10093 BIG 1-12 Treat CTC is a phase II trial, conducted in 70 hospitals and 6 CTC laboratories across 5 European countries. Patients with centrally confirmed HER2 nonamplified breast cancer and ≥1 centrally confirmed CTC per 15 ml of blood by CellSearch® following surgery and (neo)adjuvant chemotherapy were randomized (1 : 1) to 6 cycles of trastuzumab intravenously versus 18 weeks of observation. Randomization was stratified for center, locally confirmed estrogen receptor status and adjuvant versus neoadjuvant chemotherapy. The primary end point was rate of detection of ≥1 CTC per 15 ml of blood at week 18. Secondary end points were invasive disease-free survival (iDFS) and cardiac safety., Results: Between 30 April 2013 and 17 October 2016, 1317 patients were screened; 95 (7.2%) had detectable CTC(s), and 63 (4.8%) were randomized to trastuzumab (n = 31) or observation (n = 32). Fifty-eight patients were assessable for the primary end point, 29 in each arm. In 9 of the 58 patients, CTC(s) were still detected at week 18 : 5 in the trastuzumab and 4 in the observation arm (one-sided Fisher's exact test, P = 0.765). An Independent Data Monitoring Committee recommended stopping further accrual for futility for the primary end point. Median follow-up at database lock was 13 months (IQR 4-16.5). The 1-year iDFS was 93.8% (95% CI 77.3-98.4) in the observation versus 84.8% (95% CI 63.4-94.2) in the trastuzumab arm. No grade 2-4 cardiac events were observed in the trastuzumab arm., Conclusion: Trastuzumab does not decrease the detection rate of CTCs in HER2 nonamplified, nonmetastatic breast cancer.

Interaction of von Willebrand factor (VWF) with platelet glycoprotein Ib (GPIb) and interaction of collagen with GPVI are essential for thrombus formation on ruptured or eroded atherosclerotic plaques (atherothrombosis). GPIb and GPVI signal through Bruton tyrosine kinase (Btk), which can be blocked irreversibly by oral application of ibrutinib, an established therapy for chronic lymphocytic leukemia (CLL) with long-term safety. We found that ibrutinib and the novel Btk inhibitors acalabrutinib and ONO/GS-4059 block GPVI-dependent static platelet aggregation in blood exposed to human plaque homogenate and collagen but not to ADP or arachidonic acid. Moreover, Btk inhibitors prevented platelet thrombus formation on human atherosclerotic plaque homogenate and plaque tissue sections from arterially flowing blood, whereas integrin α 2 β 1 and VWF-dependent platelet adhesion to collagen, which is important for physiologic hemostasis, was not affected. This plaque-selective platelet inhibition was also observed in CLL patients taking 450 mg of ibrutinib and in volunteers after much lower and intermittent dosing of the drug. We conclude that Btk inhibitors, by targeting GPIb and GPVI signal transduction, suppress platelet thrombus accretion from flowing blood on atherosclerotic plaque but spare hemostatic platelet function. Btk inhibitors hold promise as the first culprit lesion-focused oral antiplatelet drugs and are effective at low doses., (© 2018 by The American Society of Hematology.)

Psychedelic drugs such as lysergic acid diethylamide (LSD) were used extensively in psychiatry in the past and their therapeutic potential is beginning to be re-examined today. Psychedelic psychotherapy typically involves a patient lying with their eyes-closed during peak drug effects, while listening to music and being supervised by trained psychotherapists. In this context, music is considered to be a key element in the therapeutic model; working in synergy with the drug to evoke therapeutically meaningful thoughts, emotions and imagery. The underlying mechanisms involved in this process have, however, never been formally investigated. Here we studied the interaction between LSD and music-listening on eyes-closed imagery by means of a placebo-controlled, functional magnetic resonance imaging (fMRI) study. Twelve healthy volunteers received intravenously administered LSD (75µg) and, on a separate occasion, placebo, before being scanned under eyes-closed resting conditions with and without music-listening. The parahippocampal cortex (PHC) has previously been linked with (1) music-evoked emotion, (2) the action of psychedelics, and (3) mental imagery. Imaging analyses therefore focused on changes in the connectivity profile of this particular structure. Results revealed increased PHC-visual cortex (VC) functional connectivity and PHC to VC information flow in the interaction between music and LSD. This latter result correlated positively with ratings of enhanced eyes-closed visual imagery, including imagery of an autobiographical nature. These findings suggest a plausible mechanism by which LSD works in combination with music listening to enhance certain subjective experiences that may be useful in a therapeutic context., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

Purpose: The long-term results of RTOG 91-11 suggested increased deaths not attributed to larynx cancer after concomitant chemoradiotherapy (CRT) despite no apparent increase in late effects. Because the timing of events was not reported by RTOG 91-11, one possibility is that severe late dysphagia (SLD) develops beyond five years and leads to unreported treatment-related deaths. Here we explore the timing of SLD after CRT., Methods: Patients who would have met eligibility criteria for RTOG 91-11 and were treated with CRT between 1993 and 2013 were identified. Events occurring beyond 3months after treatment and suggestive of SLD were recorded including esophageal stricture dilations, hospital admissions for aspiration pneumonia or feeding-tube insertion. Feeding-tube dependence beyond one year was also considered SLD. The cumulative incidence of SLD and its components was quantified using Gray's competing risk analysis with recurrence or death considered competing risks., Results: Eighty-four patients were included with a median follow-up of 43months. The 5-year overall survival was 70% (95% CI 58-80%). No death was directly a result of treatment-induced late dysphagia. The 5-year incidence of SLD was 26.5%. While 15 of 18 (83%) first stricture dilations occurred within 5years after CRT, 3 of 5 (60%) aspiration admissions and 5 of 8 late feeding tube insertions occurred beyond five years from CRT., Conclusions: SLD is common after CRT for larynx cancer and can occur beyond 5years from the end of treatment, emphasizing the importance of survivorship follow-up. Despite the incidence of SLD, death related to dysphagia is uncommon., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Extracranial internal carotid artery aneurysms are a rare entity in the adult population. Very little information is known in the pediatric population. We present a case of a 15-year-old male with an isolated internal carotid artery aneurysm and a review of the literature., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The GeparQuinto study showed that adding bevacizumab to 24 weeks of anthracycline-taxane-based neoadjuvant chemotherapy increases pathological complete response (pCR) rates overall and specifically in patients with triple-negative breast cancer (TNBC). No difference in pCR rate was observed for adding everolimus to paclitaxel in nonearly responding patients. Here, we present disease-free (DFS) and overall survival (OS) analyses., Patients and Methods: Patients (n = 1948) with HER2-negative tumors of a median tumor size of 4 cm were randomly assigned to neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel (EC-T) with or without eight infusions of bevacizumab every 3 weeks before surgery. Patients without clinical response to EC ± Bevacizumab were randomized to 12 weekly cycles paclitaxel with or without everolimus 5 mg/day. To detect a hazard ratio (HR) of 0.75 (α = 0.05, β = 0.8) 379 events had to be observed in the bevacizumab arms., Results: With a median follow-up of 3.8 years, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was not different for patients receiving bevacizumab (HR 1.03; P = 0.784 for DFS and HR 0.974; P = 0.842 for OS) compared with patients receiving chemotherapy alone. Patients with TNBC similarly showed no improvement in DFS (HR = 0.99; P = 0.941) and OS (HR = 1.02; P = 0.891) when treated with bevacizumab. No other predefined subgroup (HR+/HER2-; locally advanced (cT4 or cN3) or not; cT1-3 or cT4; pCR or not) showed a significant benefit. No difference in DFS (HR 0.997; P = 0.987) and OS (HR 1.11; P = 0.658) was observed for nonearly responding patients receiving paclitaxel with or without everolimus overall as well as in subgroups., Conclusions: Long-term results, in opposite to the results of pCR, do not support the neoadjuvant use of bevacizumab in addition to an anthracycline-taxane-based chemotherapy or everolimus in addition to paclitaxel for nonearly responding patients., Clinical Trial Number: NCT 00567554, www.clinicaltrials.gov., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Regardless of the paradigm used to implement a brain-computer interface (BCI), all systems suffer from BCI-inefficiency. In the case of patients the inefficiency can be high. Some solutions have been proposed to overcome this problem, however they have not been completely successful yet., Methods: EEG from 10 healthy users was recorded during neuromuscular electrical stimulation (NMES) of hands and feet and during motor imagery (MI) of the same limbs. Features and classifiers were computed using part of these data to decode MI., Results: Offline analyses showed that it was possible to decode MI using a classifier based on afferent patterns induced by NMES and even infer a better model than with MI data., Conclusion: Afferent NMES motor patterns can support the calibration of BCI systems and be used to decode MI., Significance: This finding might be a new way to train sensorimotor rhythm (SMR) based BCI systems for healthy users having difficulties to attain BCI control. It might also be an alternative to train MI-based BCIs for users who cannot perform real movements but have remaining afferents (ALS, stroke patients)., (Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

In the HD15 trial of the German Hodgkin Study Group, the negative predictive value (NPV) of positron emission tomography (PET) using [(18)F]-fluorodeoxyglucose in advanced-stage Hodgkin lymphoma (HL) was evaluated. A total of 817 patients were enrolled and randomly assigned to receive BEACOPP-based chemotherapy. After completion of chemotherapy, residual disease measuring more than or equal to 2.5 cm in diameter was assessed by PET in 311 patients. The NPV of PET was defined as the proportion of PET(-) patients without progression, relapse, or irradiation within 12 months after PET review panel. The progression-free survival was 96% for PET(-) patients (95% confidence interval [CI], 94%-99%) and 86% for PET(+) patients (95% CI, 78%-95%, P = .011). The NPV for PET in this analysis was 94% (95% CI, 91%-97%). Thus, consolidation radiotherapy can be omitted in PET(-) patients with residual disease without increasing the risk for progression or early relapse compared with patients in complete remission. The impact of this finding on the overall survival at 5 years must be awaited. Until then, response adapted therapy guided by PET for HL patients seems to be a promising approach that should be further evaluated in clinical trials. This trial is registered at http://isrctn.org study as #ISRCTN32443041.

Background: Topotecan is an active drug in small-cell lung cancer (SCLC). In our previous study, a combination of topotecan with cisplatin was associated with a median overall survival of 7.6 or 8.7 months, depending on the duration of treatment. We have replaced cisplatin by carboplatin in this trial, with the objective of creating a more convenient schedule for our patients. Furthermore, we have also compared the standard 5-day schedule with an experimental 3-day schedule., Patients and Methods: A total of 100 patients with metastatic disease were included. Patients were randomly assigned to receive either topotecan 0.75 mg/m2, days 1-5, and carboplatin AUC 5, day 5 (arm A) or topotecan 1.25 mg/m2, days 1-3, and carboplatin AUC 5, day 3 (arm B). Six cycles were given at a 3-week interval., Results: A total of 91 patients were assessable for response. The response during therapy was 86.9% in arm A and 80.0% in arm B. Median survival in arm A was 11.8 months and in arm B 11.6 months (P=0.37)., Conclusions: The combination of topotecan and carboplatin is active in extensive-disease SCLC. Toxicity and median survival were comparable in both arms. Three days of treatment seems to be similar to the 5-day regimen.

In the case of accidental radiation exposure, biological dosimetry has an important role. Previous studies have indicated that the flow cytometric micronucleus (MN) assay in human transferrin receptor positive reticulocytes (Tf-Ret) in blood could be a sensitive biomarker for chromosome damage. In the present investigation, the utility and sensitivity of this method was studied in 44 young patients from Belarus, who were treated with 131I for thyroid cancer. Red marrow (RM) is the critical organ in radioiodine therapy (RIT). In our patients, it was exposed to 100-700 mSv low-dose rate irradiation within 2-4 days. About 3 days after 131I administration, the frequency of micronucleated-Tf-Ret (f(MN-Tf-Ret)) increases within 1 day to a maximum and declines in the following 2-5 days to its value before treatment. A total dose of 100 mSv was easily detectable. The sensitivity of the assay after acute irradiation may be 50 mSv. The method should be useful for monitoring individuals after a radiation accident, provided blood samples can be obtained within a few days after exposure. The time-course of f(MN-Tf-Ret) is interpreted using a model, which considers the exponential exposure of red marrow in RIT as well as the kinetics of erythroblast maturation and reticulocyte migration into the peripheral circulation. Similar modelling was done on published data of MN in immature mouse erythrocytes. Striking similarities in the kinetic and in the yield of MN-induction were found between these two species. This lends support for the use of the mouse as a model for the MN-induction in humans.

Biomonitoring tries to determine the consequences for humans of exposures to environmental or pharmaceutical agents. Different end points have been employed to assess the burden of genomic damage. This is the first report comparing a recently introduced new end point, the reticulocyte-micronuclei analyzed by flow cytometry with the widely used lymphocyte-micronucleus assay, applied to two exposure scenarios leading to enhanced genomic damage. Radioiodine therapy was chosen to represent a short time exposure and hemodialysis treatment in end-stage renal failure was chosen to represent a chronic exposure. The results show that iodine radiation induced measurable genomic damage in the lymphocyte-micronucleus assay as well as in the reticulocyte-micronucleus test. Of two groups of patients under hemodialysis treatment, a reduced genomic damage was found with the lymphocyte-micronucleus test, but not with the reticulocyte-micronucleus test in the group undergoing daily hemodialysis, which removes uremic toxins more efficiently as compared to conventional hemodialysis, the treatment applied in the other group. The limited life-span of reticulocytes may make them less suitable for accumulation of chronic low level damage than lymphocytes. In conclusion, the lymphocyte-micronucleus test may be applicable to more exposure situations (including low chronic exposure), but the reticulocyte-micronucleus assay may be easier to perform in a clinical setting. The latter reflects a more rapid reduction of genomic damage after an acute exposure.

The T-cell receptor mutant frequency (TCR-Mf) was measured in 53 young adults, who were treated with radioiodine for thyroid cancer. Patients came from the southern part of Belarus. This region had suffered the most from the Chernobyl Disaster. TCR-Mf was determined by flow cytometry before and after 1 to maximal 10 treatments. Before treatment, TCR-Mf of patients was 2.0 x 10(-14). This Mf value is in the same range as that of young healthy students. After radioiodine therapy (RIT), TCR-Mf increases within about half a year to a maximum. The increase per one mGy to red marrow was 8.7 x 10(-7). After the maximum TCR-Mf declines exponentially. The half-life of TCR mutants was found to be 3.2 years. On the basis of these data, a calibration curve for the use of TCR-Mf as a biological dosimeter is given.

In the MACS-BR6 version of the GPA assay [Int. J. Radiat. Res. 70 (1996) 131] variant red blood cells (RBC) are isolated from 5 x 10(8) normal RBC by magnetic cell separation (MACS) before detection and quantification by immunolabelling and flow cytometry as in the classical BR6 assay. In the present work it is described how the MACS-BR6 assay is improved by internal standardisation with FITC-labelled RBC. This modification of the assay has the advantage that (i) the analysis of variants is not disturbed by the overwhelming number of normal RBC that (ii) the precision of the assay is improved and finally that (iii) a sufficient number of variants is available for further investigations. Tn positive RBC behave in MACS like variants. It is demonstrated that in normal individuals Tn cells (frequency: approximately 2 x 10(-8)) do not disturb the assay., (Copyright 2002 Elsevier Science B.V.)

Platelet phospholipid composition was analyzed before and after extracorporeal removal of low density lipoproteins (LDL) by LDL apheresis in six patients with familial hypercholesterolemia. Elevated levels of total plasma cholesterol and the portion of plasma cholesterol carried by LDL were reduced by 56 and 66% after LDL apheresis. Platelet cholesterol contents remained unaffected. While the phosphatidylcholine (PC):sphingomyelin (SM) ratio in plasma lipoproteins was increased by 22% following apheresis, the same parameter was lowered by 14% in platelets. LDL apheresis induced decreases in the percentages of distinct molecular species containing arachidonic acid in platelet diacyl subgroups of PC, phosphatidylinositol (PI) and phosphatidylserine (PS) as well as in alkenylacyl (plasmalogen) phosphatidylethanolamine (PE). Directly after apheresis, the percentages of molecular species with arachidonic acid of diacyl PC, diacyl PI and alkenylacyl PE were reduced by 20, 23 and 8%, respectively. Two days after the procedure, total arachidonic acid of diacyl PC, diacyl PS and alkenylacyl PE was lowered by 11, 20 and 8%. Overall, the amount of phospholipid bound arachidonic acid was reduced by 16% after apheresis (from 79.1 to 66.4 nmol/10(8) platelets). The results are thus in agreement with previous data indicating decreased phospholipid bound arachidonic acid in red blood cells after apheresis (Engelman B. Bräutigam C, Kulschar R et al. Biochim Biophys Acta 1994:1196:154). Urinary 2,3-dinor thromboxane B2, an estimate of platelet thromboxane A2 (TXA2) production, tended to be decreased following the procedure. The percentage change in the TXA2 metabolite was positively related to the magnitude of change induced by apheresis in phospholipid bound arachidonic acid. In summary, the results suggest that in patients with hypercholesterolemia, the level of plasma LDL is an important determinant of the arachidonic acid content of several platelet phospholipids.

The fraction of HPRT deficient T lymphocytes was measured in the HPRT +/- female mouse between birth and an age of about 2 years. The animals were the F1 offspring of the HPRT deficient strain 129MF1 and HPRT competent C57BL/6J-mice. T lymphocytes from spleen were cloned in vitro and HPRT deficient clones were detected by double-labeling with [3H]thymidine and [14C]hypoxanthine. During the first weeks of life the fraction of deficient lymphocytes sharply decreases from about 50% at birth to 10-30% at an age of 10 weeks. In adult animals the fraction of HPRT deficient T cells smoothly further decreases to values about 10% at 80-90 weeks. The equation gamma(t)=[0.547 x exp(-0.405 x t)] + [0.453 x exp(-0.0116 x t)] was found to be a good approximation of the time course of HPRT deficient cells in spleen; gamma(t) is the fraction of deficient cells per competent cell and t is the age of animals in weeks. It is postulated that the selection against HPRT deficient T lymphocytes is the consequence of the reduced proliferative capacity of HPRT deficient cells (=selection factor). The time course of the ratio of deficient cells can be described as a function of the proliferation rate of the HPRT competent T cells and this selection factor. The sharp initial decrease is explained by a high selection pressure against HPRT deficient cells in young animals when the proliferation rate of the expanding T cell population is high and when T cells proliferate in the bone marrow. In adult animals the selection pressure against HPRT deficient cells is reduced, since T cells arise in general in peripheral lymphatic organs, where the salvage pathway is of lesser importance compared to the de novo purine synthesis. Implications of the selection against HPRT deficient lymphocytes for the widely used HPRT mutation assay are discussed.

A method is described for determining the frequency of cells with a mutation in an autosomal gene coding for a membrane protein. Using a monoclonal antibody to H-2Kk surface antigen and magnetic cell separation (MACS) more than 10(4)-fold enrichment of the H-2Kk negative population was achieved, as tested with artificial mixtures containing a known number of antigen-negative cells. After a second magnetic sorting mutant frequencies as low as 10(-6) could be measured. The number of clonogenic mutants was evaluated by limiting dilution cloning and verification of the mutant phenotype by FACScan (flow cytometry) analysis in a representative number of clones. The spontaneous frequency of H-2Kk deficient mutants was 0.80 x 10(-6), and this increased after irradiation with 6 Gy X rays to 3.38 x 10(-6) within the next 8 weeks. About 50 mutant clones were screened for the presence of other class 1 antigens on the cell surface by FACScan analysis. All mutants continued to express other class 1 antigens.

In radiobiology the reduction of the dose-rate in general diminishes the degree of the biological effect per unit dose. This phenomenon is characterized by the dose-rate effectiveness factor (DREF). DREF is the factor by which a risk per unit dose obtained from data at high dose and high dose-rate overestimates the risk at low doses and/or low dose-rates. In general, DREF is in the range of 2 to 10. In the first part of this review, a short survey of the modern microdosimetric approach for a better understanding of radiation load on the cellular level and the significance of dose-rate is given. Experiments on the influence of dose-rate on the mutagenicity of ionizing radiation in cultured cells are reviewed. In contrast to other biological effects, in most experiments the reduction of the dose-rate had no or even a reverse dose-rate effect (DREF < or = 1). In the second part results on the influence of dose-rates on the induction of HGPRT-deficient T-lymphocytes in mice irradiated in vivo are given. Mutagenicity decreases with dose-rate and DREF values between 3-10 were measured. Possible reasons for the discrepancy between in vitro and in vivo experiments are discussed.

Two monoclonal antibodies were found to give enhanced affinity for beta-lipotropin when mixed, as evidenced by competitive radioimmunoassay. Both monoclonals were found to react with a pentapeptide Ala-Glu-Leu-Glu-Tyr, which is a sequence of high local hydrophilicity within the N-terminal section of beta-lipotropin.

By the use of the mutagenic substance hydrazine sulphate it is shown that the currently used single determination method for determining point mutations in host-mediated assays with calculation of mutation frequencies can lead to erroneous results. The microbiological basis for a linear-method is presented in which the population growth of the auxotrophic and substance-induced mutants used int he test can be described mathematically during their logarithmic growth phase with regression lines.