Background levels and brain organoid impact of RF field exposure in a healthcare environment

Introduction: This study is an introduction to the empirical and impact evaluation of radiofrequency electromagnetic field (RF-EMF) radiation exposure in a healthcare environment, focusing on an indoor microenvironment. It explores the expression of various genes associated with cellular responses, cell proliferation, senescence, and apoptotic cell death. The assessment analyzes current personal mobile communications (2G-5G FR1), providing a clear understanding of RF-EMF exposure and compliance with regulatory limits. Methods: The signals from different wireless communication systems at Hospital Universitario de Canarias (HUC) in Tenerife, Canary Islands, Spain, were examined in 11 locations. Four measurement campaigns were performed with frequencyselective exposimeters (PEMs) and an EME Spy 200 MVG, and experimental electric field values were compared as a long-term exposition. The frequency with the highest contribution (2.174 V/m) observed (1840 MHz) in UMTS was selected for biological effects evaluation. Results: The study focuses on four locations with the highest exposure to communication systems (downlinks), analyzing the results to verify compliance with regulations that ensure the safety of patients, the general public, and healthcare workers. LTE B20 (DL), GSM+UMTS 900 (DL), GSM 1800 (DL), UMTS 2100 (DL), and LTE B7 (DL) exhibited relatively higher E/m values throughout the campaigns, and these values consistently remained below the ICNIRP reference levels, signifying a consistently low level of exposure. In addition, this work presents the biological effects on neural stem cells (NSCs) using 3D brain organoids (BOs) exposed to RF signals in a validated and commercial experimental setting: the Gigahertz Transverse Electromagnetic cell (GTEM). The GTEM allows for the creation of homogeneous field electromagnetic fields in a small, enclosed setting and guarantees exposure conditions in a wide range of frequencies. BOs are an in vitro 3D cell-culture technology that reproduces the cellular composition and structure of the developing brain. Analyzing the expression of several genes associated with cellular responses, cell proliferation, senescence, and apoptotic cell death,wefound that exposure of BOs at 1840MHzdid not affectmRNAexpression in brain genes related to apoptosis or senescence. However, a decrease in gene expression for cell proliferation and cell activity markers was observed during the differentiation stage of BOs. Discussion: The discussion emphasizes the coexistence and evolution of various heterogeneous networks and services throughout the four measurement campaigns. Across all measured results, the levels of the obtained E-field were consistently well below the exposure limits set by internationally accepted standards and guidelines. These obtained values have been established in order to consider their potential effects on cell proliferation and cell activity, especially in differentiating biological organisms. Consequently, the results obtained and the methodology presented could serve as a foundational framework for establishing the basis of RF-EMF assessment in future heterogeneous 5G developments, particularly in the millimeter wave (mmWave) frequency range, where the forecast is for massive high-node density networks.The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported at Instituto de Salud Carlos III project “(PI19CIII/00033) TMPY 508/19” “Metrics development for electromagnetic safety assessment in healthcare centers in the context of 5G” from the Sub-Directorate-General for Research Assessment and Promotion. This research was funded by the Grant PID2021-126715OB-I00 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe,” and by a grant of the Instituto de Salud Carlos III (ISCIII) PI22CIII/00055.S

Dickkopf-1 Can Lead to Immune Evasion in Metastatic Castration-Resistant Prostate Cancer

PURPOSE Metastatic castration-resistant prostate cancer (mCRPC) with low androgen receptor (AR) and without neuroendocrine signaling, termed double-negative prostate cancer (DNPC), is increasingly prevalent in patients treated with AR signaling inhibitors and is in need of new biomarkers and therapeutic targets. METHODS Candidate genes enriched in DNPC were determined using differential gene expression analysis of discovery and validation cohorts of mCRPC biopsies. Laboratory studies were carried out in human mCRPC organoid cultures, prostate cancer (PCa) cell lines, and mouse xenograft models. Epigenetic studies were carried out in a rapid autopsy cohort. RESULTS Dickkopf-1 (DKK1) expression is increased in DNPC relative to prostate-specific antigen (PSA)–expressing mCRPC in the Stand Up to Cancer/Prostate Cancer Foundation discovery cohort (11.2 v 0.28 reads per kilobase per million mapped reads; q < 0.05; n = 117) and in the University of Washington/Fred Hutchinson Cancer Research Center cohort (9.2 v 0.99 fragments per kilobase of transcript per million mapped reads; P < .0001). DKK1 expression can be regulated by activated Wnt signaling in vitro and correlates with activating canonical Wnt signaling mutations and low PSA mRNA in mCRPC biopsies ( P < .05). DKK1 hypomethylation was associated with increased DKK1 mRNA expression (Pearson r = −0.66; P < .0001) in a rapid autopsy cohort (n = 7). DKK1-high mCRPC biopsies are infiltrated with significantly higher numbers of quiescent natural killer (NK) cells ( P < .005) and lower numbers of activated NK cells ( P < .0005). Growth inhibition of the human PCa model PC3 by the anti-DKK1 monoclonal antibody DKN-01 depends on the presence of NK cells in a severe combined immunodeficient xenograft mouse model. CONCLUSION These results support DKK1 as a contributor to the immunosuppressive tumor microenvironment of DNPC. These data have provided the rationale for a clinical trial targeting DKK1 in mCRPC (ClinicalTrials.gov identifier: NCT03837353 )

Effect of Androgen Suppression on Clinical Outcomes in Hospitalized Men With COVID-19: The HITCH Randomized Clinical Trial.

ImportanceSARS-CoV-2 entry requires the TMPRSS2 cell surface protease. Antiandrogen therapies reduce expression of TMPRSS2.ObjectiveTo determine if temporary androgen suppression induced by degarelix improves clinical outcomes of inpatients hospitalized with COVID-19.Design, setting, and participantsThe Hormonal Intervention for the Treatment in Veterans With COVID-19 Requiring Hospitalization (HITCH) phase 2, placebo-controlled, double-blind, randomized clinical trial compared efficacy of degarelix plus standard care vs placebo plus standard care on clinical outcomes in men hospitalized with COVID-19 but not requiring invasive mechanical ventilation. Inpatients were enrolled at 14 Department of Veterans Affairs hospitals from July 22, 2020, to April 8, 2021. Data were analyzed from August 9 to October 15, 2021.InterventionsPatients stratified by age, history of hypertension, and disease severity were centrally randomized 2:1 to degarelix, (1-time subcutaneous dose of 240 mg) or a saline placebo. Standard care included but was not limited to supplemental oxygen, antibiotics, vasopressor support, peritoneal dialysis or hemodialysis, intravenous fluids, remdesivir, convalescent plasma, and dexamethasone.Main outcomes and measuresThe composite primary end point was mortality, ongoing need for hospitalization, or requirement for mechanical ventilation at day 15 after randomization. Secondary end points were time to clinical improvement, inpatient mortality, length of hospitalization, duration of mechanical ventilation, time to achieve a temperature within reference range, maximum severity of COVID-19, and the composite end point at 30 days.ResultsThe trial was stopped for futility after the planned interim analysis, at which time there were 96 evaluable patients, including 62 patients randomized to the degarelix group and 34 patients in the placebo group, out of 198 initially planned. The median (range) age was 70.5 (48-85) years. Common comorbidities included chronic obstructive pulmonary disorder (15 patients [15.6%]), hypertension (75 patients [78.1%]), cardiovascular disease (27 patients [28.1%]), asthma (12 patients [12.5%]), diabetes (49 patients [51.0%]), and chronic respiratory failure requiring supplemental oxygen at baseline prior to COVID-19 (9 patients [9.4%]). For the primary end point, there was no significant difference between the degarelix and placebo groups (19 patients [30.6%] vs 9 patients [26.5%]; P = .67). Similarly, no differences were observed between degarelix and placebo groups in any secondary end points, including inpatient mortality (11 patients [17.7%] vs 6 patients [17.6%]) or all-cause mortality (11 patients [17.7%] vs 7 patents [20.6%]). There were no differences between degarelix and placebo groups in the overall rates of adverse events (13 patients [21.0%] vs 8 patients [23.5%) and serious adverse events (19 patients [30.6%] vs 13 patients [32.4%]), nor unexpected safety concerns.Conclusions and relevanceIn this randomized clinical trial of androgen suppression vs placebo and usual care for men hospitalized with COVID-19, degarelix did not result in amelioration of COVID-19 severity.Trial registrationClinicalTrials.gov Identifier: NCT04397718