Low Irradiation Research Articles

Low Dose Total Body Irradiation Improves CD19 CAR-T Expansion, Persistence, and Trafficking, Leading to Enhanced Efficacy in Large B-Cell Lymphoma

Anti-CD19 chimeric antigen receptor T-cell (CART19) is associated with high response rates in large B-cell lymphoma (LBCL). However, a significant subset of patients relapses due to several mechanisms that include poor expansion, lack of CART19 persistence, and immunosuppressive tumor microenvironment. We hypothesized that low dose total body irradiation (LDTBI) may interfere with these mechanisms and thus enhance the efficacy of CART19 cells in LBCL. To test this hypothesis, we utilized a syngeneic mouse model of LBCL, as they are immunocompetent, to best emulate patients treated in clinic. This model involves transplanting BALB/c mice with GFP/Luciferase transduced mouse derived B cell lymphoma (A20) cells and generating murine CART19 (mCART19). We tested mCART19 cytotoxicity in vitro against A20 cells with or without radiation. We found that exposing A20 cells to 1 Gy radiation prior to co-culturing them with mCART19 led to a significant improvement of the mCART19 cytotoxicity (E:T ratio 2.5:1; p=0.029). This is consistent with our in vitro findings for human LBCL cell lines, where weobserved that exposing LBCL cell lines to 1 Gy radiation significantly improved human CART19 cytotoxicity (E:T ratio 2.5:1: OCI-Ly10 cells: p=0.009; SU-DHL-4 cells: p=0.048). Next, we assessed the activity of mCART19 cells in vivo. Animals were lymphodepleted using cyclophosphamide (Cy) administered 24 hours before mCART19 treatment. LDTBI at 1 Gy was delivered 4 hours before mCART19 administration. In addition to evaluating the benefit of single LDTBI prior to mCART19, we also delivered a second dose of LDTBI 9 days after mCART19 treatment. Thus, we evaluated 6 cohorts as follows: (1) Untreated n=4, (2) Cy/LDTBI n=5 (3) Cy/LDTBI/LDTBI n=3, (4) Cy/mCART19 n=5, (5) Cy/LDTBI/mCART19 n=5, (6) Cy/LDTBI/mCART19/LDTBI n=5. Adding LDTBI to Cy provided a minor improvement compared to untreated controls (median overall survival [OS]= 21 days vs 16.5 days; p=0.009). As expected, Cy/mCART19 improved median OS compared to controls (median OS= 35 day; p=0.003). Strikingly, 8/10 of the mice treated with Cy/LDTBI/mCART19 remained in complete remission (CR) at 6 months post-treatment ( p<0.001), Figure 1. Since one dose of LDTBI prior to mCART19 was very effective, adding the second dose of LDTBI did not result in additional survival benefit. Peripheral blood (PB) was monitored regularly, we observed a 2.8-fold increase of mCART19 expansion in the Cy/LDTBI/mCART19 cohort when compared with the Cy/mCART19 cohort ( p<0.001) 9 days post treatment. Importantly, bone marrow aspirates were performed 6 months post treatment in animals that remained alive, demonstrating sustained B-cell aplasia in 7/8 mice (Cy/LDTBI/mCART19 cohorts) which strongly suggests mCART19 persistence. One animal showed B-cell recovery but remained in CR with no relapse suggesting potential cure. Mice that received Cy/mCART19 with no LDTBI showed evidence of B-cell reappearance 7 days prior to overt relapse. Next, we assessed mCART19 trafficking into the tumor tissues by establishing new cohorts of (1) Cy/mCART19 n=4, (2) Cy/LDTBI/ mCART19 n=4 and harvesting tumor-infiltrated spleen and liver 3 days post treatment. Flow cytometry revealed that LDTBI cohort had significant increase in the amount of mCART19 in the spleen and the liver (3.15-fold; p=0.041, and 2-fold; p=0.012, respectively) compared to Cy/mCART19 cohort, suggesting that LDTBI improves mCART19 tumor-trafficking ability. We have previously reported that exposing human LBCL cells to 1Gy radiation in vitro increases expression of FAS when compared to non-irradiated controls and that FAS blockade impairs CART19 cytotoxicity. Hence, we evaluated the expression of FAS in murine LBCL A20 cells harvested from the syngeneic mouse model 3 days post LDTBI. Consistently, we observed 3.1-fold increase in FAS expression, ( p=0.033). In conclusion, our results show a novel and efficacious approach to harnessing LDTBI with CART19. Based on our findings, LDTBI enhances the efficacy of CART19 leading to improved survival in a syngeneic mouse model. Mechanistically, radiation improves CART19 efficacy by boosting CART19 expansion, persistence, trafficking into tumor sites, and upregulation of FAS in tumor cells, pointing to a clinically translatable benefit.

An Intravital Imaging Protocol to Visualize and Phenotype the Hematopoietic Niche of Clonal Hematopoiesis

Clonal Hematopoiesis of indeterminate potential (CHIP) is a condition where blood cells are produced from a few clones of hematopoietic stem cells (HSCs) carrying leukemia-associated driver mutations 1. Although selective pressures from low-grade inflammation of the bone marrow microenvironment have been shown to promote mutant cell expansion 2-7, we focus on the disease-initiating niche, which is defined as a subset of marrow cells surrounding rare HSCs. Indeed, as we have recently described, clonal expansion of acute myeloid leukemia and activated HSCs 8,9 was not uniform, and only occurred in a subset of marrow spaces harboring bone remodeling activities. To identify the disease-initiating niche for therapeutic targeting, we developed an intravital imaging protocol to visualize the rare pre-malignant clones in the minimally perturbed microenvironment and phenotype their niche. The standard practice to generate CHIP models relies on transplanting syngeneic or allogeneic cells into a sub-lethally irradiated recipient. However, concerns arise as irradiation compromises the microenvironment 10. Successful engraftment in non-conditioned mice can be achieved by injecting a high number of cells (1.5 x 10 7 cells) 11,12, but modeling early clonal expansion events from single cells remain challenging, as a crowd of cells is often observed in proximity. Here, we established a low dose (0.5-1.5 Gy), whole body or local irradiation regimen that preserves the integrity of the bone marrow microenvironment. We performed high-resolution in-vivo imaging to capture dynamics of single cells and cells undergoing early expansion. Specifically, as little as 0.5Gy irradiation enabled survival of the transplanted cells (2x10 6 GFP + healthy whole bone marrow) in non-irradiated side, and allowed direct visualization of early clonal expansion in vivo through 16 weeks . Engraftment was negligible in non-irradiated mice.Through in-vivo, video-rate tracking of Rhodamine dextran dye (70kDa) leakage from vessels into the extravascular space showed no increase in permeability 13 or signs of vessel dilation, suggesting minimal inflammation after the radiation insult (N= 3 mice, data points are individual vessel segments. Mann-Whitney U test). Preliminary findings with in-vitro cultures of mesenchymal stromal cells (MSCs) have also suggested that the MSCs retain their ability for tri-lineage differentiation after the low-dose irradiation. With this imaging protocol, we showed that hot spots of cell expansion exist in the Tet2 +/- murine model. To capture the highly localized niche factors responsible for these hot spots, we implemented image-guided live-cell labeling adapted from the previously published Image-seq protocols 9. As illustrated in Figure 1, a small channel is etched in the bone with plasma-mediated laser ablation. The micropipette was then inserted to the region of interest for delivery of fluorescent antibodies under image guidance. By administering FITC-conjugated anti-CD45 antibodies into the marrow cavities, we can label and recover ~10,000 live cells with 98% viability from two regions of interest, suitable for next generation single cell sequencing. The technique can be expanded to employ antibody cocktails to visualize and enrich particular cell lineages of interest during cell isolation, while preserving spatial information. Its compatibility with standard cell isolation protocols for FACS may help collect cellular targets that are geometrically inaccessible for cell aspiration. In conclusion, we established a working model to visualize expansion of healthy and Tet2 +/- hematopoietic cells in vivo. This can be followed by image-assisted live-cell tagging to isolate local microenvironment cells and study cell-niche coordination at high spatial precision. The imaging protocol may also be broadly applied to study microenvironment regulations in non-malignant clonal disorders.

Final Results from Phase 1 Study of Briquilimab, an Anti-CD117 Monoclonal Antibody, in Combination with Low Dose Irradiation and Fludarabine Conditioning, Shows Durable Remissions in Older Adults with Acute Myeloid Leukemia in Complete Remission and Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation

Background: Allogeneic hematopoietic cell transplantation (HCT) with non-myeloablative conditioning (NMA) is a potential cure for AML and MDS in older/frail patients. NMA is associated with better tolerability but higher relapse rates compared to more intensive regimens. In a phase 1 study (NCT#04429191), briquilimab (JSP191), a first-in-class monoclonal antibody (mAb) that inhibits stem cell factor binding to CD117 (c-Kit) to deplete hematopoietic stem and progenitor cells (HSPC), in combination with standard NMA conditioning of low dose total body radiation (TBI) and fludarabine (Flu) for HCT, was evaluated in older adults with AML and MDS. Pre-clinical experiments suggest briquilimab synergizes with low dose TBI to deplete normal and malignant HSPC to facilitate donor cell engraftment. Final 1-year efficacy endpoints for all subjects enrolled in this study are presented. Methods: 32 subjects, median age 70 yrs (range 62-79), with AML in morphologic CR (CR1 or CR2+) (n=13), MDS (n=16), or AML not in CR (n =3), and HLA-matched related or unrelated donors were enrolled. Following infusion of briquilimab 0.6 mg/kg, serum levels were assessed to determine start of Flu at 30 mg/m 2/day on Transplant Day (TD)-4, -3, -2, and TBI 2-3 Gy on TD0. Peripheral blood grafts were infused on TD0 (10-14 days after JSP191). GVHD prophylaxis was tacrolimus, sirolimus, and mycophenolate mofetil. Primary endpoints were safety, tolerability, and briquilimab pharmacokinetics. Secondary endpoints included engraftment, chimerism, measurable residual disease (MRD) clearance, acute GVHD (aGVHD), chronic GVHD (cGVHD), NRM, RFS, and OS at 1 year. Results: Summary of main efficacy outcomes is presented in Fig 1. 10 of 13 AML in CR and 14 of 16 MDS subjects had MRD at pre-HCT screening assessed by cytogenetics, flow cytometry, and/or next generation sequencing. There were no infusion toxicities and no briquilimab-related SAEs. Consistent with our previous reports, briquilimab exhibited predictable clearance prior to donor cell infusion, and all subjects engrafted, with neutrophil recovery between TD+19 and TD+26. Compared to baseline marrow, briquilimab alone depleted HSPC with a mean decrease of 62.4±22.7% prior to Flu/TBI (Fig 2). The 28 evaluable subjects at TD+90 achieved median donor myeloid chimerism of 99% (range 96-100%) and median total chimerism of 95% (range 81-100%). There was one secondary graft failure without relapse, who received a 2 nd HCT. Among 13 AML in CR subjects, by 1 year, there were 3 relapses, 1 NRM (GVHD), 9 subjects were alive, and 8 were MRD negative. The 1 subject who was MRD positive at 1 year had only a detectable DNMT3A mutation at low level. 1 of 13 AML in CR subjects had TP53+ disease at screening and this subject was alive and MRD negative at 1 year post-AHCT. Among 16 MDS subjects, by 1 year, there were 5 disease progression/relapses, 1 subject withdrew consent due to persistent disease 3 months post-HCT, 1 NRM (sepsis), 8 subjects were alive, and 6 were MRD negative. 5 of 16 MDS subjects had TP53+ disease, 3 of whom had persistent disease/progressed/relapsed prior to 1 year post-HCT, and the other 2 of whom had MRD positive disease/molecular relapse at 1 year post-HCT. Median time to MRD negativity in all subjects who converted from MRD-positive disease to MRD-negative disease was TD+28. All 3 subjects with AML not in CR had disease progression before 4 months post-AHCT. There was no apparent correlation between level of HSPC depletion at the assessed timepoint (Fig 2) and relapse or survival. Of the 32 enrolled subjects, 4 had MAGIC Grade 2 aGVHD, 1 had MAGIC grade 3-4 aGVHD, 13 had mild/moderate cGVHD, and none had severe cGVHD. Conclusions: These results demonstrate that targeting CD117 with briquilimab together with TBI/Flu as a novel conditioning regimen is safe, well-tolerated, facilitates full donor myeloid chimerism, and sustained clearance of MRD in older adults with AML in CR and MDS without TP53 undergoing NMA AHCT.

Different mechanisms of X-ray irradiation-induced male and female sterility in Aedes aegypti

BackgroundAedes aegypti (Ae. aegypti) is the major vector that transmits many diseases including dengue, Zika, and filariasis in tropical and subtropical regions. Due to the growing resistance to chemical-based insecticides, biological control methods have become an emerging direction to control mosquito populations. The sterile insect technique (SIT) deploys high doses of ionizing radiation to sterilize male mosquitoes before the release. The Wolbachia-based population suppression method of the incompatible insect technique (IIT) involves the release of Wolbachia-infected males to sterilize uninfected field females. Due to the lack of perfect sex separation tools, a low percentage of female contamination is detected in the male population. To prevent the unintentional release of these Wolbachia-infected females which might result in population replacement, a low dose of X-ray irradiation is deployed to sterilize any female escapees. However, it remains unclear whether these irradiation-induced male and female sterilizations share common mechanisms.ResultsIn this work, we set out to define the minimum dose of X-ray radiation required for complete female sterilization in Ae. aegypti (NEA-EHI strain). Further results showed that this minimum dose of X-ray irradiation for female sterilization significantly reduced male fertility. Similar results have been reported previously in several operational trials. By addressing the underlying causes of the sterility, our results showed that male sterility is likely due to chromosomal damage in the germ cells induced by irradiation. In contrast, female sterility appears to differ and is likely initiated by the elimination of the somatic supporting cells, which results in the blockage of the ovariole maturation. Building upon these findings, we identified the minimum dose of X-ray irradiation on the Wolbachia-infected NEA-EHI (wAlbB-SG) strain, which is currently being used in the IIT-SIT field trial. Compared to the uninfected parental strain, a lower irradiation dose could fully sterilize wAlbB-SG females. This suggests that Wolbachia-carrying mosquitoes are more sensitive to irradiation, consistent with a previous report showing that a lower irradiation dose fully sterilized Wolbachia-infected Ae. aegypti females (Brazil and Mexican strains) compared to those uninfected controls.ConclusionsOur findings thus reveal the distinct mechanisms of ionizing X-ray irradiation-induced male or female sterility in Ae. aegypti mosquitoes, which may help the design of X-ray irradiation-based vector control methods.

Investigation on temperature dependence of recent high-efficiency silicon solar modules

The temperature dependence of photovoltaic modules varies with temperature and irradiance. For recent high-efficiency solar modules such as silicon heterojunction (SHJ) solar modules and tunneling oxide passivated contact (TOPCon) solar modules, it is not clear how their temperature dependence changes with temperature and irradiance. In this study, the temperature dependence of SHJ and TOPCon solar modules was studied by measuring I–V curves with the irradiance ranging from 200 to 1000 W/m2 and temperature ranging from 25 to 75 °C. The passivated emitter and rear cell (PERC) solar modules were measured as a reference. The results indicate that the temperature dependence of short-circuit current (Isc) for the three modules is almost invariable with temperature and irradiance. The temperature dependence of open-circuit voltage (Voc) and maximum power (Pm) decreasees with the increasing module temperature, and increasees with the increasing irradiance. It can be observed that the absolute magnitude of (∂Pm/∂T)/Pm for SHJ is the smallest, which is more obvious at high irradiance. An interesting finding is that the temperature dependence of fill factor (FF) for SHJ solar module increases with increasing irradiance, which is opposite to PERC and TOPCon solar modules. This phenomenon is related to the temperature dependence of series resistance. In addition, the temperature dependence is not linear at low temperature and irradiance. The obtained results in this paper can provide useful insight into predicting performance ratio of PERC, SHJ and TOPCon solar modules.

Evaluation of the bifaciality coefficient of bifacial photovoltaic modules under real operating conditions

Among the parameters that define a bifacial photovoltaic module, the bifaciality coefficients indicate the rear and front side ratio of the most representative IV curve points of a photovoltaic panel, that is, Isc, Voc and Pm. However, these parameters are defined under the ideal Standard Test Conditions (STC). Therefore, to provide a realistic insight regarding the performance of bifacial modules, it is necessary to evaluate these coefficients under real operating conditions. For such purpose, an outdoor campaign was performed to experimentally measure the maximum power bifaciality coefficient of two modified bifacial modules that resemble a rear and a front monofacial panel respectively. As a first result, if the measurements are translated to STC, using a linear approximation, the bifaciality matches the value indicated by the manufacturer. Additionally, the operating bifaciality coefficient shows a linear decrease trend, proportional to the irradiance level decrease. This result implies that on cloudy days, the average bifaciality factor is below the corresponding one from sunny days. Finally, for irradiances below 200 W/m2, there is a non-linear increase in the bifaciality, with greater values than the corresponding to the ideal STC conditions, which presumably are caused by the non-linearity performance of photovoltaic modules at low irradiances.

Creation of NV Centers in Diamond under 155 MeV Electron Irradiation

AbstractSingle‐crystal diamond substrates presenting a high concentration of negatively charged nitrogen‐vacancy centers (NV−) are on high demand for the development of optically pumped solid‐state sensors such as magnetometers, thermometers, or electrometers. While nitrogen impurities can be easily incorporated during crystal growth, the creation of vacancies requires further treatment. Electron irradiation and annealing is often chosen in this context, offering advantages with respect to irradiation by heavier particles that negatively affect the crystal lattice structure and consequently the NV− optical and spin properties. A thorough investigation of electron irradiation possibilities is needed to optimize the process and improve the sensitivity of NV‐based sensors. In this work, the effect of electron irradiation is examined in a previously unexplored regime: extremely high energy electrons, at 155 MeV. A simulation model is developed to estimate the concentration of created vacancies and an increase of NV− concentration by more than three orders of magnitude following irradiation of a nitrogen‐rich HPHT diamond over a very large sample volume is experimentally demonstrated, which translates into an important gain in sensitivity. Moreover, the impact of electron irradiation in this peculiar regime on other figures of merits relevant for NV sensing is discussed, including charge state conversion efficiency and spin relaxation time. Finally, the effect of extremely high energy irradiation is compared with the more conventional low energy irradiation process, employing 200 keV electrons from a transmission electron microscope, for different substrates and irradiation fluences, evidencing 60‐fold higher yield of vacancy creation per electron at 155 MeV.

Synergistic effects in ZnO nanorod films by pulsed electrodeposition on graphene oxide towards enhanced photocatalytic degradation

In this work the synthesis, characterization and photocatalytic activity of novel graphene oxide-supported ZnO nanostructured film are reported. The ZnO film was deposited onto GO layer in a two-step procedure varying the deposition mode. The electrodeposited ZnO films were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform Infrared (FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS). The effect of the electrodeposition mode and GO presence on the properties of the ZnO nanostructured film was assessed. The applicability towards the adsorption, photodegradation of methylene blue (MB) for the obtained films was analyzed. The results indicated the electrodeposition pulses result in a strong interaction between ZnO and GO results, lower c-axis strain of the deposited ZnO and higher oxygen vacancies. Synergistic effect of oxygen vacancies and morphology towards degradation performance was indicated. Both adsorption and photocatalysis towards the degradation of MB on the modified ZnO films were observed, 52 % degradation efficiency being recorded in 90 min with a rate constant of 0.00171 min−1 under low UV irradiation, with respect to 5 % corresponding to ZnO film obtained in single step by direct mode and in absence of GO layer. A recycling experiment indicated excellent stability of the photocatalyst, the degradation efficiency reaching 98 % after 3 successive runs.

Photocatalytic degradation of tetrabromobisphenol A by Z-scheme WO3/ZnIn2S4 heterojunction: Efficiency, mechanism and toxicity evaluation

Occurrence of brominated flame retardants especially tetrabromobisphenol A (TBBPA) in water bodies poses a serious threat to aquatic ecosystems. Heterogeneous photocatalysis is a versatile technology that can efficiently degrade organic contaminants. However, existing studies on photocatalytic degradation of TBBPA are all achieved under intense light irradiation and high initial concentrations of TBBPA, which are far from real environmental conditions and not conducive to practical application. In this study, series of Z-scheme heterojunctions of WO3/ZnIn2S4 photocatalysts were prepared and used for the high-efficiency photocatalytic degradation of TBBPA at lower light irradiation intensity (100 W) and lower TBBPA concentration (5.4 mg/L). Among them, WO3/ZnIn2S4-3 (molar ratio of 1:3) exhibited the highest photocatalytic activity due to the formation of Z-Scheme heterojunction which effectively facilitated the separation of photogenerated charges and endowed WO3/ZnIn2S4-3 higher redox ability. Thus, under light illumination, 91.6% degradation of TBBPA was achieved at an initial pH of 8.0 within 150 min, with a pseudo-first-order rate constant of 0.01572 min−1. Electron spin resonance spectroscopy and radical scavenger experiments confirmed that ·O2− radicals were the primary reactive oxygen species driving the TBBPA degradation. By applying LC-MS/MS, the degradation products were identified and possible degradation pathways were proposed. Finally, potential toxicity for PBBPA and generated intermediates were evaluated using luminescent bacteria, which revealed the toxicity of PBBPA was reduced effectively during the photocatalytic degradation process. Overall, the Z-scheme WO3/ZnIn2S4 photocatalyst provides a promising way for the application of photocatalytic technology in actual wastewater treatment.

The influence of solute elements on grain size, hardness and irradiation-induced defect clusters in dilute Fe-based alloys

The precipitation of solutes is the primary factor that leads to the occurrence of irradiation hardening and embrittlement, thus limiting the service life of reactor pressure vessel (RPV) steels. In this study, four model alloys (Fe-1.35Mn-0.75Ni, Fe-1.35Mn-0.20Si, Fe-0.75Ni-0.20Si and Fe-1.35Mn-0.75Ni-0.20Si) were used to investigate the influence of solute elements on grain size, hardness, irradiation hardening, and defect clustering behavior. The materials were irradiated with 3.5 MeV Fe ions to doses of 0.1, 0.3, 1.0, and 3.0 dpa at 290 °C. Results indicated that the addition of solute Mn resulted in grain refinement while the addition of solutes Ni and Si led to grain coarsening. The strength of the model alloys was affected by the change in grain size. A definite dose rate effect was found in all four model alloys under irradiation, where irradiation with a higher dose rate led to a lower irradiation hardening effect and irradiation with a lower dose rate induced a higher hardening effect. Atom probe tomography (APT) results revealed that the precipitated solutes were always coupled with interstitial defect clusters. Solute Mn had a strong influence on cluster nucleation and a weak influence on cluster size. Solutes Si and Ni significantly promoted the nucleation and growth of clusters, and Ni had a greater influence on the nucleation and growth of clusters than Si. Meanwhile, solute Si consistently exhibited a low fraction in the clusters when the solute Mn element was presented in the alloys.

An irradiation system for nuclear and materials research in a medical cyclotron

Development and commissioning of an irradiation system and experimental setup for nuclear research and materials analysis in a medical cyclotron facility is described. The setup, Low Energy in-Vacuum Irradiation System-LEVIS, is installed at the end of the existing R&D beamline. The components of LEVIS and their functions are explained and the characteristics such as energy, current and profile of the beam are measured. Different types of radiation detectors are installed and tested in the chamber for future applications of non-destructive analysis methods.

Keratinocytes Exposed to Blue or Red Light: Proteomic Characterization Showed Cytoplasmic Thioredoxin Reductase 1 and Aldo-Keto Reductase Family 1 Member C3 Triggered Expression.

Several cell-signaling mechanisms are activated by visible light radiation in human keratinocytes, but the key regulatory proteins involved in this specific cellular response have not yet been identified. Human keratinocytes (HaCaT cells) were exposed to blue or red light at low or high irradiance for 3 days in cycles of 12 h of light and 12 h of dark. The cell viability, apoptotic rate and cell cycle progression were analyzed in all experimental conditions. The proteomic profile, oxidative stress and mitochondrial morphology were additionally evaluated in the HaCaT cells following exposure to high-irradiance blue or red light. Low-irradiance blue or red light exposure did not show an alteration in the cell viability, cell death or cell cycle progression. High-irradiance blue or red light reduced the cell viability, induced cell death and cell cycle G2/M arrest, increased the reactive oxygen species (ROS) and altered the mitochondrial density and morphology. The proteomic profile revealed a pivotal role of Cytoplasmic thioredoxin reductase 1 (TXNRD1) and Aldo-keto reductase family 1 member C3 (AKR1C3) in the response of the HaCaT cells to high-irradiance blue or red light exposure. Blue or red light exposure affected the viability of keratinocytes, activating a specific oxidative stress response and inducing mitochondrial dysfunction. Our results can help to address the targets for the therapeutic use of light and to develop adequate preventive strategies for skin damage. This in vitro study supports further in vivo investigations of the biological effects of light on human keratinocytes.

Research on radiation sensitive biomarkers and status of radiation safety literacy under low dose irradiation: Radiation biomarkers and radiation safety culture

ObjectiveTo analyze the health status and radiation sensitivity index of radiation workers in provincial, county and township hospitals. To explore the methods of evaluation indicators, evaluation standards and scoring principles of radiation safety culture in medical institutions. MethodsIn 2021, the radiation safety status of all 172 medical institutions in a city was investigated by using retrospective investigation, current situation investigation and laboratory study. The occupational health monitoring data of all 1547 radiation workers were statistically analyzed, and the radiation safety status and health indicators of radiation workers in provincial, county and township level hospitals were compared. ResultsThe results of occupational health monitoring of radiation workers showed that there were statistically significant differences in ALT, lens opacity (P < 0.05) and lymphocyte micronucleus (P < 0.05) between the two groups, and there were statistically significant differences in the influence of radiation service on the detection rate of lens opacity (P < 0.05). The survey results of radiation safety culture construction in medical institutions show that there are differences in the level of radiation safety culture in hospitals of different grades. The radiation safety culture construction of provincial and municipal public hospitals is obviously better than that of county hospitals, especially township hospitals. ConclusionInterventional radiologists and nuclear medicine workers engaged in iodine therapy were exposed to higher radiation agents, and radiation workers in township health centers were not aware of radiation protection, and there was a certain occupational risk. At the same time, the evaluation index of radiation safety literacy in medical institutions was determined, Disease prevention and control personnel stationed in hospitals is an effective measure to strengthen the construction of radiation safety culture in hospitals.

A simplified three-diode model for photovoltaic module: cell modeling and performance analysis

Purpose Estimation of solar cell parameters, mathematical modeling and the actual performance analysis of photovoltaic (PV) cells at various ecological conditions are very important in the design and analysis of maximum power point trackers and power converters. This study aims to propose the analysis and modeling of a simplified three-diode model based on the manufacturer’s performance data. Design/methodology/approach A novel technique is presented to evaluate the PV cell constraints and simplify the existing equation using analytical and iterative methods. To examine the current equation, this study focuses on three crucial operational points: open circuit, short circuit and maximum operating points. The number of parameters needed to estimate these built-in models is decreased from nine to five by an effective iteration method, considerably reducing computational requirements. Findings The proposed model, in contrast to the previous complex nine-parameter three-diode model, simplifies the modeling and analysis process by requiring only five parameters. To ensure the reliability and accuracy of this proposed model, its results were carefully compared with datasheet values under standard test conditions (STC). This model was implemented using MATLAB/Simulink and validated using a polycrystalline solar cell under STC conditions. Originality/value The proposed three-diode model clearly outperforms the earlier existing two-diode model in terms of accuracy and performance, especially in lower irradiance settings, according to the results and comparison analysis.

Haploidentical Hematopoietic Cell Transplant with Post-Transplant Cyclophosphamide Expedites Donor-Derived Immune Reconstitution in a Pediatric Severe Aplastic Anemia Cohort

Severe aplastic anemia (SAA) is a life-threatening, idiopathic process involving the immune-mediated destruction of hematopoietic stem cells. Treatment involves immunosuppressive therapy (IST) and/or allogeneic hematopoietic cell transplantation (HCT). The latter has recently been optimized with use of a post-transplant cyclophosphamide (PTCy) based graft-versus-host disease (GvHD) platform, permitting successful HCT with only half-HLA-matched haploidentical donors. In pediatrics, this platform results in &amp;gt;90% overall survival with low rates of GvHD and graft failure. However, reports on donor chimerism and immune reconstitution are limited. We hypothesized that a PTCy platform would expedite CD3 donor engraftment and CD4 T cell recovery. In a phase III clinical trial, we treated three cohorts of pediatric (age &amp;lt;/=25 years) patients with SAA requiring alloHCT: MUD, MSD, and HAPLO. The MUD cohort included n=15 recipients of 7-8/8 HLA-matched unrelated donor grafts (n=5 7/8, n=10 8/8) with median age 14 years (range 2-17 years), following cyclophosphamide (Cy) 50 mg/kg, fludarabine (Flu) 200 mg/m 2, rabbit anti-thymocyte globulin (rATG) 9 mg/kg total dose rabbit and low dose total body irradiation (TBI) at 200 cGy. The MSD cohort included n=9 recipients of 8/8 HLA-matched sibling donor grafts with median age 15 years (range 12-24 years), following Cy 200 mg/kg and 9 mg/kg rATG. The HAPLO cohort included n=4 recipients of 4/8 HLA-matched related donor grafts with median age 8.5 years (range 2-21 years) following Cy 29 mg/kg, Flu 150 mg/m 2, 9 mg/kg rATG, and low dose TBI at 200 cGy. GvHD prophylaxis consisted of 30 days of mycophenolate mofetil, and 100 days of a calcineurin inhibitor (followed by an 8-10 week taper), with the HAPLO cohort additionally receiving post-transplant Cy (PTCy) 50 mg/kg/day on days +3 and +4. Peripheral blood lymphocyte counts and peripheral blood and bone marrow donor chimerism were evaluated on days +100, +180 and +365. Recipient characteristics were largely equivalent between cohorts, with 43% receiving IST prior to HCT. Clonality was overrepresented in the HAPLO cohort (2 of 4, 1 with monosomy 7 myelodysplastic syndrome and 1 with a large PNH clone), with only 2 of 15 in the MUD and none in the MSD cohorts. Active controlled infections at the time of HCT were additionally overrepresented in the HAPLO cohort, with disseminated pseudomonas in 1. The MUD cohort had 1 with Rhizopus invasive sinusitis (none in the MSD cohort). Achievement of neutrophil engraftment was statistically significantly delayed in the HAPLO cohort at a median of 17 days compared to 12 for MSD and 14 for MUD, p=0.004), however there were no episodes of primary or secondary graft failure. With only a single late death from intracranial hemorrhage in the MUD cohort, OS was equivalent at 2 years (100% in MSD and HAPLO cohorts, 93.3% in MUD). GvHD rates were low with only 1 (MUD) experiencing grade II acute GvHD, and 1 (MUD) experiencing mild chronic GvHD. Immune reconstitution varied by cohort with statistically significantly greater CD3 peripheral blood donor chimerism (p&amp;lt;0.001) as well as CD4 (p=0.04) and CD8 (p=0.03) T cell counts over time for the HAPLO recipients (CD3 chimerism in Fig 1, CD4 count in Fig 2; 2-way ANOVA fixed effects model). Considering a CD4 &amp;gt;200 cell/uL as clinically meaningful, we assessed the proportion of each cohort achieving this milestone at each timepoint. While each cohort had an increase in proportion achieving CD4&amp;gt;200 over time, the HAPLO cohort reached 50% with CD4 &amp;gt;200 at day +100, compared to 11% MUD and 0% MSD (p=0.09). At day +180, the proportion with CD4 &amp;gt;200 were 36% MUD, 25% MSD and 75% HAPLO (1 yr: 90% MUD, 100% MSD and HAPLO). Donor availability remains a challenge to successful transplant for patients with SAA, and haploidentical matches overcome donor limited accessibility. PTCy as GvHD prophylaxis is associated with low incidences of graft failure and severe GvHD. While PTCy might be anticipated to inhibit donor T cells and immune reconstitution, our data, albeit limited by small cohorts, demonstrates superior and more efficient CD3 donor engraftment and CD4 T cell count recovery following HAPLO HCT with PTCy compared to non-PTCy based MUD and MSD cohorts.

Impact of Graft Source [Cord Blood Supported By CD34+ Selected Cells (Haplo-Cord) Vs. Matched Donor] on Transplant Outcomes in Myelofibrosis

Introduction: Allogeneic hematopoietic cell transplantation (allo-HCT) is curative for patients with myelofibrosis (MF). Here, we evaluated the impact of donor type [cord blood transplant supported by CD34+ cells (haplo-cord) vs adult matched donor] on outcomes in MF. Methods: All adult patients with primary or secondary (post-ET or post-PV) MF, including those progressing to acute leukemia (AML) who underwent their first allo-HCT at NewYork-Presbyterian Hospital/Weill Cornell Medicine between 01/2015 and 06/2022 were included. Results: 40 patients were transplanted. Median age was 63 years (range 21-77). 23% had a Karnofsky performance scale (KPS) of &amp;lt;80. Two had undergone splenectomy prior to HCT. The median spleen size was 18cm (10-28). Median number of pre-HCT molecular mutations was 2 (range 0-7). 16 (40%) had MF-3 (Table 1). 24 (60%) underwent a matched sibling donor (MSD) (n=9) or unrelated donor (MUD) (n=15) HCT, and 16 (40%) underwent a cord-based (CB) HCT. 39 received Fludarabine/Melphalan +/- low dose total body irradiation (TBI), one underwent myeloablative conditioning with TBI/etoposide based on extensive extramedullary disease. The median time to neutrophil engraftment in the MSD/MUD group was 14 days (IQR 14-18) vs 30 days in the CB group (IQR 15-36) and (p=0.1). The median time to platelet engraftment was 22 days (IQR 17-38) in MSD/MUD vs 49 days (IQR 26-60) in the CB group (P=0.07). The CI of absolute neutrophil count (ANC) and platelet engraftment by day 60 for MSD/MUD vs CB was 92% (95% CI 65-98%) vs 80% (95% CI 45-94%) (p=0.09) and 75% (95% CI 51%- 88%) vs 59% (95% CI 27-81%) (p=0.36), respectively. One patient in the MSD/MUD died without neutrophil engraftment compared to 3 in CB group. 5 patients in each group died without platelet engraftment. Median follow-up for all alive patients was 53 months. Overall survival (OS) for the cohort was 62% at 1 year (95% CI 49-79) and 34% at 3 years (95% CI 21-55). OS at 3 years was similar between MSD/MUD group and CB (32% vs 37%, P=0.9) (figure 1). Graft versus host disease relapse free survival (GRFS) at 3 years was not significantly different in MSD/MUD group, compared to CB group (15% vs 33%, P=0.64). Cumulative incidence of relapse at 3 years in MSD/MUD group was 28% (95% CI 10-49), and 12% (95% CI 1.8-34) in CB group (p=0.356). Non-relapse mortality (NRM) at 1 year was 33% (95% CI 15-52) in MSD/MUD group and 38% (95% CI 15-61) in CB group. NRM at 3 years was 54% (95% CI 29-73) in MSD/MUD group and 48% (95% CI 19-72) on CB group (P=0.95). Discussion: In our small cohort, we showed that OS after haplo-cord transplant was comparable to adult matched donors' grafts (MSD or MUD). While the haplo-cord platforms have been shown to decrease the time to engraftment (11 days for neutrophils and 22 days for platelets) compared with double cord transplants or haploidentical transplants (van Besien K et al . Haematologica 2016, van Besien K et al. Blood Adv 2019), in patients with MF, we saw a trend towards delayed engraftment compared to patients transplanted with adult matched donors' grafts (MSD or MUD). This suggests that the CD34 selected cells may not be able to provide an adequate myeloid bridge and overcome the low cellular content in the CB for adult patients with extensive marrow fibrosis. Larger studies are needed to compare best alternative graft (CB-based versus haploidentical or mismatched unrelated donors) for patients with MF that lack a matched donor.

Effect of low dose irradiation of heavy ion on electrochemical corrosion and IASCC behavior of austenitic steel

The impacts of low dose irradiation on the behavior of electrochemical corrosion and irradiation assisted stress corrosion cracking for 321 stainless steel were studied using Fe2+ ion irradiation to simulate neutron radiation damage in primary circuit environment of pressurized water reactor. Low dose irradiation can improve the pitting resistance and reduce the cracking tendency of the alloy in B-Li solution to a certain extent, which was related to the δ phase content on the near-surface of the sample: The higher δ phase content on the near-surface of the 2 dpa irradiated sample was observed by grazing incident X-ray diffraction. In addition, the pits was significantly increased near micro-cracks for the unirradiated sample, indicating that the existence of pits induced the initiation of cracks. The research results provided an important reference for the failure mechanism of irradiation assisted stress corrosion cracking of core components.

Combined anticancer effects of neutron radiation and genistein on prostate cancer cells

Prostate cancer is the most frequent cancer in men and the second largest cause of cancer-related mortality after lung cancer. Today, studies on neutron radiation therapy show that this method alone is not able to prevent the progression of the disease in most patients with prostate cancer, so it is better to combine neutron radiation with an auxiliary antitumor such as genistein. We found that genistein has anticancer properties and few antioxidant capabilities and could cause the death of prostate cancer cells, mostly through triggering apoptosis. Here the purpose of this study was to evaluate the effect of very low dose rate neutron irradiation emitted from 241Am-Be neutron source as well as the effect of the combination of neutron irradiation and adding the optimal concentration of genistein (480 μM) on the attenuation of prostate cancer PC3 cells in 3D culture environment. MTT assay, Neutral red assay, NO assay, Catalase activity, Reduced glutathione (GSH), Cytochrome c releasing, and Comet assay were used to assess the effect and type of mortality caused by neutron radiation and also neutron and genistein combination in prostate cancer cells. The results of cytotoxicity test reveal that very low dose rate neutron radiation (0.6 mGy/h) with or without genistein at 5, 10, 15, and 20h reduced the survival of prostate cancer cells. Moreover, the rate of necrosis due to the neutron effect at different irradiation times enhanced with the increasing time. Despite significant anticancer effect of Genistein, it cannot be used simultaneously with neutron radiation for prostate cancer treatment.

Active Breathing Coordinator reduces radiation dose to the stomach in patients with left breast cancer

Background/Purpose Gastric dose parameters comparison for deep inspiration breath-hold (DIBH) or free breathing (FB) mode during radiotherapy (RT) for left-sided breast cancer patients (LSBCPs) has not been investigated before. This study aimed to analyze the impact of Active Breath Coordinator (ABC)-DIBH technique on the dose received by the stomach during RT for LSBCPs and to provide organ-specific dosimetric parameters. Materials and methods The study included 73 LSBCPs. The dosimetric parameters of the stomach were compared between FB and DIBH mode. The correlation between the stomach volume and dosimetric parameters was analyzed. Results Compared to FB mode, statistically significant reductions were observed in gastric dose parameters in ABC-DIBH mode, including Dmax (46.60 vs 17.25, p < 0.001), D1cc (38.42 vs 9.60, p < 0.001), Dmean (4.10 vs 0.80, p < 0.001), V40Gy (0.50 vs 0.00, p < 0.001), V30Gy (6.30 vs 0.00, p < 0.001), V20Gy (20.80 vs 0.00, p < 0.001), V10Gy (51.10 vs 0.77, p < 0.001), and V5Gy (93.20 vs 9.60, p < 0.001). ABC-DIBH increased the distance between the stomach and the breast PTV when compared to FB, from 1.3 cm to 2.8 cm (p < 0.001). Physiologic decrease in stomach volume was not found from FB to ABC-DIBH (415.54 cm3 vs 411.61 cm3, p = 0.260). The stomach volume showed a positive correlation with V40Gy (r2 = 0.289; p < 0.05), V30Gy (r2 = 0.287; p < 0.05), V20Gy (r2 = 0.343; p < 0.05), V10Gy (r2 = 0.039; p < 0.001), V5Gy (r2 = 0.439; p < 0.001), Dmax (r2 = 0.269; p < 0.05) and D1cc (r2 = 0.278; p < 0.05) in FB mode. While in ABC-DIBH mode, most stomach dosimetric parameters were not correlated with gastric volume. Conclusions The implementation of ABC-DIBH in LSBCPs radiotherapy resulted in lower irradiation of the stomach. Larger stomach volume was associated with statistically significantly higher dose irradiation in FB mode. To reduce radiotherapy related side effects in FB mode, patients should be fast for at least 2 hours before the CT simulation and treatment.

Impact of repeated short light exposures on sustained pupil responses in an fMRI environment.

Light triggers numerous non-image-forming, or non-visual, biological effects. The brain correlates of these non-image-forming effects have been investigated, notably using magnetic resonance imaging and short light exposures varying in irradiance and spectral quality. However, it is not clear whether non-image-forming responses estimation may be biased by having light in sequential blocks, for example, through a potential carryover effect of one light onto the next. We reasoned that pupil light reflex was an easy readout of one of the non-image-forming effects of light that could be used to address this issue. We characterised the sustained pupil light reflex in 13-16 healthy young individuals under short light exposures during three distinct cognitive processes (executive, emotional and attentional). Light conditions pseudo-randomly alternated between monochromatic orange light (0.16 melanopic equivalent daylight illuminance lux) and polychromatic blue-enriched white light of three different levels (37, 92, 190 melanopic equivalent daylight illuminance lux). As expected, higher melanopic irradiance was associated with larger sustained pupil light reflex in each cognitive domain. This result was stable over the light sequence under higher melanopic irradiance levels compared with lower ones. Exploratory frequency-domain analyses further revealed that sustained pupil light reflex was more variable under lower melanopic irradiance levels. Importantly, sustained pupil light reflex varied across tasks independently of the light condition, pointing to a potential impact of light history and/or cognitive context on sustained pupil light reflex. Together, our results emphasise that the distinct contribution and adaptation of the different retinal photoreceptors influence the non-image-forming effects of light and therefore potentially their brain correlates.