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The use of nanoparticles to enhance the effect of radiation-based cancer treatments is a growing field of study and recently, even nanoparticle-induced improvement of proton therapy performance has been investigated. Aiming at a clinical implementation of this approach, it is essential to characterize the mechanisms underlying the synergistic effects of nanoparticles combined with proton irradiation. In this study, we investigated the effect of platinum- and gadolinium-based nanoparticles on the nanoscale damage induced by a proton beam of therapeutically relevant energy (150 MeV) using plasmid DNA molecular probe. Two conditions of irradiation (0.44 and 3.6 keV/μm) were considered to mimic the beam properties at the entrance and at the end of the proton track. We demonstrate that the two metal-containing nanoparticles amplify, in particular, the induction of nanosize damages (>2 nm) which are most lethal for cells. More importantly, this effect is even more pronounced at the end of the proton track. This work gives a new insight into the underlying mechanisms on the nanoscale and indicates that the addition of metal-based nanoparticles is a promising strategy not only to increase the cell killing action of fast protons, but also to improve tumor targeting.

Models of recognition memory have postulated that the mammillo-thalamic tract (MTT)/anterior thalamic nucleus (AN) complex would be critical for recollection while the Mediodorsal nucleus (MD) of the thalamus would support familiarity and indirectly also be involved in recollection (Aggleton et al., 2011). 12 patients with left thalamic stroke underwent a neuropsychological assessment, three verbal recognition memory tasks assessing familiarity and recollection each using different procedures and a high-resolution structural MRI. Patients showed poor recollection on all three tasks. In contrast, familiarity was spared in each task. No patient had significant AN lesions. Critically, a subset of 5 patients had lesions of the MD without lesions of the MTT. They also showed impaired recollection but preserved familiarity. Recollection is therefore impaired following MD damage, but familiarity is not. This suggests that models of familiarity, which assign a critical role to the MD, should be reappraised.

BackgroundThis study’s aim was to develop our dosimetric methodology using a commercial workstation for the routine evaluation of the organs at risk during peptide receptor radionuclide therapy (PRRT) with 177Lu.MethodsFirst, planar and SPECT sensitivity factors were determined on phantoms. The reconstruction parameters were optimized by SPECT/CT image acquisition using a NEMA IEC phantom containing a 500 ml bottle of 177Lu, to simulate a kidney. The recovery coefficients were determined on various phantoms. For the red marrow, this was calculated using a NEMA IEC phantom that contained a centrally placed bottle of 80 ml of 177Lu (to model the L2-L4 red marrow) flanked by two 200 ml bottles with 177Lu to simulate the kidneys.Then, SPECT/CT images were acquired at 4, 24, 72, and 192 h after injection in 12 patients with neuroendocrine tumors who underwent PRRT with 177Lu-DOTATATE. SPECT data were reconstructed using the iterative ordered subset expectation maximization (OSEM) method, with six iterations and ten subsets, attenuation, scatter, recovery resolution corrections, and a Gaussian post-filter of 0.11 cm. The liver, spleen, kidneys, and red marrow dose per administered activity (AD/A admin) values were calculated with the Medical Internal Radiation Dose (MIRD) formalism and the residence times (Dosimetry toolkit® application) using standard and CT imaging-based organ masses (OLINDA/EXM® V1.0 software).ResultsSensitivity factors of 6.11 ± 0.01 and 5.67 ± 0.08 counts/s/MBq were obtained with planar and SPECT/CT acquisitions, respectively. A recovery coefficient of 0.78 was obtained for the modeled L2–L4 red marrow. The mean AD/A admin values were 0.43 ± 0.13 mGy/MBq [0.27–0.91] for kidneys, 0.54 ± 0.58 mGy/MBq [0.12–2.26] for liver, 0.61 ± 0.13 mGy/MBq [0.42–0.89] for spleen, and 0.04 ± 0.02 mGy/MBq [0.01–0.09] for red marrow. The AD/A admin values varied when calculated using the personalized and standard organ mass, particularly for kidneys (p = 1 × 10−7), spleen (p = 0.0069), and red marrow (p = 0.0027). Intra-patient differences were observed especially in organs close to or including tumor cells or metastases.ConclusionsThe obtained AD/A admin values were in agreement with the literature data. This study shows the technical feasibility of patient dosimetry in clinical practice and the need to obtain patient-specific information.

Recently, the addition of nanoparticles (NPs) has been proposed as a new strategy to enhance the effect of radiotherapy particularly in the treatment of aggressive tumors such as glioblastoma. The physical processes involved in radiosensitisation by nanoparticles have been well studied although further understanding of its biological impact is still lacking, and this includes the localisation of these NPs in the target cells. Most studies were performed with NPs tagged with fluorescent markers. However, the presence of these markers can influence the NPs uptake and localisation. In this study, a set of methods was used to unambiguously and fully characterise the uptake of label-free NPs, their co-localisation with cell organelles, and their radiosensitising efficacy. This set was applied to the case of gadolinium-based nanoparticles (GdBN) used to amplify the radiation killing of U87 glioblastoma cells extracted from highly aggressive human tumor. For the first time, Synchrotron Radiation Deep UV (SR-DUV) microscopy is proposed as a new tool to track label-free GdBN. It confirmed the localisation of the NPs in the cytoplasm of U87 cells and the absence of NPs in the nucleus. In a second step, Transmission Electron Microscopy (TEM) demonstrated that GdBN penetrate cells by endocytosis. Third, using confocal microscopy it was found that GdBN co-localise with lysosomes but not with mitochondria. Finally, clonogenic assay measurements proved that the presence of NPs in the lysosomes induces a neat amplification of the killing of glioblastoma cells irradiated by gamma rays. The set of combined experimental protocols—TEM, SR-DUV and confocal microscopy—demonstrates a new standard method to study the localisation of label-free NPs together with their radiosensitising properties. This will further the understanding of NP-induced radiosentisation and contribute to the development of nanoagents for radiotherapy.

Dear Editor, Allogeneic or autologous hematopoietic stem cell transplantation （HSCT） allows many patients with hematological malignancies to obtain prolonged survival and often disease cure. Autologous HSCT is particularly effective in acute promyelocytic leukemia （APL）, a subtype of acute myeloid leukemia （AML） after relapse with conventional treatment. However, iatrogenic endocrine disturbances and reproductive failure are frequently-encountered late effects, which have a major impact on the quality oflife.l Conditioning regimens with total body irradiation （TBI） and intensive chemotherapy before autologons or allogeneic HSCT are known to cause permanent infertility, a risk that can be prevented by sperm banking.2

Therapists have discussed for a long time whether attempts to voluntarily suppress the intrusion of trauma memories are helpful to combat the distressing impacts of trauma. Mary et al. studied survivors of the 2015 Paris terrorist attacks who developed posttraumatic stress disorder and those who did not (see the Perspective by Ersche). Using functional magnetic resonance imaging, they investigated the neural networks underlying the control and suppression of memory retrieval. The results suggest that the characteristic symptoms of the disorder are not related to the memory itself but to its maladaptive control. These results offer new insights into the development of post-traumatic stress disorder and potential avenues for treatment. Science , this issue p. eaay8477 ; see also p. 734 A brain imaging study of survivors of the 2015 Paris terror attacks suggests that memory suppression shields against posttraumatic stress disorder. In the aftermath of trauma, little is known about why the unwanted and unbidden recollection of traumatic memories persists in some individuals but not others. We implemented neutral and inoffensive intrusive memories in the laboratory in a group of 102 individuals exposed to the 2015 Paris terrorist attacks and 73 nonexposed individuals, who were not in Paris during the attacks. While reexperiencing these intrusive memories, nonexposed individuals and exposed individuals without posttraumatic stress disorder (PTSD) could adaptively suppress memory activity, but exposed individuals with PTSD could not. These findings suggest that the capacity to suppress memory is central to positive posttraumatic adaptation. A generalized disruption of the memory control system could explain the maladaptive and unsuccessful suppression attempts often seen in PTSD, and this disruption should be targeted by specific treatments.

Efforts to exclude past experiences from conscious awareness can lead to forgetting. Memory suppression is central to affective disorders, but we still do not really know whether emotions, including their physiological causes, are also impacted by this process in normal functioning individuals. In two studies, we measured the after-effects of suppressing negative memories on cardiac response in healthy participants. Results of Study 1 revealed that efficient control of memories was associated with long-term inhibition of the cardiac deceleration that is normally induced by disgusting stimuli. Attempts to suppress sad memories, by contrast, aggravated the cardiac response, an effect that was closely related to the inability to forget this specific material. In Study 2, electroencephalography revealed a reduction in power in the theta (3–8 Hz), alpha (8–12 Hz) and low-beta (13–20 Hz) bands during the suppression of unwanted memories, compared with their voluntary recall. Interestingly, however, the reduction of power in the theta frequency band during memory control was related to a subsequent inhibition of the cardiac response. These results provide a neurophysiological basis for the influence of memory control mechanisms on the cardiac system, opening up new avenues and questions for treating intrusive memories using motivated forgetting.

Background Autism spectrum disorder (ASD) is associated with atypical neural activity in resting state. Most of the studies have focused on abnormalities in alpha frequency as a marker of ASD dysfunctions. However, few have explored alpha synchronization within a specific interest in resting-state networks, namely the default mode network (DMN), the sensorimotor network (SMN), and the dorsal attention network (DAN). These functional connectivity analyses provide relevant insight into the neurophysiological correlates of multimodal integration in ASD. Methods Using high temporal resolution EEG, the present study investigates the functional connectivity in the alpha band within and between the DMN, SMN, and the DAN. We examined eyes-closed EEG alpha lagged phase synchronization, using standardized low-resolution brain electromagnetic tomography (sLORETA) in 29 participants with ASD and 38 developing (TD) controls (age, sex, and IQ matched). Results We observed reduced functional connectivity in the ASD group relative to TD controls, within and between the DMN, the SMN, and the DAN. We identified three hubs of dysconnectivity in ASD: the posterior cingulate cortex, the precuneus, and the medial frontal gyrus. These three regions also presented decreased current source density in the alpha band. Conclusion These results shed light on possible multimodal integration impairments affecting the communication between bottom-up and top-down information. The observed hypoconnectivity between the DMN, SMN, and DAN could also be related to difficulties in switching between externally oriented attention and internally oriented thoughts.

Aberrant predictions of future threat lead to maladaptive avoidance in individuals with post-traumatic stress disorder (PTSD). How this disruption in prediction influences the control of memory states orchestrated by the dorsolateral prefrontal cortex is unknown. We combined computational modeling and brain connectivity analyses to reveal how individuals exposed and nonexposed to the 2015 Paris terrorist attacks formed and controlled beliefs about future intrusive re-experiencing implemented in the laboratory during a memory suppression task. Exposed individuals with PTSD used beliefs excessively to control hippocampal activity during the task. When this predictive control failed, the prediction-error associated with unwanted intrusions was poorly downregulated by reactive mechanisms. This imbalance was linked to higher severity of avoidance symptoms, but not to general disturbances such as anxiety or negative affect. Conversely, trauma-exposed participants without PTSD and nonexposed individuals were able to optimally balance predictive and reactive control during the memory suppression task. These findings highlight a potential pathological mechanism occurring in individuals with PTSD rooted in the relationship between the brain’s predictive and control mechanisms. It remains unclear how predictions of future threat affect memory recall, specifically in the case of post-traumatic stress disorder (PTSD). Here, the authors combined computational modeling and brain connectivity analyses to show that individuals with PTSD have exaggerated predictive control and reduced reactive control in a memory suppression task.

Purpose Training zones are generally assessed by gas-exchange thresholds (GET). Several mathematical analyses of heart rate variability (HRV) are proposed for indirect GET determination. Our study aimed to investigate the accordance of the detrend fluctuation analysis (DFA α1) for determining GET with first (VT1) and second ventilatory (VT2) thresholds in well-trained subjects. Methods Eighteen female and 38 male sub-elite cyclists performed a maximal incremental cycling test of 2-min stage duration with continuous gas exchange and HR measurements. Power output (PO), Oxygen uptake ( V ˙ O 2 ) and HR at VT1 and VT2 were compared with DFA α1 0.75 (HRVT1) and 0.50 (HRVT2). Agreements between PO, V ˙ O 2 and HR values were analyzed using Bland–Altman analysis. Results Large limits of agreement between VT1 and HRVT1 were observed for measures of V ˙ O 2 expressed in mL.min −1 .kg −1 [− 21.3; + 14.1], HR [ 39.2; + 26.9] bpm and PO [− 118; + 83] watts. Indeed, agreements were also low between VT2 and HRVT2 for measures of V ˙ O 2 [− 26.7; + 4.3] mL.min −1 .kg −1 , HR [− 45.5; + 10.6] bpm and PO [− 157; + 35] watts. Our results also showed a sex effect: women obtained worst predictions based on DFA α1 than men for HR ( p  = 0.014), PO ( p  = 0.044) at VT1 and V ˙ O 2 ( p  = 0.045), HR ( p  = 0.003) and PO ( p  = 0.004) at VT2. Conclusion There was unsatisfactory agreement between the GET and DFA α1 methods for VT1 and VT2 determination in both sex well-trained cyclists. Trial registration  number 2233534 on 2024/03/05 retrospectively registered.