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In situ-forming biocompatible hydrogels have great potential in various medical applications. Here, we introduce a pH-responsive, self-healable, and biocompatible hydrogel for cell scaffolds and the development of a tumor spheroid phantom for magnetic resonance imaging. The hydrogel (pMAD) was synthesized via amino-yne click chemistry between poly(2-methacryloyloxyethyl phosphorylcholine- co -2-aminoethylmethacrylamide) and dialkyne polyethylene glycol. Rheology analysis, compressive mechanical testing, and gravimetric analysis were employed to investigate the gelation time, mechanical properties, equilibrium swelling, and degradability of pMAD hydrogels. The reversible enamine and imine bond mechanisms leading to the sol-to-gel transition in acidic conditions (pH ≤ 5) were observed. The pMAD hydrogel demonstrated potential as a cellular scaffold, exhibiting high viability and NIH-3T3 fibroblast cell encapsulation under mild conditions (37 °C, pH 7.4). Additionally, the pMAD hydrogel also demonstrated the capability for in vitro magnetic resonance imaging of glioblastoma tumor spheroids based on the chemical exchange saturation transfer effect. Given its advantages, the pMAD hydrogel emerges as a promising material for diverse biomedical applications, including cell carriers, bioimaging, and therapeutic agent delivery.

Background: T 2 * mapping can characterize tumor hypoxia, which may be associated with resistance to therapy. Acquiring T 2 * maps during MR-guided radiotherapy could inform treatment adaptation by, for example, escalating the dose to resistant sub-volumes., Purpose: The purpose of this work is to demonstrate the feasibility of the accelerated T 2 * mapping technique using model-based image reconstruction with integrated trajectory auto-correction (TrACR) for MR-guided radiotherapy on an MR-Linear accelerator (MR-Linac)., Materials and Methods: The proposed method was validated in a numerical phantom, where two T 2 * mapping approaches (sequential and joint) were compared for different noise levels (0,0.1,0.5,1) and gradient delays ([1, -1] and [1, -2] in units of dwell time for x- and y-axis, respectively). Fully sampled k-space was retrospectively undersampled using two different undersampling patterns. Root mean square errors (RMSEs) were calculated between reconstructed T 2 * maps and ground truth. In vivo data was acquired twice weekly in one prostate and one head and neck cancer patient undergoing treatment on a 1.5 T MR-Linac. Data were retrospectively undersampled and T 2 * maps reconstructed, with and without trajectory corrections were compared., Results: Numerical simulations demonstrated that, for all noise levels, T 2 * maps reconstructed with a joint approach demonstrated less error compared to an uncorrected and sequential approach. For a noise level of 0.1, uniform undersampling and gradient delay [1, -1] (in units of dwell time for x- and y-axis, respectively), RMSEs for sequential and joint approaches were 13.01 and 9.32 ms, respectively, which reduced to 10.92 and 5.89 ms for a gradient delay of [1, 2]. Similarly, for alternate undersampling and gradient delay [1, -1], RMSEs for sequential and joint approaches were 9.80 and 8.90 ms, respectively, which reduced to 9.10 and 5.40 ms for gradient delay [1, 2]. For in vivo data, T 2 * maps reconstructed with our proposed approach resulted in less artifacts and improved visual appearance compared to the uncorrected approach. For both prostate and head and neck cancer patients, T 2 * maps reconstructed from different treatment fractions showed changes within the planning target volume (PTV)., Conclusion: Using the proposed approach, a retrospective data-driven gradient delay correction can be performed, which is particularly relevant for hybrid devices, where full information on the machine configuration is not available for image reconstruction. T 2 * maps were acquired in under 5 min and can be integrated into MR-guided radiotherapy treatment workflows, which minimizes patient burden and leaves time for additional imaging for online adaptive radiotherapy on an MR-Linac., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Our study evaluated whether an MRI reporting system highlighting areas of contiguous and discontinuous extramural venous invasion (EMVI) can improve the accuracy of gross tumour volume (GTV) delineation. Initially, 27 consecutive patients with locally advanced rectal cancer treated between 2012 and 2014 were evaluated. We used an MRI reporting proforma that documented the position of the primary tumour, lymph nodes and EMVI. The new GTVs delineated were compared with historical radiotherapy treatment volumes to identify the frequency of GTV geographical miss. We observed that the delineation of involved nodes and areas of EMVI was more likely to represent sources of uncertainty wherein nodal GTV geographical miss was evident in 5 out of 27 patients (19%). Complete EMVI GTV geographical miss occurred in two patients (7%). We re-evaluated our radiotherapy practice in a further 27 patients after the implementation of a modified MRI reporting system. An improvement was seen; nodal miss was observed in two patients (7%) and partial EMVI miss in one patient (4%), although these areas were encompassed in the planning target volume (PTV). Our study shows that extramural venous invasion and involved nodes need to be highlighted on MRI to improve the accuracy of rectal cancer GTV delineation.

Earlier age of cannabis usage poses higher risk of Cannabis Use Disorder and adverse consequences, such as addiction, anxiety, dysphoria, psychosis, largely attributed to its principal psychoactive component, Δ9-tetrahydrocannabinol (THC) and altered dopaminergic function. As dopamine D1-D2 receptor heteromer activation causes anxiety and anhedonia, this signaling complex was postulated to contribute to THC-induced affective symptoms. To investigate this, we administered THC repeatedly to adolescent monkeys and adolescent or adult rats. Drug-naïve adolescent rat had lower striatal densities of D1-D2 heteromer compared to adult rat. Repeated administration of THC to adolescent rat or adolescent monkey did not alter D1-D2 heteromer expression in nucleus accumbens or dorsal striatum but upregulated it in adult rat. Behaviourally, THC-treated adult, but not adolescent rat manifested anxiety and anhedonia-like behaviour, with elevated composite negative emotionality scores that correlated with striatal D1-D2 density. THC modified downstream markers of D1-D2 activation in adult, but not adolescent striatum. THC administered with cannabidiol did not alter D1-D2 expression. In adult rat, co-administration of CB1 receptor (CB1R) inverse agonist with THC attenuated D1-D2 upregulation, implicating cannabinoids in the regulation of striatal D1-D2 heteromer expression. THC exposure revealed an adaptable age-specific, anxiogenic, anti-reward mechanism operant in adult striatum but deficient in adolescent rat and monkey striatum that may confer increased sensitivity to THC reward in adolescence while limiting its negative effects, thus promoting continued use and increasing vulnerability to long-term adverse cannabis effects., Competing Interests: 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. Susan R George and Bertha K Madras report financial support was provided by National Institute of Health., (© 2023 Published by Elsevier B.V.)

Background: The first-line treatment for basal cell carcinoma (BCC) involved either surgical excision (SE) or Mohs micrographic surgery (MMS). The current waiting time for MMS and whether this is associated with worsening of outcome is unknown. We aim to look at the waiting time for MMS upon review at the Outpatient Specialist Dermatology Clinic and the increase in lesion size during this time period., Methods: A retrospective analysis of all patients who underwent MMS for biopsy-proven BCC over a duration of 5 years was performed. Variables analysed included patient age, sex, location, histologic subtype, lesion size at initial presentation, lesion size during MMS, defect size following MMS, waiting time for MMS, and projected defect size if lesions were treated with SE at earlier time point., Results: A total of 233 patients were included in the final analysis. The mean wait time between referral to MMS was 215.8±125.7 days. The mean maximum diameter of lesions was 9.34±5.23 mm at referral for MMS and 11.91±6.60 mm at presentation for MMS, hence an increase of 3.01±3.03 mm (p=0.001, paired t-test), which equates to 1.41±0.42 times increase. The mean maximum diameter of the actual defect size post-MMS was 18.03±9.45mm, while the projected diameter of defect post SE was 15.29±5.71 mm, hence, smaller by 3.27±5.51 mm (p=0.001, paired t-test) compared with actual defect size post-MMS., Conclusion: This study highlights that the lesion grows significantly during the long wait for MMS. Hence, an increase in capacity for MMS is essential to reduce the waiting time for surgery which could lead to a defect which is easier to reconstruct with better outcome for patients., Competing Interests: Conflict of interest There is no conflict of interest to report., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: Radiomic models present an avenue to improve oesophageal adenocarcinoma assessment through quantitative medical image analysis. However, model selection is complicated by the abundance of available predictors and the uncertainty of their relevance and reproducibility. This analysis reviews recent research to facilitate precedent-based model selection for prospective validation studies., Methods: This analysis reviews research on 18F-FDG PET/CT, PET/MRI and CT radiomics in oesophageal adenocarcinoma between 2016 and 2021. Model design, testing and reporting are evaluated according to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) score and Radiomics Quality Score (RQS). Key results and limitations are analysed to identify opportunities for future research in the area., Results: Radiomic models of stage and therapeutic response demonstrated discriminative capacity, though clinical applications require greater sensitivity. Although radiomic models predict survival within institutions, generalisability is limited. Few radiomic features have been recommended independently by multiple studies., Conclusions: Future research must prioritise prospective validation of previously proposed models to further clinical translation., (© 2022. The Author(s).)

The efficient encapsulation of small molecule active ingredients has been a challenge for many decades across many commercial applications. Recently, successful attempts to address this issue have included deposition of thin metal shells onto liquid filled polymer microcapsules or emulsion droplets to provide an impermeable barrier to diffusion. In this work we have developed a novel method to protect small molecule active ingredients by deposition of thin mineral shells. Platinum nanoparticles are used to catalyse and direct growth of a calcium phosphate shell onto liquid filled polymer microcapsules under various reaction conditions. Findings indicate that a non-porous protective shell is formed on the majority of the microcapsule population, with small concentrations of the core material being released only from those microcapsules with defects, over a 7 days period, when conducting forced release studies into a solvent for the core oil. The resulting microcapsules show no significant cell toxicity when exposed to HEK 293 cells for 72 h., 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Brain tumors represent the highest cause of mortality in the pediatric oncological population. Diagnosis is commonly performed with magnetic resonance imaging. Survival biomarkers are challenging to identify due to the relatively low numbers of individual tumor types. 69 children with biopsy-confirmed brain tumors were recruited into this study. All participants had perfusion and diffusion weighted imaging performed at diagnosis. Imaging data were processed using conventional methods, and a Bayesian survival analysis performed. Unsupervised and supervised machine learning were performed with the survival features, to determine novel sub-groups related to survival. Sub-group analysis was undertaken to understand differences in imaging features. Survival analysis showed that a combination of diffusion and perfusion imaging were able to determine two novel sub-groups of brain tumors with different survival characteristics (p < 0.01), which were subsequently classified with high accuracy (98%) by a neural network. Analysis of high-grade tumors showed a marked difference in survival (p = 0.029) between the two clusters with high risk and low risk imaging features. This study has developed a novel model of survival for pediatric brain tumors. Tumor perfusion plays a key role in determining survival and should be considered as a high priority for future imaging protocols., (© 2021. The Author(s).)

Investigations of the human germline and programming are challenging because of limited access to embryonic material. However, the pig as a model may provide insights into transcriptional network and epigenetic reprogramming applicable to both species. Here we show that, during the pre- and early migratory stages, pig primordial germ cells (PGCs) initiate large-scale epigenomic reprogramming, including DNA demethylation involving TET-mediated hydroxylation and, potentially, base excision repair (BER). There is also macroH2A1 depletion and increased H3K27me3 as well as X chromosome reactivation (XCR) in females. Concomitantly, there is dampening of glycolytic metabolism genes and re-expression of some pluripotency genes like those in preimplantation embryos. We identified evolutionarily young transposable elements and gene coding regions resistant to DNA demethylation in acutely hypomethylated gonadal PGCs, with potential for transgenerational epigenetic inheritance. Detailed insights into the pig germline will likely contribute significantly to advances in human germline biology, including in vitro gametogenesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

There is evidence that ATM mutated in ataxia-telangiectasia (A-T) plays a key role in protecting against mitochondrial dysfunction, the mechanism for which remains unresolved. We demonstrate here that ATM-deficient cells are exquisitely sensitive to nutrient deprivation, which can be explained by defective cross talk between the endoplasmic reticulum (ER) and the mitochondrion. Tethering between these two organelles in response to stress was reduced in cells lacking ATM, and consistent with this, Ca 2+ release and transfer between ER and mitochondria was reduced dramatically when compared with control cells. The impact of this on mitochondrial function was evident from an increase in oxygen consumption rates and a defect in mitophagy in ATM-deficient cells. Our findings reveal that ER-mitochondrial connectivity through IP3R1-GRP75-VDAC1, to maintain Ca 2+ homeostasis, as well as an abnormality in mitochondrial fusion defective in response to nutrient stress, can account for at least part of the mitochondrial dysfunction observed in A-T cells., Competing Interests: None of the authors have a conflict of interest. This study was not funded by any commercial entity and has not attracted any intellectual property protection or patents., (© 2020 The Authors.)