Curcumin inhibits the invasion and migration of pancreatic cancer cells by upregulating TFPI-2 to regulate ERK- and JNK-mediated epithelial-mesenchymal transition.

PURPOSE: Pancreatic cancer (PC) is one of the most deadly human malignancies. Curcumin is a natural polyphenolic compound with wide-ranging pharmacological effects. Growing evidence suggests that curcumin has anticancer activity against PC, but the mechanism remains incompletely elucidated. This study aimed to investigate the effects and mechanisms of curcumin on the invasion and migration of PC cells. METHODS: Effect of curcumin on tissue factor pathway inhibitor (TFPI)-2 mRNA expression in PC cells was initially identified using qRT-PCR. Cytotoxicity of curcumin was assessed with MTT assays and IC50 was calculated. Involvement of ERK and JNK pathways, as well as protein expression of TFPI-2 and epithelial-mesenchymal transition (EMT)-related markers, were detected using immunoblotting. Invasion and migration of PC cells were examined using Transwell assays. TFPI-2 expression was manipulated by transfection with siRNA and shRNA. Rescue assays were used to validate the effect of curcumin on cell invasion and migration via TFPI-2. RESULTS: Curcumin increased the expression of TFPI-2 mRNA and protein in PC cells and attenuated cell invasion and migration. Curcumin also inhibited ERK and JNK pathways and EMT in PC cells. Knockdown of TFPI-2 partially reversed the inhibition of ERK and JNK pathways and EMT by curcumin. Mechanistically, curcumin upregulated TFPI-2, thereby inhibiting the ERK and JNK pathways, leading to the inhibition of EMT in PC cells. CONCLUSION: Collectively, curcumin inhibits ERK- and JNK-mediated EMT through upregulating TFPI-2, which in turn suppresses the migration and invasion of PC cells. These findings provide new insights into the antitumor mechanism of curcumin.

Modelling DTPA therapy following Am contamination in rats.

A major challenge in modelling the decorporation of actinides (An), such as americium (Am), with DTPA (diethylenetriaminepentaacetic acid) is the fact that standard biokinetic models become inadequate for assessing radionuclide intake and estimating the resulting dose, as DTPA perturbs the regular biokinetics of the radionuclide. At present, most attempts existing in the literature are empirical and developed mainly for the interpretation of one or a limited number of specific incorporation cases. Recently, several approaches have been presented with the aim of developing a generic model, one of which reported the unperturbed biokinetics of plutonium (Pu), the chelation process and the behaviour of the chelated compound An-DTPA with a single model structure. The aim of the approach described in this present work is the development of a generic model that is able to describe the biokinetics of Am, DTPA and the chelate Am-DTPA simultaneously. Since accidental intakes in humans present many unknowns and large uncertainties, data from controlled studies in animals were used. In these studies, different amounts of DTPA were administered at different times after contamination with known quantities of Am. To account for the enhancement of faecal excretion and reduction in liver retention, DTPA is assumed to chelate Am not only in extracellular fluids, but also in hepatocytes. A good agreement was found between the predictions of the proposed model and the experimental results for urinary and faecal excretion and accumulation and retention in the liver. However, the decorporation from the skeletal compartment could not be reproduced satisfactorily under these simple assumptions.

An encoder-decoder network for direct image reconstruction on sinograms of a long axial field of view PET.

PURPOSE: Deep learning is an emerging reconstruction method for positron emission tomography (PET), which can tackle complex PET corrections in an integrated procedure. This paper optimizes the direct PET reconstruction from sinogram on a long axial field of view (LAFOV) PET. METHODS: This paper proposes a novel deep learning architecture to reduce the biases during direct reconstruction from sinograms to images. This architecture is based on an encoder-decoder network, where the perceptual loss is used with pre-trained convolutional layers. It is trained and tested on data of 80 patients acquired from recent Siemens Biograph Vision Quadra long axial FOV (LAFOV) PET/CT. The patients are randomly split into a training dataset of 60 patients, a validation dataset of 10 patients, and a test dataset of 10 patients. The 3D sinograms are converted into 2D sinogram slices and used as input to the network. In addition, the vendor reconstructed images are considered as ground truths. Finally, the proposed method is compared with DeepPET, a benchmark deep learning method for PET reconstruction. RESULTS: Compared with DeepPET, the proposed network significantly reduces the root-mean-squared error (NRMSE) from 0.63 to 0.6 (p < 0.01) and increases the structural similarity index (SSIM) and peak signal-to-noise ratio (PSNR) from 0.93 to 0.95 (p < 0.01) and from 82.02 to 82.36 (p < 0.01), respectively. The reconstruction time is approximately 10 s per patient, which is shortened by 23 times compared with the conventional method. The errors of mean standardized uptake values (SUVmean) for lesions between ground truth and the predicted result are reduced from 33.5 to 18.7% (p = 0.03). In addition, the error of max SUV is reduced from 32.7 to 21.8% (p = 0.02). CONCLUSION: The results demonstrate the feasibility of using deep learning to reconstruct images with acceptable image quality and short reconstruction time. It is shown that the proposed method can improve the quality of deep learning-based reconstructed images without additional CT images for attenuation and scattering corrections. This study demonstrated the feasibility of deep learning to rapidly reconstruct images without additional CT images for complex corrections from actual clinical measurements on LAFOV PET. Despite improving the current development, AI-based reconstruction does not work appropriately for untrained scenarios due to limited extrapolation capability and cannot completely replace conventional reconstruction currently.

Heterogeneity of dose distribution in normal tissues in case of radiopharmaceutical therapy with alpha-emitting radionuclides.

Heterogeneity of dose distribution has been shown at different spatial scales in diagnostic nuclear medicine. In cancer treatment using new radiopharmaceuticals with alpha-particle emitters, it has shown an extensive degree of dose heterogeneity affecting both tumour control and toxicity of organs at risk. This review aims to provide an overview of generalized internal dosimetry in nuclear medicine and highlight the need of consideration of the dose heterogeneity within organs at risk. The current methods used for patient dosimetry in radiopharmaceutical therapy are summarized. Bio-distribution and dose heterogeneities of alpha-particle emitting pharmaceutical 223Ra (Xofigo) within bone tissues are presented as an example. In line with the strategical research agendas of the Multidisciplinary European Low Dose Initiative (MELODI) and the European Radiation Dosimetry Group (EURADOS), future research direction of pharmacokinetic modelling and dosimetry in patient radiopharmaceutical therapy are recommended.

Measurement, model prediction and uncertainty quantification of plasma clearance of cerium citrate in humans.

Double tracer studies in healthy human volunteers with stable isotopes of cerium citrate were performed with the aim of investigating the gastro-intestinal absorption of cerium (Ce), its plasma clearance and urinary excretion. In the present work, results of the clearance of Ce in blood plasma are shown after simultaneous intravenous and oral administration of a Ce tracer. Inductively coupled plasma mass spectrometry was used to determine the tracer concentrations in plasma. The results show that about 80% of the injected Ce citrate cleared from the plasma within the 5 mins post-administration. The data obtained are compared to a revised biokinetic model of Ce, which was initially developed by the International Commission on Radiological Protection (ICRP). The measured plasma clearance of Ce citrate was mostly consistent with that predicted by the ICRP biokinetic model. Furthermore, in an effort to quantify the uncertainty of the model prediction, the laboratory animal data on which the ICRP biokinetic Ce model is based, was analyzed. The measured plasma clearance and its uncertainty was also compared to the plasma clearance uncertainty predicted by the model. It was found that the measured plasma clearance during the first 15 min after administration is in a good agreement with the modelled plasma clearance. In general, the measured clearance falls inside the 95% confidence interval predicted by the biokinetic model.

Uncertainty analysis in internal dose calculations for cerium considering the uncertainties of biokinetic parameters and S values.

Radioactive cerium and other lanthanides can be transported through the aquatic system into foodstuffs and then be incorporated by humans. Information on the uncertainty of reported dose coefficients for exposed members of the public is then needed for risk analysis. In this study, uncertainties of dose coefficients due to the ingestion of the radionuclides 141Ce and 144Ce were estimated. According to the schema of internal dose calculation, a general statistical method based on the propagation of uncertainty was developed. The method takes into account the uncertainties contributed by the biokinetic models and by the so-called S values. These S-values were derived by using Monte Carlo radiation transport simulations with five adult non-reference voxel computational phantoms that have been developed at Helmholtz Zentrum München, Germany. Random and Latin hypercube sampling techniques were applied to sample parameters of biokinetic models and S values. The uncertainty factors, expressed as the square root of the 97.5th and 2.5th percentile ratios, for organ equivalent dose coefficients of 141Ce were found to be in the range of 1.2-5.1 and for 144Ce in the range of 1.2-7.4. The uncertainty factor of the detriment-weighted dose coefficient for 141Ce is 2.5 and for 144Ce 3.9. It is concluded that a general statistical method for calculating the uncertainty of dose coefficients was developed and applied to the lanthanide cerium. The dose uncertainties obtained provide improved dose coefficients for radiation risk analysis of humans. Furthermore, these uncertainties can be used to identify those parameters most important in internal dose calculations by applying sensitivity analyses.

Internal microdosimetry of alpha-emitting radionuclides.

At the tissue level, energy deposition in cells is determined by the microdistribution of alpha-emitting radionuclides in relation to sensitive target cells. Furthermore, the highly localized energy deposition of alpha particle tracks and the limited range of alpha particles in tissue produce a highly inhomogeneous energy deposition in traversed cell nuclei. Thus, energy deposition in cell nuclei in a given tissue is characterized by the probability of alpha particle hits and, in the case of a hit, by the energy deposited there. In classical microdosimetry, the randomness of energy deposition in cellular sites is described by a stochastic quantity, the specific energy, which approximates the macroscopic dose for a sufficiently large number of energy deposition events. Typical examples of the alpha-emitting radionuclides in internal microdosimetry are radon progeny and plutonium in the lungs, plutonium and americium in bones, and radium in targeted radionuclide therapy. Several microdosimetric approaches have been proposed to relate specific energy distributions to radiobiological effects, such as hit-related concepts, LET and track length-based models, effect-specific interpretations of specific energy distributions, such as the dual radiation action theory or the hit-size effectiveness function, and finally track structure models. Since microdosimetry characterizes only the initial step of energy deposition, microdosimetric concepts are most successful in exposure situations where biological effects are dominated by energy deposition, but not by subsequently operating biological mechanisms. Indeed, the simulation of the combined action of physical and biological factors may eventually require the application of track structure models at the nanometer scale.

Finding sensitive parameters in internal dose calculations for radiopharmaceuticals commonly used in clinical nuclear medicine.

Internal dosimetry after incorporation of radionuclides requires standardized biokinetic and dosimetric models. The aim of the present work was to identify the parameters and the components of the models which contribute most to dosimetric uncertainty. For this a method was developed allowing for the calculation of the uncertainties of the absorbed dose coefficients. More specifically, the sampling-based regression method and the variance-based method were used to develop and apply a global method of sensitivity analysis. This method was then used to quantify the impact of various biokinetic and dosimetric parameters on the uncertainty of internal doses associated with the incorporation of seven common radiopharmaceuticals. It turned out that the correlation between biokinetic parameters and time-integrated activity or calculated absorbed dose is strongest when the source and target organ are identical, in accordance with the ICRP and the MIRD approach. According to the ICRP approach, the parameter Fs which describes the fractional distribution of any incorporated radioactivity to organ S, has the greatest correlation with the time-integrated activity in the corresponding source organ or with the calculated dose in the corresponding target organ. In contrast, the MIRD approach suggested several biokinetic parameters with similar correlation. The dosimetric parameters usually contribute more to uncertainty in the calculated dose coefficients than the biokinetic parameters, in both approaches. The results obtained are helpful for the revision of biokinetic models for radiopharmaceuticals, because the most important parameters in clinical applications can now be identified and investigated in future studies.

Biokinetic measurements and modelling of urinary excretion of cerium citrate in humans.

Tracer kinetics in healthy human volunteers was studied applying stable isotopes of cerium citrate to obtain biokinetic human data for the urinary excretion of cerium. These data were then used to compare and validate the biokinetic model for lanthanides (cerium) proposed by Taylor and Leggett (Radiat Prot Dosim 105:193-198, 2003), which is substantially improved and more realistic than the biokinetic model currently recommended by the International Commission on Radiological Protection (ICRP Publication 67, 1993); both models are primarily based on animal data. In the present study, 16 adults were investigated and two cerium tracers were simultaneously administered, both intravenously and/or orally. The cerium concentrations in urine were determined by inductively coupled plasma mass spectrometry. Ingested cerium citrate was poorly absorbed, and its low excretion was similar to the prediction of the biokinetic model of Taylor and Leggett. In contrast, after injection of cerium citrate its urinary excretion was rapidly increased, and the model underestimated the experimental results. These results suggest that urinary excretion of cerium may be dependent on the administered chemical form of cerium (speciation).

Joint EURADOS-EANM initiative for an advanced computational framework for the assessment of external dose rates from nuclear medicine patients.

BACKGROUND: In order to ensure adequate radiation protection of critical groups such as staff, caregivers and the general public coming into proximity of nuclear medicine (NM) patients, it is necessary to consider the impact of the radiation emitted by the patients during their stay at the hospital or after leaving the hospital. Current risk assessments are based on ambient dose rate measurements in a single position at a specified distance from the patient and carried out at several time points after administration of the radiopharmaceutical to estimate the whole-body retention. The limitations of such an approach are addressed in this study by developing and validating a more advanced computational dosimetry approach using Monte Carlo (MC) simulations in combination with flexible and realistic computational phantoms and time activity distribution curves from reference biokinetic models. RESULTS: Measurements of the ambient dose rate equivalent H*(10) at 1 m from the NM patient have been successfully compared against MC simulations with 5 different codes using the ICRP adult reference computational voxel phantoms, for typical clinical procedures with 99mTc-HDP/MDP, 18FDG and Na131I. All measurement data fall in the 95% confidence intervals, determined for the average simulated results. Moreover, the different MC codes (MCNP-X, PHITS, GATE, GEANT4, TRIPOLI-4®) have been compared for a more realistic scenario where the effective dose rate E of an exposed individual was determined in positions facing and aside the patient model at 30 cm, 50 cm and 100 cm. The variation between codes was lower than 8% for all the radiopharmaceuticals at 1 m, and varied from 5 to 16% for the face-to face and side-by-side configuration at 30 cm and 50 cm. A sensitivity study on the influence of patient model morphology demonstrated that the relative standard deviation of H*(10) at 1 m for the range of included patient models remained under 16% for time points up to 120 min post administration. CONCLUSIONS: The validated computational approach will be further used for the evaluation of effective dose rates per unit administered activity for a variety of close-contact configurations and a range of radiopharmaceuticals as part of risk assessment studies. Together with the choice of appropriate dose constraints this would facilitate the setting of release criteria and patient restrictions.

Internal radiation exposure from TENORM for workers conducting cleaning activities on equipment used at geothermal energy plant.

Geothermal energy is predicted to be one of the most important renewable energy sources in the near future. In geothermal energy plants, the secondary products such as the scale containing naturally occurring radioactive material (NORM) and adhering to the surface of equipment produce radiation fields. The workers who maintain and clean such equipment are at a risk to be exposed by the technically enhanced NORM (TENORM). To estimate the risks of radiation exposure to the workers, we assessed internal doses resulting from the cleaning activities on 150 heat exchanging boards used at a geothermal energy plant, focusing on 222Rn, 226Ra, 210Pb, 228Ra and 228Th. The experiment was performed with the subjects of workers and office workers as control, supplying prepared foods and drinks. Using the analytical results of 210Pb, 226Ra, 228Ra, and 228Th in the excretions of subjects, committed effect doses were determined. The annual internal dose for the workers with protective clothing due to the cleaning activities on removing scale, assuming the cleaning activities requires 170 h (standard monthly working time) a year, was obtained as 26 µSv/y and the total dose including 222Rn inhalation dose was calculated as 323 µSv/y. The additional dose for the cleaning workers was less than the dose limit of 20000 µSv/y for radiation workers, even less than for general population (1000 µSv/y) recommended by International Commission on Radiological Protection (ICRP). However, the elevated inhalation dose for workers conducting cleaning activities may present a health hazard to workers if they deal with excessive materials containing TENORM, work for excessive time or are under inappropriate safety measures.

Radical recombination and antioxidants: a hypothesis on the FLASH effect mechanism.

PURPOSE: FLASH (ultra-high dose rate) radiotherapy spares normal tissue while keeping tumor control. However, the mechanism of the FLASH effect remains unclear and may have consequences beyond the irradiated area. MATERIALS AND METHODS: We reanalyze the available results of ultra-high-dose-rate-related experiments to find out the key points of the mechanism of the FLASH effect. Then, we present a hypothesis on the mechanism of the FLASH effect: FLASH beams generate a high transient concentration of peroxyl radicals leading to a high fraction of radical recombination, which results in less oxidation damage to normal tissue. For the cells containing higher concentrations of antioxidants, the fractions of radical recombination are smaller because the antioxidants compete to react with peroxyl radicals. Therefore the damages by different dose rate beams differ slightly in this condition. Since some tumors contain a higher level of antioxidants, this may be the reason for the loss of the protective effect in tumors irradiated by FLASH beams. The high concentration of antioxidants in tumors results in slight radiolytic oxygen consumption, and consequently the protective effect observed in in vitro experiment cannot be observed in in vivo experiment. To quantitatively elaborate our hypothesis, a kinetic model is implemented to simulate the reactions induced by irradiation. Two parameters are defined to abstractly study the factors affecting the reaction, such as dose rate, antioxidants, total dose and reaction rate constants. RESULTS AND CONCLUSIONS: We find that the explanation of the difference between in vivo and in vitro experiments is crucial to understanding the mechanism of the FLASH effect. Our hypothesis agrees with the results of related experiments. Based on the kinetic model, the effects of these factors on the FLASH effect are quantitatively investigated.

Heterogeneity of absorbed dose distribution in kidney tissues and dose-response modelling of nephrotoxicity in radiopharmaceutical therapy with beta-particle emitters: A review.

Absorbed dose heterogeneity in kidney tissues is an important issue in radiopharmaceutical therapy. The effect of absorbed dose heterogeneity in nephrotoxicity is, however, not fully understood yet, which hampers the implementation of treatment optimization by obscuring the interpretation of clinical response data and the selection of optimal treatment options. Although some dosimetry methods have been developed for kidney dosimetry to the level of microscopic renal substructures, the clinical assessment of the microscopic distribution of radiopharmaceuticals in kidney tissues currently remains a challenge. This restricts the anatomical resolution of clinical dosimetry, which hinders a thorough clinical investigation of the impact of absorbed dose heterogeneity. The potential of absorbed dose-response modelling to support individual treatment optimization in radiopharmaceutical therapy is recognized and gaining attraction. However, biophysical modelling is currently underexplored for the kidney, where particular modelling challenges arise from the convolution of a complex functional organization of renal tissues with the function-mediated dose distribution of radiopharmaceuticals. This article reviews and discusses the heterogeneity of absorbed dose distribution in kidney tissues and the absorbed dose-response modelling of nephrotoxicity in radiopharmaceutical therapy. The review focuses mainly on the peptide receptor radionuclide therapy with beta-particle emitting somatostatin analogues, for which the scientific literature reflects over two decades of clinical experience. Additionally, detailed research perspectives are proposed to address various identified challenges to progress in this field.

Estimation of relative biological effectiveness of 225Ac compared to 177Lu during [225Ac]Ac-PSMA and [177Lu]Lu-PSMA radiopharmaceutical therapy using TOPAS/TOPAS-nBio/MEDRAS.

AIM: Over recent years, [225Ac]Ac-PSMA and [177Lu]Lu-PSMA radiopharmaceutical therapy have evolved as a promising treatment option for advanced prostate cancer. Especially for alpha particle emitter treatments, there is still a need for improving dosimetry, which requires accurate values of relative biological effectiveness (RBE). To achieve that, consideration of DNA damages in the cell nucleus and knowledge of the energy deposition in the location of the DNA at the nanometer scale are required. Monte Carlo particle track structure simulations provide access to interactions at this level. The aim of this study was to estimate the RBE of 225Ac compared to 177Lu. The initial damage distribution after radionuclide decay and the residual damage after DNA repair were considered. METHODS: This study employed the TOol for PArtcile Simulation (TOPAS) based on the Geant4 simulation toolkit. Simulation of the nuclear DNA and damage scoring were performed using the TOPAS-nBio extension of TOPAS. DNA repair was modeled utilizing the Python-based program MEDRAS (Mechanistic DNA Repair and Survival). Five different cell geometries of equal volume and two radionuclide internalization assumptions as well as two cell arrangement scenarios were investigated. The radionuclide activity (number of source points) was adopted based on SPECT images of patients undergoing the above-mentioned therapies. RESULTS: Based on the simulated dose-effect curves, the RBE of 225Ac compared to 177Lu was determined in a wide range of absorbed doses to the nucleus. In the case of spherical geometry, 3D cell arrangement and full radionuclide internalization, the RBE based on the initial damage had a constant value of approximately 2.14. Accounting for damage repair resulted in RBE values ranging between 9.38 and 1.46 for 225Ac absorbed doses to the nucleus between 0 and 50 Gy, respectively. CONCLUSION: In this work, the consideration of DNA repair of the damage from [225Ac]Ac-PSMA and [177Lu]Lu-PSMA revealed a dose dependency of the RBE. Hence, this work suggested that DNA repair is an important aspect to understand response to different radiation qualities.

Analysis of the Risk Factors of Breast Cancer-Related Lymphedema and Construction and Evaluation of a Prediction Model.

Objective: The occurrence of breast cancer-related lymphedema (BCRL) in postoperative breast cancer survivors is described and the independent risk factors of BCRL are analyzed. A BCRL nomogram prediction model is constructed, and its effectiveness is evaluated to screen out high-risk patients with BCRL. Methods: A univariate analysis was carried out to determine the risk factors possibly related to BCRL, and a logistic regression analysis was utilized to determine the independent risk factors related to BCRL. A BCRL nomogram prediction model was built, and a nomogram was drawn by R software v4.1.0. The area under the curve (AUC) of the receiver operating characteristic (ROC) and the Hosmer-Lemeshow test were used to evaluate the efficacy of the constructed model to assess its clinical application value. Results: The risk factors independently associated with BCRL were body mass index (BMI), handedness on the operation side, no BCRL-related rehabilitation plan, axillary lymph node dissection (ALND), taxane-based chemotherapy, and radiotherapy (all p < 0.05). The BCRL nomogram prediction model was built on this basis, and the results of the efficacy evaluation showed a good fit: AUC = 0.952 (95% confidence interval: 0.930-0.973) for the ROC and χ2 = 6.963, p = 0.540 for the Hosmer-Lemeshow test. Conclusions: The risk factors for BCRL included higher BMI, handedness on the operation side, no BCRL-related rehabilitation plan, ALND, taxane-based chemotherapy, and radiotherapy. In addition, the BCRL nomogram prediction model accurately calculated the risk of possible BCRL among breast cancer survivors and effectively screened for high-risk patients with BCRL. Therefore, this prediction model can provide a basis for rehabilitation physicians and therapists to formulate early and individualized prevention and treatment programs.

A Computational Model for Oxygen Depletion Hypothesis in FLASH Effect.

Experiments have reported low normal tissue toxicities during FLASH irradiation, but the mechanism has not been elaborated. Several hypotheses have been proposed to explain the mechanism. One hypothesis is oxygen depletion. We analyze the time-dependent change of oxygen concentration in the tissue to study the oxygen depletion hypothesis using a computational model. The effects of physical, chemical and physiological parameters on oxygen depletion were explored. The kinetic equation of the model is solved numerically using the finite difference method with rational boundary conditions. Results of oxygen distribution is supported by the experiments of oxygen-sensitivity electrodes and experiments on the expression and distribution of the hypoxia-inducible factors. The analysis of parameters shows that the steady-state oxygen distribution before irradiation is determined by the oxygen consumption rate of the tissue and the microvessel density. The change of oxygen concentration after irradiation has been found to follow a negative exponential function, and the time constant is mainly determined by the microvessel density. The change of oxygen during exposure increases with dose rate and tends to be saturated because of oxygen diffusion. When the dose rate is high enough, the same dose results in the same reduction of oxygen concentration regardless of dose rate. The analysis of the FLASH effect in the brain tissue based on this model does not support the explanation of the oxygen depletion hypothesis. The oxygen depletion hypothesis remains controversial because the oxygen in most normal tissues cannot be depleted to radiation resistance level by FLASH irradiation.

Correlation between focal lesion sites and language deficits in the acute phase of post-stroke aphasia.

INTRODUCTION: Focal lesion sites can predict the language function of patients with aphasia during the subacute or chronic phases. However, the relationship between focal lesion sites and language deficits in the acute phase remains unclear. Therefore, our study aimed to investigate the relationship between focal lesion sites and fluency, auditory comprehension, repetition and naming deficits in patients with acute aphasia to further understand the pathophysiological mechanism of aphasia. MATERIAL AND METHODS: We included a total of 52 patients with acute aphasia who had their first-ever stroke between June 2018 and June 2021 to investigate the association between focal lesion sites and fluency, auditory comprehension, repetition and naming deficits. Language function was assessed by the Western Aphasia Battery scale within one month of onset. The lesion sites were independently assessed by three professional speech and language pathologists according to the main sulcus of the brain within 1-2 days after stroke. RESULTS: Lesions involving the superior temporal gyrus, middle frontal gyrus, inferior frontal gyrus, precentral gyrus, postcentral gyrus, supramarginal gyrus, angular gyrus and insula were significantly associated with low fluency. Lesions involving the superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus, middle frontal gyrus, inferior frontal gyrus, supramarginal gyrus and angular gyrus significantly resulted in auditory comprehension impairment. Lesions involving the superior temporal gyrus, middle temporal gyrus, middle frontal gyrus, inferior frontal gyrus, precentral gyrus, postcentral gyrus, supramarginal gyrus, angular gyrus and insula significantly resulted in repetition and naming deficits. CONCLUSIONS: Our study suggests that focal lesion sites could lead to different language function impairments in the acute phase of post-stroke aphasia, which adds to our understanding of speech pathology and provides a direction for future research and treatment.

Long non­coding RNA 01614 hyperactivates WNT/ß­catenin signaling to promote pancreatic cancer progression by suppressing GSK­3ß.

Pancreatic cancer (PC) is a lethal type of cancer for which effective therapies are limited. Long non­coding RNAs (lncRNAs) represent a critical type of regulator category, mediating the tumorigenesis and development of various tumor types, including PC. However, the expression patterns and functions of numerous lncRNAs in PC remain poorly understood. In the present study, linc01614 was identified as a PC­related lncRNA. linc01614 was notably upregulated in PC tissues and cell lines and was associated with the poor disease­free survival of patients with PC according to the analysis of The Cancer Genome Atlas­derived datasets. Functionally, linc01614 knockdown suppressed PC cell proliferation, migration and invasion in vitro, and inhibited tumor proliferation in vitro and in vivo. Mechanistically, linc01614 overexpression stabilized the level of ß­catenin protein to hyperactivate the WNT/ß­catenin signaling pathway in PC cells. Further analyses revealed that linc01614 bound to GSK­3ß and perturbed the interaction between GSK­3ß and AXIN1, thereby preventing the formation of the ß­catenin degradation complex and reducing the degradation of ß­catenin. In summary, the present findings reveal that linc01614 may function as an oncogene and promote the progression of PC and may thus be considered as a potential therapeutic target in the future.

Low-frequency repetitive transcranial magnetic stimulation to the right Broca mirror area for improving auditory comprehension in a sensory aphasia after stroke: a case report.

Aphasia is a common consequence of stroke and repetitive transcranial magnetic stimulation (rTMS) may be a promising brain stimulation technique in the treatment of aphasia. However, there are few reports about the therapeutic effect of rTMS for Broca's area in patients with sensory aphasia. This study reported one stroke patient with sensory aphasia who received 6 treatment sessions of low-frequency rTMS before speech and language therapy. The target area was the Broca mirror area in the right hemisphere. After treatment, the auditory comprehension of the patient improved from 46 to 112, the naming improved from 18 to 32, and the AQ improved from 34.2 to 42.6. However, the level of functional language, spontaneous speech and repetition did not show obvious improvement.

Multi-scale Monte Carlo simulations of gold nanoparticle-induced DNA damages for kilovoltage X-ray irradiation in a xenograft mouse model using TOPAS-nBio.

Background: Gold nanoparticles (AuNPs) are considered as promising agents to increase the radiosensitivity of tumor cells. However, the biological mechanisms of radiation enhancement effects of AuNPs are still not well understood. We present a multi-scale Monte Carlo simulation framework within TOPAS-nBio to investigate the increase of DNA damage due to the presence of AuNPs in mouse tumor models. Methods: A tumor was placed inside a voxel mouse model and irradiated with either 100 kVp or 200 kVp x-ray beams. Phase spaces were employed to transfer particles from the macroscopic (voxel) scale to the microscopic scale, which consists of a cell geometry including a detailed mouse DNA model. Radiosensitizing effects were calculated in the presence and absence of hybrid nanoparticles with a Fe2O3 core surrounded by a gold layer (AuFeNPs). To simulate DNA damage even for very small energy tracks, Geant4-DNA physics and chemistry models were used on microscopic scale. Results: An AuFeNP induced enhancement of both dose and DNA strand breaks has been established for different scenarios. Produced chemical radicals including hydroxyl molecules, which were assumed to be responsible for DNA damage through chemical reactions, were found to be significantly increased. We further observed a dependency of the results on the location of the cells within the tumor for 200 kVp x-ray beams. Conclusions: Our multi-scale approach allows to study irradiation induced physical and chemical effects on cells. We showed a potential increase in cell radiosensitization caused by relatively small concentrations of AuFeNPs. Our new methodology allows the individual adjustment of parameters in each simulation step and therefore can be used for other studies investigating the radiosensitizing effects of AuFeNPs or AuNPs in living cells.