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This review article aims to synthesize existing data on radiation-induced heart diseases in patients undergoing chest radiation therapy and also explores cardiac-sparing techniques to mitigate cardiotoxic effects. We conducted a comprehensive database search to review and consolidate data regarding chest radiotherapy and effects on the heart as well as techniques to minimize exposure to the heart. The research findings demonstrate associations between radiation exposure to cardiac substructures and subsequent cardiotoxicity. This review also stresses the importance of identifying patients at high-risk for cardiotoxicity as well as advocates for the adoption of stringent cardiac dose constraints in these patients. Advanced cardiac-sparing techniques, notably respiratory motion management, have emerged as pivotal strategies to minimize the likelihood of cardiac events. This narrative review emphasizes the critical role of these innovations in optimizing cardiac health during radiation treatment.

Herpes simplex virus type 1 (HSV-1) is a globally widespread virus that causes and associates with a wide range of diseases, including herpes simplex encephalitis, herpes simplex keratitis, and herpes labialis. The interaction between HSV-1 and the host involves complex immune response mechanisms, including recognition of viral invasion, maintenance of latent infection, and triggering of reactivation. Antiviral therapy is the core treatment for HSV-1 infections. Meanwhile, vaccine development employs different strategies and methods, and several promising vaccine types have emerged, such as live attenuated, protein subunit, and nucleic acid vaccines, offering new possibilities for the prevention of HSV-1 infection. Moreover, HSV-1 can be modified into a therapeutic vector for gene therapy and tumour immunotherapy. This review provides an in-depth summary of HSV-1 infection-associated innate and adaptive immune responses, disease pathogenesis, current therapeutic approaches, recent advances in vaccine development, and vector therapy applications for cancer treatment. Through a systematic review of multiple aspects of HSV-1, this study aims to provide a comprehensive and detailed reference for the public on the prevention, control, and treatment of HSV-1.

High strain rates and continuous real-time data acquisition are difficult to balance in existing impact indentation techniques. Meanwhile, the inaccuracy of the testing P-h curves limits the development of quantitative applications for dynamic testing of mechanical properties at micro region. This article develops a momentum exchange impact indentation testing method, which extends the testing range of strain rate to above 105 s−1, and at the same time avoids secondary impact. Impact indentation tests are conducted on single-crystal aluminum specimens with impact velocity from 76.9 to 176 mm/s. Based on calibrated data, the comparison of calculation methods for dynamic hardness is carried out. The dynamic elastic modulus is obtained by means of the Oliver-Pharr method, which increases from 71.9 to 89.4 GPa with increasing impact velocity. A multi-dimensional data analysis method is proposed based on the obtained experimental data to quantitatively study the damping and stiffness characteristics of materials. This testing method is particularly useful for quantitatively obtaining the micro region dynamic mechanical properties of solid materials at high strain rates.

Abstract Combination of tumor immunotherapy with photothermal therapy (PTT) is a feasible tactic to overcome the drawback of immunotherapy such as poor immune response. Via triggering the immunogenic cells death (ICD), PTT can stimulate the activity of immune cells, but meanwhile, the level of adenosine is elevated via the CD73-induced decomposition of ATP which is overexpressed accompanying with the PTT process, resulting in negative feedback to impair the immune stimulation. Herein, we developed a novel biomimetic photothermal nanodrug to specifically block CD73 for inhibition of adenosine production and more efficient priming of the suppressive immune microenvironments. The nanodrug, named as AptEM@CBA, is constructed by encapsulation of photothermal agent black phosphorus quantum dots (BPQDs) and selective CD73 inhibitor α, β-Methyleneadenosine 5′-diphosphate (AMPCP) in chitosan nanogels, which are further covered with aptamer AS1411 modified erythrocyte membrane (EM) for biomimetic camouflage. With AS1411 induced active targeting and EM induced long blood circulation time, the enrichment of the nanodrug tumor sites is promoted. The photothermal treatment promotes the maturation of dendritic cells. Meanwhile, the release of AMPCP suppress the adenosine generation via CD73 blockade, alleviating the impairment of adenosine to dendritic cells and suppressing regulatory T cells, synergically stimulate the activity of T cells. The combination of CD73 blockade with PTT, not only suppresses the growth of primary implanted tumors, but also boosts strong antitumor immunity to inhibit the growth of distal tumors, providing good potential for tumor photoimmunotherapy.

Abstract High‐fat diet (HFD)‐induced obesity is a crucial risk factor for metabolic syndrome, mainly due to adipose tissue dysfunctions associated with it. However, the underlying mechanism remains unclear. This study has used genetic screening to identify an obesity‐associated human lncRNA LINK‐A as a critical molecule bridging the metabolic microenvironment and energy expenditure in vivo by establishing the HFD‐induced obesity knock‐in (KI) mouse model. Mechanistically, HFD LINK‐A KI mice induce the infiltration of inflammatory factors, including IL‐1β and CXCL16, through the LINK‐A/HB‐EGF/HIF1α feedback loop axis in a self‐amplified manner, thereby promoting the adipose tissue microenvironment remodeling and adaptive thermogenesis disorder, ultimately leading to obesity and insulin resistance. Notably, LINK‐A expression is positively correlated with inflammatory factor expression in individuals who are overweight. Of note, targeting LINK‐A via nucleic acid drug antisense oligonucleotides (ASO) attenuate HFD‐induced obesity and metabolic syndrome, pointing out LINK‐A as a valuable and effective therapeutic target for treating HFD‐induced obesity. Briefly, the results reveale the roles of lncRNAs (such as LINK‐A) in remodeling tissue inflammatory microenvironments to promote HFD‐induced obesity.

Abstract Respiration induced motion is a well-recognized challenge in many clinical practices including upper body imaging, lung tumor motion tracking and radiation therapy. In this work, we present a recurrent neural network algorithm that was implemented in a photonic delay-line reservoir computer (RC) for real-time respiratory motion prediction. The respiratory motion signals are quasi-periodic waveforms subject to a variety of non-linear distortions. In this work, we demonstrated for the first time that RC can be effective in predicting short to medium range of respiratory motions within practical timescales. A double-sliding window technology is explored to enable the real-time establishment of an individually trained model for each patient and the real-time processing of live-streamed respiratory motion data. A breathing dataset from a total of 76 patients with breathing speeds ranging from 3 to 20 breaths per minute (BPM) is studied. Motion prediction of look-ahead times of 66.6, 166.6, and 333 ms are investigated. With a 333 ms look-ahead time, the real-time RC model achieves an average normalized mean square error (NMSE) of 0.025, an average mean absolute error (MAE) of 0.34 mm, an average root mean square error (RMSE) of 0.45 mm, an average therapeutic beam efficiency (TBE) of 94.14% for an absolute error (AE)

Abstract Background Medication recommendation based on electronic medical record (EMR) is a research hot spot in smart healthcare. For developing computational medication recommendation methods based on EMR, an important challenge is the lack of a large number of longitudinal EMR data with time correlation. Faced with this challenge, this paper proposes a new EMR-based medication recommendation model called MR-KPA, which combines knowledge-enhanced pre-training with the deep adversarial network to improve medication recommendation from both feature representation and the fine-tuning process. Firstly, a knowledge-enhanced pre-training visit model is proposed to realize domain knowledge-based external feature fusion and pre-training-based internal feature mining for improving the feature representation. Secondly, a medication recommendation model based on the deep adversarial network is developed to optimize the fine-tuning process of pre-training visit model and alleviate over-fitting of model caused by the task gap between pre-training and recommendation. Result The experimental results on EMRs from medical and health institutions in Hainan Province, China show that the proposed MR-KPA model can effectively improve the accuracy of medication recommendation on small-scale longitudinal EMR data compared with existing representative methods. Conclusion The advantages of the proposed MR-KPA are mainly attributed to knowledge enhancement based on ontology embedding, the pre-training visit model and adversarial training. Each of these three optimizations is very effective for improving the capability of medication recommendation on small-scale longitudinal EMR data, and the pre-training visit model has the most significant improvement effect. These three optimizations are also complementary, and their integration makes the proposed MR-KPA model achieve the best recommendation effect.

Rice-based products exported from China to Europe have repeatedly encountered technical trade barriers. Using panel data from 24 states of the European Union during 2001–2017, this study builds a theoretical model to investigate the impact of implementation, intensity and structure of the Rapid Alert System for Food and Feed (RASFF) on China-EU rice-based product trade. The study found that RASFF has a serious inhibitory effect on the trade of traditional rice-based products because of detecting GM ingredients, showing an obvious lag effect, diffusion effect and structure effect. The negative effect occurs in entry process, and the inhibitory effect of border rejection and information notifications results in time lag, but the marginal effect of alerts for market links is insignificant. Moreover, the positive information disclosure effect of technical barriers implemented by individual members is much smaller than the negative diffusion effect. Finally, countermeasures and suggestions are proposed, including the source supervision of the test, the supervision of GM variety approval and GM seed production, the establishment of an early-warning and rapid-response mechanism to technical barriers of agricultural products, and food enterprise information.

Cancer cells exploit immune checkpoint pathways, such as PD-1/PD-L1, to evade elimination by the immune system. Here, the authors demonstrate that TMUB1 regulates post-translational modifications of PD-L1 and that targeting the TMUB1/PD-L1 interaction promotes anti-tumour T cells responses

Abstract Background Accurately predicting drug-target binding affinity (DTA) in silico plays an important role in drug discovery. Most of the computational methods developed for predicting DTA use machine learning models, especially deep neural networks, and depend on large-scale labelled data. However, it is difficult to learn enough feature representation from tens of millions of compounds and hundreds of thousands of proteins only based on relatively limited labelled drug-target data. There are a large number of unknown drugs, which never appear in the labelled drug-target data. This is a kind of out-of-distribution problems in bio-medicine. Some recent studies adopted self-supervised pre-training tasks to learn structural information of amino acid sequences for enhancing the feature representation of proteins. However, the task gap between pre-training and DTA prediction brings the catastrophic forgetting problem, which hinders the full application of feature representation in DTA prediction and seriously affects the generalization capability of models for unknown drug discovery. Results To address these problems, we propose the GeneralizedDTA, which is a new DTA prediction model oriented to unknown drug discovery, by combining pre-training and multi-task learning. We introduce self-supervised protein and drug pre-training tasks to learn richer structural information from amino acid sequences of proteins and molecular graphs of drug compounds, in order to alleviate the problem of high variance caused by encoding based on deep neural networks and accelerate the convergence of prediction model on small-scale labelled data. We also develop a multi-task learning framework with a dual adaptation mechanism to narrow the task gap between pre-training and prediction for preventing overfitting and improving the generalization capability of DTA prediction model on unknown drug discovery. To validate the effectiveness of our model, we construct an unknown drug data set to simulate the scenario of unknown drug discovery. Compared with existing DTA prediction models, the experimental results show that our model has the higher generalization capability in the DTA prediction of unknown drugs. Conclusions The advantages of our model are mainly attributed to two kinds of pre-training tasks and the multi-task learning framework, which can learn richer structural information of proteins and drugs from large-scale unlabeled data, and then effectively integrate it into the downstream prediction task for obtaining a high-quality DTA prediction in unknown drug discovery.

Abstract Background A range pull-back device, such as a machine-related range shifter (MRS) or a universal patient-related range shifter (UPRS), is needed in pencil beam scanning technique to treat shallow tumors. Methods Three UPRS made by QFix (Avondale, PA, USA) allow treating targets across the body: U-shaped bolus (UB), anterior lateral bolus (ALB), and couch top bolus. Head-and-neck (HN) patients who used the UPRS were tested. The in-air spot sizes were measured and compared in this study at air gaps: 6 cm, 16 cm, and 26 cm. Measurements were performed in a solid water phantom using a single-field optimization pencil beam scanning field with the ALB placed at 0, 10, and 20 cm air gaps. The two-dimensional dose maps at the middle of the spread-out Bragg peak were measured using ion chamber array MatriXX PT (IBA-Dosimetry, Schwarzenbruck, Germany) located at isocenter and compared with the treatment planning system. Results A UPRS can be consistently placed close to the patient and maintains a relatively small spot size resulting in improved dose distributions. However, when a UPRS is non-removable (e.g. thick couch top), the quality of volumetric imaging is degraded due to their high Z material construction, hindering the value of Image-Guided Radiation Therapy (IGRT). Limitations of using UPRS with small air gaps include reduced couch weight limit, potential collision with patient or immobilization devices, and challenges using non-coplanar fields with certain UPRS. Our experience showed the combination of a U-shaped bolus exclusively for an HN target and an MRS as the complimentary device for head-and-neck targets as well as for all other treatment sites may be ideal to preserve the dosimetric advantages of pencil beam scanning proton treatments across the body. Conclusion We have described how to implement UPRS and MRS for various clinical indications using the PBS technique, and comprehensively reviewed the advantage and disadvantages of UPRS and MRS. We recommend the removable UB only to be employed for the brain and HN treatments while an automated MRS is used for all proton beams that require RS but not convenient or feasible to use UB.

PurposesTo evaluate the plan quality and robustness of both dose and dose rate of proton pencil beam scanning (PBS) transmission FLASH delivery in lung cancer treatment.Methods and materialsAn in-house FLASH planning platform was used to optimize 10 lung cancer patients previously consecutively treated with proton stereotactic body radiation therapy (SBRT) to receive 3 and 5 transmission beams (Trx-3fds and Trx-5fds, respectively) to 34 Gy in a single fraction. Perturbation scenarios (n=12) for setup and range uncertainties (5 mm and 3.5%) were introduced, and dose-volume histogram and dose-rate-volume histogram bands were generated. Conventional proton SBRT clinical plans were used as a reference. RTOG 0915 dose metrics and 40 Gy/s dose rate coverage (V40Gy/s) were used to assess the dose and dose rate robustness.ResultsTrx-5fds yields a comparable iCTV D2% of 105.3%, whereas Trx-3fds resulted in inferior D2% of 111.9% to the clinical SBRT plans with D2% of 105.6% (p

Purpose: To evaluate a novel spine implant, carbon-fiber-reinforced polyetheretherketone (CFR-PEEK), for proton and photon treatment planning. Materials and Methods: We compared target coverage and sparing of organs-at-risk (OARs) for a spinal phantom with 4 different spine configurations: (a) normal (no implant); (b) Titanium; (c) CFR-PEEK; and (d) hybrid (CFR-PEEK with Titanium tulip head). The spinal phantom was imaged via computed tomography (CT) scan, and the iterative Metal Artifact Reduction (iMAR) CT set was used for planning. A representative spinal chordoma target and associated OARs were contoured. The prescription dose was 50 Gy to the initial target volume, followed by a 24 Gy boost, for which multi-field optimization (MFO) proton plans were developed with a 3 mm setup and 3.5% range uncertainties. For photon planning, volumetric modulated arc therapy (VMAT) plans were developed for the initial and boost plans. OAR dose constraints were set according to our institutional guidelines. Results: For the 4 spine configurations, the proton plans achieved similar nominal target coverage and OARs sparing. While evaluating coverage and OAR dose under uncertainty scenario analysis for initial clinical target volume (CTV) 50 Gy 95% and 90% coverage, higher means and the narrower band of doses variations were achieved for the normal and CFR-PEEK plans. Similarly, uncertainty analysis of spinal cord D max showed tighter distribution for normal and CFR-PEEK plans. Overall plan quality showed no significant difference for photon planning when compared to normal spine versus other inserts. However, for proton planning, there is a larger difference for the normal spine insert scenario versus the Titanium insert scenario. For each insert scenario comparison between photon and proton plans, there was a larger difference for OARs: heart and spinal cord. Conclusion: The CFR-PEEK implant has similar clinical properties to a normal spine for proton planning, allowing us to pass protons through the material and achieve superior target coverage and OAR sparing under nominal and uncertainty conditions.

Purpose: This review article aims to consolidate information regarding existing and emerging implanted devices used in patients undergoing radiation therapy and to categorize levels of attention needed for each device, including which devices require monitoring throughout treatment. Methods and Materials: Based on the collective information from scholar searches, manufacturers’ technical reports, and institutional experiences in the past years, commonly present devices in patients with cancer are compiled. This work summarizes cardiac pacemaker, implanted cardiac defibrillator, hepatic pump, intrathecal pain pump, neurostimulator, shunt, loop recorder, and mediport. Three different classifications of implanted devices can be made based on the potential effect of radiation: life-dependent, nonlife-dependent but with adverse effects if overdosed, and devices without electronic circuits. Implanted devices that contain electronic circuits that would be life-dependent or have adverse effects if overdosed, include cardiac pacemakers, implanted cardiac defibrillators, programmable hepatic pumps, pain pumps, neurostimulators, and loop recorders. Results: Dose exposure to these devices need to be calculated or measured in vivo, especially for cardiac implanted devices, and they should be minimized to assure continued healthy functioning. Treatment planning techniques should be chosen to reduce entry, exit and internal scatter dose. Lower energy photon beams should be used to decrease potential neutron contamination. Implanted devices without electronic circuits are less of a concern. If a patient is life-dependent on the implanted device, it is not recommended to treat the patient with proton therapy. Conclusions: This study reviewed the management of patients with commonly seen implanted devices and summarized a workflow for identifying and planning when a patient has implanted devices. Classifications of implanted devices could help clinicians make proper decisions in regard to patients with specific implanted devices. Lastly, the management of such devices in the era of the pandemic is also discussed in this review article.

Liver fibrosis is a common pathological process of end-stage liver diseases. However, the role of microRNA (miRNA) in liver fibrosis is poorly understood. The activated hepatic stellate cells (HSCs) are the major source of fibrogenic cells and play a central role in liver fibrosis. In this study, we investigated the differential expression of miRNAs in resting and transforming growth factor β1 (TGF-β1) activated HSCs by microarray analysis and found that miR-455-3p was significantly downregulated during HSCs activation. In addition, the reduction of miR-455-3p was correlated with liver fibrosis in mice with carbon tetrachloride (CCl4), bile duct ligation (BDL), and high-fat diet (HFD)-induced liver fibrosis. Our functional analyses demonstrated that miR-455-3p inhibited expression of profibrotic markers and cell proliferation in HSCs in vitro. Moreover, miR-455-3p regulated heat shock factor 1 (HSF1) expression by binding to the 3′ UTR of its mRNA directly. Overexpression of HSF1 facilitated HSCs activation and proliferation by promoting heat shock protein 47 (Hsp47) expression, leading to activation of the TGF-β/Smad4 signaling pathway. To explore the clinical potential of miR-455-3p, we injected ago-miR-455-3p into mice with CCl4-, BDL-, and HFD-induced hepatic fibrosis in vivo. The overexpression of miR-455-3p suppressed HSF1 expression and reduced fibrosis marker expression, which resulted in alleviated liver fibrosis in mice. In conclusion, our present study suggests that miR-455-3p inhibits the activation of HSCs through targeting HSF1 involved in the Hsp47/TGF-β/Smad4 signaling pathway. Therefore, miR-455-3p might be a promising therapeutic target for liver fibrosis. Keywords: miR-455-3p, HSF1, hepatic stellate cells, liver fibrosis

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with dysregulation of liver metabolism and inflammation. G-protein coupled bile acid receptor 1 (TGR5) is a cell surface receptor that is involved in multiple metabolic pathways. However, the functions of TGR5 in regulating macrophage innate immune activation in NASH remain unclear. Here, we found that TGR5 expression was decreased in liver tissues from humans and mice with NASH. Compared to wild type (WT) mice, TGR5-knockout (TGR5−/−) mice exhibited exacerbated liver damage, increased levels of proinflammatory factors, and enhanced M1 macrophage polarization. Moreover, TGR5 deficiency facilitated M1 macrophage polarization by promoting NLRP3 inflammasome activation and caspase-1 cleavage. Taken together, our findings revealed that TGR5 signaling attenuated liver steatosis and inflammation and inhibited NLRP3-mediated M1 macrophage polarization in NASH.

Liver fibrosis is a major endpoint of patients with chronic liver diseases. The molecular mechanisms behind liver fibrosis remain largely unknown. Many studies have indicated the role of microRNA (miRNA) in hepatic tumorigenesis. But the role of miRNA in liver fibrosis is little known. Activated hepatic stellate cells (HSCs) can secret extracellular matrix proteins (ECM) and are the major contributors to liver fibrosis/cirrhosis. Here, a microarray assay of quiescent and transforming growth factor β1 (TGF-β1) activated HSCs indicated that miR-98 might play a crucial role in liver fibrosis. We found that miR-98 was significantly downregulated in activated HSCs. miR-98 overexpression inhibited HSCs activation. Furthermore, we hypothesized that miR-98 regulated hepatic leukemia factor (HLF) expression by binding to the 3′ UTR of its mRNA directly, as evidenced by luciferase reporter assay. HLF overexpression increased HSCs activation by inducing hypoxia inducible factor-1 alpha (HIF-1α) expression, resulting in the activation of TGF-β/Smad2/3 signaling pathway. Besides, low expression of miR-98 was also found in liver tissues from various fibrotic murine models, including carbon tetrachloride (CCl4), bile duct ligation (BDL), and high-fat diet (HFD)-induced liver fibrosis. miR-98 overexpression in vivo by ago-miR-98 injection could attenuate CCl4-, BDL-, and HFD-induced murine hepatic fibrosis. Meanwhile, miR-98 overexpression suppressed HLF expression and reduced fibrosis marker expression. Collectively, our study demonstrates that miR-98 suppress HSCs activation by targeting HLF directly and interacting with HIF-1α/TGF-β/Smad2/3 signaling pathway, which may be an effective therapeutic target for liver fibrosis.

Abstract Objective The newly released Respiratory Gating for Scanners (RGSC; Varian Medical Systems, Palo Alto, CA, USA) system has limited existing quality assurance (QA) protocols and pertinent publications. Herein, we report our experiences of the RGSC system acceptance and QA. Methods The RGSC system integration was tested with peripheral equipment, spatial reproducibility, and dynamic localization accuracy for regular and irregular breathing patterns, respectively. A QUASAR Respiratory Motion Phantom and a mathematical fitting method were used for data acquisition and analysis. Results The results showed that the RGSC system could accurately measure regular motion periods of 3–10 s. For irregular breathing patterns, differences from the existing Real‐time Position Management (RPM; Varian Medical Systems, Palo Alto, CA) system were observed. For dynamic localization measurements, the RGSC system showed 76% agreement with the programmed test data within ±5% tolerance in terms of fitting period. As s comparison, the RPM system showed 66% agreement within ±5% tolerance, and 65% for the RGSC versus RPM measurements. Conclusions New functions and positioning accuracy improve the RGSC system's ability to achieve higher dynamic treatment precision. A 4D phantom is helpful for the QA tests. Further investigation is required for the whole RGSC system performance QA.

The pulsed power technology has been applied to many defense and industrial fields. Different applications have different demands on the parameters of the pulsed power systems. However, the parameters of the current pulsed power systems are usually fixed and cannot be changed easily. As a special nonlinear device, metal-oxide varistor was considered to be applied for generating square pulses. Moreover, the magnetic switches are widely used in the field of the pulsed power technology due to the special switching characteristic. This paper proposed a high voltage pulse generator with pulse width adjustable based on the magnetic switch and metal-oxide varistor. The pulse forming network and metal-oxide varistor were combined to generate quasi-square pulses, the magnetic switch was used as a crowbar switch to sharpen the falling edge and the pulse width was adjusted by changing the reset current. The paper carried on theoretical analysis as well as simulation study, and developed preliminary experiment based on the simulation results. In the preliminary experiment, the falling edge of the voltage waveforms obtained on a dummy water load is less than 50 ns, the flat-top is about 7 kV and the pulse width is adjustable within 200 ns-900 ns. This kind of pulse generator with pulse width adjustable can be applied to many fields such as corona plasma generation, industrial dedusting and medical disinfection.

Developing epoxy structural adhesives with excellent high‐temperature adhesion remains a great challenge. The incorporation of fillers can enhance the performance of epoxy adhesives, albeit at the expense of reduced high‐temperature adhesion properties. Polyhedral oligomeric silsesquioxanes (POSS) is considered a promising filler for enhancing high‐temperature adhesion properties due to its excellent compatibility and nano cage‐structured. Herein, the rigid cage‐structured was covalently introduced epoxy adhesives to improve the high‐temperature adhesion properties. The introduction of 1 wt% POSS significantly increased the high‐temperature (120°C) adhesion strength by 197% and toughness by 283%. The POSS‐reinforced adhesive also featured excellent wide temperature adaptability, indicating that it maintained high adhesion strength at various temperatures. Furthermore, POSS drastically enhanced the transparency of epoxy adhesive by three times. It is highly anticipated that this work will open a new avenue of designing epoxy adhesives with the excellent high‐temperature adhesion properties and transparency. [ABSTRACT FROM AUTHOR]