Longitudinal registration of thoracic CT images with radiation-induced lung diseases: A divide-and-conquer approach based on component structure wise registration using coherent point drift.

BACKGROUND AND OBJECTIVE: Registration of pulmonary computed tomography (CT) images with radiation-induced lung diseases (RILD) was essential to investigate the voxel-wise relationship between the formation of RILD and the radiation dose received by different tissues. Although various approaches had been developed for the registration of lung CTs, their performances remained clinically unsatisfactory for registration of lung CT images with RILD. The main difficulties arose from the longitudinal change in lung parenchyma, including RILD and volumetric change of lung cancers, after radiation therapy, leading to inaccurate registration and artifacts caused by erroneous matching of the RILD tissues. METHODS: To overcome the influence of the parenchymal changes, a divide-and-conquer approach rooted in the coherent point drift (CPD) paradigm was proposed. The proposed method was based on two kernel ideas. One was the idea of component structure wise registration. Specifically, the proposed method relaxed the intrinsic assumption of equal isotropic covariances in CPD by decomposing a lung and its surrounding tissues into component structures and independently registering the component structures pairwise by CPD. The other was the idea of defining a vascular subtree centered at a matched branch point as a component structure. This idea could not only provide a sufficient number of matched feature points within a parenchyma, but avoid being corrupted by the false feature points resided in the RILD tissues due to globally and indiscriminately sampling using mathematical operators. The overall deformation model was built by using the Thin Plate Spline based on all matched points. RESULTS: This study recruited 30 pairs of lung CT images with RILD, 15 of which were used for internal validation (leave-one-out cross-validation) and the other 15 for external validation. The experimental results showed that the proposed algorithm achieved a mean and a mean of maximum 1 % of average surface distances <2 and 8 mm, respectively, and a mean and a maximum target registration error <2 mm and 5 mm on both internal and external validation datasets. The paired two-sample t-tests corroborated that the proposed algorithm outperformed a recent method, the Stavropoulou's method, on the external validation dataset (p < 0.05). CONCLUSIONS: The proposed algorithm effectively reduced the influence of parenchymal changes, resulting in a reasonably accurate and artifact-free registration.

Precisely Manipulating Steric Hindrance Effect on DNA Walker for Tunable Detection of MicroRNA Using Enzymatic Strand Displacement Amplification.

The spatial constraints imposed by the DNA structure have significant implications for the walking efficiency of three-dimensional DNA walkers. However, accurately quantifying and manipulating steric hindrance remains a challenging task. This study presents a steric hindrance-controlled DNA walker utilizing an enzymatic strand displacement amplification (ESDA) strategy for detecting microRNA-21 (miR-21) with tunable dynamic range and sensitivity. The steric hindrance of the DNA walker was precisely manipulated by varying the length of empty bases from 6.5 Što 27.4 Šat the end of the track strand and adjusting the volumetric dimensions of the hairpin structure from 9.13 nm3 to 26.2 nm3 at the terminus of the single-foot DNA walking strand. This method demonstrated a tunable limit of detection for miR-21 ranging from 3.6 aM to 35.6 nM, along with a dynamic range from ∼100-fold to ∼166 000-fold. Impressively, it exhibited successful identification of cancer cells and clinical serum samples with high miR-21 expression. The proposed novel strategy not only enables tunable detection of miRNA through the regulation of steric hindrance but also achieves accurate and quantitative analysis of the steric hindrance effect, promising broader applications in personalized medicine, early disease detection, and drug development.

Cytokines in cerebrospinal fluid as a prognostic predictor after treatment of nusinersen in SMA patients.

OBJECTIVES: Recent studies have suggested that neuroinflammation may play a role in the progression of spinal muscular atrophy (SMA), and this may influence the efficacy of antisense oligonucleotide treatment. This study explored the biomarkers associated with SMA and the efficacy of nusinersen therapy. METHODS: Fifteen patients with SMA were enrolled and their motor function (World Health Organization motor milestone, Hammersmith Functional Motor Scale Expanded (HFMSE), and Revised Upper Limb Module [RULM] scores, and 6-minute walking test) was evaluated before, during (63 days), and after (6 months) nusinersen treatment. The concentrations of monocyte chemoactive protein 1 (MCP1), tumour necrosis factor-alpha (TNF-α), and interleukin (IL)-10 in the cerebrospinal fluid were measured at the indicated time points, and their correlations with motor function were analysed. RESULTS: A significant increase in MCP1 was observed after 6 month's treatment compared with that before treatment, while TNF-α gradually decreased over the course of treatment. IL-10 levels were negatively correlated with HFMSE scores before treatment, and reductions in IL-10 levels were correlated with improvements in RULM scores. CONCLUSIONS: This study suggests that neuroinflammation may be associated with the severity of SMA and with the therapeutic effects of nusinersen, which could have clinical implications in the treatment of SMA.

Orchestrating NK and T cells via tri-specific nano-antibodies for synergistic antitumor immunity.

The functions of natural killer (NK) and T cells in innate and adaptive immunity, as well as their functions in tumor eradication, are complementary and intertwined. Here we show that utilization of multi-specific antibodies or nano-antibodies capable of simultaneously targeting both NK and T cells could be a valuable approach in cancer immunotherapy. Here, we introduce a tri-specific Nano-Antibody (Tri-NAb), generated by immobilizing three types of monoclonal antibodies (mAbs), using an optimized albumin/polyester composite nanoparticle conjugated with anti-Fc antibody. This Tri-NAb, targeting PDL1, 4-1BB, and NKG2A (or TIGIT) simultaneously, effectively binds to NK and CD8+ T cells, triggering their activation and proliferation, while facilitating their interaction with tumor cells, thereby inducing efficient tumor killing. Importantly, the antitumor efficacy of Tri-NAb is validated in multiple models, including patient-derived tumor organoids and humanized mice, highlighting the translational potential of NK and T cell co-targeting.

Photocontrollable DNA Walker-Based Molecular Circuit for the Tunable Detection of MicroRNA-21 Using Metal-Organic Frameworks as Label-Free Fluorescence Tags.

Tunable detection of microRNA is crucial to meet the desired demand for sample species with varying concentrations in clinical settings. Herein, we present a DNA walker-based molecular circuit for the detection of miRNA-21 (miR-21) with tunable dynamic ranges and sensitivity levels ranging from fM to pM. The phosphate-activated fluorescence of UiO-66-NH2 metal-organic framework nanoparticles was used as label-free fluorescence tags due to their competitive coordination effect with the Zr atom, which significantly inhibited the ligand-to-metal charge transfer. To achieve a tunable detection performance for miR-21, the ultraviolet sensitive o-nitrobenzyl was induced as a photocleavable linker, which was inserted at various sites between the loop and the stem of the hairpin probe to regulate the DNA strand displacement reaction. The dynamic range can be precisely regulated from 700- to 67,000-fold with tunable limits of detection ranging from 2.5 fM to 36.7 pM. Impressively, a Boolean logic tree and complex molecular circuit were constructed for logic computation and cancer diagnosis in clinical blood samples. This intelligent biosensing method presents a powerful solution for converting complex biosensing systems into actionable healthcare decisions and will facilitate early disease diagnosis.

Automated marker-free longitudinal infrared breast image registration by GA-PSO.

The automated marker-free longitudinal Infrared (IR) breast image registration overcomes several challenges like no anatomic fiducial markers on the body surface, blurry boundaries, heat pattern variation by environmental and physiological factors, nonrigid deformation, etc, has the ability of quantitative pixel-wise analysis with the heat energy and patterns change in a time course study. To achieve the goal, scale-invariant feature transform, Harris corner, and Hessian matrix were employed to generate the feature points as anatomic fiducial markers, and hybrid genetic algorithm and particle swarm optimization minimizing the matching errors was used to find the appropriate corresponding pairs between the 1st IR image and thenth IR image. Moreover, the mechanism of the IR spectrogram hardware system has a high level of reproducibility. The performance of the proposed longitudinal image registration system was evaluated by the simulated experiments and the clinical trial. In the simulated experiments, the mean difference of our system is 1.64 mm, which increases 57.58% accuracy than manual determination and makes a 17.4% improvement than the previous study. In the clinical trial, 80 patients were captured several times of IR breast images during chemotherapy. Most of them were well aligned in the spatiotemporal domain. In the few cases with evident heat pattern dissipation and spatial deviation, it still provided a reliable comparison of vascular variation. Therefore, the proposed system is accurate and robust, which could be considered as a reliable tool for longitudinal approaches to breast cancer diagnosis.

Synthetic lethality in human bladder cancer cells by curcumin via concurrent Aurora A inhibition and autophagy induction.

Combination therapies to induce mixed-type cell death and synthetic lethality have the potential to overcome drug resistance in cancer. In this study, we demonstrated that the curcumin-enhanced cytotoxicity of cisplatin/carboplatin in combination with gemcitabine was associated with Aurora A suppression-mediated G2/M arrest, and thus apoptosis, as well as MEK/ERK-mediated autophagy in human bladder cancer cells. Animal study data confirmed that curcumin combined with cisplatin/gemcitabine reduced tumorigenesis of xenograft in mice and this phenomenon was associated with elevated expressions of p-ERK and reduced p-Aurora A in tumors. Gene analyses using data repositories further revealed that reduced Aurora A expression alone did not significantly elevate the sensitivity of human bladder carcinoma cells to these anticancer drugs. Unlike other major cancer types, human bladder urothelial carcinoma tissue coexpressed higher AURKA and lower MAP1LC3B than normal tissue, and reduced Aurora A and induction of autophagy have been clinically associated with a better prognosis in patients with early but not advanced stage bladder cancer. Therefore, our results suggest that treatment strategies can utilize the synthetic lethal pair to concurrently suppress oncogenic Aurora A and induce autophagy by coadministrating curcumin with anticancer drugs for early-stage bladder cancer with high expression of Aurora A.

Progress in nanoparticle-based regulation of immune cells.

Immune cells are indispensable defenders of the human body, clearing exogenous pathogens and toxicities or endogenous malignant and aging cells. Immune cell dysfunction can cause an inability to recognize, react, and remove these hazards, resulting in cancers, inflammatory diseases, autoimmune diseases, and infections. Immune cells regulation has shown great promise in treating disease, and immune agonists are usually used to treat cancers and infections caused by immune suppression. In contrast, immunosuppressants are used to treat inflammatory and autoimmune diseases. However, the key to maintaining health is to restore balance to the immune system, as excessive activation or inhibition of immune cells is a common complication of immunotherapy. Nanoparticles are efficient drug delivery systems widely used to deliver small molecule inhibitors, nucleic acid, and proteins. Using nanoparticles for the targeted delivery of drugs to immune cells provides opportunities to regulate immune cell function. In this review, we summarize the current progress of nanoparticle-based strategies for regulating immune function and discuss the prospects of future nanoparticle design to improve immunotherapy.

DNA Tile and Invading Stacking Primer-Assisted CRISPR-Cas12a Multiple Amplification System for Entropy-Driven Electrochemical Detection of MicroRNA with Tunable Sensitivity.

Conventional electrochemical detection of microRNA (miRNA) encounters issues of poor sensitivity and fixed dynamic range. Here, we report a DNA tile and invading stacking primer-assisted CRISPR-Cas12a multiple amplification strategy to construct an entropy-controlled electrochemical biosensor for the detection of miRNA with tunable sensitivity and dynamic range. To amplify the signal, a cascade amplification of the CRISPR-Cas12a system along with invading stacking primer signal amplification (ISPSA) was designed to detect trace amounts of miRNA-31 (miR-31). The target miR-31 could activate ISPSA and produce numerous DNAs, triggering the cleavage of the single-stranded linker probe (LP) that connects a methylene blue-labeled DNA tile with a DNA tetrahedron to form a Y-shaped DNA scaffold on the electrode. Based on the decrease of current, miR-31 can be accurately and efficiently detected. Impressively, by changing the loop length of the LP, it is possible to finely tune the entropic contribution while keeping the enthalpic contribution constant. This strategy has shown a tunable limit of detection for miRNA from 0.31 fM to 0.56 pM, as well as a dynamic range from ∼2200-fold to ∼270,000-fold. Moreover, it demonstrated satisfactory results in identifying cancer cells with a high expression of miR-31. Our strategy broadens the application of conventional electrochemical biosensing and provides a tunable strategy for detecting miRNAs at varying concentrations.

Benchmark Dose Assessment for Coke Oven Emissions-Induced Mitochondrial DNA Copy Number Damage Effects.

Objective: The study aimed to estimate the benchmark dose (BMD) of coke oven emissions (COEs) exposure based on mitochondrial damage with the mitochondrial DNA copy number (mtDNAcn) as a biomarker. Methods: A total of 782 subjects were recruited, including 238 controls and 544 exposed workers. The mtDNAcn of peripheral leukocytes was detected through the real-time fluorescence-based quantitative polymerase chain reaction. Three BMD approaches were used to calculate the BMD of COEs exposure based on the mitochondrial damage and its 95% confidence lower limit (BMDL). Results: The mtDNAcn of the exposure group was lower than that of the control group (0.60 ± 0.29 vs. 1.03 ± 0.31; P < 0.001). A dose-response relationship was shown between the mtDNAcn damage and COEs. Using the Benchmark Dose Software, the occupational exposure limits (OELs) for COEs exposure in males was 0.00190 mg/m 3. The OELs for COEs exposure using the BBMD were 0.00170 mg/m 3 for the total population, 0.00158 mg/m 3 for males, and 0.00174 mg/m 3 for females. In possible risk obtained from animal studies (PROAST), the OELs of the total population, males, and females were 0.00184, 0.00178, and 0.00192 mg/m 3, respectively. Conclusion: Based on our conservative estimate, the BMDL of mitochondrial damage caused by COEs is 0.002 mg/m 3. This value will provide a benchmark for determining possible OELs.

d-Penicillamine@Ag/Cu Nanocluster-Based Fluorescent Nanoneuron for Logic Screening Phosphonate-Type Organophosphate Pesticides and Steganographically Encrypting Information.

Organophosphate pesticides are used in agriculture due to their high effectiveness and low persistence in eradicating insects and pests. However, conventional detection methods encounter the limitation of undesired detection specificity. Thus, screening phosphonate-type organophosphate pesticides (OOPs) from their analogues, phosphorothioate organophosphate pesticides (SOPs), remains a challenge. Here, we reported a d-penicillamine@Ag/Cu nanocluster (DPA@Ag/Cu NCs)-based fluorescence assay to screen OOPs from 21 kinds of organophosphate pesticides, which can be used for logic sensing and information encryption. Acetylthiocholine chloride was enzymatically split by acetylcholinesterase (AChE) to produce thiocholine, which reduced the fluorescence of DPA@Ag/Cu NCs due to the transmission of electrons from DPA@Ag/Cu NCs donor to the thiol group acceptor. Impressively, OOPs acted as an AChE inhibitor and retained the high fluorescence of DPA@Ag/Cu NCs due to the stronger positive electricity of the phosphorus atom. Conversely, SOPs possessed weak toxicity to AChE, which led to low fluorescence intensity. By setting 21 kinds of organophosphate pesticides as the inputs and the fluorescence of the resulting products as the outputs, DPA@Ag/Cu NCs could serve as a fluorescent nanoneuron to construct Boolean logic tree and complex logic circuit for molecular computing. As a proof of concept, by converting the selective response patterns of DPA@Ag/Cu NCs into binary strings, molecular crypto-steganography for encoding, storing, and concealing information was successfully achieved. This study is expected to advance the progress and practical application of nanoclusters in the area of logic detection and information security while also enhancing the relationship between molecular sensors and the world of information.

Pain management in patients with hepatocellular carcinoma after transcatheter arterial chemoembolisation: A retrospective study.

BACKGROUND: Pain after transcatheter arterial chemoembolisation (TACE) can seriously affect the prognosis of patients and the insertion of additional medical resources. AIM: To develop an early warning model for predicting pain after TACE to enable the implementation of preventive analgesic measures. METHODS: We retrospectively collected the clinical data of 857 patients (from January 2016 to January 2020) and prospectively enrolled 368 patients (from February 2020 to October 2022; as verification cohort) with hepatocellular carcinoma (HCC) who received TACE in the Hepatic Surgery Center of Tongji Hospital. Five predictive models were established using machine learning algorithms, namely, random forest model (RFM), support vector machine model, artificial neural network model, naive Bayes model and decision tree model. The efficacy of these models in predicting postoperative pain was evaluated through receiver operating characteristic curve analysis, decision curve analysis and clinical impact curve analysis. RESULTS: A total of 24 candidate variables were included in the predictive models using the iterative algorithms. Age, preoperative pain, number of embolised tumours, distance from the liver capsule, dosage of iodised oil and preoperative prothrombin activity were closely associated with postoperative pain. The accuracy of the predictive model was compared between the training [area under the curve (AUC) = 0.798; 95% confidence interval (CI): 0.745-0.851] and verification (AUC = 0.871; 95%CI: 0.818-0.924) cohorts, with RFM having the best predictive efficiency (training cohort: AUC = 0.869, 95%CI: 0.816-0.922; internal verification cohort: AUC = 0.871; 95%CI: 0.818-0.924). CONCLUSION: The five predictive models based on advanced machine learning algorithms, especially RFM, can accurately predict the risk of pain after TACE in patients with HCC. RFM can be used to assess the risk of pain for facilitating preventive treatment and improving the prognosis.

Effect of Arsenic Exposure and Cigarette Smoking on Total and Cause-Specific Mortality: An Occupational Cohort With 27 Follow-up Years.

BACKGROUND: The relationship between arsenic exposure and all-cause mortality and the joint effects of arsenic exposure and smoking have been poorly described in previous studies. METHODS: After 27 years of follow-up, a total of 1738 miners were included in the analysis. Different statistical methods were used to explore the relationship between arsenic exposure and smoking and the risk of all-cause mortality and various causes of death. RESULTS: A total of 694 deaths occurred during the 36,199.79 person-years of follow-up. Cancer was the leading cause of death, and arsenic-exposed workers had significantly higher mortality rates for all-cause, cancer, and cerebrovascular disease. All-cause, cancer, cerebrovascular disease, and respiratory disease increased with cumulative arsenic exposure. CONCLUSIONS: We demonstrated the negative effects of smoking and arsenic exposure on all-cause mortality. More effective actions should be taken to reduce arsenic exposure in miners.

Circulating microRNAs as Potential Biomarkers for the Diagnosis of Endometrial Cancer: a Meta-Analysis.

Endometrial cancer (EC) is the most common female genital tract malignancy worldwide. Many investigators have confirmed the possibility of using circulating miRNAs to diagnose EC; however, the results were inconsistent. Therefore, we performed the current meta-analysis to systematically evaluate the diagnostic value of circulating miRNAs in EC. We carefully searched relevant articles published prior to February 15, 2022 in the databases of PubMed, Embase, Web of Science, Cochrane Library, Wanfang database, and China National Knowledge Infrastructure (CNKI) based on PRISMA statement. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were calculated to test the diagnostic accuracy. Furthermore, subgroup analyses were performed to identify the potential sources of heterogeneity, and the Deeks' funnel plot asymmetry test was used to evaluate the potential publication bias. Twenty-one studies from 12 articles including a total of 2305 participants (1341 EC patients and 964 controls) were included in the current diagnostic meta-analysis. The overall pooled results of miRNA for EC diagnosis were: sensitivity, 0.84 (95% CI: 0.79-0.88); specificity, 0.87 (95% CI: 0.79-0.91); PLR, 6.3 (95% CI: 3.9-10.0); NLR, 0.18 (95% CI: 0.13-0.25); DOR, 35 (95% CI: 17-71); and AUC was 0.91 (95% CI: 0.89-0.94). Subgroup analysis suggested that miRNA cluster, serum type, and large sample sizes showed a better diagnostic accuracy. Moreover, there was no significant publication bias. Circulating miRNAs have great potential as novel non-invasive biomarkers for EC diagnosis.

Purinergic ATP triggers moxibustion-induced local anti-nociceptive effect on inflammatory pain model.

Purinergic signalling adenosine and its A1 receptors have been demonstrated to get involved in the mechanism of acupuncture (needling therapy) analgesia. However, whether purinergic signalling would be responsible for the local analgesic effect of moxibustion therapy, the predominant member in acupuncture family procedures also could trigger analgesic effect on pain diseases, it still remains unclear. In this study, we applied moxibustion to generate analgesic effect on complete Freund's adjuvant (CFA)-induced inflammatory pain rats and detected the purine released from moxibustioned-acupoint by high-performance liquid chromatography (HPLC) approach. Intramuscular injection of ARL67156 into the acupoint Zusanli (ST36) to inhibit the breakdown of ATP showed the analgesic effect of moxibustion was increased while intramuscular injection of ATPase to speed up ATP hydrolysis caused a reduced moxibustion-induced analgesia. These data implied that purinergic ATP at the location of ST36 acupoint is a potentially beneficial factor for moxibustion-induced analgesia.