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The recently emerged BA.2.86, JN.1, EG.5, EG.5.1, and HV.1 variants have a growth advantage. In this study, we explore the structural bases of receptor binding and immune evasion for the Omicron BA.2.86, JN.1, EG.5, EG.5.1, and HV.1 sub-variants. Our findings reveal that BA.2.86 exhibits strong receptor binding, whereas its JN.1 sub-lineage displays a decreased binding affinity to human ACE2 (hACE2). Through complex structure analyses, we observed that the reversion of R493Q in BA.2.86 receptor binding domain (RBD) plays a facilitating role in receptor binding, while the L455S substitution in JN.1 RBD restores optimal affinity. Furthermore, the structure of monoclonal antibody (mAb) S309 complexed with BA.2.86 RBD highlights the importance of the K356T mutation, which brings a new N-glycosylation motif, altering the binding pattern of mAbs belonging to RBD-5 represented by S309. These findings emphasize the importance of closely monitoring BA.2.86 and its sub-lineages to prevent another wave of SARS-CoV-2 infections.
Subject(s)
Angiotensin-Converting Enzyme 2 , Antibodies, Monoclonal , COVID-19 , Immune Evasion , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Humans , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , COVID-19/immunology , COVID-19/virology , COVID-19/metabolism , Binding Sites , Models, Molecular , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/metabolism , Antibodies, Viral/immunology , Antibodies, Viral/metabolism , MutationABSTRACT
Cyanine derivatives are organic dyes widely used for optical imaging. However, their potential in longitudinal optoacoustic imaging and photothermal therapy remains limited due to challenges such as poor chemical stability, poor photostability, and low photothermal conversion. In this study, we present a new structural modification for cyanine dyes by introducing a strongly electron-withdrawing group (barbiturate), resulting in a new series of barbiturate-cyanine dyes (BC810, BC885, and BC1010) with suppressed fluorescence and enhanced stability. Furthermore, the introduction of BC1010 into block copolymers (PEG114-b-PCL60) induces aggregation-caused quenching, further boosting the photothermal performance. The photophysical properties of nanoparticles (BC1010-NPs) include their remarkably broad absorption range from 900 to 1200 nm for optoacoustic imaging, allowing imaging applications in NIR-I and NIR-II windows. The combined effect of these strategies, including improved photostability, enhanced nonradiative relaxation, and aggregation-caused quenching, enables the detection of optoacoustic signals with high sensitivity and effective photothermal treatment of in vivo tumor models when BC1010-NPs are administered before irradiation with a 1064 nm laser. This research introduces a barbiturate-functionalized cyanine derivative with optimal properties for efficient optoacoustics-guided theranostic applications. This new compound holds significant potential for biomedical use, facilitating advancements in optoacoustic-guided diagnostic and therapeutic approaches.
Subject(s)
Barbiturates , Carbocyanines , Nanoparticles , Photoacoustic Techniques , Phototherapy , Animals , Photoacoustic Techniques/methods , Carbocyanines/chemistry , Carbocyanines/administration & dosage , Nanoparticles/chemistry , Barbiturates/chemistry , Barbiturates/administration & dosage , Phototherapy/methods , Humans , Mice, Inbred BALB C , Female , Mice, Nude , Cell Line, Tumor , Fluorescent Dyes/chemistry , Fluorescent Dyes/administration & dosage , Mice , Photothermal Therapy/methods , Neoplasms/therapyABSTRACT
The objective of this study was to discriminate thyroid and parathyroid tissues using Raman spectroscopy combined with an improved support vector machine (SVM) algorithm. In thyroid surgery, there is a risk of inadvertently removing the parathyroid glands. At present, there is a lack of research on using Raman spectroscopy to discriminate parathyroid and thyroid tissues. In this article, samples were obtained from 43 individuals with thyroid and parathyroid tissues for Raman spectroscopy analysis. This study employed partial least squares (PLS) to reduce dimensions of data, and three optimization algorithms are used to improve the classification accuracy of SVM algorithm model in spectral analysis. The results show that PLS-GA-SVM algorithm has higher diagnostic accuracy and better reliability. The sensitivity of this algorithm is 94.67% and the accuracy is 94.44%. It can be concluded that Raman spectroscopy combined with the PLS-GA-SVM diagnostic algorithm has significant potential for discriminating thyroid and parathyroid tissues.
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BACKGROUND: This randomized, parallel-controlled, double-blinded, phase III equivalence study evaluated the equivalence of a proposed pertuzumab biosimilar QL1209 to the pertuzumab (Perjeta®) each with trastuzumab and docetaxel in neoadjuvant treatment of early or locally advanced breast cancer patients with HER2-positive, ER/PR-negative. METHODS: Eligible patients were randomly (1:1) assigned to receive 4 cycles of neoadjuvant QL1209 or pertuzumab each with trastuzumab and docetaxel, and adjuvant treatment. The primary endpoint was total pathologic complete response (tpCR), with equivalence margins of 0.76 to 1.32. RESULTS: Among the 585 patients enrolled, 257 and 259 patients were assigned to the QL1209 and pertuzumab groups, respectively. The tpCR rates were comparable in the QL1209 (109/255, 42.75%; 90% CI 37.65 to 47.84) and pertuzumab (117/259, 45.17%; 90% CI 40.09 to 50.26) groups. The tpCR risk ratio was 0.95 (90% CI, 0.80 to 1.11), and the 90% CI fell within the predefined equivalence margin. The most common grade ≥3 treatment-related adverse event was decreased neutrophil count (10. 9% vs. 12.7%) in the QL1209 and pertuzumab groups. CONCLUSIONS: QL1209 demonstrated equivalent efficacy and comparable safety profile to the reference pertuzumab in neoadjuvant treatment of HER2-positive, ER/PR-negative, early, or locally advanced breast cancer. TRIAL REGISTRATION: Chinadrugtrials.org CTR20201073; ClinicalTrials.gov NCT04629846.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Biosimilar Pharmaceuticals , Breast Neoplasms , Docetaxel , Neoadjuvant Therapy , Receptor, ErbB-2 , Trastuzumab , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Trastuzumab/administration & dosage , Trastuzumab/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Docetaxel/administration & dosage , Receptor, ErbB-2/metabolism , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Double-Blind Method , Adult , Biosimilar Pharmaceuticals/administration & dosage , Biosimilar Pharmaceuticals/therapeutic use , Aged , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolismABSTRACT
Purpose: This study aims to identify the key factors influencing health-related quality of life (HRQoL) of pediatric acute myeloid leukemia (AML) patients following their initial diagnosis and examine their impact on the five-year survival prognosis. Methods: A chart review and follow-up were conducted for children with AML who participated in a prospective cohort study between 2017 and 2020. We identified factors influencing HRQoL through Pediatric Quality of Life Inventory™ (PedsQL™ 4.0), PedsQL™ Cancer Module 3.0 (CM 3.0) and PedsQL™ Family Impact Module 2.0 (FIM 2.0), as well as assessed the impact of impaired HRQoL on the overall outcomes of patients. Results: Sixty-four subjects enrolled in the study had complete HRQoL outcome data, and 61 of them completed the 5-year follow-up. In CM 3.0, age was positively associated with parental proxy reports (p = 0.040), whereas divorced families were negatively associated with child self-reports (p = 0.045). A positive medical history correlates with FIM 2.0 (p = 0.025). Residence (p = 0.046), the occupation of caregivers (p = 0.014), disease severity (p = 0.024), and the only child (p = 0.029) exhibited statistically significant associations with the impairment of HRQoL. Impaired HRQoL scores shown by the PedsQL™4.0 parent proxy report (p = 0.013) and FIM 2.0 (p = 0.011) were associated with a reduced 5-year survival rate. Conclusions: This study demonstrated that early impairment of HRQoL in pediatric acute myeloid leukemia patients has predictive value for long-term prognosis. Once validated, these findings may provide some guidance to clinicians treating children with AML.
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To evaluate the effects of gene mutations on Bruton tyrosine kinase inhibitor, zanubrutinib's effectiveness in patients with diffuse large B-cell lymphoma (DLBCL), we examined pooled data from four single-arm studies (BGB-3111-AU-003 [NCT02343120], BGB-3111-207 [NCT03145064], BGB-3111_GA101_Study_001 [NCT02569476], BGB-3111-213 [NCT03520920]; n = 121). Objective response rate (ORR) was higher, though not statistically significant, in patients with activated B-cell-like (ABC)- and unclassified DLBCL (42.9% [21/49]) versus those with germinal-center B-cell-like DLBCL (14.3% [1/7]; p = 0.15). Patients with CD79B mutations had better ORR (60%) versus patients with wild-type alleles (25.9%, p < 0.01). Higher TCL1A expression correlated with better zanubrutinib response (p = 0.03), longer progression-free survival (p = 0.01), and longer overall survival (p = 0.12). TCL1A expression was higher in ABC-DLBCL (p < 0.001) and MYD88/CD79B-mutated subtypes (p < 0.0001). Eighteen patients with high MYC/BCL-2 expression responded better to zanubrutinib (ORR = 61 vs. 29%, p = 0.02). Our results support assessing CD79B mutations, co-expressor DLBCL, and TCL1A expression status to identify patients with DLBCL who will benefit from zanubrutinib.
Subject(s)
CD79 Antigens , Lymphoma, Large B-Cell, Diffuse , Mutation , Proto-Oncogene Proteins c-bcl-2 , Proto-Oncogene Proteins c-myc , Proto-Oncogene Proteins , Pyrimidines , Humans , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/mortality , Lymphoma, Large B-Cell, Diffuse/pathology , Proto-Oncogene Proteins c-bcl-2/genetics , Middle Aged , Female , Male , Aged , Pyrimidines/therapeutic use , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , CD79 Antigens/genetics , Proto-Oncogene Proteins/genetics , Adult , Piperidines/therapeutic use , Pyrazoles/therapeutic use , Aged, 80 and over , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Antineoplastic Agents/therapeutic use , Gene Expression Regulation, Neoplastic/drug effects , Treatment Outcome , Germinal Center/pathology , Germinal Center/metabolism , Germinal Center/drug effectsABSTRACT
Novel strategies utilizing light in the second near-infrared region (NIR-II; 900-1,880 nm wavelengths) offer the potential to visualize and treat solid tumours with enhanced precision. Over the past few decades, numerous techniques leveraging NIR-II light have been developed with the aim of precisely eliminating tumours while maximally preserving organ function. During cancer surgery, NIR-II optical imaging enables the visualization of clinically occult lesions and surrounding vital structures with increased sensitivity and resolution, thereby enhancing surgical quality and improving patient prognosis. Furthermore, the use of NIR-II light promises to improve cancer phototherapy by enabling the selective delivery of increased therapeutic energy to tissues at greater depths. Initial clinical studies of NIR-II-based imaging and phototherapy have indicated impressive potential to decrease cancer recurrence, reduce complications and prolong survival. Despite the encouraging results achieved, clinical translation of innovative NIR-II techniques remains challenging and inefficient; multidisciplinary cooperation is necessary to bridge the gap between preclinical research and clinical practice, and thus accelerate the translation of technical advances into clinical benefits. In this Review, we summarize the available clinical data on NIR-II-based imaging and phototherapy, demonstrating the feasibility and utility of integrating these technologies into the treatment of cancer. We also introduce emerging NIR-II-based approaches with substantial potential to further enhance patient outcomes, while also highlighting the challenges associated with imminent clinical studies of these modalities.
Subject(s)
Infrared Rays , Neoplasms , Humans , Neoplasms/therapy , Neoplasms/diagnostic imaging , Neoplasms/radiotherapy , Infrared Rays/therapeutic use , Phototherapy/methods , Optical Imaging/methods , Medical Oncology/methodsABSTRACT
Near-infrared-II (NIR-II) fluorescence imaging is pivotal in biomedical research. Organic probes exhibit high potential in clinical translation, due to advantages such as precise structure design, low toxicity, and post-modifications convenience. In related preparation, enhancement of NIR-II tail emission from NIR-I dyes is an efficient method. In particular, the promotion of twisted intramolecular charge transfer (TICT) of relevant NIR-I dyes is a convenient protocol. However, present TICT-type probes still show disadvantages in relatively low emission, large particle sizes, or limited choice of NIR-I dyes, etc. Herein, the synthesis of stable small-sized polymer NIR-II fluoroprobes (e.g., 7.2 nm), integrating TICT and Förster resonance energy transfer process to synergistically enhance the NIR-II emission is reported. Strong enhanced emissions can be obtained from various NIR-I dyes and lanthanide elements (e.g., twelvefold at 1250 nm from Nd-DTPA/IR-808 sample). The fluorophore provides high-resolution angiography, with high-contrast imaging on middle cerebral artery occlusion model mice for distinguishing occlusion. The fluorophore can be rapidly excreted from the kidney (urine ≈65% within 4 h) in normal mice and exhibits long-term renal retention on acute kidney injury mice, showing potential applications in the prognosis of kidney diseases. This development provides an effective strategy to design and synthesize effective NIR-II fluoroprobes.
ABSTRACT
This study aimed to unveil the central mechanism of moxibustion treating chronic inflammatory visceral pain (CIVP) from the angle of circRNA-miRNA-mRNA networks in the spinal cord. The rat CIVP model was established using a mixture of 5% (w/v) 2,4,6-trinitrobenzene sulfonic acid and 50% ethanol at a volume ratio of 2:1 via enema. Rats in the moxibustion group received herb-partitioned moxibustion at Tianshu (ST25, bilateral) and Qihai (CV6) points. The abdominal withdrawal reflex (AWR), mechanical withdrawal threshold (MWT), and thermal withdrawal latency (TWL) were adopted for pain behavior observation and pain sensitivity assessment. The circRNA, miRNA, and mRNA expression profiles were detected using the high-throughput sequencing technique. Relevant databases and bioinformatics analysis methods were used to screen for differentially expressed (DE) RNAs and build a circRNA-miRNA-mRNA (competing endogenous RNA) ceRNA regulatory network. The real-time quantitative PCR was employed to verify the sequencing result. CIVP rat models had a significantly higher AWR and lower TWL and MWT than normal rats. Between normal and model rats, there were 103 DE-circRNAs, 16 DE-miRNAs, and 397 DE-mRNAs in the spinal cord. Compared with the model group, the moxibustion group had a lower AWR and higher TWL and MWT; between these two groups, there were 118 DE-circRNAs, 15 DE-miRNAs, and 804 DE-mRNAs in the spinal cord. Two ceRNA networks were chosen to be verified. As a result, moxibustion's analgesic effect on visceral pain in CIVP rats may be associated with regulating the circRNA_02767/rno-miR-483-3p/Gfap network in the spinal cord and improving central sensitization.
Subject(s)
Gene Regulatory Networks , MicroRNAs , Moxibustion , RNA, Circular , RNA, Messenger , Rats, Sprague-Dawley , Spinal Cord , Visceral Pain , Animals , Moxibustion/methods , MicroRNAs/genetics , MicroRNAs/metabolism , RNA, Circular/genetics , RNA, Circular/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Spinal Cord/metabolism , Spinal Cord/pathology , Visceral Pain/genetics , Visceral Pain/therapy , Male , Inflammation/genetics , Inflammation/pathology , Chronic Pain/therapy , Chronic Pain/genetics , Rats , Gene Expression RegulationABSTRACT
Neurodevelopmental cell communication plays a crucial role in neuroblastoma prognosis. However, determining the impact of these communication pathways on prognosis is challenging due to limited sample sizes and patchy clinical survival information of single cell RNA-seq data. To address this, we have developed the cell communication pathway prognostic model (CCPPM) in this study. CCPPM involves the identification of communication pathways through single-cell RNA-seq data, screening of prognosis-significant pathways using bulk RNA-seq data, conducting functional and attribute analysis of these pathways, and analyzing the post-effects of communication within these pathways. By employing the CCPPM, we have identified ten communication pathways significantly influencing neuroblastoma, all related to axongenesis and neural projection development, especially the BMP7-(BMPR1B-ACVR2B) communication pathway was found to promote tumor cell migration by activating the transcription factor SMAD1 and regulating UNK and MYCBP2. Notably, BMP7 expression was higher in neuroblastoma samples with distant metastases. In summary, CCPPM offers a novel approach to studying the influence of cell communication pathways on disease prognosis and identified detrimental communication pathways related to neurodevelopment.
Subject(s)
Cell Communication , Neuroblastoma , Signal Transduction , Neuroblastoma/pathology , Neuroblastoma/metabolism , Neuroblastoma/genetics , Humans , Prognosis , Gene Expression Regulation, Neoplastic , Single-Cell Analysis/methods , Computational Biology/methods , Cell Line, Tumor , Gene Expression Profiling , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/genetics , Bone Morphogenetic Protein 7/metabolism , Bone Morphogenetic Protein 7/genetics , Cell MovementABSTRACT
Objective. The primary objective of this study is to address the reconstruction time challenge in magnetic particle imaging (MPI) by introducing a novel approach named SNR-peak-based frequency selection (SPFS). The focus is on improving spatial resolution without compromising reconstruction speed, thereby enhancing the clinical potential of MPI for real-time imaging.Approach. To overcome the trade-off between reconstruction time and spatial resolution in MPI, the researchers propose SPFS as an innovative frequency selection method. Unlike conventional SNR-based selection, SPFS prioritizes frequencies with signal-to-noise ratio (SNR) peaks that capture crucial system matrix information. This adaptability to varying quantities of selected frequencies enhances versatility in the reconstruction process. The study compares the spatial resolution of MPI reconstruction using both SNR-based and SPFS frequency selection methods, utilizing simulated and real device data.Main results.The research findings demonstrate that the SPFS approach substantially improves image resolution in MPI, especially when dealing with a limited number of frequency components. By focusing on SNR peaks associated with critical system matrix information, SPFS mitigates the spatial resolution degradation observed in conventional SNR-based selection methods. The study validates the effectiveness of SPFS through the assessment of MPI reconstruction spatial resolution using both simulated and real device data, highlighting its potential to address a critical limitation in the field.Significance.The introduction of SPFS represents a significant breakthrough in MPI technology. The method not only accelerates reconstruction time but also enhances spatial resolution, thus expanding the clinical potential of MPI for various applications. The improved real-time imaging capabilities of MPI, facilitated by SPFS, hold promise for advancements in drug delivery, plaque assessment, tumor treatment, cerebral perfusion evaluation, immunotherapy guidance, andin vivocell tracking.
Subject(s)
Image Processing, Computer-Assisted , Signal-To-Noise Ratio , Image Processing, Computer-Assisted/methods , Time Factors , Phantoms, Imaging , Molecular Imaging/methodsABSTRACT
Introduction: As an effective alternative choice to traditional mono-therapy, multifunctional nanoplatforms hold great promise for cancer therapy. Based on the strategies of Fenton-like reactions and reactive oxygen species (ROS)-mediated therapy, black phosphorus (BP) nanoplatform BP@Cu2O@L-Arg (BCL) co-assembly of cuprous oxide (Cu2O) and L-Arginine (L-Arg) nanoparticles was developed and evaluated for synergistic cascade breast cancer therapy. Methods: Cu2O particles were generated in situ on the surface of the BP nanosheets, followed by L-Arg incorporation through electrostatic interactions. In vitro ROS/nitric oxide (NO) generation and glutathione (GSH) depletion were evaluated. In vitro and in vivo anti-cancer activity were also assessed. Finally, immune response of BCL under ultrasound was investigated. Results: Cu2O was incorporated into BP to exhaust the overexpressed intracellular GSH in cancer cells via the Fenton reaction, thereby decreasing ROS consumption. Apart from being used as biocompatible carriers, BP nanoparticles served as sonosensitizers to produce excessive ROS under ultrasound irradiation. The enhanced ROS accumulation accelerated the oxidation of L-Arg, which further promoted NO generation for gas therapy. In vitro experiments revealed the outstanding therapeutic killing effects of BCL under ultrasound via mechanisms involving GSH deletion and excessive ROS and NO generation. In vivo studies have illustrated that the nanocomplex modified the immune response by promoting macrophage and CD8+ cell infiltration and inhibiting MDSC infiltration. Discussion: BCL nanoparticles exhibited multifunctional characteristics for GSH depletion-induced ROS/NO generation, making a new multitherapy strategy for cascade breast cancer therapy.
Subject(s)
Nanoparticles , Neoplasms , Humans , Reactive Oxygen Species , Nitric Oxide , Arginine , Glutathione , Cell Line, Tumor , Hydrogen Peroxide , Tumor MicroenvironmentABSTRACT
Organic dye-based agents with near-infrared (NIR)-II absorption have great potential for cancer theranostics because of the deeper tissue penetration and good biocompatibility. However, proper design is required to develop NIR-II-absorbing dyes with good optical properties. We proposed to construct chalcogen atom-modulated croconaine for NIR-II light-triggered photothermal theranostics. By introducing different chalcogen atoms (O, S, Se, or Te) into the structure of croconaine, the light absorption of croconaine can be precisely regulated from the NIR-I to the NIR-II range due to the heavy-atom effect. Especially, Te-substituted croconaine (CRTe) and its nanoformulations exhibit superior NIR-II responsiveness, a high photothermal conversion efficiency (70.6%), and good photostability. With their favorable tumor accumulation, CRTe-NPs from tumor regions can be visualized by NIR-II optoacoustic systems with high resolution and high contrast; meanwhile, their superior photothermal performance also contributes to efficient cell killing and tumor elimination upon 1064 nm laser irradiation. Therefore, this work provides an efficient strategy for the molecular design of NIR-II organic photothermal agents.
Subject(s)
Chalcogens , Nanoparticles , Neoplasms , Humans , Theranostic Nanomedicine , Neoplasms/drug therapy , Coloring Agents/chemistry , Chalcogens/pharmacology , Nanoparticles/chemistry , Phototherapy , Cell Line, TumorABSTRACT
Background: Hepatoblastoma is the most prevalent primary hepatic malignancy in children, comprising 80% of pediatric hepatic malignancies and 1% of all pediatric malignancies. However, traditional treatments have proven inadequate in effectively curing hepatoblastoma, leading to a poor prognosis. Methods: A literature search was conducted on multiple electronic databases (PubMed and Google Scholar). A total of 86 articles were eligible for inclusion in this review. Result: This review aims to consolidate recent developments in hepatoblastoma research, focusing on the latest advances in cancer-associated genomics, epigenetic studies, transcriptional programs and molecular subtypes. We also discuss the current treatment approaches and forthcoming strategies to address cancer-associated biological challenges. Conclusion: To provide a comprehensive summary of the molecular mechanisms associated with hepatoblastoma occurrence, this review highlights three key aspects: genomics, epigenetics, and transcriptomics. Our review aims to facilitate the exploration of novel molecular mechanisms and the development of innovative clinical treatment strategies for hepatoblastoma.
ABSTRACT
KDELR (Erd2 [ER retention defective 2] in yeasts) is a receptor protein that retrieves endoplasmic reticulum (ER)-resident proteins from the Golgi apparatus. However, the role of the KDELR-mediated ER-retrieval system in regulating cellular homeostasis remains elusive. Here, we show that the absence of Erd2 triggers the unfolded protein response (UPR) and enhances mitochondrial respiration and reactive oxygen species in an UPR-dependent manner in the fission yeast Schizosaccharomyces pombe. Moreover, we perform transcriptomic analysis and find that the expression of genes related to mitochondrial respiration and the tricarboxylic acid cycle is upregulated in a UPR-dependent manner in cells lacking Erd2. The increased mitochondrial respiration and reactive oxygen species production is required for cell survival in the absence of Erd2. Therefore, our findings reveal a novel role of the KDELR-Erd2-mediated ER-retrieval system in modulating mitochondrial functions and highlight its importance for cellular homeostasis in the fission yeast.
Subject(s)
Endoplasmic Reticulum , Mitochondria , Schizosaccharomyces , Unfolded Protein Response , Endoplasmic Reticulum/genetics , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum Stress , Mitochondria/genetics , Mitochondria/metabolism , Reactive Oxygen Species/metabolism , Schizosaccharomyces/genetics , Schizosaccharomyces/metabolismABSTRACT
BACKGROUND: Kinematic analysis has been recommended to quantify the upper limb motor function after stroke. However, previous studies have rarely reported the kinematic data of the post-stroke patients with moderate to severe upper limb paresis due to the poor accomplishment of the complex tasks. METHODS: 27 post-stroke individuals and 20 non-disabled people participated in the study. The trunk and upper limb movements during the Hand-to-mouth task were captured by the motion capture system and upper extremity kinematic analysis software automatically. The subgroup analysis within stroke group were conducted layering by the Fugl-Meyer Assessment for Upper Extremity scores (severe: 16-31; moderate: 32-50). FINDINGS: The paretic upper limbs in the stroke group tended to use more trunk and shoulder compensatory strategies to offset the impact of spasticity and weakness compared with non-disabled controls. The less-affected limbs in the stroke group also showed abnormal kinematic data. There were significant differences between the kinematic metrics of severe and moderate subgroups. INTERPRETATION: The Hand-to-mouth task is a good and feasible option for kinematic analysis of these patients. It is essential to layer the severity of the paresis and put more emphasis on trunk movements in the future kinematic studies.
Subject(s)
Stroke Rehabilitation , Stroke , Humans , Biomechanical Phenomena , Upper Extremity , Stroke/complications , Paresis/etiologyABSTRACT
BACKGROUND: Previous studies have suggested that vitamin D may possess anti-infection properties, but the relationship between vitamin D and Trichomonas vaginalis infection remains unexplored. METHODS: Using data from the National Health and Nutrition Examination Survey between 2013 and 2016, we conducted multivariate regression analyses and subgroup analyses to investigate the association between 25-hydroxyvitamin D (25[OH]D) levels and T. vaginalis infection, ensuring the robustness of our results. RESULTS: The final sample included data from 4318 individuals aged 20 to 59 years, among which 92 were diagnosed with T. vaginalis infection. For every 10 nmol/L increase in serum 25(OH)D level, there was a 22% reduction in the likelihood of T. vaginalis infection incidence (adjusted odds ratio [aOR], 0.78; 95% confidence interval [CI], 0.69-0.90). Similarly, higher concentration tertiles demonstrated relatively lower infection ratios compared with the tertile with the lowest 25(OH)D concentration (aOR, 0.54 [95% CI, 0.30-0.95; P = 0.030] for T2; aOR, 0.23 [95% CI, 0.09-0.61; P < 0.001] for T3). CONCLUSIONS: Our cross-sectional study indicates a negative association between 25(OH)D levels and the prevalence of T. vaginalis infection. However, further high-quality evidence is needed to establish a causal relationship between 25(OH)D levels and T. vaginalis infection, as well as to evaluate the potential role of vitamin D supplementation in preventing T. vaginalis infection.
Subject(s)
Trichomonas Infections , Trichomonas vaginalis , Vitamin D/analogs & derivatives , Adult , Humans , United States/epidemiology , Nutrition Surveys , Cross-Sectional Studies , Trichomonas Infections/epidemiologyABSTRACT
Currently, the secondary development and modification of clinical drugs has become one of the research priorities. Researchers have developed a variety of TME-responsive nanomedicine carriers to solve certain clinical problems. Unfortunately, endogenous stimuli such as reactive oxygen species (ROS), as an important prerequisite for effective therapeutic efficacy, are not enough to achieve the expected drug release process, therefore, it is difficult to achieve a continuous and efficient treatment process. Herein, a self-supply ROS-responsive cascade polyprodrug (PMTO) is designed. The encapsulation of the chemotherapy drug mitoxantrone (MTO) in a polymer backbone could effectively reduce systemic toxicity when transported in vivo. After PMTO is degraded by endogenous ROS of the TME, another part of the polyprodrug backbone becomes cinnamaldehyde (CA), which can further enhance intracellular ROS, thereby achieving a sustained drug release process. Meanwhile, due to the disruption of the intracellular redox environment, the efficacy of chemotherapy drugs is enhanced. Finally, the anticancer treatment efficacy is further enhanced due to the mild hyperthermia effect of PMTO. In conclusion, the designed PMTO demonstrates remarkable antitumor efficacy, effectively addressing the limitations associated with MTO.
Subject(s)
Acrolein/analogs & derivatives , Mitoxantrone , Reactive Oxygen Species , Mitoxantrone/chemistry , Mitoxantrone/pharmacology , Mitoxantrone/pharmacokinetics , Reactive Oxygen Species/metabolism , Animals , Humans , Mice , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Hyperthermia, Induced/methods , Prodrugs/chemistry , Prodrugs/pharmacology , Acrolein/chemistry , Acrolein/pharmacology , Mice, Inbred BALB C , Drug Liberation , Female , Mice, Nude , Drug Carriers/chemistry , Polymers/chemistryABSTRACT
Objective. Imaging of superparamagnetic iron oxide nanoparticles based on their non-linear response to alternating magnetic fields shows promise for imaging cells and vasculature in healthy and diseased tissue. Such imaging can be achieved through x-space reconstruction typically along a unidirectional Cartesian trajectory, which rapidly convolutes the particle distribution with a 'anisotropic blurring' point spread function (PSF), leading to images with anisotropic resolution.Approach. Here we propose combining the time domine-system matrix and x-space reconstruction methods into a forward model, where the output of the forward model is the PSF-blurred x-space reconstructed image. We then treat the blur as an inverse problem solved by Kaczmarz iteration.Main results. After we have proposed the method optimization, the normal resolution of simulation and device images has been increased from 3.5 mm and 5.25 mm to 1.5 mm and 3.25 mm, which has reached the level in the tangential resolution. Quantitative indicators of image quality such as PSNR and SSIM have also been greatly improved.Significance. Simulation and imaging of real phantoms indicate that our approach provides better isotropic resolution and image quality than the x-space method alone or other methods for removing PSF blur. Using our proposed method to optimize the image quality of x-space reconstructed images using unidirectional Cartesian trajectories, it will promote the clinical application of MPI in the future.