A novel splicing mutation DNAH5 c.13,338 + 5G > C is involved in the pathogenesis of primary ciliary dyskinesia in a family with primary familial brain calcification.

BACKGROUND: Primary ciliary dyskinesia (PCD) is an autosomal recessive hereditary disease characterized by recurrent respiratory infections. In clinical manifestations, DNAH5 (NM_001361.3) is one of the recessive pathogenic genes. Primary familial brain calcification (PFBC) is a neurodegenerative disease characterized by bilateral calcification in the basal ganglia and other brain regions. PFBC can be inherited in an autosomal dominant or recessive manner. A family with PCD caused by a DNAH5 compound heterozygous variant and PFBC caused by a MYORG homozygous variant was analyzed. METHODS: In this study, we recruited three generations of Han families with primary ciliary dyskinesia combined with primary familial brain calcification. Their clinical phenotype data were collected, next-generation sequencing was performed to screen suspected pathogenic mutations in the proband and segregation analysis of families was carried out by Sanger sequencing. The mutant and wild-type plasmids were constructed and transfected into HEK293T cells instantaneously, and splicing patterns were detected by Minigene splicing assay. The structure and function of mutations were analyzed by bioinformatics analysis. RESULTS: The clinical phenotypes of the proband (II10) and his sister (II8) were bronchiectasis, recurrent pulmonary infection, multiple symmetric calcifications of bilateral globus pallidus and cerebellar dentate nucleus, paranasal sinusitis in the whole group, and electron microscopy of bronchial mucosa showed that the ciliary axoneme was defective. There was also total visceral inversion in II10 but not in II8. A novel splice variant C.13,338 + 5G > C and a frameshift variant C.4314delT (p. Asn1438lysfs *10) were found in the DNAH5 gene in proband (II10) and II8. c.347_348dupCTGGCCTTCCGC homozygous insertion variation was found in the MYORG of the proband. The two pathogenic genes were co-segregated in the family. Minigene showed that DNAH5 c.13,338 + 5G > C has two abnormal splicing modes: One is that part of the intron bases where the mutation site located is translated, resulting in early translation termination of DNAH5; The other is the mutation resulting in the deletion of exon76. CONCLUSIONS: The newly identified DNAH5 splicing mutation c.13,338 + 5G > C is involved in the pathogenesis of PCD in the family, and forms a compound heterozygote with the pathogenic variant DNAH5 c.4314delT lead to the pathogenesis of PCD.

Dynamic Regularized Adaptive Cluster Optimization (DRACO) for Quantitative Cardiac Cine MRI in Complex Arrhythmias.

BACKGROUND: Irregular cardiac motion can render conventional segmented cine MRI nondiagnostic. Clustering has been proposed for cardiac motion binning and may be optimized for complex arrhythmias. PURPOSE: To develop an adaptive cluster optimization method for irregular cardiac motion, and to generate the corresponding time-resolved cine images. STUDY TYPE: Prospective. SUBJECTS: Thirteen with atrial fibrillation, four with premature ventricular contractions, and one patient in sinus rhythm. FIELD STRENGTH/SEQUENCE: Free-running balanced steady state free precession (bSSFP) with sorted golden-step, reference real-time sequence. ASSESSMENT: Each subject underwent both the sorted golden-step bSSFP and the reference Cartesian real-time imaging. Golden-step bSSFP images were reconstructed using the dynamic regularized adaptive cluster optimization (DRACO) method and k-means clustering. Image quality (4-point Likert scale), signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), edge sharpness, and ventricular function were assessed. STATISTICAL TESTS: Paired t-tests, Friedman test, regression analysis, Fleiss' Kappa, Bland-Altman analysis. Significance level P < 0.05. RESULTS: The DRACO method had the highest percent of images with scores ≥3 (96% for diastolic frame, 93% for systolic frame, and 93% for multiphase cine) and the percentages were significantly higher compared with both the k-means and real-time methods. Image quality scores, SNR, and CNR were significantly different between DRACO vs. k-means and between DRACO vs. real-time. Cardiac function analysis showed no significant differences between DRACO vs. the reference real-time. CONCLUSION: DRACO with time-resolved reconstruction generated high quality images and has early promise for quantitative cine cardiac MRI in patients with complex arrhythmias including atrial fibrillation. TECHNICAL EFFICACY: Stage 2.

Clinical phenotype and genetic function analysis of a family with hypomyelinating leukodystrophy-7 caused by POLR3A mutation.

Hypomyelinating leukodystrophy (HLD) is a rare genetic heterogeneous disease that can affect myelin development in the central nervous system. This study aims to analyze the clinical phenotype and genetic function of a family with HLD-7 caused by POLR3A mutation. The proband (IV6) in this family mainly showed progressive cognitive decline, dentin dysplasia, and hypogonadotropic hypogonadism. Her three old brothers (IV1, IV2, and IV4) also had different degrees of ataxia, dystonia, or dysarthria besides the aforementioned manifestations. Their brain magnetic resonance imaging showed bilateral periventricular white matter atrophy, brain atrophy, and corpus callosum atrophy and thinning. The proband and her two living brothers (IV2 and IV4) were detected to carry a homozygous mutation of the POLR3A (NM_007055.4) gene c. 2300G > T (p.Cys767Phe), and her consanguineous married parents (III1 and III2) were p.Cys767Phe heterozygous carriers. In the constructed POLR3A wild-type and p.Cys767Phe mutant cells, it was seen that overexpression of wild-type POLR3A protein significantly enhanced Pol III transcription of 5S rRNA and tRNA Leu-CAA. However, although the mutant POLR3A protein overexpression was increased compared to the wild-type protein overexpression, it did not show the expected further enhancement of Pol III function. On the contrary, Pol III transcription function was frustrated (POLR3A, BC200, and tRNA Leu-CAA expression decreased), and MBP and 18S rRNA expressions were decreased. This study indicates that the POLR3A p.Cys767Phe variant caused increased expression of mutated POLR3A protein and abnormal expression of Pol III transcripts, and the mutant POLR3A protein function was abnormal.

Pedigree Analysis of Nonclassical Cholesteryl Ester Storage Disease with Dominant Inheritance in a LIPA I378T Heterozygous Carrier.

BACKGROUND: Cholesterol ester storage disorder (CESD; OMIM: 278,000) was formerly assumed to be an autosomal recessive allelic genetic condition connected to diminished lysosomal acid lipase (LAL) activity due to LIPA gene abnormalities. CESD is characterized by abnormal liver function and lipid metabolism, and in severe cases, liver failure can occur leading to death. In this study, one Chinese nonclassical CESD pedigree with dominant inheritance was phenotyped and analyzed for the corresponding gene alterations. METHODS: Seven males and eight females from nonclassical CESD pedigree were recruited. Clinical features and LAL activities were documented. Whole genome Next-generation sequencing (NGS) was used to screen candidate genes and mutations, Sanger sequencing confirmed predicted mutations, and qPCR detected LIPA mRNA expression. RESULTS: Eight individuals of the pedigree were speculatively thought to have CESD. LAL activity was discovered to be lowered in four living members of the pedigree, but undetectable in the other four deceased members who died of probable hepatic failure. Three of the four living relatives had abnormal lipid metabolism and all four had liver dysfunctions. By liver biopsy, the proband exhibited diffuse vesicular fatty changes in noticeably enlarged hepatocytes and Kupffer cell hyperplasia. Surprisingly, only a newly discovered heterozygous mutation, c.1133T>C (p. Ile378Thr) on LIPA, was found by gene sequencing in the proband. All living family members who carried the p.I378T variant displayed reduced LAL activity. CONCLUSIONS: Phenotypic analyses indicate that this may be an autosomal dominant nonclassical CESD pedigree with a LIPA gene mutation.

Challenges and opportunities in oncology drug development and clinical research in China.

As one of the world's most populous countries, China bears a heavy burden and a broad spectrum of cancers, including unique types, providing a unique environment for drug research and development. In recent years, China has leapt forward in oncology drug development and clinical trials, presenting new opportunities and challenges.

Adult type I Gaucher disease with splenectomy caused by a compound heterozygous GBA1 mutation in a Chinese patient: a case report.

Gaucher disease (GD) is an autosomal recessive ailment resulting from glucocerebrosidase deficiency caused by a mutation in the GBA1 gene, leading to multi-organ problems in the liver, spleen, and bone marrow. In China, GD is extremely uncommon and has a lower incidence rate than worldwide. In this study, we report the case of an adult male with an enlarged spleen for 13 years who presented with abdominal distension, severe loss of appetite and weight, reduction of the three-line due to hypersplenism, frequent nosebleeds, and bloody stools. Regrettably, the unexpected discovery of splenic pathology suggestive of splenic Gaucher disease was only made after a splenectomy due to a lack of knowledge about rare disorders. Our patient's delayed diagnosis may have been due to the department where he was originally treated, but it highlights the need for multidisciplinary consultation in splenomegaly of unknown etiology. We then investigated the patient's clinical phenotypes and gene mutation features using genetically phenotypical analysis. The analysis of the GBA1 gene sequence indicated that the patient carried a compound heterozygous mutation consisting of two potentially disease-causing mutations: c.907C > A (p. Leu303Ile) and c.1448 T > C (p. Leu483Pro). While previous research has linked the p. Leu483Pro mutation site to neurologic GD phenotypes (GD2 and GD3), the patients in this investigation were identified as having non-neuronopathic GD1. The other mutation, p. Leu303Ile, is a new GD-related mutation not indexed in PubMed that enriches the GBA1 gene mutation spectrum. Biosignature analysis has shown that both mutations alter the protein's three-dimensional structure, which may be a pathogenic mechanism for GD1 in this patient.

Hypoxia-informed RBE-weighted beam orientation optimization for intensity modulated proton therapy.

BACKGROUND: Variable relative biological effectiveness (RBE) models in treatment planning have been proposed to optimize the therapeutic ratio of proton therapy. It has been reported that proton RBE decreases with increasing tumor oxygen level, offering an opportunity to address hypoxia-related radioresistance with RBE-weighted optimization. PURPOSE: Here, we obtain a voxel-level estimation of partial oxygen pressure to weigh RBE values in a single biologically informed beam orientation optimization (BOO) algorithm. METHODS: Three glioblastoma patients with [18 F]-fluoromisonidazole (FMISO)-PET/CT images were selected from the institutional database. Oxygen values were derived from tracer uptake using a nonlinear least squares curve fitting. McNamara RBE, calculated from proton dose, was then weighed using oxygen enhancement ratios (OER) for each voxel and incorporated into the dose fidelity term of the BOO algorithm. The nonlinear optimization problem was solved using a split-Bregman approach, with FISTA as the solver. The proposed hypoxia informed RBE-weighted method (HypRBE) was compared to dose fidelity terms using the constant RBE of 1.1 (cRBE) and the normoxic McNamara RBE model (RegRBE). Tumor homogeneity index (HI), maximum biological dose (Dmax), and D95%, as well as OAR therapeutic index (TI = gEUDCTV /gEUDOAR ) were evaluated along with worst-case statistics after normalization to normal tissue isotoxicity. RESULTS: Compared to [cRBE, RegRBE], HypRBE increased tumor HI, Dmax, and D95% across all plans by on average [31.3%, 31.8%], [48.6%, 27.1%], and [50.4%, 23.8%], respectively. In the worst-case scenario, the parameters increase on average by [12.5%, 14.7%], [7.3%,-8.9%], and [22.3%, 2.1%]. Despite increased OAR Dmean and Dmax by [8.0%, 3.0%] and [13.1%, -0.1%], HypRBE increased average TI by [22.0%, 21.1%]. Worst-case OAR Dmean, Dmax, and TI worsened by [17.9%, 4.3%], [24.5%, -1.2%], and [9.6%, 10.5%], but in the best cases, HypRBE escalates tumor coverage significantly without compromising OAR dose, increasing the therapeutic ratio. CONCLUSIONS: We have developed an optimization algorithm whose dose fidelity term accounts for hypoxia-informed RBE values. We have shown that HypRBE selects bE:\Alok\aaeams better suited to deliver high physical dose to low RBE, hypoxic tumor regions while sparing the radiosensitive normal tissue.

ECG-free cine MRI with data-driven clustering of cardiac motion for quantification of ventricular function.

BACKGROUND: Despite the widespread use of cine MRI for evaluation of cardiac function, existing real-time methods do not easily enable quantification of ventricular function. Moreover, segmented cine MRI assumes periodicity of cardiac motion. We aim to develop a self-gated, cine MRI acquisition scheme with data-driven cluster-based binning of cardiac motion. METHODS: A Cartesian golden-step balanced steady-state free precession sequence with sorted k-space ordering was designed. Image data were acquired with breath-holding. Principal component analysis and k-means clustering were used for binning of cardiac phases. Cluster compactness in the time dimension was assessed using temporal variability, and dispersion in the spatial dimension was assessed using the Calinski-Harabasz index. The proposed and the reference electrocardiogram (ECG)-gated cine methods were compared using a four-point image quality score, SNR and CNR values, and Bland-Altman analyses of ventricular function. RESULTS: A total of 10 subjects with sinus rhythm and 8 subjects with arrhythmias underwent cardiac MRI at 3.0 T. The temporal variability was 45.6 ms (cluster) versus 24.6 ms (ECG-based) (p < 0.001), and the Calinski-Harabasz index was 59.1 ± 9.1 (cluster) versus 22.0 ± 7.1 (ECG based) (p < 0.001). In subjects with sinus rhythm, 100% of the end-systolic and end-diastolic images from both the cluster and reference approach received the highest image quality score of 4. Relative to the reference cine images, the cluster-based multiphase (cine) image quality consistently received a one-point lower score (p < 0.05), whereas the SNR and CNR values were not significantly different (p = 0.20). In cases with arrhythmias, 97.9% of the end-systolic and end-diastolic images from the cluster approach received an image quality score of 3 or more. The mean bias values for biventricular ejection fraction and volumes derived from the cluster approach versus reference cine were negligible. CONCLUSION: ECG-free cine cardiac MRI with data-driven clustering for binning of cardiac motion is feasible and enables quantification of cardiac function.

Dosimetric predictors for genitourinary toxicity in MR-guided stereotactic body radiation therapy (SBRT): Substructure with fraction-wise analysis.

BACKGROUND: MR-guided radiation therapy (MRgRT) systems provide superior soft tissue contrast than x-ray based systems and can acquire real-time cine for treatment gating. These features allow treatment planning margins to be reduced, allowing for improved critical structure sparing and reduced treatment toxicity. Despite this improvement, genitourinary (GU) toxicity continues to affect many patients. PURPOSE: (1) To identify dosimetric predictors, potentially in combination with clinical parameters, of GU toxicity following SBRT by leveraging MRgRT to accurately monitor daily dose, beyond predicted dose calculated during planning. (2) Improve awareness of toxicity-sensitive bladder substructures, specifically the trigone and urethra. METHODS: Sixty-nine prostate cancer patients (NCT04384770 clinical trial) were treated on a ViewRay MRIdian MRgRT system, with 40 Gy prescribed to 95% of the PTV in over five fractions. Overall, 17 (24.6%) prostate patients reported acute grade 2 GU toxicity. The CTV, PTV, bladder, bladder wall, trigone, urethra, rectum, and rectal wall were contoured on the planning and daily treatment MRIs. Planning and daily treatment DVHs (0.1 Gy increments), organ doses (min, max, mean), and organ volumes were recorded. Daily dose was estimated by transferring the planning dose distributions to the daily MRI based on the daily setup alignment. Patients were partitioned into a training (55) and testing set (14). Dose features were pre-filtered using a t-test followed by maximum relevance minimum redundancy (MRMR) algorithm. Logistic regression was investigated with regularization to select dosimetric predictors. Specifically, two approaches: time-group least absolute shrinkage and selection (LASSO), and interactive grouped greedy algorithm (IGA) were investigated. Shared features across the planning and five treatment fractions were grouped to encourage consistency and stability. The conventional flat non-temporally grouped LASSO was also evaluated to provide a solid benchmark. After feature selection, a final logistic regression model was trained. Dosimetric regression models were compared to a clinical regression model with only clinical parameters (age, baseline IPSS, prostate gland size, ADT usage, etc.) and a hybrid model, combining the best performing dosimetric features with the clinical parameters, was evaluated. Final model performance was evaluated on the testing set using accuracy, sensitivity, and specificity determined by the optimal threshold of the training set. RESULTS: IGA had the best testing performance with an accuracy/sensitivity/specificity of 0.79/0.67/0.82, selecting 12 groups covering the bladder (V19.8 Gy, V20.5 Gy), bladder wall (19.7 Gy), trigone (15.9, 18.2, 43.3 Gy), urethra (V41.4 Gy, V41.7 Gy), CTV (V41.9 Gy), rectum (V8.5 Gy), and rectal wall (1.2, 44.1 Gy) dose features. Absolute bladder V19.8 Gy and V20.5 Gy were the most important features, followed by relative trigone 15.9  and 18.2 Gy. Inclusion of clinical parameters in the hybrid model with IGA did not significantly change regression performance. CONCLUSION: Overall, IGA feature selection resulted in the best GU toxicity prediction performance. This exploratory study demonstrated the feasibility of identification and analysis of dosimetric toxicity predictors with awareness to sensitive substructures and daily dose to potentially provide consistent and stable dosimetric metrics to guide treatment planning. Further patient accruement is warranted to further assess dosimetric predictor and perform validation.

Impact of Interfractional Bladder and Trigone Displacement and Deformation on Radiation Exposure and Subsequent Acute Genitourinary Toxicity: A Post Hoc Analysis of Patients Treated with Magnetic Resonance Imaging-Guided Prostate Stereotactic Body Radiation Therapy in a Phase 3 Randomized Trial.

PURPOSE: Emerging data suggest that trigone dosimetry may be more associated with poststereotactic body radiation therapy (SBRT) urinary toxicity than whole bladder dosimetry. We quantify the dosimetric effect of interfractional displacement and deformation of the whole bladder and trigone during prostate SBRT using on-board, pretreatment 0.35T magnetic resonance images (MRI). METHODS AND MATERIALS: Seventy-seven patients treated with MRI-guided prostate SBRT (40 Gy/5 fractions) on the MRI arm of a phase 3 single-center randomized trial were included. Bladder and trigone structures were contoured on images obtained from a 0.35T simulation MRI and 5 on-board pretreatment MRIs. Dice similarity coefficient (DSC) scores and changes in volume between simulation and daily treatments were calculated. Dosimetric parameters including Dmax, D0.03 cc, Dmean, V40 Gy, V39 Gy, V38 Gy, and V20 Gy for the bladder and trigone for the simulation and daily treatments were collected. Both physician-scored (Common Terminology Criteria for Adverse Events, version 4.03 scale) as well as patient-reported (International Prostate Symptom Scores and the Expanded Prostate Cancer Index Composite-26 scores) acute genitourinary (GU) toxicity outcomes were collected and analyzed. RESULTS: The average treatment bladder volume was about 30% smaller than the simulation bladder volume; however, the trigone volume remained fairly consistent despite being positively correlated with total bladder volume. Overall, the trigone accounted for <2% of the bladder volume. Median DSC for the bladder was 0.79, whereas the median DSC of the trigone was only 0.33. No statistically significant associations between our selected bladder and trigonal dosimetric parameters and grade ≥2 GU toxicity were identified, although numerically, patients with GU toxicity (grade ≥2) had higher intermediate doses to the bladder (V20 Gy and Dmean) and larger volumes exposed to higher doses in the trigone (V40 Gy, V39 Gy, and V38 Gy). CONCLUSIONS: The trigone exhibits little volume change, but considerable interfractional displacement/deformation. As a result, the relative volume of the trigone receiving high doses during prostate SBRT varies substantially between fractions, which could influence GU toxicity and may not be predicted by radiation planning dosimetry.

Development of antibody-drug conjugates in cancer: Overview and prospects.

In recent years, remarkable breakthroughs have been reported on antibody-drug conjugates (ADCs), with 15 ADCs successfully entering the market over the past decade. This substantial development has positioned ADCs as one of the fastest-growing domains in the realm of anticancer drugs, demonstrating their efficacy in treating a wide array of malignancies. Nonetheless, there is still an unmet clinical need for wider application, better efficacy, and fewer side effects of ADCs. An ADC generally comprises an antibody, a linker and a payload, and the combination has profound effects on drug structure, pharmacokinetic profile and efficacy. Hence, optimization of the key components provides an opportunity to develop ADCs with higher potency and fewer side effects. In this review, we comprehensively reviewed the current development and the prospects of ADC, provided an analysis of marketed ADCs and the ongoing pipelines globally as well as in China, highlighted several ADC platforms and technologies specific to different pharmaceutical enterprises and biotech companies, and also discussed the new related technologies, possibility of next-generation ADCs and the directions of clinical research.

A correlation study between prostate necrosis rate calculated by 3D Slicer software and clinical efficacy of prostatic artery embolization, along with an analysis of predictors of clinical success after prostatic artery embolization.

PURPOSE: To analyze the correlation between the prostate necrosis rate at 1-month after prostatic artery embolization (PAE) and the clinical efficacy at 1-year after PAE, and to explore potential predictors of clinical success after PAE for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH). METHODS: The prostate magnetic resonance imaging data at 1-month after PAE were imported into 3D Slicer software for calculating the prostate necrosis rate and thus analyzing the relationship between the prostate necrosis rate at 1-month after PAE and the efficacy score ratio at 1-year after PAE. The 151 patients with PAE technical success were divided into a clinical success group (n = 126) and a clinical failure group (n = 25). Independent predictors of clinical success after PAE were analyzed by multifactorial logistic regression, and the predictive performance of each factor was evaluated by applying the receiver operating characteristic curve and the area under the curve (AUC). RESULTS: There was a linear negative correlation between the prostate necrosis rate at 1-month after PAE and the efficacy score ratio at 1-year after surgery (P < 0.001). In the clinical success group, both the initial prostate volume (PV) and the prostate necrosis rate at 1-month after PAE were significantly higher than in the clinical failure group (P < 0.001), and acute urinary retention (AUR) and adenomatous-dominant BPH were also associated with clinical success (P < 0.05). Multifactorial logistic regression analysis revealed that larger initial PV, a higher prostate necrosis rate at 1-month after surgery, and AUR were independent predictors of clinical success after PAE. The AUC values for these three indicators and their combination were 0.720, 0.928, 0.599, and 0.951, respectively, in which the prostate necrosis rate at 1-month after PAE demonstrating a high predictive value. CONCLUSION: The higher the prostate necrosis rate at 1-month after PAE, the better the clinical efficacy at 1-year after PAE is likely to be, and the prostate necrosis rate at 1-month after PAE is expected to become a predictor of clinical success after PAE.

FTO up-regulation induced by MYC suppresses tumour progression in Epstein-Barr virus-associated gastric cancer.

BACKGROUND: Epstein-Barr virus-associated gastric cancer (EBVaGC) is regarded as a distinct molecular subtype of GC, accounting for approximately 9% of all GC cases. Clinically, EBVaGC patients are found to have a significantly lower frequency of lymph node metastasis and better prognosis than uninfected individuals. RNA N6-methyladenosine (m6A) modification has an indispensable role in modulating tumour progression in various cancer types. However, its impact on EBVaGC remains unclear. METHODS: Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and m6A dot blot were conducted to compare the m6A modification levels between EBVaGC and EBV-negative GC (EBVnGC) cells. Western blot, real-time quantitative PCR (RT-qPCR) and immunohistochemistry were applied to explore the underlying mechanism of the reduced m6A modification in EBVaGC. The biological function of fat mass and obesity-associated protein (FTO) was determined in vivo and in vitro. The target genes of FTO were screened by MeRIP-seq, RT-qPCR and Western blot. The m6A binding proteins of target genes were verified by RNA pulldown and RNA immunoprecipitation assays. Chromatin immunoprecipitation and Luciferase report assays were performed to investigate the mechanism how EBV up-regulated FTO expression. RESULTS: M6A demethylase FTO was notably increased in EBVaGC, leading to a reduction in m6A modification, and higher FTO expression was associated with better clinical outcomes. Furthermore, FTO depressed EBVaGC cell metastasis and aggressiveness by reducing the expression of target gene AP-1 transcription factor subunit (FOS). Methylated FOS mRNA was specifically recognized by the m6A 'reader' insulin-like growth factor 2 mRNA binding protein 1/2 (IGF2BP1/2), which enhanced its transcripts stability. Moreover, MYC activated by EBV in EBVaGC elevated FTO expression by binding to a specific region of the FTO promoter. CONCLUSIONS: Mechanistically, our work uncovered a crucial suppressive role of FTO in EBVaGC metastasis and invasiveness via an m6A-FOS-IGF2BP1/2-dependent manner, suggesting a promising biomarker panel for GC metastatic prediction and therapy.

Potential regulatory role of the Nrf2/HMGB1/TLR4/NF-κB signaling pathway in lupus nephritis.

OBJECTIVES: Systemic lupus erythematosus is an autoimmune disease that involves multiple organ systems. One of its major complications, lupus nephritis (LN), is associated with a high mortality rate, and children-onset LN have a more severe course and worse prognosis than adults. Oxidative stress and inflammatory responses are involved in LN development and pathogenesis. Thus, this study aimed to explore the role of signaling regulation of the Nrf2/HMGB1/TLR/NF-κB pathway in LN pathogenesis and unravel the expression of TLR4+CXCR4+ plasma cells subset (PCs) in LN. METHODS: C57BL/6 and MRL/lpr mice were divided into four groups: control, model, vector control, and Nrf2 overexpression groups. The vector control and Nrf2 overexpression groups were injected with adenoviral vectors into the kidney in situ. Pathological changes in kidney tissues were observed by hematoxylin-eosin staining. The expression of Nrf2, HMGB1, TLR4, NF-κB, and downstream inflammatory factors in kidney samples was analyzed by quantitative polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. The ratios of TLR4+CXCR4+ PC subsets in the blood and kidneys of mice were determined by flow cytometry. RESULTS: In MRL/lpr mice, Nrf2 was downregulated while HMGB1/TLR4/NF-κB pathway proteins were upregulated. Nrf2 overexpression decreased the expression of HMGB1, TLR4, NF-κB, and its downstream inflammatory cytokines (IL-1ß and TNFα). These cytokines were negatively correlated with an increase in Nrf2 content. PC and TLR4 + CXCR4 + PCs in the blood and kidney samples were significantly increased in MRL/lpr mice; however, they were decreased upon Nrf2 overexpression. CONCLUSION: This study showed severe kidney injury in an LN mouse model and an increased ratio of TLR4 + CXCR4 + PCs. Furthermore, we observed that Nrf2 regulates LN immune response through the Nrf2/HMGB1/TLR4/NF-κB pathway, which can be considered an important target for LN treatment. The clinical value of the findings of our study requires further investigation.

Pharmarcomechanical thrombectomy combined with transluminal balloon angioplasty for treating transplant renal vein thrombosis.

Renal vein thrombosis (RVT) is a rare vascular complication that occurs after renal transplantation and usually results in irreversible kidney damage and graft loss. We report the case of a patient who underwent right iliac fossa allogeneic kidney transplantation and developed RVT combined with ipsilateral thrombosis from the popliteal to the femoral veins, with extension to the common iliac veins, 4 months after transplantation. Under unfractionated heparin anticoagulation, an Aegisy (Life Tech Scientific Co., Ltd., Shenzhen, China) vena cava filter was placed to prevent pulmonary embolism. Percutaneous mechanical thrombectomy combined with balloon angioplasty was performed to aspirate the thrombus and successfully dilate the narrow venous lumen. The patient's renal function was restored postoperatively. Ultrasonography showed the allograft and ipsilateral lower extremity deep veins to be fluent and patent. To conclude, in patients with RVT after renal transplantation, percutaneous mechanical thrombectomy in conjunction with balloon angioplasty can be performed with desirable outcomes and no severe adverse effects. This method reduces the risk of bleeding from exposure to systemic intravenous thrombolysis and avoids surgery-associated trauma.

Targeting Adhesive Tumor Adventitia via Injectable Electrospun Short Fibers in Perfusion of Intraperitoneal Sporadic Tumors.

Intraperitoneal sporadic tumor is a common and complicated syndrome in cancers, causing a high rate of death, and people find that intraperitoneal chemotherapy (IPC) can treat intraperitoneal sporadic tumors better than intravenous chemotherapy and surgery. However, the effectiveness and side effects of IPC are controversial, and the operation process of IPC is complicated. Herein, the injectable paclitaxel-loaded (PTX-loaded) electrospun short fibers are constructed through a series process of electrospinning, homogenizing, crosslinking, and subsequent polydopamine coating and folate acid (FA) modification. The evenly dispersed short fibers exhibited effective tumor cell killing and good injectable ability, which is convenient to use and greatly improved the complex operation procedure. Mussel-like protein poly-dopamine coating and FA modification endowed short fibers with the ability of targeted adhesion to tumors, and therefore the short fibers further acted as a kind of micro membrane that could release drugs to tumors at close range, maintaining local high drug concentration and prevent paclitaxel killing normal tissues. Thus, the target-adhesive injectable electrospun short fibers are expected to be the potential candidate for cancer treatment, especially the intraperitoneal sporadic tumors, which are hard to treat by surgery or intravenous chemotherapy.

Understanding the heterogeneity of alloreactive natural killer cell function in kidney transplantation.

Human Natural Killer (NK) cells are heterogeneous lymphocytes regulated by variegated arrays of germline-encoded activating and inhibitory receptors. They acquire the ability to detect polymorphic self-antigen via NKG2A/HLA-E or KIR/HLA-I ligand interactions through an education process. Correlations among HLA/KIR genes, kidney transplantation pathology and outcomes suggest that NK cells participate in allograft injury, but mechanisms linking NK HLA/KIR education to antibody-independent pathological functions remain unclear. We used CyTOF to characterize pre- and post-transplant peripheral blood NK cell phenotypes/functions before and after stimulation with allogeneic donor cells. Unsupervised clustering identified unique NK cell subpopulations present in varying proportions across patients, each of which responded heterogeneously to donor cells based on donor ligand expression patterns. Analyses of pre-transplant blood showed that educated, NKG2A/KIR-expressing NK cells responded greater than non-educated subsets to donor stimulators, and this heightened alloreactivity persisted > 6 months post-transplant despite immunosuppression. In distinct test and validation sets of patients participating in two clinical trials, pre-transplant donor-induced release of NK cell Ksp37, a cytotoxicity mediator, correlated with 2-year and 5-year eGFR. The findings explain previously reported associations between NK cell genotypes and transplant outcomes and suggest that pre-transplant NK cell analysis could function as a risk-assessment biomarker for transplant outcomes.

A quantitative CBCT pipeline based on 2D antiscatter grid and grid-based scatter sampling for image-guided radiation therapy.

BACKGROUND: Quantitative accuracy is critical for expanding the role of cone beam CT (CBCT) imaging from target localization to quantitative treatment monitoring and plan adaptations in radiation therapy. Despite advances in CBCT image quality improvement methods, quantitative accuracy gap between CBCT and multi-detector CT (MDCT) remains. PURPOSE: In this work, a physics-driven approach was investigated that combined robust scatter rejection, raw data correction and iterative image reconstruction to further improve CBCT image quality and quantitative accuracy, referred to as quantitative CBCT (qCBCT). METHODS: QCBCT approach includes tungsten 2D antiscatter grid hardware, residual scatter correction with grid-based scatter sampling, image lag, and beam hardening correction for offset detector geometry linac-mounted CBCT. Images were reconstructed with iterative image reconstruction to reduce image noise. qCBCT was evaluated using a variety of phantoms to investigate the effect of object size and its composition on image quality, and image quality was benchmarked against clinical CBCT and gold standard MDCT images used for treatment planning. RESULTS: QCBCT provided statistically significant improvement in CT number accuracy and reduced image artifacts when compared to clinical CBCT images. When compared to gold standard MDCT, mean HU errors in qCBCT and clinical CBCT were 17 ± 9 and 38 ± 29 HU, respectively. Magnitude of phantom size dependent HU variations were comparable between MDCT and qCBCT images. With iterative reconstruction, contrast-to-noise ratio improved by 25% when compared to clinical CBCT protocols. CONCLUSIONS: Combination of novel scatter suppression techniques and other data correction methods in qCBCT provided CT number accuracy comparable to gold standard MDCT used for treatment planning. This approach may potentially improve CBCT's promise in fulfilling the tasks that demand high quantitative accuracy, such as online dose calculations and treatment response assessment, in image guided radiation therapy.

2D antiscatter grid and scatter sampling based CBCT pipeline for image guided radiation therapy.

Poor tissue visualization and quantitative accuracy in CBCT is a major barrier in expanding the role of CBCT imaging from target localization to quantitative treatment monitoring and plan adaptations in radiation therapy sessions. To further improve image quality in CBCT, 2D antiscatter grid based scatter rejection was combined with a raw data processing pipeline and iterative image reconstruction. The culmination of these steps was referred as quantitative CBCT, qCBCT. qCBCT data processing steps include 2D antiscatter grid implementation, measurement based residual scatter, image lag, and beam hardening correction for offset detector geometry CBCT with a bow tie filter. Images were reconstructed with iterative image reconstruction to reduce image noise. To evaluate image quality, qCBCT acquisitions were performed using a variety of phantoms to investigate the effect of object size and its composition on image quality. qCBCT image quality was benchmarked against clinical CBCT and MDCT images. Addition of image lag and beam hardening correction to scatter suppression reduced HU degradation in qCBCT by 10 HU and 40 HU, respectively. When compared to gold standard MDCT, mean HU errors in qCBCT and clinical CBCT were 10 HU and 27 HU, respectively. HU inaccuracy due to change in phantom size was 22 HU and 85 HU in qCBCT and clinical CBCT images, respectively. With iterative reconstruction, contrast to noise ratio improved by a factor of 1.25 when compared to clinical CBCT protocols. Robust artifact and noise suppression in qCBCT images can reduce the image quality gap between CBCT and MDCT, improving the promise of qCBCT in fulfilling the tasks that demand high quantitative accuracy, such as CBCT based dose calculations and treatment response assessment in image guided radiation therapy.

Evaluation of FAPI PET imaging in gastric cancer: a systematic review and meta-analysis.

Purpose: Recent studies suggest that 68Ga-FAPI PET/CT demonstrated superiority over 18F-FDG PET/CT in the evaluation of various cancer types, especially in gastric cancer (GC). By comprehensively reviewing and analysing the differences between 68Ga-FAPI and 18F-FDG in GC, some evidence is provided to foster the broader clinical application of FAPI PET imaging. Methods: In this review, studies published up to July 3, 2023, that employed radionuclide labelled FAPI as a diagnostic radiotracer for PET in GC were analysed. These studies were sourced from both the PubMed and Web of Science databases. Our statistical analysis involved a bivariate meta-analysis of the diagnostic data and a meta-analysis of the quantitative metrics. These were performed using R language. Results: The meta-analysis included 14 studies, with 527 patients, of which 358 were diagnosed with GC. Overall, 68Ga-FAPI showed higher pooled sensitivity (0.84 [95% CI 0.67-0.94] vs. 0.46 [95% CI 0.32-0.60]), specificity (0.91 [95% CI 0.76-0.98] vs. 0.88 [95% CI 0.74-0.96]) and area under the curve (AUC) (0.92 [95% CI 0.77-0.98] vs. 0.52 [95% CI 0.38-0.86]) than 18F-FDG. The evidence showed superior pooled sensitivities of 68Ga-FAPI PET over 18F-FDG for primary tumours, local recurrence, lymph node metastases, distant metastases, and peritoneal metastases. Furthermore, 68Ga-FAPI PET provided higher maximum standardized uptake value (SUVmax) and tumour-to-background ratios (TBR). For bone metastases, while 68Ga-FAPI PET demonstrated slightly lower patient-based pooled sensitivity (0.93 vs. 1.00), it significantly outperformed 18F-FDG in the lesion-based analysis (0.95 vs. 0.65). However, SUVmax (mean difference [MD] 1.79 [95% CI -3.87-7.45]) and TBR (MD 5.01 [95% CI -0.78-10.80]) of bone metastases showed no significant difference between 68Ga-FAPI PET/CT and 18F-FDG PET/CT. Conclusion: Compared with 18F-FDG, 68Ga-FAPI PET imaging showed improved diagnostic accuracy in the evaluation of GC. It can be effectively applied to the early diagnosis, initial staging, and detection of recurrence/metastases of GC. 68Ga-FAPI may have the potential of replacing 18F-FDG in GC in future applications.