Human Placenta-Derived Mesenchymal Stem Cells Improve Neurological Function in Rats with Intrauterine Hypoxic-Ischaemic Encephalopathy by Reducing Apoptosis and Inflammatory Reactions.

BACKGROUND: Hypoxic-ischaemic encephalopathy (HIE) is a major cause of neonatal disability and mortality. Although hypothermia therapy offers some neuroprotection, the recovery of neurological function is limited. Therefore, new synergistic therapies are necessary to improve the prognosis. Mesenchymal stem cell-based therapy is emerging as a promising treatment option for HIE. In this study, we studied the therapeutic efficacy of human placenta-derived mesenchymal stem cells (PD-MSCs) in the HIE rat model and analyzed the underlying therapeutic mechanisms. METHODS: Rats were divided into 6 groups (n = 9 for each) as follows: control, HIE model, HIE + normal saline, and HIE + PD-MSC transplantation at days 7, 14 and 28 postpartum. Following PD-MSC transplantation, neurological behavior was evaluated using rotarod tests, traction tests, and the Morris water maze test. The degree of brain tissue damage was assessed by histological examination and Nissl staining. Expression levels of apoptosis-related proteins and inflammatory factors were quantified by Western blotting and enzyme-linked immunosorbent assays. Immunofluorescence was used to investigate the ability of PD-MSCs to repair the morphology and function of hippocampal neurons with hypoxic-ischaemic (HI) injury. RESULTS: PD-MSC transplantation enhanced motor coordination and muscle strength in HIE rats. This treatment also improved spatial memory ability by repairing pathological damage and preventing the loss of neurons in the cerebral cortex. The most effective treatment was observed in the HIE + PD-MSC transplantation at day 7 group. Expression levels of microtubule-associated protein-2 (MAP-2), B-cell lymphoma-2 (BCL-2), interleukin (IL)-10, and transforming growth factor (TGF -ß1) were significantly higher in the HIE + PD-MSC treatment groups compared to the HIE group, whereas the levels of BCL-2-associated X protein (BAX), BCL-2-associated agonist of cell death (BAD), IL-1ß and tumour necrosis factor α (TNF-α) were significantly lower. CONCLUSIONS: We demonstrated that intravenous injection of PD-MSC at 7, 14 and 28 days after intrauterine HI damage in a rat model could improve learning, memory, and motor function, possibly by inhibiting apoptosis and inflammatory damage. These findings indicate that autologous PD-MSC therapy could have potential application for the treatment of HIE.

Identification of gene variation feature for targeted therapy of non-small cell lung cancer through combined method of DNA and RNA sequencing.

Next generation sequencing (NGS) is typically used to reveal tumor gene variation feature for targeted therapy of various types of human cancers, including non-small cell lung cancer (NSCLC). Here, we report the role and potential applicable value of combining DNA and RNA sequencing in gene variation detection in NSCLC. 386 NSCLC patients with stage II-IV were enrolled and detected using NGS sequencing of DNA and RNA panels that covered all well-documented target driver genes from the Chinese Society of Clinical Oncology (CSCO). The rate of epidermal growth factor receptor (EGFR) single nucleotide variation (SNV)/indel, mesenchymal-epithelial transition factor (MET) copy number variation (CNV) and anaplastic lymphoma kinase (ALK) fusion were 52.1%, 4.1% and 6.0% in the NSCLC cohort. The landscapes of SNV/indel, CNV and gene fusion in the cohort were depicted as well. Meanwhile, we assessed detection efficacy of DNA and RNA sequencing in gene fusion. Detected number and types of gene fusion using the RNA sequencing were better than those using the DNA sequencing. Gene fusion with intergenic region was only detected by DNA sequencing and MET exon 14 skipping (METΔex14) was more easily identified by RNA sequencing. Finally, we investigated clinical correlations of SNV/indel/CNV/fusion with clinicopathologic features in the NSCLC cohort. Taken together, RNA sequencing significantly complements deficiency of DNA sequencing for gene fusion, which cooperatively presents comprehensive and reliable gene variation features and facilitate the identification of potential drug targets for NSCLC patients.

Development and multi-institutional validation of a deep learning model for grading of vesicoureteral reflux on voiding cystourethrogram: a retrospective multicenter study.

Background: Voiding cystourethrography (VCUG) is the gold standard for the diagnosis and grading of vesicoureteral reflux (VUR). However, VUR grading from voiding cystourethrograms is highly subjective with low reliability. This study aimed to develop a deep learning model to improve reliability for VUR grading on VCUG and compare its performance to that of clinicians. Methods: In this retrospective study in China, VCUG images were collected between January 2019 and September 2022 from our institution as an internal dataset for training and 4 external data sets as external testing set for validation. Samples were divided into training (N = 1000) and validation sets (N = 500), internal testing set (N = 168), and external testing set (N = 280). An ensemble learning-based model, Deep-VCUG, using Res-Net 101 and the voting methods was developed to predict VUR grade. The grading performance was assessed using heatmaps, area under the receiver operating characteristic curve (AUC), sensitivity, specificity, accuracy, and F1 score in the internal and external testing set. The performances of four clinicians (2 pediatric urologists and 2 radiologists) with and without the Deep-VCUG assisted to predict VUR grade were explored in external testing sets. Findings: A total of 1948 VCUG images were collected (Internal dataset = 1668; multi-center external dataset = 280). For assessing unilateral VUR grading, the Deep-VCUG achieved AUCs of 0.962 (95% confidence interval [CI]: 0.943-0.978) and 0.944 (95% [CI]: 0.921-0.964) in the internal and external testing sets, respectively, for bilateral VUR grading, the Deep-VCUG also achieved high AUCs of 0.960 (95% [CI]: 0.922-0.983) and 0.924 (95% [CI]: 0.887-0.957). The Deep-VCUG model using voting method outperformed single model and clinician in terms of classification based on VCUG image. Moreover, Under the Dee-VCUG assisted, the classification ability of junior and senior clinicians was significantly improved. Interpretation: The Deep-VCUG model is a generalizable, objective, and accurate tool for vesicoureteral reflux grading based on VCUG imaging and had good assistance with clinicians to VUR grading applicability. Funding: This study was supported by Natural Science Foundation of China, "Fuqing Scholar" Student Scientific Research Program of Shanghai Medical College, Fudan University, and the Program of Greater Bay Area Institute of Precision Medicine (Guangzhou).

Data mining-based identification of epigenetic signatures with discrimination potential of lung adenocarcinoma and squamous cell carcinoma.

BACKGROUND: Mounting evidence suggests that lung adenocarcinoma (LAC) and lung squamous cell carcinoma (LSC) have different biological behaviors and therapeutic regimens in clinical practice. However, limited improvements in molecular differential diagnosis of the two entities have been achieved in recent decades. We aimed to find novel markers that could define non-small cell lung cancer (NSCLC) subtypes. METHODS: We first explored publically available databases to search for DNA methylation signatures that enable a precise discrimination of LAC and LSC. Next-generation sequencing (NGS) was then used to analyze the methylation status and sites of candidate genes in LAC/LSC tissue samples, and a quantitative methylation-sensitive PCR (qMS-PCR) assay was conducted to test the performance of the selected maker in tissue samples and bronchoalveolar lavage fluid (BALF) specimens. RESULTS: We screened 19 top-ranked methylation loci that are differentially methylated between LAC and LSC. Among these hits, 6 methylation sites are enriched within the PREX1 gene promoter, thus becoming our focus. NGS analysis confirmed markedly higher PREX1 methylation levels in LAC than in LSC and revealed the right sites for detection of PREX1 methylation. Furthermore, PREX1 methylation analysis in lung cancer tissue samples defined 9 of 11 pathologically proven LACs, as well as 12 of 14 LSCs. In addition, ~ 80% LAC BALF samples showed methylated PREX1 compared to substantially lower test positivity (0-9%) of it in LSC and other lung conditions (P < 0.01). CONCLUSION: Our pilot study identified a unique epigenetic signature that could effectively distinguish LAC from LSC in various lung samples. It may enhance our in-depth understanding of the biology of lung cancer and pave the way for better accurate diagnosis and treatment stratification in the future.

Pan-cancer analysis of homeodomain-containing gene C10 and its carcinogenesis in lung adenocarcinoma.

We found elevated homeodomain-containing gene C10 (HOXC10) showed dual roles in cancers' prognosis. Some signal pathways associated with tumor were totally positively enriched in HOXC10 for whole cancers. On the contrary, Notch signaling, Wnt-beta catenin signaling, myogenesis, and Hedgehog signaling were almost negatively enriched in HOXC10. Some pathways showed dual roles such as Kras signaling, interferon gram and alpha response, IL6/JAK/STAT3, IL2/STAT5 signaling. HOXC10 was associated with tumor mutation burden and microsatellite instability. HOXC10 also was associated with tumor microenvironment and immune status. HOXC10 was negatively associated with immune score in most cancers except colon adenocarcinoma. The correlations of HOXC10 with immune-related genes presented dual roles in different cancers. Results from our clinical samples indicated that HOXC10 was an independent predictor for distant metastasis-free survival in lung adenocarcinoma (LUAD). Notably, the high levels of HOXC10 were positively correlated with the expression of angiogenic markers, vascular endothelial growth factor and microvessel density, and the number of CTC clusters. Our results demonstrated that aberrant expression happened in most cancers, which also affected the clinical prognosis and involved in progression via multiple signal pathways cancers. HOXC10 overexpression plays an important role in the aggression and metastasis in LUAD, which indicated a potential therapeutic target and an independent factor for the prognosis for LUAD patients.

Overall survival following stereotactic radiosurgery for ten or more brain metastases: a systematic review and meta-analysis.

BACKGROUND: Brain metastases are the most common intracranial tumours. Variation exists in the use of stereotactic radiosurgery for patients with 10 or more brain metastases. Concerns include an increasing number of brain metastases being associated with poor survival, the lack of prospective, randomised data and an increased risk of toxicity. METHODS: We performed a systematic review and meta-analysis to assess overall survival of patients with ten or more brain metastases treated with stereotactic radiosurgery as primary therapy. The search strings were applied to MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL). Log hazard ratios and standard errors were estimated from each included study. A random-effects meta-analysis using the DerSimonian and Laird method was applied using the derived log hazard ratios and standard errors on studies which included a control group. RESULTS: 15 studies were included for systematic review. 12 studies were used for pooled analysis for overall survival at set time points, with a predicted 12 month survival of 20-40%. The random-effects meta-analysis in five studies of overall survival comparing ten or greater metastases against control showed statistically worse overall survival in the 10 + metastases group (1.10, 95% confidence interval 1.03-1.18, p-value = < 0.01, I2 = 6%). A funnel plot showed no evidence of bias. There was insufficient information for a meta-analysis of toxicity. DISCUSSION: Overall survival outcomes of patients with ten or more brain metastases treated with SRS is acceptable and should not be a deterrent for its use. There is a lack of prospective data and insufficient real-world data to draw conclusions on toxicity. PROSPERO ID: CRD42021246115.

This systematic review and meta-analysis is the first of its kind in the literature and provides information on overall survival outcomes and toxicities encountered in patients with ten or more brain metastases treated with stereotactic radiosurgery. Centres treating patients with ten or more brain metastases are doing so based only on retrospective real-world data analyses, the vast majority of which are from single centres and single radiotherapy platforms. This review provides an additional evidence resource for practitioners of stereotactic radiosurgery to aide in the management of this difficult patient group. The methods used to predict survival outcomes through the calculation of log hazard ratios and standard errors allowed analysis of small, retrospective case series. To our knowledge, this is the first meta-analysis of this patient group gives evidence for acceptable overall survival outcomes post-treatment, and provides further evidence for the use of stereotactic radiosurgery for these patients.Overall survival following stereotactic radiosurgery for ten or more brain metastases: a systematic review and meta-analysis.

Optimized allotopic expression of mitochondrial ND6 transgene restored complex I and apoptosis deficiencies caused by LHON-linked ND6 14484T > C mutation.

BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease due to mutations in mitochondrial DNA. However, there is no effective treatment for this disease. LHON-linked ND6 14484T > C (p.M64V) mutation caused complex I deficiency, diminished ATP production, increased production of reactive oxygen species (ROS), elevated apoptosis, and impaired mitophagy. Here, we investigated if the allotopic expression of human mitochondrial ND6 transgene corrected the mitochondrial dysfunctions due to LHON-associated m.14484T > C mutation. METHODS: Nucleus-versions of ND6 was generated by changing 6 non-universal codons with universal codons and added to mitochondrial targeting sequence of COX8. Stable transfectants were generated by transferring human ND6 cDNA expressed in a pCDH-puro vector into mutant cybrids carrying the m.14484T > C mutation and control cybrids. The effect of allotopic expression of ND6 on oxidative phosphorylation (OXPHOS) was evaluated using Blue Native gel electrophoresis and extracellular flux analyzer. Assessment of ROS production in cell lines was performed by flow cytometry with MitoSOX Red reagent. Analyses for apoptosis and mitophagy were undertaken via flow cytometry, TUNEL and immunofluorescence assays. RESULTS: The transfer of human ND6 into the cybrids carrying the m.14484T > C mutation raised the levels of ND6, ND1 and ND4L but did not change the levels of other mitochondrial proteins. The overexpression of ND6 led to 20~23% increases in the assembly and activity of complex I, and ~ 53% and ~ 33% increases in the levels of mitochondrial ATP and ΔΨm in the mutant cybrids bearing m.14484T > C mutation. Furthermore, mutant cybrids with overexpression of ND6 exhibited marked reductions in the levels of mitochondrial ROS. Strikingly, ND6 overexpression markedly inhibited the apoptosis process and restored impaired mitophagy in the cells carrying m.14484T > C mutation. However, overexpression of ND6 did not affect the ND6 level and mitochondrial functions in the wild-type cybrids, indicating that this ND6 level appeared to be the maximum threshold level to maintain the normal cell function. CONCLUSION: We demonstrated that allotopic expression of nucleus-versions of ND6 restored complex I, apoptosis and mitophagy deficiencies caused by the m.14484T > C mutation. The restoration of m.14484T > C mutation-induced mitochondrial dysfunctions by overexpression of ND6 is a step toward therapeutic interventions for LHON and mitochondrial diseases.

Asymmetric [3 + 2] Photocycloaddition of ß-Keto Esters and Vinyl Azides by Dual Photoredox/Nickel Catalysis.

Photocatalytic [3 + 2] cycloadditions and control of stereochemistry have remained a substantial challenge, particularly in the context of heterocycle synthesis; sporadic successful examples have involved enantioselective [3 + 2] photocycloaddition between redox-active direct group-containing cyclopropanes and alkenes for creation of cyclopentanes. Herein, we report a cooperative catalytic system comprising a chiral nickel Lewis acid catalyst and an organic photocatalyst fueled by visible-light irradiation that allows for the hitherto elusive asymmetric [3 + 2] photocycloaddition of ß-keto esters with vinyl azides under redox-neutral conditions. This protocol enables highly enantioselective construction of polycyclic densely substituted 3,4-dihydro-2H-pyrrole heterocycles featuring two contiguous tetrasubstituted carbon stereocenters, including a useful chiral N,O-ketal motif that is not easily accessible with other catalytic methods. Mechanistic studies revealed that the overall reactivity relies on the seamless integration of dual roles of nickel catalysts by the catalytic formation of the substrate/Ni complex, assisting both photoredox event and enantioselective radical addition.

Asymmetry of Posterior Condyles in Resection Plane and Axial Curvature for Total Knee Arthroplasty.

OBJECTIVE: Understanding the morphology of the distal femur is essential for improving bone-implant match in total knee arthroplasty (TKA) and understanding the mechanisms behind knee kinematics. However, little is known about the asymmetry of the posterior condyles. Thus, this study aimed to thoroughly investigate asymmetries in sizes and shapes between the medial and lateral posterior condyles before and after femoral resections during TKA in osteoarthritic (OA) knees. METHODS: Three-dimensional femoral models of 74 OA knees were constructed using computed tomography images. The morphologic measurements of the posterior condyle pre- and post-simulated osteotomy for TKA included the radii of the posterior condyles fitted to a circle on the sagittal and axial planes of the femoral coordinate system, the inclination angle of the articular surface and resected surface, and the width and height of the resected surface. Differences in the data were assessed using Student's t-test, and correlations were evaluated using the Pearson product-moment correlation. RESULTS: The radii of the medial posterior condyles fitted to the circle were, on average, 6 mm larger than those of the lateral condyles on the axial plane (p < 0.001) and 0.7 mm smaller than those of the lateral condyles on the sagittal plane (p = 0.046). The inclination angles of the medial and lateral posterior condyles on the axial plane were significantly different with both pre-simulated and post-simulated osteotomy, respectively (both p < 0.001). The resected plane of the lateral posterior condyles displaced opposite inclination directions between the distal and proximal portions. Neither heights or widths of the medial posterior condyles were significantly different from those of their lateral counterparts (both p > 0.107). CONCLUSIONS: This study found asymmetrical inclination of the resected surface and coronal radii between the medial and lateral posterior condyles, which may relate to the posterolateral overhang of the lateral condyle after TKA and the progression of the knee OA. These findings provides valuable morphological information and may help improve the implant designs for TKA.

Immunogenic cell death-related gene landscape predicts the overall survival and immune infiltration status of ovarian cancer.

Background: Ovarian cancer (OC) is the most troubling malignant tumor of the female reproductive system. It has a low early diagnosis rate and a high tumor recurrence rate after treatment. Immunogenic cell death (ICD) is a unique form of regulated cell death that can activate the adaptive immune system through the release of DAMPs and cytokines in immunocompromised hosts and establish long-term immunologic memory. Therefore, this study aims to explore the prognostic value and underlying mechanisms of ICD-related genes in OC on the basis of characteristics. Methods: The gene expression profiles and related clinical information of OC were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. ICD-related genes were collected from the Genecards database. ICD-related prognostic genes were obtained by intersecting ICD-related genes with the OC prognostic-related genes that were analyzed in the TCGA database. Functional enrichment, genetic mutation, and immune infiltration correlation analyses were further performed to identify underlying mechanisms. Subsequently, we developed a TCGA cohort-based prognostic risk model that included a nine-gene signature through univariate and multivariate Cox regression and LASSO regression analyses. Meanwhile, external validation was performed on two sets of GEO cohorts and the TCGA training cohort for three other common tumors in women. In addition, a nomogram was established by integrating clinicopathological features and ICD-related gene signature to predict survival probability. Finally, functional enrichment and immune infiltration analyses were performed on the two risk subgroups. Results: By utilizing nine genes (ERBB2, RB1, CCR7, CD38, IFNB1, ANXA2, CXCL9, SLC9A1, and SLAMF7), we constructed an ICD-related prognostic signature. Subsequently, patients were subdivided into high- and low-risk subgroups in accordance with the median value of the risk score. In multivariate Cox regression analyses, risk score was an independent prognostic factor (hazard ratio = 2.783; p < 0.01). In the TCGA training cohort and the two GEO validation cohorts, patients with high-risk scores had worse prognosis than those with low-risk scores (p < 0.05). The time-dependent receiver operating characteristic curve further validated the prognostic power of the gene signature. Finally, gene set enrichment analysis indicated that multiple oncological pathways were significantly enriched in the high-risk subgroup. By contrast, the low-risk subgroup was strongly related to the immune-related signaling pathways. Immune infiltration analysis further illustrated that most immune cells showed higher levels of infiltration in the low-risk subgroup than in the high-risk subgroup. Conclusion: We constructed a novel ICD-related gene model for forecasting the prognosis and immune infiltration status of patients with OC. In the future, new ICD-related genes may provide novel potential targets for the therapeutic intervention of OC.

The position of entry point in total knee arthroplasty is associate with femoral bowing both in coronal and sagittal planes.

Objective: To investigate the femoral entry point of the intramedullary (IM) guiding rod applied to total knee arthroplasty (TKA) in Chinese subjects and the relationship with femoral bowing in the coronal and sagittal planes through three-dimensional (3D) validation methods. Methods: Computed tomography (CT) images of 80 femurs in Chinese subjects were imported into Mimics 19.0 to construct 3D models. All operations were conducted by Rhinoceros software 5.0. The position of the IM rod entry point was assessed by calculating the distance between the entry point and the apex of the intercondylar notch (AIN) in the coronal and sagittal planes. The coronal femoral bowing angle (cFBA) and sagittal femoral bowing angle (sFBA) were also measured. Results: The average optimal entry point was 0.17 mm medial and 12.37 mm anterior to the AIN in males, while it was 0.02 mm lateral and 16.13 mm anterior to the AIN in females. There was a significant difference between males and females in the sagittal plane (t = -6.570, p = 0.000). The mean cFBA was 1.68 ± 2.29°, and the mean sFBA was 12.66 ± 1.98°. The sFBA was strongly correlated with the anterior distance of the proper entry point, and the cFBA was moderately correlated with the lateral distance of the proper entry point. Conclusions: There was a strong correlation between the position of the entry point and the femoral bowing angle in both the coronal and sagittal planes. Thus, to achieve better alignment, the position of the entry point should be measured individually based on femoral bowing.

Identifying Topics and Evolutionary Trends of Literature on Brain Metastases Using Latent Dirichlet Allocation.

Research on brain metastases kept innovating. We aimed to illustrate what topics the research focused on and how it varied in different periods of all the studies on brain metastases with topic modelling. We used the latent Dirichlet allocation model to analyse the titles and abstracts of 50,176 articles on brain metastases retrieved from Web of Science, Embase and MEDLINE. We further stratified the articles to find out the topic trends of different periods. Our study identified that a rising number of studies on brain metastases were published in recent decades at a higher rate than all cancer articles. Overall, the major themes focused on treatment and histopathology. Radiotherapy took over the first and third places in the top 20 topics. Since the 2010's, increasing attention concerned about gene mutations. Targeted therapy was a popular topic of brain metastases research after 2020.

A New Reference Axis for Tibial Component Rotation in Total Knee Arthroplasty: A Three-dimensional Computed Tomography Analysis.

The purpose of this study was to introduce a new reference axis for tibial rotation in total knee arthroplasty (TKA) and verify its reliability. A consecutive series of 80 knees that underwent TKA from 2018 to 2020 as well as 80 healthy knees were analyzed using a three-dimensional tibial model. A coordinate system was established based on the standard TKA tibial cut. The line connecting the lateral-tibial eminence and the medial 1/3rd of the tibial tubercle or the medial border of the tibial tubercle was identified as the lateral eminence line (LE line) and the medial lateral eminence line (MLE line), respectively. To evaluate the reliability of the new reference axis, Akagi's line, the medial third of the tibial tubercle (1/3 line) was compared with the LE and MLE lines by measuring the angle between the lines and the Z-axis. In the coronal view, the intersection angle (TPA), which is composed of the line connecting the center of the medial and lateral tibial plateau with the Z-axis, was measured. The mean angle between Akagi's line and the Z-axis in the healthy group and the osteoarthritis (OA) group was 87.57 ± 3.48° and 87.61 ± 3.47°, respectively. The mean angle between the LE line and Z-axis in the healthy and OA groups was 87.15 ± 4.13° and 86.78 ± 3.95°, respectively. A weak correlation was found between the TPA and Akagi's line and the 1/3 line. A moderate correlation was observed between the TPA and LE lines. There were no significant differences between the healthy and OA groups (P > 0.05) in any of the four reference axes. The LE line showed excellent intra- and inter-observer reliability and reproducibility. The novel and easily drawn LE line is a preferable option for tibial component rotational alignment in TKA.

The Presence of Cartilage Affects Femoral Rotational Alignment in Total Knee Arthroplasty.

OBJECTIVE: To assess the difference between the posterior condylar angle (PCA) and the mechanical lateral distal femoral angle (mLDFA) in the osseous and cartilaginous contours in a non-arthritic Chinese population. METHODS: Computed tomography (CT) and magnetic resonance imaging (MRI) were obtained from 83 patients with knee injuries before arthroscopy, and femur and distal femoral cartilage three-dimensional (3D) models were constructed. The 3D cartilage model was arranged to share physical space with the 3D femoral model, and then PCA and mLDFA were measured on the osseous and cartilaginous contours, respectively. The differences between the measurements with and without cartilage were evaluated. RESULTS: The average PCA with cartilage was 2.88 ± 1.35° and without was 2.73 ± 1.34°. The difference was significant in all patients and females but not in males. The average mLDFA with cartilage was 84.73 ± 2.15° and without cartilage was 84.83 ± 2.26°, but the difference was statistically insignificant in all groups. CONCLUSION: PCA on the osseous and cartilaginous contours significantly differed with and without cartilage in the female group, suggesting that cartilage thickness should be considered during preoperative femoral rotational resection planning.

Improving on whole-brain radiotherapy in patients with large brain metastases: A planning study to support the AROMA clinical trial.

PURPOSE: To develop a novel dose-escalated volumetric modulated arc therapy (VMAT) strategy for patients with single or multiple large brain metastases which can deliver a higher dose to individual lesions for better local control (LC), and to compare dosimetry between whole brain radiotherapy (WBRT), hippocampal-sparing whole brain radiotherapy (HS-WBRT) and different VMAT-based focal radiotherapy approaches. METHODS AND MATERIALS: We identified 20 patients with one to ten brain metastases and at least one lesion larger than 15 cm3 who had received WBRT as part of routine care. For each patient, we designed and evaluated five radiotherapy treatment plans, including WBRT, HS-WBRT and three VMAT dosing models. A dose of 20 Gy in 5 fractions was prescribed to the whole brain or target volumes depending on the plan, with higher doses to smaller lesions and dose-escalated inner planning target volumes (DE-iPTV) in VMAT plans, respectively. Treatment plans were evaluated using the efficiency index, mean dose and D0.1 cc to the target volumes and organs at risk. RESULTS: Compared with WBRT, VMAT plans achieved a significantly more efficient dose distribution in brain lesions, especially with our DE-iPTV model, while minimising the dose to the normal brain and other organs at risks (OARs) (p < 0.05). CONCLUSIONS: VMAT plans obtained higher doses to brain metastases and minimised doses to OARs. Dose-escalated VMAT for larger lesions allows higher radiotherapy doses to be delivered to larger lesions while maintaining safe doses to OARs.

Deep learning-based quantification of temporalis muscle has prognostic value in patients with glioblastoma.

BACKGROUND: Glioblastoma is the commonest malignant brain tumour. Sarcopenia is associated with worse cancer survival, but manually quantifying muscle on imaging is time-consuming. We present a deep learning-based system for quantification of temporalis muscle, a surrogate for skeletal muscle mass, and assess its prognostic value in glioblastoma. METHODS: A neural network for temporalis segmentation was trained with 366 MRI head images from 132 patients from 4 different glioblastoma data sets and used to quantify muscle cross-sectional area (CSA). Association between temporalis CSA and survival was determined in 96 glioblastoma patients from internal and external data sets. RESULTS: The model achieved high segmentation accuracy (Dice coefficient 0.893). Median age was 55 and 58 years and 75.6 and 64.7% were males in the in-house and TCGA-GBM data sets, respectively. CSA was an independently significant predictor for survival in both the in-house and TCGA-GBM data sets (HR 0.464, 95% CI 0.218-0.988, p = 0.046; HR 0.466, 95% CI 0.235-0.925, p = 0.029, respectively). CONCLUSIONS: Temporalis CSA is a prognostic marker in patients with glioblastoma, rapidly and accurately assessable with deep learning. We are the first to show that a head/neck muscle-derived sarcopenia metric generated using deep learning is associated with oncological outcomes and one of the first to show deep learning-based muscle quantification has prognostic value in cancer.

Towards a better understanding of Fagopyrum dibotrys: a systematic review.

Fagopyrum dibotrys (F. dibotrys) (D.Don) H.Hara is a well-known edible herbal medicine in Asian countries. It has been widely used for the treatment of lung diseases, swelling, etc., and is also an important part of many Chinese medicine prescriptions. At present, more than 100 compounds have been isolated and identified from F. dibotrys, and these compounds can be primarily divided into flavonoids, phenols, terpenes, steroids, and fatty acids. Flavonoids and phenolic compounds are considered to be the main active ingredients of F. dibotrys. Previous pharmacological studies have shown that F. dibotrys possesses anti-inflammatory, anti-cancer, anti-oxidant, anti-bacterial, and anti-diabetic activities. Additional studies on functional genes have led to a better understanding of the metabolic pathways and regulatory factors related with the flavonoid active ingredients in F. dibotrys. In this paper, we systemically reviewed the research advances on the phytochemistry and pharmacology of F. dibotrys, as well as the functional genes related to the synthesis of active ingredients, aiming to promote the development and utilization of F. dibotrys.

LINC00173.v1 promotes angiogenesis and progression of lung squamous cell carcinoma by sponging miR-511-5p to regulate VEGFA expression.

BACKGROUND: Anti-angiogenic therapy represents a promising strategy for non-small-cell lung cancer (NSCLC) but its application in lung squamous cell carcinoma (SQC) is limited due to the high-risk adverse effects. Accumulating evidence indicates that long noncoding RNAs (lncRNAs) mediate in tumor progression by participating in the regulation of VEGF in NSCLC, which might guide the development of new antiangiogenic strategies. METHODS: Differential lncRNA expression in SQC was analyzed in AE-meta and TCGA datasets, and further confirmed in lung cancer tissues and adjacent normal tissues with RT-qPCR and in-situ hybridization. Statistical analysis was performed to evaluate the clinical correlation between LINC00173.v1 expression and survival characteristics. A tube formation assay, chick embryo chorioallantoic membrane assay and animal experiments were conducted to detect the effect of LINC00173.v1 on the proliferation and migration of vascular endothelial cells and tumorigenesis of SQC in vivo. Bioinformatics analysis, RNA immunoprecipitation and luciferase reporter assays were performed to elucidate the downstream target of LINC00173.v1. The therapeutic efficacy of antisense oligonucleotide (ASO) against LINC00173.v1 was further investigated in vivo. Chromatin immunoprecipitation and high throughput data processing and visualization were performed to identify the cause of LINC00173.v1 overexpression in SQC. RESULTS: LINC00173.v1 was specifically upregulated in SQC tissues, which predicted poorer overall and progression-free survival in SQC patients. Overexpression of LINC00173.v1 promoted, while silencing LINC00173.v1 inhibited the proliferation and migration of vascular endothelial cells and the tumorigenesis of SQC cells in vitro and in vivo. Our results further revealed that LINC00173.v1 promoted the proliferation and migration of vascular endothelial cells and the tumorigenesis of SQC cells by upregulating VEGFA expression by sponging miR-511-5p. Importantly, inhibition of LINC00173.v1 via the ASO strategy reduced the tumor growth of SQC cells, and enhanced the therapeutic sensitivity of SQC cells to cisplatin in vivo. Moreover, our results showed that squamous cell carcinoma-specific factor ΔNp63α contributed to LINC00173.v1 overexpression in SQC. CONCLUSION: Our findings clarify the underlying mechanism by which LINC00173.v1 promotes the proliferation and migration of vascular endothelial cells and the tumorigenesis of SQC, demonstrating that LINC00173.v1-targeted drug in combination with cisplatin may serve as a rational regimen against SQC.

Downregulation of the circadian rhythm regulator HLF promotes multiple-organ distant metastases in non-small cell lung cancer through PPAR/NF-κb signaling.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death due to its early recurrence and widespread metastatic potential. Accumulating studies have reported that dysregulation of circadian rhythms-associated regulators is implicated in the recurrence and metastasis of NSCLC. Therefore, identification of metastasis-associated circadian rhythm genes is clinically necessary. Here we report that the circadian gene hepatic leukemia factor (HLF), which was dramatically reduced in early-relapsed NSCLC tissues, was significantly correlated with early progression and distant metastasis in NSCLC patients. Upregulating HLF inhibited, while silencing HLF promoted lung colonization, as well as metastasis of NSCLC cells to bone, liver and brain in vivo. Importantly, downexpression of HLF promoted anaerobic metabolism to support anchorage-independent growth of NSCLC cells under low nutritional condition by activating NF-κB/p65 signaling through disrupting translocation of PPARα and PPARγ. Further investigations revealed that both genetic deletion and methylation contribute to downexpression of HLF in NSCLC tissues. In conclusion, our results shed light on a plausible mechanism by which HLF inhibits distant metastasis in NSCLC, suggesting that HLF may serve as a novel target for clinical intervention in NSCLC.