BRAFV600E promotes anchorage-independent growth but inhibits anchorage-dependent growth in hTERT/Cdk4-Immortalized normal human bronchial epithelial cells.

Certain oncogenes, including mutant RAS and BRAF, induce a type of senescence known as oncogene-induced senescence (OIS) in normal cells in a cell-type-specific manner. OIS serves as a barrier to transformation by activated oncogenes. Our previous studies showed that mutant KRASV12 did not efficiently induce OIS in an hTERT/Cdk4-immortalized normal human bronchial epithelial cell line (HBEC3), but it did enhance both anchorage-dependent and anchorage-independent growth. In this study, we investigated whether mutant BRAF, a well-known inducer of OIS, could trigger OIS in HBEC3 cells. We also assessed the impact of mutant BRAF on the growth of HBEC3 cells, as no previous studies have examined this using a normal bronchial epithelial cell line model. We established an HBEC3 cell line, designated as HBEC3-BIN, that expresses mutant BRAFV600E in a doxycycline-regulated manner. Unlike our previous finding that KRASV12 upregulated both pERK and pAKT, mutant BRAFV600E upregulated pERK but not pAKT in HBEC3-BIN cells. Similar to KRASV12, BRAFV600E did not efficiently induce OIS. Interestingly, while BRAFV600E inhibited colony formation in anchorage-dependent conditions, it dramatically enhanced colony formation in anchorage-independent conditions in HBEC3-BIN. In HBEC3 cells without BRAFV600E or KRASV12 expression, p21 was only detected in the cytoplasm, and its localization was not altered by the expression of BRAFV600E or KRASV12. Next-generation sequencing analysis revealed an enrichment of gene sets known to be involved in carcinogenesis, including IL3/JAK/STAT3, IL2, STAT5, and the EMT pathway. Our results indicate that, unlike KRASV12, which promoted both, BRAFV600E enhances anchorage-independent growth but inhibits anchorage-dependent growth of HBEC3. This contrast may result from differences in activation signaling in the downstream pathways. Furthermore, HBEC3 cells appear to be inherently resistant to OIS, which may be partly due to the fact that p21 remains localized in the cytoplasm upon expression of BRAFV600E or KRASV12.

Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells.

Histone H3 lysine-9 di-methylation (H3K9me2) and lysine-27 tri-methylation (H3K27me3) are linked to repression of gene expression, but the functions of repressive histone methylation dynamics during inflammatory responses remain enigmatic. Here, we report that lysine demethylases 7A (KDM7A) and 6A (UTX) play crucial roles in tumor necrosis factor (TNF)-α signaling in endothelial cells (ECs), where they are regulated by a novel TNF-α-responsive microRNA, miR-3679-5p. TNF-α rapidly induces co-occupancy of KDM7A and UTX at nuclear factor kappa-B (NF-κB)-associated elements in human ECs. KDM7A and UTX demethylate H3K9me2 and H3K27me3, respectively, and are both required for activation of NF-κB-dependent inflammatory genes. Chromosome conformation capture-based methods furthermore uncover increased interactions between TNF-α-induced super enhancers at NF-κB-relevant loci, coinciding with KDM7A and UTX recruitments. Simultaneous pharmacological inhibition of KDM7A and UTX significantly reduces leukocyte adhesion in mice, establishing the biological and potential translational relevance of this mechanism. Collectively, these findings suggest that rapid erasure of repressive histone marks by KDM7A and UTX is essential for NF-κB-dependent regulation of genes that control inflammatory responses of ECs.

Types of anomalies in two-dimensional video-based gait analysis in uncontrolled environments.

Two-dimensional video-based pose estimation is a technique that can be used to estimate human skeletal coordinates from video data alone. It is also being applied to gait analysis and in particularly, due to its simplicity of measurement, it has the potential to be applied to gait analysis of large populations. However, it is considered difficult to completely homogenize the environment and settings during the measurement of large populations. Therefore, it is necessary to appropriately deal with technical errors that are not related to the biological factors of interest. In this study, by analyzing a large cohort database, we have identified four major types of anomalies that occur during gait analysis using OpenPose in uncontrolled environments: anatomical, biomechanical, and physical anomalies and errors due to estimation. We have also developed a workflow for identifying and correcting these anomalies and confirmed that this workflow is reproducible through simulation experiments. Our results will help obtain a comprehensive understanding of the anomalies to be addressed during pre-processing for 2D video-based gait analysis of large populations.

Ablation of Kidney Tumors in Patients with Substantial Kidney Impairment: Current Status.

PURPOSE OF REVIEW: To review the current status of kidney tumor ablation in patients with substantial kidney impairment. RECENT FINDINGS: Few reports of kidney tumor ablation in such patients have recently been published. The reported prevalence of patients with stage 4 or 5 chronic kidney disease (CKD) among patients undergoing ablation is 2.0%-10%. In patients with stage 4 or 5 CKD, local tumor control rates were 88%-100%. The effect of ablation on CKD stage is unclear, and the observed deteriorations in kidney function are consistent with both the effect of cryoablation and the natural course of advanced CKD. According to guidelines, active surveillance may be selected. The goals of treatment are complete tumor removal and maintenance of kidney function, both of which can be met by ablation. Given the limited treatment options, ablation may play a pivotal role in the management of patients with advanced CKD.

Robotic systems in interventional oncology: a narrative review of the current status.

Interventional oncology offers minimally invasive treatments for malignant tumors for curative and palliative purposes based on the percutaneous insertion of needles or catheters into the target location under image guidance. Robotic systems have been gaining increasing attention as tools that provide potential advantages for image-guided interventions. Among the robotic systems developed for intervention, those relevant to the oncology field are mainly those for guiding or driving the needles in non-vascular interventional procedures such as biopsy and tumor ablation. Needle-guiding robots support planning the needle path and align the needle robotically according to the planned trajectory, which is combined with subsequent manual needle insertion by the physician through the needle guide. Needle-driving robots can advance the needle robotically after determining its orientation. Although a wide variety of robotic systems have been developed, only a limited number of these systems have reached the clinical phase or commercialization thus far. The results of previous studies suggest that such interventional robots have the potential to increase the accuracy of needle placement, facilitate out-of-plane needle insertion, decrease the learning curve, and reduce radiation exposure. On the other hand, increased complexity and costs may be a concern when using robotic systems compared with conventional manual procedures. Further data should be collected to comprehensively assess the value of robotic systems in interventional oncology.

Photon-Counting Detector CT: Potential for 75% Reduction in Contrast Medium Amount: A Phantom Study.

This study aimed to evaluate the potential reduction in contrast medium utilization using photon-counting detector computed tomography (PCD-CT). One PCD-CT scan (CT1) and three conventional (non-PCD-CT) CT scans (CT2-CT4) were performed using a multi-energy CT phantom that contained eight rods with different iodine concentrations (0.2, 0.5, 1, 2, 5, 10, 15, and 20 mg/ml). The CT values of the seven groups (CT1 for 40, 50, 60, and 70 keV; and CT2-4) were measured. Noise and contrast-to-noise ratio (CNR) were assessed for the eight rods at various iodine concentrations. CT2 and CT1 (40 keV) respectively required 20 mg/ml and 5 mg/ml of iodine, indicating that a comparable contrast effect could be obtained with approximately one-fourth of the contrast medium amount. The standard deviation values increased at lower energy levels irrespective of the iodine concentration. The CNR exhibited a decreasing trend with lower iodine concentrations, while it remained relatively stable across all iodine levels (40-70 keV). This study demonstrated that virtual monochromatic 40 keV images offer a similar contrast effect with a reduced contrast medium amount when compared to conventional CT systems at 120 kV.

Arterial embolization via retrograde approach using steerable microcatheter and triaxial system.

We report a case of postoperative pseudoaneurysm, successfully treated with selective arterial embolization, using a steerable microcatheter and triaxial system via retrograde approach. A pseudoaneurysm was detected in the dorsal pancreatic artery, a severely narrow and steeply inverted branch of the superior mesenteric artery, making microcatheter insertion via the antegrade approach challenging. However, a steerable microcatheter was advanced beyond the orifice and the tip was reversed, changing the route to retrograde allowing for easy insertion of the microguidewire. Subsequently, a small microcatheter was advanced beyond the pseudoaneurysm into the dorsal pancreatic artery, and arterial embolization was successfully completed without complications.

Is cryoablation a valid option for renal cell carcinomas in direct contact with critical organs?

PURPOSE: This study aimed to assess the outcomes of percutaneous cryoablation (PCA) for renal cell carcinomas (RCCs) contacting critical organs without intervening fat tissue. MATERIAL AND METHODS: Twenty-three patients with 24 RCCs (mean size, 28.8 mm) contacting critical organs on preprocedural images were included. The organ displacement techniques, technical success, efficacy, and adverse events per Clavien-Dindo classification were retrospectively reviewed. RESULTS: The organs contacting the RCCs included the colon (n = 16), pancreas (n = 3), duodenum (n = 3), small intestine (n = 1), and stomach (n = 1). In all procedures, hydrodissection was conducted, and probe traction was additionally utilized in one to displace organs. Two procedures were terminated with an insufficient ice-ball margin (<6 mm) due to recurring proximity of the colon or thermal sink effect by renal hilar vessels, yielding a technical success rate of 91.6% (22/24). No severe adverse events were noted. All patients were alive without any metastases during a median follow-up of 34.4 months. The primary and secondary technical efficacy rates were 91.6% (22/24) and 95.8% (23/24) of tumors, respectively. CONCLUSION: PCA can be a valid option for RCCs contacting critical organs with a good safety profile and sufficient technical efficacy.

Network-based systematic dissection of exercise-induced inhibition of myosteatosis in older individuals.

Accumulated fat in skeletal muscle (i.e. myosteatosis), common in sedentary older individuals, compromises skeletal muscle health and function. A mechanistic understanding of how physical activity levels dictate fat accumulation represents a critical step towards establishment of therapies that promote healthy ageing. Using a network medicine paradigm that characterized the transcriptomic response of aged muscle to exercise versus immobilization protocols, this study explored the shared molecular cascade that regulates the fate of fibro-adipogenic progenitors (FAPs), the cell population primarily responsible for fat accumulation. Specifically, gene set enrichment analyses with network propagation revealed Pgc-1α as a functional hub of a large gene regulatory network underlying the regulation of FAPs by physical activity in aged muscle, but not in young counterparts. Integrated in silico and in situ approaches to induce Pgc-1α overexpression in aged muscle promoted mitochondrial fatty acid oxidation and inhibited FAP adipogenesis. These findings suggest that the Pgc-1α-mitochondrial fatty acid oxidation axis is a shared mechanism by which physical activity regulates age-related myosteatosis. The network medicine paradigm introduced provides mechanistic insight into exercise adaptation in elderly skeletal muscle and offers translational opportunities to advance exercise prescription for older populations. KEY POINTS: Fat accumulation is a quintessential feature of aged skeletal muscle. While increasing physical activity levels has been proposed as an effective strategy to reduce the fat in skeletal muscle (i.e. myosteatosis), the molecular cascade underlying these benefits has been poorly defined. This study implemented a series of network medicine approaches and uncovered Pgc-1α as a mechanistic driver of the regulation of fibro-adipogenic progenitors (FAPs) by physical activity. Integrated in silico and in situ approaches to induce Pgc-1α overexpression promoted mitochondrial fatty acid oxidation and inhibited FAP adipogenesis. Together, the findings of the current study suggest a novel hypothesis that physical activity reduces myosteatosis via upregulation of Pgc-1α-mediated mitochondrial fatty acid oxidation and subsequent inhibition of FAP adipogenesis.

Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma.

BACKGROUND: Driver alterations may represent novel candidates for driver gene-guided therapy; however, intrahepatic cholangiocarcinoma (ICC) with multiple genomic aberrations makes them intractable. Therefore, the pathogenesis and metabolic changes of ICC need to be understood to develop new treatment strategies. We aimed to unravel the evolution of ICC and identify ICC-specific metabolic characteristics to investigate the metabolic pathway associated with ICC development using multiregional sampling to encompass the intra- and inter-tumoral heterogeneity. METHODS: We performed the genomic, transcriptomic, proteomic and metabolomic analysis of 39-77 ICC tumour samples and eleven normal samples. Further, we analysed their cell proliferation and viability. RESULTS: We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case exhibited neutral evolution, regardless of their tumour stage. Upregulation of BCAT1 and BCAT2 indicated the involvement of 'Val Leu Ile degradation pathway'. ICCs exhibit the accumulation of ubiquitous metabolites, such as branched-chain amino acids including valine, leucine, and isoleucine, to negatively affect cancer prognosis. We revealed that this metabolic pathway was almost ubiquitously altered in all cases with genomic diversity and might play important roles in tumour progression and overall survival. CONCLUSIONS: We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions.

RoDiCE: robust differential protein co-expression analysis for cancer complexome.

MOTIVATION: The full spectrum of abnormalities in cancer-associated protein complexes remains largely unknown. Comparing the co-expression structure of each protein complex between tumor and healthy cells may provide insights regarding cancer-specific protein dysfunction. However, the technical limitations of mass spectrometry-based proteomics, including contamination with biological protein variants, causes noise that leads to non-negligible over- (or under-) estimating co-expression. RESULTS: We propose a robust algorithm for identifying protein complex aberrations in cancer based on differential protein co-expression testing. Our method based on a copula is sufficient for improving identification accuracy with noisy data compared to conventional linear correlation-based approaches. As an application, we use large-scale proteomic data from renal cancer to show that important protein complexes, regulatory signaling pathways and drug targets can be identified. The proposed approach surpasses traditional linear correlations to provide insights into higher-order differential co-expression structures. AVAILABILITY AND IMPLEMENTATION: https://github.com/ymatts/RoDiCE. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Trends in CD4+ Cell Counts, Viral Load, Treatment, Testing History, and Sociodemographic Characteristics of Newly Diagnosed HIV Patients in Osaka, Japan, From 2003 through 2017: A Descriptive Study.

BACKGROUND: The CD4 cell count of patients during diagnosis and distribution of CD4 cell counts in the patient population are important to understand infection-diagnosis interval and incidence rate of human immunodeficiency virus (HIV) infection, respectively. However, this information has not been published in Japan. This study aimed to describe the change in CD4 cell count trends and clarify the change in patients' characteristics in association with the CD4 cell count information. METHODS: A descriptive study was conducted to analyze the medical records of patients with HIV who visited one of the largest acquired immunodeficiency syndrome (AIDS) core hospitals in western Japan. The basic characteristics, CD4 cell counts, viral loads, and diagnosis-treatment intervals between the first (2003-2010) and second (2011-2017) halves of the study duration were compared. RESULTS: The distribution of CD4 cell counts significantly changed between 2003-2010 and 2011-2017 (χ2 = 20.42, P < 0.001). The proportion of CD4 cell count <200 cells/mm3 increased (38.8% in 2003 to 45.9% in 2017), whereas CD4 cell count ≥500 cells/mm3 decreased (19.4% in 2003 to 12.2% in 2017). Moreover, the distributions of age groups, history of HIV screening test, patient outcomes, HIV viral load, and diagnosis-treatment interval also significantly changed (χ2 = 25.55, P < 0.001; χ2 = 8.37, P = 0.015; χ2 = 6.07, P = 0.014; χ2 = 13.36, P = 0.020; χ2 = 173.76, P < 0.001, respectively). CONCLUSION: This study demonstrated the fundamental trends of the HIV epidemic in Osaka, Japan between 2003-2010 and 2011-2017 and indicated that the incidence rate of HIV was decreasing in Japan.

Navicular Bone Fracture after Radiofrequency Ablation in a Patient with Osteoid Osteoma.

Osteoid osteoma (OO) is a benign bone tumor that presents with nocturnal pain. Computed tomography (CT)- guided radiofrequency ablation (RFA) has been widely performed for OO, and major adverse events post-RFA are rare. We report a case of OO in the left navicular bone of a 15-year-old male. He underwent RFA for OO, and the pain improved temporarily. At the 1-month follow-up, the patient complained of left foot pain, and a CT examination revealed a fracture of the ablated navicular bone. Fractures are rare but must be taken into account after bone RFA.

Complications of Percutaneous Cryoablation for Renal Tumors and Methods for Avoiding Them.

Percutaneous cryoablation of renal tumors is widely used because of its high efficacy and safety. This high safety can be attributed, at least in part, to the visibility of the ablated area as an "ice ball". This therapy has fewer complications (incidence, 0-7.2%) and is less invasive than surgery. Minor bleeding is inevitable in most kidney-related procedures, and indeed the most common complication of this therapy is bleeding (hematoma and hematuria). However, patients require treatment such as transfusion or transarterial embolization in only 0-4% of bleeding cases. Various other complications such as ureteral or collecting system injury, bowel injury, nerve injury, skin injury, infection, pneumothorax, and tract seeding also occur, but they are usually minor and asymptomatic. However, operators should know and avoid the various complications associated with this therapy. This study aimed to summarize the complications of percutaneous cryoablation for renal tumors and provide some techniques for achieving safe procedures.

Omental Abscess after Laparoscopic Proximal Gastrectomy Successfully Treated with Percutaneous Drainage.

We report the case details of a 65-year-old Japanese man with an omental abscess that was discovered 43 days after he underwent a laparoscopic proximal gastrectomy for gastric cancer. His chief complaint was mild abdominal pain that had persisted for several days. The abscess was diagnosed as a rare postoperative complication. We hesitated to perform a reoperation given the invasiveness of general anesthesia and surgery, plus the possibility of postoperative adhesions and because the patient's general condition was stable and he had only mild abdominal pain. Percutaneous drainage using a 10.2-F catheter was performed with the patient under conscious sedation and computed tomography-fluoroscopy guidance, with no complications. After the procedure, the size of the abscess cavity was remarkably reduced, and 23 days later the catheter was withdrawn.

New trend in artificial intelligence-based assistive technology for thoracic imaging.

Although there is no solid agreement for artificial intelligence (AI), it refers to a computer system with intelligence similar to that of humans. Deep learning appeared in 2006, and more than 10 years have passed since the third AI boom was triggered by improvements in computing power, algorithm development, and the use of big data. In recent years, the application and development of AI technology in the medical field have intensified internationally. There is no doubt that AI will be used in clinical practice to assist in diagnostic imaging in the future. In qualitative diagnosis, it is desirable to develop an explainable AI that at least represents the basis of the diagnostic process. However, it must be kept in mind that AI is a physician-assistant system, and the final decision should be made by the physician while understanding the limitations of AI. The aim of this article is to review the application of AI technology in diagnostic imaging from PubMed database while particularly focusing on diagnostic imaging in thorax such as lesion detection and qualitative diagnosis in order to help radiologists and clinicians to become more familiar with AI in thorax.

Clinical applications of artificial intelligence in liver imaging.

This review outlines the current status and challenges of the clinical applications of artificial intelligence in liver imaging using computed tomography or magnetic resonance imaging based on a topic analysis of PubMed search results using latent Dirichlet allocation. LDA revealed that "segmentation," "hepatocellular carcinoma and radiomics," "metastasis," "fibrosis," and "reconstruction" were current main topic keywords. Automatic liver segmentation technology using deep learning is beginning to assume new clinical significance as part of whole-body composition analysis. It has also been applied to the screening of large populations and the acquisition of training data for machine learning models and has resulted in the development of imaging biomarkers that have a significant impact on important clinical issues, such as the estimation of liver fibrosis, recurrence, and prognosis of malignant tumors. Deep learning reconstruction is expanding as a new technological clinical application of artificial intelligence and has shown results in reducing contrast and radiation doses. However, there is much missing evidence, such as external validation of machine learning models and the evaluation of the diagnostic performance of specific diseases using deep learning reconstruction, suggesting that the clinical application of these technologies is still in development.

[Minimally Invasive Surgery for Mediastinal Diseases in Our Institute:Innovations and Surgical Practice].

Since the early 1990s, minimally invasive surgery has been introduced in many surgical fields. The progress of technology and increased interest in minimally invasive surgery has led to innovation from surgery with a large incision to complete thoracoscopic surgery in many facilities. We started thoracoscopic mediastinal surgery in 1997 and robot-assisted mediastinal surgery in 2021. Considering the approach for anterior mediastinal tumor resection, it is necessary to fully understand tumor size, tumor location, and the existence of the tumor invasion to other organs. Especially in the case of tumors located on the cranial side above the innominate vein or thymectomy with dissection of the superior pole of the thymus, ensuring surgical field visibility is essential. In our institute, from the point of cosmetics, surgical field visibility is ensured using carbon dioxide insufflation and a sternum-lifting method. Although the number of cases is limited, we report our ingenuity and actual implementation of the techniques.

An association between a positive direct antiglobulin test and HLA-DR12 in COVID-19.

SARS-CoV-2 infection has been reported to be associated with a positive direct antiglobulin test (DAT). In this study, an analysis of 40 consecutive coronavirus disease 2019 (COVID-19) cases from December 2020 to September 2021 in Japan revealed that patients of 70 years and over were predisposed to a positive DAT. DAT positivity was related to a decrease in the hemoglobin level. Anemia in DAT-positive COVID-19 patients was attributed to hemolysis, which was corroborated by high reticulocyte counts and an increase in the red blood cell distribution width. Human leukocyte antigen (HLA)-DRB1*12:01 and DRB1*12:02 were exclusively found in DAT-positive COVID-19 patients. In silico assays for the Spike protein of SARS-CoV-2 predicted several common core peptides that met the criteria for a B cell epitope and strong binding to both HLA-DRB1*12:01 and DRB1*12:02. Among these peptides, the amino acids sequence TSNFR, which is found within the S1 subunit of SARS-CoV-2 Spike protein, is shared by human blood group antigen Rhesus (Rh) CE polypeptides. In vitro analysis showed that the expression of HLA-DR in CD4+ T cells and CD8+ T cells from a DAT-positive patient was increased after pulsation with TSNFR-sequence-containing peptides. In summary, positive DAT is related to enhanced anemia and to HLA-DR12 in the Japanese population. A peptide sequence within SARS-CoV-2 Spike protein may act as an epitope for IgG binding to RBCs in DAT-positive COVID-19 patients.

Percutaneous cryoablation combined with prior transcatheter arterial embolization for renal cell carcinomas of 3 cm or larger: a prospective study.

BACKGROUND: We prospectively evaluated the safety and efficacy of percutaneous cryoablation combined with transcatheter renal arterial embolization for the treatment of tumors ≥ 3 cm in diameter. METHODS: We included patients aged ≥ 20 years with histologically proven renal cell carcinoma with a tumor diameter ≥ 3 cm who were inoperable or refused surgery. Prior to ablation, transcatheter arterial embolization was performed using a mixture of absolute ethanol and iodized oil. All cryoablation procedures were performed percutaneously under computed tomography fluoroscopy guidance. The primary endpoint was safety, which was evaluated for adverse events using CTCAE version 4.0. The secondary endpoint was survival; overall survival, progression-free survival, and cancer-specific survival were calculated. RESULTS: From October 2013 to March 2016, 19 patients (mean age, 75 ± 13 years; 5 women, 14 men) were prospectively enrolled. The mean tumor diameter was 3.9 ± 0.7 (range 3.1-5.3) cm. Four grade 3 hematologic adverse events occurred, while no symptomatic grade ≥ 3 events occurred. The median follow-up period was 68 (range 52-84) months. During the follow-up period, two patients developed local tumor progression at 3 and 42 months after the initial ablative procedure; no patient showed distant metastasis. Two patients died from causes other than RCC. Overall survival, progression-free survival, and cause-specific survival were 100%, 95%, and 100% at 3 years, and 95%, 84%, and 100% at 5 years, respectively. CONCLUSION: Percutaneous cryoablation combined with prior TAE for the treatment of tumors ≥ 3 cm in diameter was safe and achieved favorable survival.