Involvement of BCR::ABL1 in laminin adhesion of Philadelphia chromosome-positive acute lymphoblastic leukemia through upregulation of integrin α6.

BACKGROUND: Adhesion of cancer cells to extracellular matrix laminin through the integrin superfamily reportedly induces drug resistance. Heterodimers of integrin α6 (CD49f) with integrin ß1 (CD29) or ß4 (CD104) are major functional receptors for laminin. Higher CD49f expression is reportedly associated with a poorer response to induction therapy in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Moreover, a xenograft mouse model transplanted with primary BCP-ALL cells revealed that neutralized antibody against CD49f improved survival after chemotherapy. AIMS: Considering the poor outcomes in Philadelphia chromosome (Ph)-positive ALL treated with conventional chemotherapy without tyrosine kinase inhibitors, we sought to investigate an involvement of the laminin adhesion. METHODS AND RESULTS: Ph-positive ALL cell lines expressed the highest levels of CD49f among the BCP-ALL cell lines with representative translocations, while CD29 and CD104 were ubiquitously expressed in BCP-ALL cell lines. The association of Ph-positive ALL with high levels of CD49f gene expression was also confirmed in two databases of childhood ALL cohorts. Ph-positive ALL cell lines attached to laminin and their laminin-binding properties were disrupted by blocking antibodies against CD49f and CD29 but not CD104. The cell surface expression of CD49f, but not CD29 and CD104, was downregulated by imatinib treatment in Ph-positive ALL cell lines, but not in their T315I-acquired sublines. Consistently, the laminin-binding properties were disrupted by the imatinib pre-treatment in the Ph-positive ALL cell line, but not in its T315I-acquired subline. CONCLUSION: BCR::ABL1 plays an essential role in the laminin adhesion of Ph-positive ALL cells through upregulation of CD49f.

Laparoscopic sleeve gastrectomy combined with Toupet fundoplication (T-sleeve): A short report of a Japanese obesity patient with gastroesophageal reflux disease.

Laparoscopic sleeve gastrectomy (LSG) is the most frequently performed procedure in bariatric-metabolic surgery (BMS) worldwide, accounting for approximately 90% of BMS procedures in Japan. While numerous studies have reported on the safety and efficacy of LSG, gastroesophageal reflux disease (GERD) remains a major postoperative complication. Although Roux-en-Y gastric bypass (RYGB) is preferred for severe obesity with GERD, it is less suitable for Japanese patients who have a higher risk of gastric cancer due to the remnant stomach which is difficult to observe with esophago-gastro-duodenoscopy. To address de novo and exacerbation GERD after LSG, we conducted LSG with Toupet fundoplication (T-sleeve) for Japanese patients with severe obesity. In our first T-sleeve case, the patient demonstrated sufficient weight loss and improved GERD following surgery. Hence, we suggest that T-sleeve is a feasible option for Japanese patients with obesity and concurrent GERD.

Genetic Counseling and Genetic Testing for Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is one of the most common autosomal codominant Mendelian diseases. The major complications of FH include tendon and cutaneous xanthomas and coronary artery disease (CAD) associated with a substantial elevation of serum low-density lipoprotein levels (LDL). Genetic counseling and genetic testing for FH is useful for its diagnosis, risk stratification, and motivation for further LDL-lowering treatments. In this study, we summarize the epidemiology of FH based on numerous genetic studies, including its pathogenic variants, genotype-phenotype correlation, prognostic factors, screening, and usefulness of genetic counseling and genetic testing. Due to the variety of treatments available for this common Mendelian disease, genetic counseling and genetic testing for FH should be implemented in daily clinical practice.

Comparison of imaging changes in pulmonary artery diameter at the occlusion site using silk or metal clamps for pulmonary artery troubles.

OBJECTIVES: We analysed our clinical experience using silk sutures [the double-loop technique (DLT)] or DeBakey type vascular clamp (DeBakey clamp) for pulmonary artery (PA) troubles during anatomical lung resection to validate its practicality and safety. METHODS: We retrospectively reviewed the records of patients who underwent either of the above clamping techniques during anatomical lung resection at our hospital between April 2007 and August 2022. We measured the PA diameter at the occlusion site on computed tomography images acquired within 1 year pre- and postoperatively. The difference between pre- and postoperative diameters of the occlusion sites was calculated as the change in the PA diameter. We zoned the occlusion site of the PA to adjust for variation. PA deformation was evaluated as an adverse event caused by clamping. RESULTS: Ultimately, 27 and 26 patients who underwent the DLT and DeBakey clamp, respectively, were included. No additional injury due to the clamp procedure was found in either group. For zone R1/L1, defined as the main PA, the median changes in the PA diameter were 0.02 (-0.7 to 0.27) mm for the DLT and 0.36 (-0.28 to 0.89) mm for the DeBakey clamp. No significant differences were observed between the 2 groups (P = 0.106). Furthermore, no aneurysms, dissections, or stenoses were found in either group. CONCLUSIONS: The DLT and DeBakey clamp had only minimal effects on the occlusion site of the PA. The DLT is a practical thoracoscopic technique for PA bleeding when primary haemostasis has been achieved.

The Roles and Regulatory Mechanisms of Tight Junction Protein Cingulin and Transcription Factor Forkhead Box Protein O1 in Human Lung Adenocarcinoma A549 Cells and Normal Lung Epithelial Cells.

Tight junction (TJ) protein cingulin (CGN) and transcription factor forkhead box protein O1 (FOXO1) contribute to the development of various cancers. Histone deacetylase (HDAC) inhibitors have a potential therapeutic role for some cancers. HDAC inhibitors affect the expression of both CGN and FOXO1. However, the roles and regulatory mechanisms of CGN and FOXO1 are unknown in non-small cell lung cancer (NSCLC) and normal human lung epithelial (HLE) cells. In the present study, to investigate the effects of CGN and FOXO1 on the malignancy of NSCLC, we used A549 cells as human lung adenocarcinoma and primary human lung epithelial (HLE) cells as normal lung tissues and performed the knockdown of CGN and FOXO1 by siRNAs. Furthermore, to investigate the detailed mechanisms in the antitumor effects of HDAC inhibitors for NSCLC via CGN and FOXO1, A549 cells and HLE cells were treated with the HDAC inhibitors trichostatin A (TSA) and Quisinostat (JNJ-2648158). In A549 cells, the knockdown of CGN increased bicellular TJ protein claudin-2 (CLDN-2) via mitogen-activated protein kinase/adenosine monophosphate-activated protein kinase (MAPK/AMPK) pathways and induced cell migration, while the knockdown of FOXO1 increased claudin-4 (CLDN-4), decreased CGN, and induced cell proliferation. The knockdown of CGN and FOXO1 induced cell metabolism in A549 cells. TSA and Quisinostat increased CGN and tricellular TJ protein angulin-1/lipolysis-stimulated lipoprotein receptor (LSR) in A549. In normal HLE cells, the knockdown of CGN and FOXO1 increased CLDN-4, while HDAC inhibitors increased CGN and CLDN-4. In conclusion, the knockdown of CGN via FOXO1 contributes to the malignancy of NSCLC. Both HDAC inhibitors, TSA and Quisinostat, may have potential for use in therapy for lung adenocarcinoma via changes in the expression of CGN and FOXO1.

Quantitative assessment of nano-plastic aerosol particles emitted during machining of carbon fiber reinforced plastic.

Focusing on the relatively unexplored presence of micro- and nano-plastic aerosol particles, this study quantitatively assessed the emission of nano-plastic particles during the machining of carbon fiber reinforced plastic (CFRP) in the working environment. Measurements of aerosol particles smaller than 1 µm in size were performed by aerosol mass spectrometry. The findings revealed that concentrations of carbonous aerosol particles (organic aerosol and refractory black carbon (rBC)) were higher during working hours than during non-working hours. Positive matrix factorization identified CFRP particles as a significant source, contributing an average of approximately 30% of concentration of carbonous aerosol particles during working hours. This source apportionment was corroborated by the presence of bisphenol A and F fragments, principal components of the epoxy resins used in CFRP, and was corroborated by similarities to the carbon cluster ion distribution observed in rBC during CFRP pipe-cutting operations. Further, the particle size distribution suggested the existence of plastic aerosol particles smaller than 100 nm. This study established the method to quantitatively distinguish nano-plastic aerosol particles from other aerosol particles in high temporal resolution and these techniques are useful for accurately assessing exposure to nano-plastic aerosol particles in working environments.

Prognostic impact of peripheral blood WT1 mRNA dynamics in patients with acute myeloid leukemia treated with venetoclax combination therapy.

BACKGROUND: Wilms' tumor gene 1 (WT1) mRNA quantification is a useful marker of measurable residual disease in acute myeloid leukemia (AML). However, whether monitoring the WT1 mRNA levels may predict the outcome of venetoclax (VEN) combination therapy in AML is not reported. This study aims to elucidate whether WT1 mRNA dynamics could predict long-term prognosis. METHODS: 33 patients with untreated or relapsed/refractory AML evaluated for peripheral blood WT1 dynamics in VEN combination therapy were analyzed. RESULTS: The median age was 73 years (range 39-87). Azacitidine was combined with VEN in 91% of patients. Overall, the median overall survival (OS) was 334 days (95% CI 210-482), and the complete remission (CR) plus CR with incomplete hematologic recovery rate was 59%. A 1-log reduction of WT1 mRNA values by the end of cycle 2 of treatment was associated with significantly better OS and event-free survival (EFS) (median OS 482 days vs. 237 days, p = 0.049; median EFS 270 days vs. 125 days, p = 0.02). The negativity of post-treatment WT1 mRNA value during the treatment was associated with significantly better OS and EFS (median OS 482 days vs. 256 days, p = 0.02; median EFS not reached vs. 150 days, p = 0.005). Multivariate analysis confirmed the significance of these two parameters as strong EFS predictors (HR 0.26, p = 0.024 and HR 0.15, p = 0.013, respectively). The increase in WT1 mRNA values was correlated with relapse. CONCLUSION: This study demonstrates that WT1 mRNA dynamics can be a useful marker for assessing long-term prognosis of VEN combination therapy for AML.

The quantification of the airborne plastic particles of 0.43-11 µm: Procedure development and application to atmospheric environment.

The environmental degradation of microplastics results in ultrafine particles that may incur severe biological concerns. Despite this, the atmospheric existence of plastics of less than a few microns has barely been investigated due to the particle size limit of conventional analytical methods. This study develops a procedure to quantify and characterize plastic particles (including nanoplastics; less than 1 µm) in the air through fractional sampling, a simple pretreatment method, and pyrolysis-gas chromatography-mass spectrometry (pyr-GC/MS). We targeted 11 major polymers, namely, polyethylene, polypropylene, polystyrene, acrylonitrile-butadiene-styrene resin, styrene-butadiene rubber, polymethylmethacrylate, polycarbonate, polyvinyl chloride, polyethylene terephthalate (PET), polyamide 6, and polyamide 66 (PA66). The average spike and recovery rate of each polymer in the aerosol collected on the roof of a four-story building near a major road in Kyoto, Japan, amounted to 78-130%, with a coefficient of variation of less than 15%. By coupling pyr-GC/MS analysis with fractional sampling of particles within the size range of >11 µm, 11-7.0 µm, 7.0-4.7 µm, 4.7-3.3 µm, 3.3-2.1 µm, 2.1-1.1 µm, 1.1-0.65 µm, 0.65-0.43 µm, it was possible to quantify airborne nano- and microplastics by particle size. Polyethylene, polystyrene, PET, and PA66 were detected in the air, and the total mass concentration of tiny plastic particles (0.43-11 µm) amounted to 1.20 µg/m3. This translates into total particle numbers of 3.05 × 106 particles/m3 (assuming spheres), revealing a substantial number of particles under 1 µm. These results will contribute to future studies to understand the atmospheric behaviors of ultrafine plastic particles and their flow-on effects on the respiratory system.

"KAIZEN" method realizing implementation of deep-learning models for COVID-19 CT diagnosis in real world hospitals.

Numerous COVID-19 diagnostic imaging Artificial Intelligence (AI) studies exist. However, none of their models were of potential clinical use, primarily owing to methodological defects and the lack of implementation considerations for inference. In this study, all development processes of the deep-learning models are performed based on strict criteria of the "KAIZEN checklist", which is proposed based on previous AI development guidelines to overcome the deficiencies mentioned above. We develop and evaluate two binary-classification deep-learning models to triage COVID-19: a slice model examining a Computed Tomography (CT) slice to find COVID-19 lesions; a series model examining a series of CT images to find an infected patient. We collected 2,400,200 CT slices from twelve emergency centers in Japan. Area Under Curve (AUC) and accuracy were calculated for classification performance. The inference time of the system that includes these two models were measured. For validation data, the slice and series models recognized COVID-19 with AUCs and accuracies of 0.989 and 0.982, 95.9% and 93.0% respectively. For test data, the models' AUCs and accuracies were 0.958 and 0.953, 90.0% and 91.4% respectively. The average inference time per case was 2.83 s. Our deep-learning system realizes accuracy and inference speed high enough for practical use. The systems have already been implemented in four hospitals and eight are under progression. We released an application software and implementation code for free in a highly usable state to allow its use in Japan and globally.

Bovine neutrophils stimulated with Streptococcus uberis induce neutrophil extracellular traps, and cause cytotoxicity and transcriptional upregulation of inflammatory cytokine genes in bovine mammary epithelial cells.

This study aimed to understand the response of neutrophils stimulated by Streptococcus uberis, a major cause of mastitis. It was found that the production of neutrophil extracellular traps (NETs) was induced in milk clots from mastitic milk produced by S. uberis-infected bovine udders. The release of NETs from neutrophils stimulated by S. uberis was investigated. Bovine neutrophils cocultured with S. uberis in vitro released the components of NETs, which contained extracellular DNA and elastase. Bovine mammary epithelial cells (BMECs) incubated in coculture supernatants containing components of NETs, caused cytotoxicity and transcriptional upregulation of inflammatory cytokines, including of interleukin (IL) -1ß, tumor necrosis factor (TNF)-α, IL-6, and IL-8, in BMECs. These findings suggest that bovine neutrophils stimulated by S. uberis induce responses that cause exacerbated inflammation, such as NET formation, cytotoxicity against BMECs, and increased production of inflammatory cytokines. Bovine neutrophil responses stimulated by S. uberis could be involved in the progression of S. uberis-induced mastitis.

[Crucial Techniques for Chest Tube Placement and Postoperative Management].

Postoperative management of thoracic surgery with an indwelling chest tube is common, and knowledge about it is essential. A postoperative chest tube has four roles:1) to reinflate the lung, 2) to observe the condition of the thoracic cavity and acquire information regarding the outcomes, 3) to prevent complications, and 4) to treat pulmonary air leaks and empyema (chemical pleurodesis et ct). Although postoperative complications have decreased in recent years following advances in video-assisted thoracoscopic surgery( VATS) and devices such as stapling devices and vascular sealing systems (VSS), postoperative chest tube placement is still common. Therefore, a thorough knowledge of chest tube management is extremely important in thoracic surgery. Here, we have described, in detail, the management of a postoperative chest tube at our hospital.

Intensity-Modulated Radiation Therapy for Bilateral Choroidal Metastases Involving Macula and Optic Disc.

This case report discusses the case of a 76-year-old woman with choroidal metastasis from breast cancer who was treated with intensity-modulated radiation therapy (IMRT). Choroidal metastasis is a common ocular tumor, and the occurrence of this condition has increased due to improved diagnostic tools and longer survival of metastatic patients. IMRT is an innovative radiation therapy technique that reduces complications and improves the curative effect by concentrating radiation on the tumor while minimizing exposure to surrounding tissues. In this case, the patient had a history of breast cancer and was undergoing chemotherapy when she presented with vision loss and blurred vision. Imaging tests confirmed choroidal metastasis, and IMRT was performed under the guidance of a radiation oncologist. After treatment, the choroidal lesion dramatically reduced in size, and the patient's vision improved. The text concludes that radiation therapy, including IMRT, is becoming more common as a treatment for ocular metastasis to improve vision and preserve the eye. When choosing radiation therapy, it is essential to consider the size of the tumor and the impact on surrounding tissues. IMRT is an effective treatment that enables precise and concentrated irradiation of the tumor tissue while minimizing exposure to normal tissues.

Utility of ASNS gene methylation evaluated with the HPLC method as a pharmacogenomic biomarker to predict asparaginase sensitivity in BCP-ALL.

Asparaginase is an important agent for the treatment of acute lymphoblastic leukaemia (ALL), but it is occasionally associated with severe adverse events. Thus, for safer and more efficacious therapy, a clinical biomarker predicting asparaginase sensitivity is highly anticipated. Asparaginase depletes serum asparagine by deaminating asparagine into aspartic acid, and ALL cells are thought to be sensitive to asparaginase due to reduced asparagine synthetase (ASNS) activity. We have recently shown that allele-specific methylation of the ASNS gene is highly involved in asparaginase sensitivity in B-precursor ALL (BCP-ALL) by using next-generation sequence (NGS) analysis of bisulphite PCR products of the genomic DNA. Here, we sought to confirm the utility of methylation status of the ASNS gene evaluated with high-performance liquid chromatography (HPLC) analysis of bisulphite PCR products for future clinical applications. In the global methylation status of 23 CpG sites at the boundary region of promoter and exon 1 of the ASNS gene, a strong positive correlation was confirmed between the mean percent methylation evaluated with the HPLC method and that with the NGS method in 79 BCP-ALL cell lines (R2 = 0.85, p = 1.3 × 10-33) and in 63 BCP-ALL clinical samples (R2 = 0.84, p = 5.0 × 10-26). Moreover, methylation status of the ASNS gene evaluated with the HPLC method was significantly associated with in vitro asparaginase sensitivities as well as gene and protein expression levels of ASNS. These observations indicated that the ASNS gene methylation status evaluated with the HPLC method is a reliable biomarker for predicting the asparaginase sensitivity of BCP-ALL.

Impact of the hybrid emergency department on resuscitation strategies and outcomes in ventricular fibrillation.

BACKGROUND: The Hybrid emergency room (ER) is a novel resuscitation room that includes a whole-body computed tomography scanner and angiography system, which enables physicians to seamlessly conduct resuscitation, diagnosis and therapeutic interventions without patient transfer. This study aimed to assess the impact of the Hybrid ER on mortality in patients with ventricular fibrillation cardiac arrest. METHODS: This was a retrospective cohort study conducted in a tertiary hospital in Japan. We consecutively included adult cardiac arrest patients who were transferred to the emergency departments from January 2007 to May 2020, and were confirmed to be in ventricular fibrillation within 10 min from patient arrival. The study population was divided into two groups: the conventional group (from January 2007 to July 2011) and the Hybrid ER group (from August 2011 to May 2020). The primary endpoint of this study was defined as all-cause in-hospital death. Secondary endpoints included the frequency of extracorporeal cardiopulmonary resuscitation (ECPR) and percutaneous coronary intervention (PCI), and door-to-balloon time and door-to-ECPR time. RESULTS: We included 115 patients in the conventional group and 185 patients in the Hybrid ER group. In-hospital mortality was significantly decreased in the Hybrid ER group (adjusted hazard ratio, 0.79; 95% confidence interval 0.64, 0.97; p = 0.026). Door-to-ECPR time was significantly shorter in the Hybrid ER group (p < 0.001, Gehan-Breslow-Wilcoxon test), as was door-to-balloon time in this group (p = 0.004, Gehan-Breslow-Wilcoxon test). In interrupted time-series analyses, it was visually recognized that the ratio of patients who received ECPR and PCI increased, and door-to-ECPR time and door-to-balloon time were shortened from 2011 to 2012 (before and after installation of the Hybrid ER). CONCLUSION: Installation of the Hybrid ER was associated with a reduced time to ECPR and PCI and with a possible improvement in survival in patients with ventricular fibrillation cardiac arrest.

Neuroimaging biomarkers of glial activation for predicting the annual cognitive function decline in patients with Alzheimer's disease.

BACKGROUND: Glial activation is central to the pathogenesis of Alzheimer's disease (AD). However, researchers have not demonstrated its relationship to longitudinal cognitive deterioration. We aimed to compare the prognostic effects of baseline positron emission tomography (PET) imaging of glial activation and amyloid/tau pathology on the successive annual cognitive decline in patients with AD. METHODS: We selected 17 patients diagnosed with mild cognitive impairment or AD. We assessed the annual changes in global cognition and memory. Furthermore, we assessed the predictive effects of baseline amyloid and tau pathology indicated by cerebrospinal fluid (CSF) concentrations and PET imaging of glial activation (11C-DPA-713-binding potential in the area of Braak 1-3 [11C-DPA-713-BPND]) on global cognition and memory using a stepwise regression analysis. RESULTS: The final multiple regression model of annual changes in global cognition and memory scores included 11C-DPA-713-BPND as the predictor. The CSF Aß42/40 ratios and p-tau concentrations were removed from the final model. In stepwise Bayesian regression analysis, the Bayes factor-based model comparison suggested that the best model included 11C-DPA-713-BPND as the predictor of decline in global cognition and memory. CONCLUSIONS: Translocator protein-PET imaging of glial activation is a stronger predictor of AD clinical progression than the amount of amyloid/tau pathology measured using CSF concentrations. Glial activation is the primary cause of tau-induced neuronal toxicity and cognitive deterioration, thereby highlighting the potential of blocking maladaptive microglial responses as a therapeutic strategy for AD treatment.

Experimental and histological evaluation of different clamp technique for pulmonary artery.

OBJECTIVES: The double-loop technique has been used in our clinical settings for pulmonary arterioplasty and/or injured artery repair during thoracoscopic anatomical lung resection. We evaluated the pressure resistance capacity and intimal load to determine the effectiveness and safety of the double-loop technique. METHODS: The double-loop technique, DeBakey clamp, Fogarty clamp, endovascular clips and vessel loop technique were evaluated. During an experimental study, a polyvinyl alcohol main pulmonary artery model, manometer and in-deflation device were used to measure the burst pressure. The maximum clamp pressure was measured using a pressure-measuring film. Each measurement was performed 10 times. During the histological study, we measured the burst pressure and evaluated the intimal damage of the human pulmonary artery associated with the double-loop technique and DeBakey clamp. RESULTS: The experimental burst pressure (mmHg) and maximum clamp pressure (MPa) between the double-loop technique and DeBakey at the third notch were not significantly different (24.6 ± 2.8 and 21.8 ± 2.8, P = 0.094; 1.54 ± 0.12 and 1.49 ± 0.12, P = 0.954). During the histological study, the burst pressures of the double-loop technique and DeBakey at the third notch were also not significantly different (P = 0.754). Furthermore, the double-loop technique resulted in only intimal deformation in each five samples. CONCLUSIONS: The double-loop technique is feasible for thoracoscopic anatomical lung resection because it has similar pressure resistance capacity and intimal load as DeBakey at the 3rd notch.

[Minimally Invasive Robot-assisted Thoracoscopic Surgery for Mediastinal Tumor].

Robot-assisted thoracoscopic surgery( RATS) and video-assisted thoracoscopic surgery are minimally invasive surgical approaches to the chest wall that avoid sternotomy. We report on the innovations in RATS mediastinal tumor surgery performed in our department. We use a lateral approach, and the robotic arm is inserted between the third, fifth, and seventh intercostals and below the costal ribs. Carbon dioxide gas is insufflated using a pneumoclear insufflator. A small thoracotomy is made in the fifth intercostal space and an Alnote Lapsingle is placed and a scope and assistant port are implanted. The Alnote Lapsingle is used to keep the chest wall airtight and stable. The scope is moved less, reducing interference with the assistant. Tissue can now be placed in the retrieval bag with a good surgical field of view. After much trial and error, RATS mediastinal tumor surgery can now be performed more easily.

Pulmonary artery occlusion post immunotherapy for hilar node-positive lung cancer.

We present the case of a patient who developed pulmonary artery occlusion following immune-checkpoint inhibitor (ICI) therapy for non-small cell lung cancer. A 69-year-old man with squamous cell carcinoma (yc-T1cN0M0), initially diagnosed at c-stage IVA (T3N1M1b), in the upper lobe of the left lung, was scheduled to undergo salvage lung resection after ICI therapy. However, he exhibited an occlusion of the lingular pulmonary artery near the clinically metastatic hilar lymph node. To avoid severe adhesions, the patient underwent successful wedge resection without dividing pulmonary vessels and was discharged without complications. Surgeons should be prepared for pulmonary artery changes following ICI therapy.