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Background Chronic obstructive pulmonary disease (COPD) is an incurable and debilitating chronic disease characterized by progressive airflow limitation associated with abnormal levels of tissue inflammation. Therefore, stem cell-based approaches to tackle the condition are currently a focus of regenerative therapies for COPD. Extracellular vesicles (EVs) released by all cell types are crucially involved in paracrine, extracellular communication. Recent advances in the field suggest that stem cell-derived EVs possess a therapeutic potential which is comparable to the cells of their origin. Methods In this study, we assessed the potential anti-inflammatory effects of human umbilical cord mesenchymal stem cell (hUC-MSC)-derived EVs in a rat model of COPD. EVs were isolated from hUC-MSCs and characterized by the transmission electron microscope, western blotting, and nanoparticle tracking analysis. As a model of COPD, male Sprague-Dawley rats were exposed to cigarette smoke for up to 12 weeks, followed by transplantation of hUC-MSCs or application of hUC-MSC-derived EVs. Lung tissue was subjected to histological analysis using haematoxylin and eosin staining, Alcian blue-periodic acid-Schiff (AB-PAS) staining, and immunofluorescence staining. Gene expression in the lung tissue was assessed using microarray analysis. Statistical analyses were performed using GraphPad Prism 7 version 7.0 (GraphPad Software, USA). Student’s t test was used to compare between 2 groups. Comparison among more than 2 groups was done using one-way analysis of variance (ANOVA). Data presented as median ± standard deviation (SD). Results Both transplantation of hUC-MSCs and application of EVs resulted in a reduction of peribronchial and perivascular inflammation, alveolar septal thickening associated with mononuclear inflammation, and a decreased number of goblet cells. Moreover, hUC-MSCs and EVs ameliorated the loss of alveolar septa in the emphysematous lung of COPD rats and reduced the levels of NF-κB subunit p65 in the tissue. Subsequent microarray analysis revealed that both hUC-MSCs and EVs significantly regulate multiple pathways known to be associated with COPD. Conclusions In conclusion, we show that hUC-MSC-derived EVs effectively ameliorate by COPD-induced inflammation. Thus, EVs could serve as a new cell-free-based therapy for the treatment of COPD.

BackgroundTip-in endoscopic mucosal resection (EMR) is a modified EMR technique using which en bloc resection of large colorectal sessile polyps can be performed; however, its usefulness for colorectal sessile polyps of > 20 mm has not been reported. This study examined treatment outcomes of tip-in and conventional EMR for large colorectal sessile polyps of ≥ 20 mm.MethodsThis was a retrospective case–control study conducted at a single tertiary center in Japan. Subjects included those with large colorectal sessile polyps of ≥ 20 mm, excluding pedunculated-type polyps, who underwent endoscopic resection between January 2010 and January 2019. The primary outcome was endoscopic treatment outcomes when using tip-in and conventional EMR, and the secondary outcome was the local recurrence rate after endoscopic treatment.ResultsForty-three colorectal lesions were treated using tip-in EMR and 83 using conventional EMR. Tip-in EMR had a significantly higher en bloc resection rate (90.7% vs. 69.8.%), and significantly shorter treatment duration (6.64 ± 0.64 min vs. 10.47 ± 0.81 min) than conventional EMR. However, for lesions > 30 mm, en bloc resection rate was 50.0% and 52.6% for tip-in and conventional EMR, respectively, indicating no significant difference. Perforation rates with tip-in and conventional EMR were 4.6% and 3.6%, respectively, indicating no significant difference. Local recurrence was examined in 80 cases who were followed up for > 6 months after endoscopic resection; recurrence rate was 0% and 7.0% in tip-in and conventional EMR cases, respectively, without significance difference.ConclusionsTip-in EMR showed high en-block resection rate, particularly in polyps of < 30 mm, and no residual tumor was found. This technique is a potential endoscopic treatment alternative for large colorectal sessile polyps of ≥ 20 mm.

Because membrane type 1-matrix metalloproteinase 1 (MT1-MMP) and erythropoietin-producing hepatocellular receptor 2 (EphA2) expression are upregulated by the Ras/mitogen-activated protein kinase pathway, they are frequently coexpressed in malignant tumors. MT1-MMP cleaves the N-terminal ligand-binding domain of EphA2 and inactivates its ligand-dependent tumor-suppressing activity. Therefore, specific detection of the cleaved N-terminal EphA2 fragment in blood might be an effective biomarker to diagnose malignant tumors. To evaluate this possibility, we developed three monoclonal antibodies against the soluble EphA2 fragment. One of them recognized this fragment specifically, with negligible cross-reactivity to the intact form. We used the cleaved form-specific antibody to develop a quantitative enzyme-linked immunosorbent assay and confirmed the linear reactivity to the recombinant fragment. We applied this assay on commercially available serum specimens obtained from patients with several types of cancer including gastric, pancreatic, esophageal, gastroesophageal, and head-and-neck cancers, and healthy donors. Soluble EphA2 fragment levels in cancer-patient sera were higher than those in healthy donors ( n =50). In particular, levels of eight out of nine (89%) pancreatic cancer patients and ten out of seventeen (59%) gastric cancer patients significantly exceeded cutoff values obtained from the healthy donors, whereas those of esophageal and head-and-neck cancer-patient sera were low. The preliminary receiver operating characteristic curve analysis for pancreatic cancer demonstrated that the sensitivity and specificity were 89.0% and 90.0%, respectively, whereas those of the conventional digestive tumor marker CA19-9 were 88.9% and 72.0%, respectively. These results indicated that specific detection of soluble EphA2 fragment levels in serum could be potentially useful as a biomarker to diagnose pancreatic cancer.

Pulmonary TB that develops in immunocompetent adult humans is responsible for approximately 85% of the disease burden and is central for Mtb transmission. Most humans contain Mtb infection within primary granulomatous lesions, but in certain immunocompetent humans, containment fails, leading to hematogenous spread and active pulmonary disease with the formation of cavities that enable Mtb transmission via aerosols. To reveal lung-specific microenvironments conducive for Mtb survival and replication despite systemic immunity, we use fluorescence multiplex immunohistochemistry and spatial transcriptomic analyses of heterogenous TB lesions that uniquely form in the lungs of immunocompetent but TB-susceptible B6.Sst1S mice after hematogenous spread from the primary lesion. Initially, these secondary lung lesions manifested local adoptive immunity featuring tertiary lymphoid follicles similar to resistant B6 mice and contained primarily non- replicating bacilli. Following these early events, however, the B6.Sst1S mice uniquely demonstrate expansion of myeloid cell populations with the appearance of alternatively activated macrophages, dissolution of lymphoid follicles, and the accumulation of de- differentiated lung epithelial cells. These processes led to bronchogenic expansion, broncho- occlusion, and necrosuppurative pneumonia closely resembling advanced pulmonary tuberculosis in humans. To determine whether lung parenchymal cells or lung oxygenation were necessary for the pulmonary TB progression, we implanted lung and spleen fragments subcutaneously prior to the infection. The lung implants uniquely displayed the formation of the characteristic organized granulomas with necrosis and Mtb replication that paralleled TB progression in native lungs, demonstrating that the cellular composition of inflamed lung tissue, not oxygenation, is a critical determinant of pulmonary TB progression. Our data demonstrate that deleterious bi-directional interactions of aberrantly activated macrophages with the inflammation-injured lung resident cells determine lung vulnerability to virulent Mtb in immunocompetent hosts. Because these mechanisms enable Mtb transmission among humans via aerosols, they are likely evolutionary conserved and, therefore, represent appealing targets for host-directed TB therapies.

Objectives: To investigate the real-world outcomes of a population-based gastric cancer (GC) screening program in Kawasaki City, a major urban area with a growing aging population and relatively high screening participation rates. Methods: Between December 2012 and 2021, a total of 337,842 citizens in Kawasaki City underwent population-based GC screening, leading to the detection of 1087 GC cases. Esophageal cancer (EC) has been recorded since 2016, with 236 cases detected. To evaluate the short- and long-term clinical outcomes of screening-detected GC and EC, we conducted a retrospective study using the electronic medical records of patients treated at our hospital, a high-volume institution for GC and EC treatment in the city. As a control group, we included 34 GC and EC cases diagnosed based on symptoms at our hospital in 2018. Results: Among the 1087 GC cases detected through population-based screening, 102 cases treated at our hospital were included in the analysis. Of them, 91 patients (89%) were diagnosed with early-stage GC. All screening-detected GC cases underwent either surgery (27 cases) or endoscopic submucosal dissection (75 cases). The five-year survival rates for GC were 90% in males and 86% in females. Eighteen EC cases were also included in the study. The five-year survival rate for screening-detected advanced GC was 70.0%, while for screening-detected EC, it was 100%. Both survival rates were significantly higher than those for symptom-diagnosed GC (30.0%) and EC (40.8%). Conclusions: The prognosis of GC and EC detected through population-based endoscopic screening is significantly better than that of cancers diagnosed based on symptoms. This underscores the effectiveness of endoscopic screening as a valuable tool for the early detection of upper gastrointestinal tract cancers.

The diagnosis of hepatocellular carcinoma (HCC) in the early stages is important for successful clinical management. Laminin (Ln)‐γ2 expression has been reported in various types of malignant carcinomas. We recently developed a highly sensitive method to measure serum monomeric Ln‐γ2 levels using a fully automated chemiluminescent immunoassay (CLIA). Using our CLIA, we evaluated its diagnostic value in sera from patients with chronic liver disease (CLD) and patients with hepatocellular carcinoma (HCC). Serum alpha‐fetoprotein (AFP) and des‐gamma‐carboxy prothrombin (DCP) were also examined in these subjects. Median levels of Ln‐γ2 were significantly higher in patients with HCC (173.2 pg/mL; range: 39.5–986 pg/mL) compared with patients with CLD (76.7 pg/mL; range: 38.7–215.9 pg/mL) and with healthy volunteers (41.1 pg/mL; range: 10.9–79.0 pg/mL). The optimal cutoff value for Ln‐γ2 that allowed us to distinguish between HCC and nonmalignant CLD was 116.6 pg/mL. Elevated Ln‐γ2 levels were observed in 0% of healthy volunteers, 17% of patients with CLD, and 63% of patients with HCC. The positivity rate in patients with HCC for the combination of Ln‐γ2 and DCP was 89.5%, which was better than that for either of the two markers alone (63% and 68%, respectively). Among patients with early‐stage HCC (T1 or T2), the positivity rates for monomeric Ln‐γ2, AFP and DCP were 61%, 39% and 57%, respectively. Serum Ln‐γ2 may be a potential biomarker for HCC surveillance. The combination of Ln‐γ2 and DCP may be more sensitive for laboratory diagnosis of HCC than the combination of AFP and DCP. Serum monomeric Ln‐γ2 may be a potential biomarker for HCC surveillance. The combination of monomeric Ln‐γ2 and DCP may be more sensitive for laboratory diagnosis of HCC than the combination of AFP and DCP.

The development of multiple squamous cell carcinomas (SCC) in the upper aerodigestive tract, which includes the oral cavity, pharynx, larynx, and esophagus, is explained by field cancerization and is associated with alcohol consumption and cigarette smoking. We reviewed the association between alcohol consumption, multiple Lugol‐voiding lesions, and field cancerization, mainly based on the Japan Esophageal Cohort study. The Japan Esophageal Cohort study is a prospective cohort study that enrolled patients with esophageal SCC after endoscopic resection. Enrolled patients received surveillance by gastrointestinal endoscopy every 6 months and surveillance by an otolaryngologist every 12 months. The Japan Esophageal Cohort study showed that esophageal SCC and head and neck SCC that developed after endoscopic resection for esophageal SCC were associated with genetic polymorphisms related to alcohol metabolism. They were also associated with Lugol‐voiding lesions grade in the background esophageal mucosa, the score of the health risk appraisal model for predicting the risk of esophageal SCC, macrocytosis, and score on alcohol use disorders identification test. The standardized incidence ratio of head and neck SCC in patients with esophageal SCC after endoscopic resection was extremely high compared to the general population. Drinking and smoking cessation is strongly recommended to reduce the risk of metachronous esophageal SCC after treatment of esophageal SCC. Risk factors for field cancerization provide opportunities for early diagnosis and minimally invasive treatment. Lifestyle guidance of alcohol consumption and cigarette smoking for esophageal precancerous conditions, which are endoscopically visualized as multiple Lugol‐voiding lesions, may play a pivotal role in decreasing the incidence and mortality of esophageal SCC.

Laminin (Ln)-332 consists of α3, β3, and γ2 chains, which mediate epithelial cell adhesion to the basement membrane. Ln-γ2, a component of Ln-332, is frequently expressed as a monomer in the invasion front of several types of malignant tissues without simultaneous expression of Ln-α3 and/or Ln-β3 chains. Moreover, monomeric Ln-γ2 induces tumor cell proliferation and migration in vitro. These unique biological activities indicate that monomeric Ln-γ2 could be a candidate biomarker for early cancer surveillance. However, the present immune method for monomeric Ln-γ2 detection can only predict its expression, since no antibody that specifically reacts with monomeric γ2, but not with heterotrimeric γ2 chain, is commercially available. We have, therefore, developed monoclonal antibodies to specifically detect monomeric Ln-γ2, and devised a highly sensitive method to measure serum monomeric Ln-γ2 levels using a fully automated chemiluminescent immunoassay (CLIA). We evaluated its diagnostic value in sera from patients with several digestive cancers, including hepatocellular carcinoma (HCC), and found serum monomeric Ln-γ2 to be a clinically available biomarker for HCC surveillance. The combination of monomeric Ln-γ2 and prothrombin induced by Vitamin K Absence II (PIVKA-II) may be more sensitive for clinical diagnosis of HCC than any currently used combination.

Background This study aimed to evaluate the risk factors for developing metachronous primary Gastric Cancer (GC) after Endoscopic Resection (ER) for esophageal Squamous Cell Carcinoma (SCC). Methods We studied 283 patients with esophageal SCC who underwent ER. The study outcomes were as follows: (1) incidence of metachronous primary GC after ER; and (2) predictors for the development of metachronous primary GC after ER by the Cox proportional hazards model. Results The median follow-up was 43.1 months (1.81–79.1), and the 3-year cumulative incidence of metachronous primary GC was 6.5% (95%CI: 4.1–10.4). The incidence of metachronous primary GC during the follow-up period was 2.31 per 100 person-years. The frequencies of severe gastric atrophy and macrocytosis at the timing of ER were significantly higher in patients with than without metachronous primary GC (91.7% vs. 73.2%, p  = 0.0422, 20.8% vs. 5.2%, p  = 0.0046, respectively). Severe gastric atrophy was associated with the development of metachronous primary GC (sex-and-age adjusted hazard ratio (HR) [95%CI] = 4.12 [0.95–27.78], p  = 0.0093). Macrocytosis was associated with the development of metachronous primary GC (sex-and-age adjusted HR = 4.76 [1.75–13.0], p  = 0.0012) and found to be an independent predictor for metachronous primary GC by multivariate Cox proportional hazards analysis (HR [95%CI] = 4.35 [1.60–11.84], p  = 0.004). Conclusions Severe gastric atrophy and macrocytosis should be noted in the development of metachronous primary GC after ER for esophageal SCC. In particular, macrocytosis at the timing of ER was considered an important predictor. Clinical trials registry number: UMIN000001676.

Objectives To investigate endoscopic management and clinical outcomes in patients with non‐variceal upper gastrointestinal (GI) bleeding during the coronavirus disease 2019 pandemic. Methods We retrospectively analyzed the data of 332 patients with non‐variceal upper GI bleeding who underwent emergency upper GI endoscopy at three hospitals during the pandemic (April 2020–June 2021) and before the pandemic (January 2019–March 2020). The number of emergency upper GI endoscopies, time from hospital arrival to endoscopy, mortality within 30 days, rebleeding within 30 days, interventional radiology (IVR)/surgery requirement, composite outcome, rates of endoscopic hemostasis procedures, and second‐look endoscopy were investigated using logistic regression. Results Overall, 152 and 180 patients underwent emergency upper GI endoscopies during and before the pandemic, respectively. The mean time from arrival to endoscopy was longer during the pandemic than before it (11.7 vs. 6.1 h, p < 0.01). Multivariate analysis revealed that mortality within 30 days (odds ratio [OR]: 2.27, p = 0.26), rebleeding within 30 days (OR: 0.43, p = 0.17), IVR/surgery requirement (OR: 1.79, p = 0.33), and composite outcome (OR: 0.98, p = 0.96) did not differ significantly between the periods; conversely, endoscopic hemostasis procedures (OR: 0.38, p < 0.01) and second‐look endoscopies (OR: 0.04, p < 0.01) were less likely to be performed during the pandemic than before it. Conclusions Although the time from arrival to endoscopy was significantly longer during the pandemic, it did not affect mortality and rebleeding.