MicroRNA-326 negatively regulates CD155 expression in lung adenocarcinoma.

Treatment with immune checkpoint inhibitors induces a durable response in some patients with non-small-cell lung cancer, but eventually gives rise to drug resistance. Upregulation of CD155 expression is implicated as one mechanism of resistance to programmed death receptor-1 (PD-1)/PD-1 ligand (PD-L1) inhibitors, and it is therefore important to characterize the mechanisms underlying regulation of CD155 expression in tumor cells. The aim of this study was to identify microRNAs (miRNAs) that might regulate CD155 expression at the posttranscriptional level in lung cancer. Comprehensive miRNA screening with target prediction programs and a dual-luciferase reporter assay identified miR-346, miR-328-3p, miR-326, and miR-330-5p as miRNAs that bind to the 3'-UTR of CD155 mRNA. Forced expression of these miRNAs suppressed CD155 expression in lung cancer cell lines. Immunohistochemical staining of CD155 in tissue specimens from 57 patients with lung adenocarcinoma revealed the median tumor proportion score for CD155 to be 68%. The abundance of miR-326 in these specimens with a low level of CD155 expression was significantly greater than in specimens with a high level (p < 0.005). Our results thus suggest that miR-326 negatively regulates CD155 expression in lung adenocarcinoma and might therefore play a role in the development of resistance to PD-1/PD-L1 inhibitors.

Regulation of PD-L1 expression in non-small cell lung cancer by interleukin-1ß.

Introduction: Programmed cell death-ligand 1 (PD-L1) is a biomarker for prediction of the clinical efficacy of immune checkpoint inhibitors in various cancer types. The role of cytokines in regulation of PD-L1 expression in tumor cells has not been fully characterized, however. Here we show that interleukin-1ß (IL-1ß) plays a key role in regulation of PD-L1 expression in non-small cell lung cancer (NSCLC). Methods: We performed comprehensive screening of cytokine gene expression in NSCLC tissue using available single-cell RNA-Sequence data. Then we examined the role of IL-1ß in vitro to elucidate its induction of PD-L1 on NSCLC cells. Results: The IL-1ß gene is highly expressed in the tumor microenvironment, particularly in macrophages. The combination of IL-1ß and interferon-γ (IFN-γ) induced a synergistic increase in PD-L1 expression in NSCLC cell lines. IL-1ß and IFN-γ also cooperatively activated mitogen-activated protein kinase (MAPK) signaling and promoted the binding of downstream transcription factors to the PD-L1 gene promoter. Furthermore, inhibitors of MAPK signaling blocked upregulation of PD-L1 by IL-1ß and IFN-γ. Discussion: Our study reports high levels of IL-1ß in the tumor microenvironment may cooperate with IFN-γ to induce maximal PD-L1 expression in tumor cells via activation of MAPK signaling, with the IL-1ß-MAPK axis being a promising therapeutic target for attenuation of PD-L1-mediated suppression of antitumor immunity.

Impact of increased plasma levels of calreticulin on prognosis of patients with advanced lung cancer undergoing combination treatment of chemotherapy and immune checkpoint inhibitors.

BACKGROUND: Damage-associated molecular pattern (DAMP)-related immunogenic cell death triggers secondary adaptive immune responses. The relationship between DAMP levels and prognosis in patients with non-small cell lung cancer (NSCLC) who undergo a combination therapy of immune checkpoint inhibitors (ICI) and chemotherapy remains unclear. METHODS: Serial plasma samples were prospectively collected from 45 patients treated with ICI combination therapy for advanced NSCLC. Plasma concentrations of high-mobility group box 1 (HMGB1), calreticulin (CRT), annexin A1, and heat shock protein 70 were measured. Associations between increases in plasma DAMP levels and the efficacy of the ICI combination therapy were evaluated. RESULTS: The maximum fold changes in plasma levels differed across individuals but demonstrated a marked increase, especially for CRT (mean ± SEM, 11.61 ± 46.15). Increased plasma DAMP levels were not clearly associated with clinical responses. There was a significant correlation between the maximum fold change in CRT levels and progression-free survival (PFS; r = 0.49, P < 0.001). Median PFS and overall survival (OS) rates were higher in patients with a ≥ 2-fold increase in plasma CRT levels than in those with a < 2-fold increase (PFS, 14.9 versus 6.0 months, hazard ratio (HR), 0.58; P = 0.17; OS, not reached versus 21.6 months, HR, 0.31, P = 0.02). CONCLUSIONS: Plasma CRT level monitoring has the potential to predict the efficacy of ICI combination therapy and shed light on the mechanisms underlying DAMP-related immunogenic cell death.

Increased plasma levels of damage-associated molecular patterns during systemic anticancer therapy in patients with advanced lung cancer.

BACKGROUND: Immunogenic cell death (ICD) characterized by the release of damage-associated molecular patterns (DAMPs) from dying cancer cells may contribute to the synergistic antitumor effect of cytotoxic chemotherapy combined with an immune checkpoint inhibitor. The kinetics of circulating DAMP levels in cancer patients have remained largely uncharacterized, however. METHODS: We evaluated the possible effects of various systemic anticancer therapy modalities on the kinetics of plasma DAMP concentrations in a prospective observational study of patients with advanced lung cancer. The plasma concentrations of high-mobility group box 1 (HMGB1), calreticulin (CRT), heat shock protein 70 (HSP70), annexin A1, and histone H3 were thus determined in 121 such patients at four time points during the first cycle of treatment. RESULTS: The mean of the maximum fold change in HMGB1, HSP70, or annexin A1 concentration observed during treatment was significantly greater than the corresponding baseline value (P<0.005). The maximum fold changes in HMGB1 and CRT concentrations tended to be associated with clinical response as evaluated by RECIST criteria, although the changes in the levels of these two DAMPs were not correlated, suggestive of differential induction mechanisms. Among the various treatment modalities administered, platinum-based combination or single-agent chemotherapy tended to elicit robust increases in the concentrations of HMGB1 and CRT. CONCLUSIONS: Serial monitoring of plasma revealed that systemic anticancer therapy increased the circulating levels of HMGB1 and CRT and that these changes tended to be associated with clinical response, suggesting that agents capable of releasing these DAMPs into plasma might induce ICD in advanced lung cancer patients.

Inhibitory effects of a selective prostaglandin E2 receptor antagonist RQ-15986 on inflammation-related colon tumorigenesis in APC-mutant rats.

Prostaglandin E2 receptor EP4 is involved in inflammation and related tumorigenesis in the colorectum. This study aimed to investigate the chemopreventive ability of RQ-15986, a selective EP4 antagonist, in colitis-related colorectal tumorigenesis. Male Kyoto APC delta rats, which have APC mutations, were treated with azoxymethane and dextran sulfate sodium and subsequently administered RQ-15986 for eight weeks. At the end of the experiment, the development of colorectal tumor was significantly inhibited in the RQ-15986-treated group. The cell proliferation of the crypts and tumors in the colorectum was decreased following RQ-15986 treatment. RQ-15986 also suppressed the expression of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-6, interleukin-18, and monocyte chemotactic protein-1, in the colon mucosa. In addition, the expression levels of indoleamine 2,3-dioxygenase, which is involved in immune tolerance, were decreased in the colorectal epithelium and tumors of the RQ-15986-treated group. These findings indicate that RQ-15986 inhibits colitis-associated colorectal tumorigenesis by attenuating inflammation, suppressing cell proliferation, and modulating the expression of indoleamine 2,3-dioxygenase. Targeting prostaglandin E2/EP4 signaling might be a useful strategy for chemoprevention of inflammation-related colorectal cancer.

Natural history of inferior mesenteric arteriovenous malformation that led to ischemic colitis: A case report.

BACKGROUND: Ischemic colitis with inferior mesenteric arteriovenous malformation (AVM) is a rare disease. Although a few reports have been published, no report has described the natural history of idiopathic mesenteric AVM. CASE SUMMARY: A 50-year-old male was admitted to our hospital due to abdominal pain that had persisted for 3 mo and bloody diarrhea. He had no history of trauma or abdominal surgery. He had undergone two colonoscopies 6 mo and 2 years ago, and they showed only a polyp. He was diagnosed with ischemic colitis with inferior mesenteric AVM following contrast-enhanced abdominal computed tomography (CT) and underwent rectal low anterior resection. He has not had a recurrence of symptoms for 3 years. His history showed that he had undergone non-enhanced abdominal CT 2, 5, and 8 years ago when he had attacks of urinary stones. Retrospectively, dilation of blood vessels around the rectosigmoid colon could have been detected 5 years ago, and these findings gradually became more evident. CONCLUSION: This is the first report of the natural history of inferior mesenteric AVM.

Pleuropulmonary Paragonimiasis with Multiple Nodules in the Pleura.

An asymptomatic 47-year-old woman was admitted with pleural effusion and pulmonary infiltrates 1 month after ingesting raw wild boar and deer meat. Both her blood and pleural fluid were eosinophilic. Thoracoscopy revealed multiple nodules of the pleura, and biopsy samples of the nodules showed necrosis with epithelioid cell granulomas. An enzyme-linked immunosorbent assay was positive for antibodies against Paragonimus westermani, and the patient was successfully treated with praziquantel. This is the first reported case of pulmonary or pleuropulmonary paragonimiasis where several pleural nodules were observed. The detection of pleural nodules on thoracoscopy can contribute to the prompt and accurate diagnosis of paragonimiasis.

Fabrication of a Silica-Silica Nanoparticle Monolayer Array Nanocomposite Film on an Anodic Aluminum Oxide Substrate and Its Optical and Tribological Properties.

The fabrication and properties of silica nanoparticle monolayer arrays (SNMAs) immobilized on silica films on nanoporous anodic aluminum oxide (AAO) substrates by polymerization of silicic acid and a two-step spin-coating technique are reported. Reflection spectra of the obtained silica-SNMA nanocomposite films on AAO substrates were almost the same as those of the original AAO substrate. The coefficient of friction at an applied load of 0.98 N under dry conditions for a film fabricated under optimal conditions was significantly decreased by 76% with respect to that without a silica-SNMA nanocomposite film on an AAO substrate. The results also showed a lower coefficient of friction than that for MoS2 nanoparticles (commonly used for self-lubricating films) deposited on an AAO substrate. We demonstrate that the silica-SNMA nanocomposite film with an optimal nanoroughness, thickness, and wear resistance can be used as a novel coating film for AAO substrates with both a high color degree of freedom and a low coefficient of friction at a high applied load (ca. 1 N).

Fabrication of Silica Nanoparticle Monolayer Arrays Using an Anodic Aluminum Oxide Template.

Non-close-packed (NCP) silica nanoparticle monolayer arrays (SNMA) on ordered porous anodic aluminum oxide (AAO) templates were fabricated for the first time by a novel two-step spin-coating technique. The obtained NCP-SNMA-AAO was composed of silica nanoparticles (average primary particle size of 440 nm) and well-organized nanopores on the AAO substrates. NCP-SNMA-AAO with a supporting ratio of 87% silica nanoparticles showed a hydrophilic surface (water contact angle of 51.0°), while the original AAO substrate shows a hydrophobic surface (water contact angle of 107.9°). The maximum coefficient of static friction was decreased by 29% (0.327 → 0.233). The coefficient of dynamic friction was also decreased by 20% (0.281 → 0.226). We found that controlling the silica supporting ratio using the two-step spin-coating technique is an effective approach for surface modification of an AAO substrate.

Safety and efficacy of carbon dioxide insufflation during gastric endoscopic submucosal dissection.

AIM: To compare the safety and efficacy of carbon dioxide (CO2) and air insufflation during gastric endoscopic submucosal dissection (ESD). METHODS: This study involved 116 patients who underwent gastric ESD between January and December 2009. After eliminating 29 patients who fit the exclusion criteria, 87 patients, without known pulmonary dysfunction, were randomized into the CO2 insufflation (n = 36) or air insufflation (n = 51) groups. Standard ESD was performed with a CO2 regulation unit (constant rate of 1.4 L/min) used for patients undergoing CO2 insufflation. Patients received diazepam for conscious sedation and pentazocine for analgesia. Transcutaneous CO2 tension (PtcCO2) was recorded 15 min before, during, and after ESD with insufflation. PtcCO2, the correlation between PtcCO2 and procedure time, and ESD-related complications were compared between the two groups. Arterial blood gases were analyzed after ESD in the first 30 patients (12 with CO2 and 18 with air insufflation) to assess the correlation between arterial blood CO2 partial pressure (PaCO2) and PtcCO2. RESULTS: There were no differences in respiratory functions, median sedative doses, or median procedure times between the groups. Similarly, there was no significant difference in post-ESD blood gas parameters, including PaCO2, between the CO2 and air groups (44.6 mmHg vs 45 mmHg). Both groups demonstrated median pH values of 7.36, and none of the patients exhibited acidemia. No significant differences were observed between the CO2 and air groups with respect to baseline PtcCO2 (39 mmHg vs 40 mmHg), peak PtcCO2 during ESD (52 mmHg vs 51 mmHg), or median PtcCO2 after ESD (50 mmHg vs 50 mmHg). There was a strong correlation between PaCO2 and PtcCO2 (r = 0.66; P < 0.001). The incidence of Mallory-Weiss tears was significantly lower with CO2 insufflation than with air insufflation (0% vs 15.6%, P = 0.013). CO2 insufflation did not cause any adverse events, such as CO2 narcosis or gas embolisms. CONCLUSION: CO2 insufflation during gastric ESD results in similar blood gas levels as air insufflation, and also reduces the incidence of Mallory-Weiss tears.

Cluster-π electronic interaction in a superatomic Au13 cluster bearing σ-bonded acetylide ligands.

An organometallic Au13 cluster having two σ-bonded acetylide ligands was synthesized and its structure was determined by X-ray crystallography. Absorption spectral studies indicated the presence of electronic coupling between the superatomic Au13 core and the acetylide π-orbitals, which was supported by theoretical considerations.

Safety of carbon dioxide insufflation during gastric endoscopic submucosal dissection in patients with pulmonary dysfunction under conscious sedation.

BACKGROUND: Carbon dioxide (CO2) insufflation is effective for gastric endoscopic submucosal dissection (ESD). However, its safety is unknown in patients with pulmonary dysfunction. This study aimed to investigate the safety of CO2 insufflation during gastric ESD in patients with pulmonary dysfunction under conscious sedation. METHODS: We analyzed 322 consecutive patients undergoing ESD using CO2 insufflation (1.4 L/min) for gastric lesions. Pulmonary dysfunction was defined as a forced expiratory volume in 1.0 s/forced vital capacity (FEV1.0%) <70% or vital capacity <80%. Transcutaneous partial pressure of CO2 (PtcCO2) was recorded before, during, and after ESD. RESULTS: In total, 127 patients (39%) had pulmonary dysfunction. There were no significant differences in baseline PtcCO2 before ESD, peak PtcCO2 during ESD, and median PtcCO2 after ESD between the pulmonary dysfunction group and normal group. There was a significant correlation between PtcCO2 elevation from baseline and ESD procedure time (r = 0.22, P < 0.05) only in the pulmonary dysfunction group. In patients with FEV1.0% <60%, the correlation was much stronger (r = 0.39, P < 0.05). Neither the complication incidences nor the hospital stay differed between the two groups. CO2 narcosis or gas embolism was not reported in either group. CONCLUSIONS: CO2 insufflation during gastric ESD in patients with pulmonary dysfunction under conscious sedation is safe with regard to complication risk and hospital stay. However, in patients with severe obstructive lung disease, especially in those with FEV1.0% <60%, longer procedure time may induce CO2 retention, thus requiring CO2 monitoring.

Risk factors for pyrexia after endoscopic submucosal dissection of gastric lesions.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is widely used in the resection of gastric tumors en bloc, however, complications such as pyrexia frequently occur following the procedure. The study aim was to elucidate the incidence, clinical characteristics, and risk factors of post-ESD pyrexia. PATIENTS AND METHODS: We conducted a retrospective cohort study of 471 consecutive patients with 485 gastric lesions resected by ESD between December 2005 and 2010. Pyrexia was defined as body temperature above 37.5 °C, regardless of its duration. Blood tests and chest radiography were performed three times before and after ESD. Chest and abdominal computed tomography (CT) was taken on postoperative day 1. RESULTS: Post-ESD pyrexia developed in 117 patients (24.8 %), including 40 patients with pneumonia as shown by computed tomography. The pyrexia was resolved in all the patients after 1 day (median; range, 1 - 36 days). A multivariate analysis identified age (P = 0.0029) and resection diameter (P = 0.0009) as risk factors for pyrexia in patients without pneumonia, and operation time (P = 0.0025) as a risk factor for pyrexia in patients with pneumonia. CONCLUSION: The patient would be at risk for post-ESD pyrexia if a large ESD is performed in the elderly. The longer operation time would raise the risk for pneumonia-associated fever.

A novel aromatic mutagen, 5-amino-6-hydroxy-8H-benzo[6,7]azepino[5,4,3-de]quinolin-7-one (ABAQ), induces colonic preneoplastic lesions in mice.

The benzoazepinoqunolinone derivative, 5-amino-6-hydroxy-8H-benzo[6,7]azepino[5,4,3-de]quinolin-7-one (ABAQ), which is produced in a mixture of glucose and tryptophan incubated at 37 °C under physiological conditions in the presence or absence of hydroxyl radicals caused by the Fenton reaction, is a novel aromatic mutagen. In the current study, we determined the tumor-initiating potency of ABAQ using an inflammation-relate, two-stage mouse colon carcinogenesis model. Male Crj: CD-1 (ICR) mice were treated with the single intragastric administration (100 or 200 mg/kg body weight) of ABAQ followed by subsequent 1-week oral exposure to 2% dextran sodium sulfate (DSS) in drinking water. The ABAQ treatment alone resulted in high-grade dysplasia, which is a precursor to colorectal cancer, in the colon. Following the administration of DSS after ABAQ treatment, the incidence and frequency of high-grade dysplastic lesions increased; the values were highest in the mice treated with 200 mg/kg body weight of ABAQ followed by DSS. The lesions expressing ß-catenin in their nuclei and cytoplasm exhibited high proliferation activity without the expression of programmed cell death 4. These findings indicate that ABAQ has a tumor-initiating activity in the mouse colon, with or without inflammation, although the potential pro-inflammatory effect of high doses of ABAC should be investigated.

Diagnosis of the jejunoileal lymphoma by double-balloon endoscopy.

AIM: To investigate the feasibility of double-balloon endoscopy (DBE) to detect jejunoileal lymphoma, compared with fluorodeoxyglucose positron emission tomography (FDG-PET). METHODS: Between March 2004 and January 2011, we histologically confirmed involvement of malignant lymphoma of the jejunoileum in 31 patients by DBE and biopsy. In 20 patients of them, we performed with FDG-PET. We retrospectively reviewed the records of these 20 patients. Their median age was 64 years (range 50-81). In the 20 patients, the pathological diagnosis of underlying non-Hodgkin's lymphoma (NHL) comprised follicular lymphoma (FL, n = 12), diffuse large B cell lymphoma (DLBCL, n = 4), mantle cell lymphoma (MCL, n = 2), enteropathy associated T cell lymphoma (ETL, n = 1) and anaplastic large cell lymphoma (ALCL, n = 1). RESULTS: Ten cases showed accumulation by FDG-PET (50%). FDG-PET was positive in 3 of 12 FL cases (25%) while in 7 of 8 non-FL cases (88%, P < 0.05). Intestinal FL showed a significantly lower rate of positive FDG-PET, in comparison with other types of lymphoma. Cases with endoscopically elevated lesions (n = 10) showed positive FDG-PET in 2 (20%), but those with other type NHL did in 8 of 10 (80%, P < 0.05). When the cases having elevated type was compared with those not having elevated type lesion, the number of cases that showed accumulation of FDG was significantly smaller in the former than in the latter. CONCLUSION: In a significant proportion, small intestinal involvement cannot be pointed out by FDG-PET. Especially, FL is difficult to evaluate by FDG-PET but essentially requires DBE.

Clinical significance of jejunoileal involvement of non-Hodgkin's lymphoma detected by double-balloon enteroscopy.

Jejunoileal involvement of non-Hodgkin's lymphoma (NHL) is an important diagnostic factor in determining optimal treatment strategies. Here, we used double-balloon enteroscopy (DBE) to detect jejunoileal involvement of NHL and studied its clinical significance in a series of patients with NHL. Adults aged between 18 and 85 years with infiltration of the stomach, duodenum, or colon confirmed by gastrointestinal endoscopy or colonoscopy, suspected jejunoileal involvement determined by CT or FDG-PET, or any other gastrointestinal symptoms, were eligible for inclusion in the study. Among 428 patients with histologically confirmed NHL between 2004 and 2011, 83 were eligible for DBE, but 20 patients were excluded due to rejection or poor clinical status. Thus, 63 underwent DBE. The 3-year overall survival rate was significantly lower in patients with (n = 33), than without (n = 30) jejunoileal involvement of NHL confirmed by DBE (49 vs. 92 %, p < 0.005). Four participants developed aspiration pneumonia, but recovered after treatment with antibiotics.