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Trained immunity (TI) is functional memory displayed by innate immune cells (IICs). TI facilitates rapid, non-specific responses to pathogens upon secondary challenge. It is driven by immunological signaling and metabolic rewriting via epigenetic alteration, triggered by recognition of certain stimuli. Recently, immune checkpoint inhibitors have come into common use in clinical oncology settings, and genetically engineered cytotoxic T cells comprise a potent cancer treatment strategy. However, the contributions of TI in the tumor microenvironment (TME) are only beginning to be uncovered. Accumulating evidence that various microorganisms and vaccines convey tumoricidal ability suggest that TI may become a useful anti-cancer tool. The expected roles of TI in tumor therapy are the 1) promotion of proinflammatory cytokine section, 2) enhancement of phagocytosis, 3) quick expansion and recruitment of cancer-specific cytotoxic T cells to the TME through neoantigen presentation, 4) reversal of immunosuppression in the TME, and 5) removal of pathogens associated with carcinogenesis or tumor development. Medium- to long-term TI durability may reduce the risk of tumor development. Recent findings on TI usher in new aspirations for cancer treatment.

Objectives: The present study reviewed cases of Toxic megacolon (TM) treated in our department, summarized the timing and technique of surgery, and considered key points for surgical management. Methods: This single-center retrospective study included the medical records of patients clinically diagnosed with TM who underwent surgery between 1985 and 2020. The diagnostic criteria and screening scores for sepsis, such as the systemic inflammatory response syndrome (SIRS) criteria, quick Sequential Organ Failure Assessment (qSOFA) score, and Modified Early Warning Score (MEWS), were validated. The preoperative clinical features and perioperative findings were also investigated. Results: There were eight male and six female patients. Nine patients (64.3%) satisfied the criteria for toxemia proposed by Narabayashi, and 10 patients (71.4%) fulfilled the SIRS criteria. A positive qSOFA score was confirmed in 1 patient (7.1%). The MEWS was high in 2 patients (14.3%). Intestinal perforation occurred in 2 patients (14.3%), and 1 of them died from disseminated intravascular coagulation. The mortality rate of TM with perforation was 50%. Eleven patients (78.6%) underwent total colectomy with end ileostomy. Conclusions: TM does not have well-defined diagnostic criteria, in addition to developing sometimes as borderline or fulminant cases, and must be recognized at an early stage, taking various findings into consideration. The criteria proposed by Narabayashi and the SIRS criteria, which met in a high percentage of our cases, are recommended as indicators for determining the toxicity of TM. It is also important to consider surgery in the early stages of TM, even if clinical findings do not meet all the criteria.

Abstract We developed pulmonary emphysema and a type 2 airway inflammation overlap mouse model. The bronchoalveolar lavage (BAL) interleukin 13 (IL‐13), IL‐4, and IL‐5 levels in the overlap model were higher than in the pulmonary emphysema model and lower than in the type 2 airway inflammation model, but IL‐33 level in the lung was higher than in other models. IL‐33 and interferon‐γ (IFNγ) in lungs may control the severity of a type 2 airway inflammation in lung.

Abstract Genus Iris comprises numerous and diverse phytoconstituents displaying marked biological activities. The rhizomes, and aerial parts of Iris pseudacorus L. cultivars from Egypt and Japan were subjected to comparative metabolic profiling using UPLC-ESI-MS/MS. The antioxidant capacity was determined using DPPH assay. In vitro enzyme inhibition potential against α-glucosidase, tyrosinase and lipase was evaluated. In silico molecular docking was conducted on the active sites of human α-glucosidase and human pancreatic lipase. Forty-three compounds were tentatively identified including flavonoids, isoflavonoids, phenolics and xanthones. I. pseudacorus rhizomes extracts (IPR-J and IPR-E) exhibited the highest radical scavenging activity with IC50 values of 40.89 µg/mL and 97.97 µg/mL, respectively (Trolox IC50 value was 14.59 µg/mL). Moreover, IPR-J and IPR-E exhibited promising α-glucosidase inhibitory activity displaying IC50 values of 18.52 µg/mL, 57.89 µg/mL, respectively being more potent as compared to acarbose with IC50 value of 362.088 µg/mL. All extracts exerted significant lipase inhibitory activity exhibiting IC50 values of 2.35, 4.81, 2.22 and 0.42 µg/mL, respectively compared to cetilistat with IC50 value of 7.47 µg/mL. However, no tyrosinase inhibitory activity was observed for all I. pseudacorus extracts up to 500 µg/mL. In silico molecular modelling revealed that quercetin, galloyl glucose, and irilin D exhibited the highest fitting scores within the active sites of human α-glucosidase and pancreatic lipase. ADMET prediction (absorption, distribution, metabolism, excretion, and toxicity) showed that most of the phytoconstituents exhibited promising pharmacokinetic, pharmacodynamics and tolerable toxicity properties. According to our findings, I. pseudacorus might be considered as a valuable source for designing novel phytopharmaceuticals.

IntroductionVaccinations are ideal for reducing the severity of clinical manifestations and secondary complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, SARS-CoV-2 continues to cause morbidity and mortality worldwide. In contrast to parenteral vaccines such as messenger RNA vaccines, nasal vaccines are expected to be more effective in preventing viral infections in the upper respiratory tract, the primary locus for viral infection and transmission. In this study, we examined the prospects of an inactivated whole-virion (WV) vaccine administered intranasally against SARS-CoV-2.MethodsMice were immunized subcutaneously (subcutaneous vaccine) or intranasally (nasal vaccine) with the inactivated WV of SARS-CoV-2 as the antigen.ResultsThe spike protein (S)-specific IgA level was found to be higher upon nasal vaccination than after subcutaneous vaccination. The level of S-specific IgG in the serum was also increased by the nasal vaccine, although it was lower than that induced by the subcutaneous vaccine. The nasal vaccine exhibited a stronger defense against viral invasion in the upper respiratory tract than the subcutaneous vaccine and unimmunized control; however, both subcutaneous and nasal vaccines provided protection in the lower respiratory tract. Furthermore, we found that intranasally administered inactivated WV elicited robust production of S-specific IgA in the nasal mucosa and IgG in the blood of mice previously vaccinated with messenger RNA encoding the S protein.DiscussionOverall, these results suggest that a nasal vaccine containing inactivated WV can be a highly effective means of protection against SARS-CoV-2 infection.

Abstract Background Primary gastric synovial sarcoma is extremely rare, only 44 cases have been reported so far, and there have been no reports of laparoscopic endoscopic cooperative surgery for this condition. Case presentation A 45-year-old male patient presented with gastric pain. Esophagogastroduodenoscopy was performed that led to the identification of an 8-mm submucosal tumor in the anterior wall of the antrum, and a kit-negative gastrointestinal stromal tumor was suspected following biopsy. On endoscopic ultrasonography, the boundary of the tumor, mainly composed of the second layer, was depicted as a slightly unclear low-echo region, and a pointless no echo region was scattered inside. A boring biopsy revealed synovial sarcoma. Positron emission tomography did not reveal fluorodeoxyglucose (18F-FDG) accumulation in the stomach or other organs. Thus, the patient was diagnosed with a primary gastric synovial sarcoma, and laparoscopic endoscopic cooperative surgery was performed. The tumor of the antrum could not be confirmed laparoscopically from the serosa, and under intraoperative endoscopy, it had delle on the mucosal surface, which was removed by a method that does not involve releasing the gastric wall. Immunohistochemistry showed that the spindle cells were positive for EMA, BCL-2 protein, TLE-1, and SS18-SSX fusion-specific antibodies but negative for KIT and DOG-1. The final pathological diagnosis was synovial sarcoma of the stomach. The postoperative course was good, and the patient was discharged from the hospital on the 11th postoperative day. Conclusion Resection with laparoscopic endoscopic cooperative surgery (LECS), which has not been reported before, was effective for small synovial sarcomas that could not be confirmed laparoscopically. With the combination of laparoscopic and endoscopic approaches to neoplasia with a non-exposure technique (CLEAN-NET) procedure, it was possible to excise the tumor with the minimum excision range of the gastric serosa without opening the stomach.

Abstract Rationale Severe eosinophilic asthma is characterized by airway eosinophilia and corticosteroid‐resistance, commonly overlapping with type 2 inflammation. It has been reported that chemokine (C‐C motif) ligand 5 (CCL5) is involved in the exacerbation of asthma by RNA virus infections. Indeed, treatment with a virus‐associated ligand and a T helper type 2 cell (Th2) cytokine can synergistically stimulate CCL5 production in bronchial epithelial cells. We aimed to evaluate the mechanisms underlying CCL5 production in this in vitro model and to assess the potential of Janus kinase 1 (JAK1) as a novel therapeutic target via the use of ruxolitinib. Methods We stimulated primary normal human bronchial epithelial (NHBE) cells and BEAS‐2B cells with poly(I:C) along with interleukin‐13 (IL‐13) or IL‐4, and assessed CCL5 production. We also evaluated the signals involved in virus‐ and Th2‐cytokine‐induced CCL5 production and explored a therapeutic agent that attenuates the CCL5 production. Results Poly(I:C) stimulated NHBE and BEAS‐2B cells to produce CCL5. Poly(I:C) and IL‐13 increased CCL5 production. Poly(I:C)‐induced CCL5 production occurred via the TLR3–IRF3 and IFNAR/JAK1–phosphoinositide 3‐kinase (PI3K) pathways, but not the IFNAR/JAK1–STATs pathway. In addition, IL‐13 did not augment poly(I:C)‐induced CCL5 production via the canonical IL‐13R/IL‐4R/JAK1–STAT6 pathway but likely via subsequent TLR3‐IRF3‐IFNAR/JAK1‐PI3K pathways. JAK1 was identified to be a potential therapeutic target for severe eosinophilic asthma. The JAK1/2 inhibitor, ruxolitinib, was demonstrated to more effectively decrease CCL5 production in BEAS‐2B cells than fluticasone propionate. Conclusion We have demonstrated that JAK1 is a possible therapeutic target for severe corticosteroid‐resistant asthma with airway eosinophilia and persistent Th2‐type inflammation, and that ruxolitinib has potential as an alternative pharmacotherapy.

Abstract Objectives Plastic stents (PS) used for preoperative biliary drainage (PBD) of pancreatic ductal adenocarcinomas (PDAC) tend to be associated with a high incidence of recurrent biliary obstruction (RBO). Although 10‐mm diameter fully covered self‐expanding metallic stents (FCSEMS) have come into use, vigilance is still required to prevent complications, such as cholecystitis and surgical site infection. The present study examined the efficacy and safety of the 6‐mm diameter FCSEMS for PBD. Methods The present retrospective study compared the incidence of complications associated with the use of 6‐mm FCSEMS and PS. The inclusion criteria were a diagnosis of PDAC and preoperative endoscopic biliary tract drainage performed at our institution between April 2012 and June 2019. Results Of the 51 patients enrolled, 25 and 26 patients received a PS and a 6‐mm FCSEMS, respectively. The RBO incidence was significantly lower in the 6‐mm FCSEMS group (7.7%) than in the PS group (40.0%) (p = 0.009), and time to RBO was significantly longer in the 6‐mm FCSEMS group (HR = 6.008, p = 0.021). The patency rate at three months after stent placement was significantly higher in the latter group (83.5% vs. 45.3%, p = 0.009, Log‐rank test). The groups did not differ significantly in terms of complications associated with PBD, such as cholecystitis and surgical site infection. Conclusion The present findings suggested that the 6‐mm FCSEMS may be an effective drainage device for use in PBD in PDAC treatment.

Abstract Aim As the prognosis of patients who undergo resection for pancreatic cancer has improved, reports of remnant pancreatic cancer after pancreatic cancer resection have been increasing. Previous studies regarding early‐stage pancreatic cancer showed a high incidence of remnant pancreatic cancer in these patients. The aim of this study was to investigate the incidence of remnant pancreatic cancer according to the degree of progression of the initial pancreatic cancer. Methods Patients who underwent partial pancreatic resection for primary pancreatic cancer were retrospectively reviewed and divided into an early‐stage group and an advanced‐stage group according to the stage of the initial cancer. Patient characteristics and long‐term outcomes, including development of remnant pancreatic cancer, were compared between the two groups. Results This study included 321 patients who underwent partial pancreatectomy for pancreatic cancer; 32 patients in the early‐stage group and 289 patients in the advanced‐stage group. Remnant pancreatic cancer developed in 19 patients (5.9%); seven patients (21.9%) in the early‐stage group and 12 patients (4.5%) in the advanced‐stage group. The cumulative incidence of remnant pancreatic cancer according to the Kaplan–Meier method was comparable between the two groups (5‐year cumulative incidence: 20.6% vs 9.9%, early‐stage group vs advanced‐stage group; P = .1827). Conclusion Our results suggested that the potential for developing remnant pancreatic cancer was comparable between the early‐stage and the advanced‐stage groups. Therefore, the incidence of remnant pancreatic cancer may increase along with improved pancreatic cancer treatment.

Abstract Background Pre‐resection pleural lavage cytology is useful to predict tumor recurrence and the prognosis of lung cancer patients. Recently, extracellular vesicles (EVs) isolated from effusion specimens have come under the spotlight, and several studies showed that microRNA in EVs is associated with prognosis. MicroRNA‐21 (miR‐21) is a representative onco‐microRNA, and miR‐21 in EVs (EV‐miR‐21) promotes cancer dissemination by inducing mesothelial to mesenchymal transition (MMT) in the peritoneal cavity. In this study, we isolated EVs from pleural lavage fluid and focused on EV‐miR‐21 as a diagnostic factor with a relationship to pleural dissemination. Methods The Cancer Genome Atlas dataset comprising of 448 cases of lung adenocarcinoma, tissue microarray of 144 cases of lung adenocarcinoma, and pleural lavage fluid of 41 cases was used to examine miR‐21 expression levels. The function of EV‐miR‐21 was investigated in vitro. Results The miR‐21 expression level in primary sites was associated with a poor prognosis and correlated with pleural invasion of adenocarcinoma. EV‐miR‐21 levels in pleural lavage fluid were associated with positive cytology and pleural invasion in the primary sites, even in cytology‐negative cases. In vitro studies demonstrated that EV‐miR‐21 induces the MMT. Mesothelial cells in the MMT showed functions similar to cancer‐associated fibroblasts, which are an important stromal component in primary sites and disseminated pleural lesions. Conclusions EV‐miR‐21 in pleural lavage fluid is important as a diagnostic and prognostic factor. Moreover, EV‐miR‐21 induces the MMT, which can form premetastatic niches of dissemination in the pleural cavity.

Abstract Background Follicular lymphoid hyperplasia (FLH) is characterized by an increased number and size of lymphoid follicles. In some cases, the etiology of FLH is unclear. FLH in the oral and maxillofacial region is an uncommon benign entity which may resemble malignant lymphoma clinically and histologically. Case presentation We report the case of a 51-year-old woman who presented with an asymptomatic firm mass in the left posterior maxillary site. Computed tomography scan of her head and neck showed a clear circumscribed solid mass measuring 28 × 23 mm in size. There was no evidence of bone involvement. Incisional biopsy demonstrated benign lymphoid tissue. The patient underwent complete surgical resection. Histologically, the resected specimen showed scattered lymphoid follicles with germinal centers and predominant small lymphocytes in the interfollicular areas. Immunohistochemically, the lymphoid follicles were positive for CD20, CD79a, CD10, CD21, and Bcl6. The germinal centers were negative for Bcl2. Based on these findings, a diagnosis of benign FLH was made. There was no recurrence at 1 year postoperatively. Conclusions We diagnosed an extremely rare case of FLH arising from an unusual site and whose onset of entity is unknown. Careful clinical and histopathological evaluations are essential in making a differential diagnosis from a neoplastic lymphoid proliferation with a nodular growth pattern.

Abstract Background Aspiration pneumonia is a serious problem among elderly patients; it is caused by many risk factors including dysphagia, poor oral hygiene, malnutrition, and sedative medications. The aim of this study was to define a convenient procedure to objectively evaluate the risk of aspiration pneumonia in the clinical setting. Methods This prospective study included an aspiration pneumonia (AP) group, a community-acquired pneumonia (CAP) group, and a control (Con) group (patients hospitalized for lung cancer chemotherapy). We used the Oral Health Assessment Tool (OHAT), which assesses oral hygiene, and evaluated performance status, body mass index, serum albumin levels, substance P values in plasma, and oral bacterial counts. Results The oral health as assessed by the OHAT of the aspiration pneumonia group was significantly impaired compared with that of the CAP group and the control (5.13 ± 0.18, 4.40 ± 0.26, 3.90 ± 0.22, respectively; p

A 21-year-old man with mandibular prognathism was referred to Tokyo Medical University Hospital. The patient was diagnosed as having skeletal prognathism. Preoperative laboratory routine tests were performed, and the patient was found to have factor XII deficiency. On the night 2 days after osteotomy, the patient was found to have severe hematoma, so an emergency tracheotomy was performed. It is important to monitor activated partial thromboplastin time (APTT) during the perioperative period, and administer fresh frozen plasma (FFP) to increase the level of factor XII, because of the high risk of postoperative bleeding complications.

During bronchoscopy, discomfort is mainly caused by an unavoidable cough; however, there are no reports of any predictive factors for strong cough during bronchoscopy identified before the procedure. To clarify the factors underlying the discomfort status and predictive factors for strong cough during bronchoscopy, we prospectively evaluated patients who underwent bronchoscopy at Kyorin University Hospital between March 2018 and July 2019. Before and after bronchoscopy, the enrolled patients answered a questionnaire regarding the procedure. At the same time, bronchoscopists evaluated cough severity using a four-grade cough scale. We evaluated patient characteristics and predictive factors associated with bronchoscopy from the perspective of discomfort and strong cough. A total of 172 patients were ultimately enrolled in this study. On multivariate logistic regression analysis, comparison of the subjective data between the discomfort and comfort groups revealed that factors that were more common in the former group were younger age (OR = 0.96, p = 0.002), less experienced bronchoscopist (OR = 2.08, p = 0.047), and elevation of cough score per 1 point (OR = 1.69, p < 0.001). Furthermore, the predictive factors for strong cough prior to performing bronchoscopy were female sex (OR = 2.57, p = 0.009), EBUS-TBNA (OR = 2.95, p = 0.004), and prolonged examination time of more than 36 min (OR = 2.32, p = 0.022). Regarding patients' discomfort, younger age, less experienced bronchoscopist, and the elevation of cough score per 1 point were important factors for discomfort in bronchoscopy. On the other hand, female sex, EBUS-TBNA, and prolonged examination time were crucial factors for strong cough.

Abstract Background Neutrophilic inflammation is associated with poorly controlled asthma. Serum levels of sST2, a soluble IL-33 receptor, increase in neutrophilic lung diseases. We hypothesized that high serum sST2 levels in stable asthmatics are a predictor for exacerbation within a short duration. Methods This prospective observational study evaluated the serum sST2 levels of 104 asthmatic patients who were treated by a lung disease specialist with follow-ups for 3 months. Results High serum sST2 levels (> 18 ng/ml) predicted severe asthma exacerbation within 3 months. Serum sST2 levels correlated positively with asthma severity (treatment step), airway H2O2 levels, and serum IL-8 levels. High serum sST2 levels and blood neutrophilia (> 6000 /μl) were independent predictors of exacerbation. We defined a post-hoc exacerbation-risk score combining high serum sST2 level and blood neutrophilia, which stratified patients into four groups. The score predicted exacerbation-risk with an area under curve of 0.91 in the receiver operating characteristic curve analysis. Patients with the highest scores had the most severe phenotype, with 85.7% showing exacerbation, airflow limitation, and corticosteroid-insensitivity. Conclusions High serum sST2 levels predicted exacerbation within the general asthmatic population and, when combined with blood neutrophil levels, provided an exacerbation-risk score that was an accurate predictor of exacerbation occurring within 3 months.

A simple technique that uses radio-frequency sputtering with a functional element on a hematite (α-Fe2O3) target is presented for the production of maghemite (γ-Fe2O3) thin films. These films are prepared on water-cooled glass substrates in an Ar atmosphere. Investigations are done with Ti, Si, Al, Cu, Mo, and Zn, with γ-Fe2O3 being obtained only in the presence of Cu, indicating that phase transition occurs only for this metal. Mössbauer spectra and magnetization analysis reveal that the quality of the obtained γ-Fe2O3 films is higher than that of the film produced using Mg, which was reported in our previous work. High-angle annular dark-field scanning tunneling electron microscopy and electron energy-loss spectroscopy reveal that the added Cu remains in a metallic state (without oxidization), forming a Cu/γ-Fe2O3 phase-mixture in the as-deposited film. The Cu/γ-Fe2O3 composite film exhibits negative magnetoresistance (MR), with a MR ratio of approximately 0.6% at room temperature in an applied field of 10 kOe, and a negative Faraday rotation of −5708 deg cm−1 at 830 nm.

Despite the development of a range of anti-cancer agents, cancer diagnoses are still increasing in number, remaining a leading cause of death. Anticancer drug treatment is particularly important for leukemia. We screened Turkish plants and found the unique antileukemic activity of twig components in Turkish Caucasian beech, selectively inducing apoptosis in leukemia cells. This effect is unique among some kinds of beeches, presumably related to oxidative stress. This study would lead to effective use of discarded material, i.e., twig of beech, and a new anti-leukemic drug based on large tree.

Transthyretin-related amyloidosis is a slowly progressive disorder caused by deposition of insoluble amyloid plaques formed by fibrillization of mutant or defective transthyretin (TTR) monomers that leads to neurodegeneration and organ failure. Thus, any compound exhibiting TTR amyloid formation inhibitory activity or TTR amyloid fibril disrupting activity might be a potential candidate for the development of therapies for these disorders. Our aim in this study was the evaluation of the TTR amyloid fibril disrupting potential of extracts of leaves and immature fruits of two Juglans plants, i.e., Juglans mandshurica var. sachalinensis and Juglans mandshurica var. cordiformis. The TTR amyloid fibril disrupting activity was measured by Thioflavin-T (ThT) assay and PROTEOSTAT® Protein aggregation assay methods. A fifty percent acetone extract of the fruits of Juglans mandshurica var. cordiformis showed strong amyloid fibril disrupting activity, and was further fractionated using different solvents. Ethyl acetate and n-butanol fractions showed significant activity in both assays. Syringic acid was isolated and identified as main compound in both of these fractions; however, it did not show any activity. Furthermore, some of the previously reported compounds from Juglans plants including naphthoquinone derivatives and phenolic compounds were evaluated to identify the potential bioactive compounds. Among them, juglone, a naphthoquinone derivative showed promising activity. However, juglone also showed strong cytotoxicity in HEK293 cells. Thus, future studies should focus on the isolation and identification of naphthoquinone derivatives or other compounds from Juglans plan ts with potent bioactivity and low cytotoxicity.

BACKGROUND AND PURPOSE:Bronchial asthma (BA) is a chronic airway disease characterized by airway hyperresponsiveness and remodeling, which are intimately linked to chronic airway inflammation. Reactive oxygen species (ROS) such as hydrogen peroxide are generated by inflammatory cells that are involved in the pathogenesis of BA. However, the role of ROS in the management of BA patients is not yet clear. We attempted to determine the role of ROS as a biomarker in the clinical setting of BA. SUBJECTS AND METHODS:We enrolled patients with BA from 2013 through 2015 and studied the degrees of asthma control, anti-asthma treatment, pulmonary function test results, fractional exhaled nitric oxide (FeNO), serum reactive oxygen metabolite (ROM) levels, and serum levels of interleukin (IL)-6 and IL-8. RESULTS:We recruited 110 patients with BA. Serum ROM levels correlated with white blood cell (WBC) count (rs = 0.273, p = 0.004), neutrophil count (rs = 0.235, p = 0.014), CRP (rs = 0.403, p < 0.001), and IL-6 (rs = 0.339, p < 0.001). Serum ROM levels and IL-8 and CRP levels negatively correlated with %FEV1 (rs = -0.240, p = 0.012, rs = -0.362, p < 0.001, rs = -0.197, p = 0.039, respectively). Serum ROM levels were significantly higher in patients who experienced severe exacerbation within 3 months than in patients who did not (339 [302-381] vs. 376 [352-414] CARR U, p < 0.025). Receiver-operating characteristics analysis showed that ROM levels correlated significantly with the occurrence of severe exacerbation (area under the curve: 0.699, 95% CI: 0.597-0.801, p = 0.025). CONCLUSIONS:Serum levels of ROM were significantly associated with the degrees of airway obstruction, WBC counts, neutrophil counts, IL-6, and severe exacerbations. This biomarker may be useful in predicting severe exacerbations of BA.

Although Japanese herbal medicines (JHMs) are widely used in Japan, only a few studies have investigated their effects on nonalcoholic steatohepatitis (NASH). In the present study, we examined the effect of 4 kinds of JHMs [sho-saiko-to (TJ-9), inchin-ko-to (TJ-135), juzen-taiho-to (TJ-48), and keishi-bukuryo-gan (TJ-25)] on a mouse model of NASH. Db/db mice were divided into 6 groups: control diet (control), methionine- and choline-deficient diet (MCD), and MCD diet supplemented with TJ-9, TJ-135, TJ-48, and TJ-25 (TJ-9, TJ-135, TJ-48, and TJ-25, respectively). All mice were sacrificed after 4 weeks of treatment, and biochemical, pathological, and molecular analyses were performed. Serum alanine aminotransferase levels and liver histology, including necroinflammation and fibrosis, were significantly alleviated in the TJ-9 and TJ-48 groups compared with the MCD group. The expression level of transforming growth factor (TGF)-β1 mRNA in the liver was significantly suppressed by TJ-48. Although the differences were not statistically significant, the expression levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 were lower, and those of peroxisome proliferators-activated receptor (PPAR)γ were higher in the TJ-9 and/or TJ-48 groups than in the MCD group. Similarly, even though the results were not statistically significant, malondialdehyde levels in liver tissues were lower in the TJ-9 and TJ-48 groups than in the MCD group. We showed that JHMs, especially TJ-9 and TJ-48, inhibited the necroinflammation and fibrosis in the liver of a mouse model of NASH, even though the mechanisms were not fully elucidated. Further studies are needed in the future to investigate the possibility of clinical application of these medicines in the treatment for NASH.

Objective and design: The histone acetylation processes, which are believed to play a critical role in the regulation of many inflammatory genes, are reversible and regulated by histone acetyltransferases (HATs), which promote acetylation, and histone deacetylases (HDACs), which promote deacetylation. We studied the effects of lipopolysaccharide (LPS) on histone acetylation and its role in the regulation of interleukin (IL)-8 expression. Material: A human alveolar epithelial cell line A549 was used in vitro. Methods: Histone H4 acetylation at the IL-8 promoter region was assessed by a chromatin immunoprecipitation (ChIP) assay. The expression and production of IL-8 were evaluated by quantitative polymerase chain reaction and specific immunoassay. Effects of a HDAC inhibitor, trichostatin A (TSA), and a HAT inhibitor, anacardic acid, were assessed. Results: Escherichia coli-derived LPS showed a dose- and time-dependent stimulatory effect on IL-8 protein production and mRNA expression in A549 cells in vitro. LPS showed a significant stimulatory effect on histone H4 acetylation at the IL-8 promoter region by ChIP assay. Pretreatment with TSA showed a dose-dependent stimulatory effect on IL-8 release from A549 cells as compared to LPS alone. Conversely, pretreatment with anacardic acid inhibited IL-8 production and expression in A549 cells. Conclusion: These data suggest that LPS-mediated proinflammatory responses in the lungs might be modulated via changing chromatin remodeling by HAT inhibition.

To evaluate the prognostic impact of monosomal karyotype on post-remission outcome in acute myeloid leukemia, we retrospectively analyzed 2,099 patients who had achieved complete remission. Monosomal karyotype was noted in 73 patients (4%). Of these, the probability of overall survival from first complete remission was 14% at four years, which was significantly lower than that reported in patients without monosomal karyotype, primarily due to a high relapse rate (86%). Monosomal karyotype remained significantly associated with worse overall survival among patients with unfavorable cytogenetics or complex karyotype, and even in patients who underwent allogeneic hematopoietic cell transplantation during first complete remission. These findings confirm that monosomal karyotype has a significantly adverse effect on post-remission outcome in patients with acute myeloid leukemia treated with and without allogeneic hematopoietic cell transplantation in first complete remission, emphasizing the need for the development of alternative therapies for this patient population.