Geriatric Nutritional Risk Index is a predictor of tolerability of antifibrotic therapy and mortality risk in patients with idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung fibrosis of unknown aetiology. Epidemiological studies have suggested that IPF progression may negatively affect nutritional status. Weight loss during antifibrotic therapy is also frequently encountered. The association of nutritional status and outcome has not been fully evaluated in IPF patients. METHODS: This retrospective multicohort study assessed nutritional status of 301 IPF patients receiving antifibrotic therapy (Hamamatsu cohort, n = 151; Seirei cohort, n = 150). Nutritional status was evaluated using the Geriatric Nutritional Risk Index (GNRI). The GNRI was calculated based on body mass index and serum albumin. The relationship between nutritional status and tolerability of antifibrotic therapy as well as mortality was explored. RESULTS: Of 301 patients, 113 (37.5%) had malnutrition-related risk (GNRI < 98). Patients with malnutrition-related risk were older, had increased exacerbations and worse pulmonary function than those without a GNRI status <98. Malnutrition-related risk was associated with a higher incidence of discontinuation of antifibrotic therapy, particulary due to gastrointestinal disturbances. IPF patients with malnutrition-related risk (GNRI < 98) had shorter survival than those without such risk (median survival: 25.9 vs. 41.1 months, p < 0.001). In multivariate analysis, malnutrition-related risk was a prognostic indicator of antifibrotic therapy discontinuation and mortality, independent of age, sex, forced vital capacity, or gender-age-physiology index. CONCLUSION: Nutritional status has significant effects on the treatment and outcome in patients with IPF. Assessment of nutritional status may provide important information for managing patients with IPF.

Therapeutic effect and mechanism of Daikenchuto in a model of methotrexate-induced acute small intestinal mucositis.

BACKGROUND: Daikenchuto (DKT) has positive therapeutic effects on improving various gastrointestinal disorders. The present study investigated whether or not DKT has a potential therapeutic effect on chemotherapy-induced acute small intestinal mucositis (CIM) in a rat model. METHODS: Intraperitoneal injection of 10 mg/kg methotrexate (MTX) every 3 days for a total of 3 doses was used for induction of CIM in a rat model. The MTX and DKT-MTX groups were injected with MTX as above from the first day, and the DKT-MTX and DKT groups were administered 2.7% DKT via the diet at the same time. The rats were euthanized on day 15. RESULTS: The DKT-MTX group showed an improvement in the body weight and conditions of gastrointestinal disorders as well as increased levels of diamine oxidase in plasma and in the small intestinal villi. The pathology results showed that small intestinal mucosal injury in the DKT-MTX group was less severe than that in the MTX group. Immunohistochemistry for myeloperoxidase and malondialdehyde and quantitative real-time polymerase chain reaction (RT-qPCR) for TGF-ß1 and HIF-1α showed that DKT attenuated peroxidative damage. The crypts in the DKT-MTX group contained more Ki-67-positive cells than MTX group. The zonula occluden-1 and claudin-3 results showed that DKT promoted repair of the mucosal barrier. RT-qPCR for the amino acid transporters EAAT3 and BO+AT also confirmed that DKT promoted mucosal repair and thus promoted nutrient absorption. CONCLUSION: DKT protected against MTX-induced CIM in a rat model by reducing inflammation, stimulating cell proliferation, and stabilizing the mucosal barrier.

3-Phenyllactic acid generated in medicinal plant extracts fermented with plant-derived lactic acid bacteria inhibits the biofilm synthesis of Aggregatibacter actinomycetemcomitans.

In the present study, the effect of PLA on a periodontic pathogen, Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans), the biofilm, and virulence-related genes was investigated. We confirmed that two lactic acid bacteria (LAB) strains isolated from plant sources, Lactiplantibacillus plantarum MSC-C2 and Pediococcus pentosaceus K40, secrete PLA into the de Man, Rogosa & Sharpe (MRS) broth when supplemented with phenyl pyruvic acid (PPA) as a precursor to PLA. Moreover, PLA was generated in the fermentation broths of two medicinal plant extracts, Paeonia lactiflora Pall (PR) and Carthamus tinctorius (CT), when used by each LAB strain and each extract supplemented with PPA. We determined that the minimum inhibitory concentration (MIC) of PLA against A. actinomycetemcomitans was 20 mM. PLA significantly decreased biofilm formation and suppressed the transcription of pgA, ltxA, and cdtB genes, which encode the poly-N-acetylglucosamine (PGA) polysaccharide of biofilm matrix and exotoxins leukotoxin and cytolethal distending toxin (CDT), respectively. The PLA produced by the MSC-C2 and K40 strains was increased several times by the addition of PPA to the MRS broth. The anti-biofilm effect of the extracts from the fermentation broth was proportional to the increasing PLA concentration, while a cumulatively higher effect than that of PLA alone suggested a combinational effect of PLA and the other metabolites, such as lactic acid (LA). Among the two medicinal plants, PLA, produced after the addition of PPA, was higher in PR extract in case of both the LAB strains. PLA production by the MSC-C2 strain in the PR extract reached 4.8 ± 0.23 mM, which was obviously higher than that in the MRS broth (3.88 ± 0.12 mM) supplemented with 1 mg/ml PPA. The activity to inhibit biofilm formation in the fermented PR extract was clearly high. PLA formed in the fermented PR extract downregulated the dispersin B encoding the dspB gene together with pgA, ltxA, and cdtB. In conclusion, this study shows a promising activity of PLA against the A. actinomycetemcomitans biofilm and virulence genes. In addition, the combinational effect of PLA and the medicinal plant extract can be achieved by fermentation with a specific plant-derived LAB strain.

Associations of serum long-chain fatty acids with multiple organ involvement in patients with sarcoidosis.

BACKGROUND: Fatty acids have diverse immunomodulatory functions and the potential to be associated with inflammatory responses in sarcoidosis. METHODS: The serum levels of multiple long-chain fatty acids (LCFAs) were compared between 63 patients with sarcoidosis and 38 healthy controls. The associations of LCFAs with clinical outcomes of sarcoidosis were also evaluated. RESULTS: The patients with sarcoidosis had significantly lower levels of n-3 poly-unsaturated fatty acids (PUFAs) (p < 0.001) and n-6 PUFAs (p < 0.001) than the healthy controls. However, there were no significant differences in the levels of saturated fatty acids (SFAs) and mono-unsaturated fatty acids (MUFAs) between the two groups. On multivariate logistic analysis, lower levels of n-3 PUFAs, n-6 PUFAs, and n-3/n-6 ratio were predictive of sarcoidosis. Among the patients with sarcoidosis, those with multiple organ involvement had significantly lower levels of n-3 PUFAs and n-3/n-6 ratio than those with single organ involvement. There were no significant differences in the levels of n-6 PUFAs, SFAs, and MUFAs between the patients with multiple and single organ involvement. On multivariate logistic analysis, lower levels of SFAs and n-3/n-6 ratio were predictive of multiple organ involvement. The levels of LCFAs had no significant association with radiographic stage or spontaneous remission. CONCLUSIONS: Assessment of LCFA profiles may be useful for the diagnosis of sarcoidosis and evaluation of the disease activity.

Association of the Geriatric Nutritional Risk Index With the Survival of Patients With Non-Small Cell Lung Cancer After Nivolumab Therapy.

The nutritional status has the potential to affect cancer immunity. We evaluated the relationship between the nutritional status and the efficacy of nivolumab in patients with non-small cell lung cancer (NSCLC). This study was a post hoc analysis of a prospective, multicenter cohort study conducted at 14 institutions in Japan between July 2016 and December 2018. The Geriatric Nutritional Risk Index (GNRI), calculated from body weight and serum albumin, was evaluated in 158 patients with NSCLC who received nivolumab. GNRI was graded as low, moderate, and high. Low GNRI was associated with significantly shorter progression-free survival [median, 1.9 mo; 95% confidence interval (CI)=0.6-3.3 mo] than moderate (median, 4.0 mo; 95% CI=2.3-5.8 mo; P=0.017) and high GNRI (median, 3.0 mo; 95% CI=1.9-7.2 mo; P=0.014). Low GNRI was also linked to significantly shorter overall survival (OS) (median, 7.8 mo; 95% CI=2.6-12.0 mo) than moderate (median, 13.0 mo; 95% CI=9.6-15.2 mo; P=0.006) and high GNRI (median, 20.6 mo; 95% CI=15.6 mo-not reached; P<0.001). High GNRI was associated with significantly longer OS than moderate GNRI (P=0.015). In multivariate Cox proportional hazard analyses, increased GNRI was predictive of longer progression-free survival and OS, similarly as tumor programmed cell death-ligand 1 expression. In patients with NSCLC receiving nivolumab. GNRI was predictive of survival and may be useful for predicting the efficacy of immune checkpoint inhibitor therapy.

Association of the Geriatric Nutritional Risk Index with the survival of patients with non-small-cell lung cancer after platinum-based chemotherapy.

BACKGROUND: The nutritional status can potentially affect the efficacy of cancer therapy. The Geriatric Nutritional Risk Index (GNRI), a simple index for evaluating nutritional status calculated from body weight and serum albumin levels, has been reported to be associated with the prognosis of various diseases. However, the relationships between GNRI and the efficacy of platinum-based chemotherapy in patients with non-small-cell lung cancer (NSCLC) are unknown. METHODS: The pretreatment levels of GNRI were retrospectively evaluated in 148 chemo-naïve patients with advanced NSCLC who received first-line platinum-based chemotherapy and scored as low or high. RESULTS: Patients with a high GNRI had a significantly higher overall response rate (ORR; 44.5% [95% confidence interval {CI} = 35.6%-53.9%] vs. 15.8% [95% CI = 7.4%-30.4%, p = 0.002), longer median progression-free survival (PFS; 6.3 months [95% CI = 5.6-7.2 months] vs. 3.8 months [95% CI = 2.5-4.7 months], p < 0.001), and longer median overall survival (OS; 22.8 months [95% CI = 16.7-27.2 months] vs. 8.5 months [95% CI = 5.4-16.0 months], p < 0.001) than those with low GNRI. High GNRI was independently predictive of better ORR in multivariate logistic regression analysis and longer PFS and OS in multivariate Cox proportional hazard analyses. In 71 patients who received second-line non-platinum chemotherapy, patients with high GNRI exhibited significantly longer PFS and OS than those with low GNRI (both p < 0.001). CONCLUSIONS: GNRI was predictive of prolonged survival in patients with NSCLC who received first-line platinum-based chemotherapy and second-line non-platinum chemotherapy. Assessment of the nutritional status may be useful for predicting the efficacy of chemotherapy.

A Pilot Study Evaluating the Effectiveness and Safety of Daikenchuto (TJ-100) for the Treatment of Postoperative Abdominal Pain or Bloating in Patients Undergoing Hepatectomy: Study Protocol for a Randomized, Open, Controlled Trial.

This study is being performed to evaluate the effectiveness and safety of TJ-100 TSUMURA Daikenchuto (DKT) Extract Granules in preventing post-hepatectomy digestive symptoms, and to examine the effects of DKT on small intestinal mucosal atrophy using diamine oxidase (DAO) and glucagon-like peptide-2 (GLP-2) activities. This is a randomized, open, controlled trial using patients treated with usual care as the control group. Patients who meet the inclusion criteria are randomized to the study groups. Eligible patients are randomized to the DKT therapy group (DKT administration for 14 days postoperatively or until the day of discharge if a patient leaves the hospital less than 14 days after the surgery) or the usual care group (no administration of DKT (ratio 1:1). Using the NRS (numeric rating scale) as an indicator, we will attempt to show whether DKT is effective for abdominal pain and bloating after surgery by comparing both groups. We will also attempt to evaluate postoperative small intestinal mucosal atrophy using DAO and GLP-2 activities in the serum, and postoperative nutrient absorption using nutrient assessment indicators. This study is being conducted according to the CONSORT statement. A consent form was signed by all participants, and the study protocol has been approved by the Central Review Board and Local Ethics Committee (CRB7180001).

[Locally Advanced Rectal Cancer Curatively Resected after Modified FOLFOXIRI plus Bevacizumab Chemotherapy-A Case Report].

A 69-year-old man with dyschezia was diagnosed with locally advanced colorectal cancer invading the urinary bladder and pelvis. We performed ileostomy to avoid passage disturbance because curative resection was difficult. The patient received 2 courses of modified FOLFOXIRI plus bevacizumab. The size of the primary tumor and lymph nodes decreased after chemotherapy. High anterior resection with D3 lymph node dissection was performed. Histopathological analysis revealed that the tumor stage was pT3, N0, M0, StageⅡ. The patient has been receiving adjuvant chemotherapy with oral UFT/UZEL for 6months. No recurrence has been observed for the past 4 months.

Xylitol acts as an anticancer monosaccharide to induce selective cancer death via regulation of the glutathione level.

Herbal medicines and their bioactive compounds are increasingly being recognized as useful drugs for cancer treatments. The parasitic fungus Cordyceps militaris is an attractive anticancer herbal since it shows very powerful anticancer activity due to its phytocompound cordycepin. We previously discovered and reported that a high amount of xylitol is present in Cordyceps militaris extract, and that xylitol unexpectedly showed anticancer activity in a cancer-selective manner. We thus hypothesized that xylitol could become a useful supplement to help prevent various cancers, if we can clarify the specific machinery by which xylitol induces cancer cell death. It is also unclear whether xylitol acts on cancer suppression in vivo as well as in vitro. Here we show for the first time that induction of the glutathione-degrading enzyme CHAC1 is the main cause of xylitol-induced apoptotic cell death in cancer cells. The induction of CHAC1 is required for the endoplasmic reticulum (ER) stress that is triggered by xylitol in cancer cells, and is linked to a second induction of oxidative stress in the treated cells, and eventually leads to apoptotic cell death. Our in vivo approach also demonstrated that an intravenous injection of xylitol had a tumor-suppressing effect in mice, to which the xylitol-triggered ER stress also greatly contributed. We also observed that xylitol efficiently sensitized cancer cells to chemotherapeutic drugs. Based on our findings, a chemotherapeutic strategy combined with xylitol might improve the outcomes of patients facing cancer.

Antibiotic susceptibility of plant-derived lactic acid bacteria conferring health benefits to human.

Lactic acid bacteria (LAB) confer health benefits to human when administered orally. We have recently isolated several species of LAB strains from plant sources, such as fruits, vegetables, flowers, and medicinal plants. Since antibiotics used to treat bacterial infection diseases induce the emergence of drug-resistant bacteria in intestinal microflora, it is important to evaluate the susceptibility of LAB strains to antibiotics to ensure the safety and security of processed foods. The aim of the present study is to determine the minimum inhibitory concentration (MIC) of antibiotics against several plant-derived LAB strains. When aminoglycoside antibiotics, such as streptomycin (SM), kanamycin (KM), and gentamicin (GM), were evaluated using LAB susceptibility test medium (LSM), the MIC was higher than when using Mueller-Hinton (MH) medium. Etest, which is an antibiotic susceptibility assay method consisting of a predefined gradient of antibiotic concentrations on a plastic strip, is used to determine the MIC of antibiotics world-wide. In the present study, we demonstrated that Etest was particularly valuable while testing LAB strains. We also show that the low susceptibility of the plant-derived LAB strains against each antibiotic tested is due to intrinsic resistance and not acquired resistance. This finding is based on the whole-genome sequence information reflecting the horizontal spread of the drug-resistance genes in the LAB strains.

Nonthrombogenic, stretchable, active multielectrode array for electroanatomical mapping.

High-precision monitoring of electrophysiological signals with high spatial and temporal resolutions is one of the most important subjects for elucidating physiology functions. Recently, ultraflexible multielectrode arrays (MEAs) have been fabricated to establish conformal contacts with the surface of organs and to measure propagation of electrophysiological signals with high spatial-temporal resolution; however, plastic substrates have high Young's modulus, causing difficulties in creating appropriate stretchability and blood compatibility for applying them on the dynamically moving and surgical bleeding surface of the heart. Here, we have successfully fabricated an active MEA that simultaneously achieves nonthrombogenicity, stretchability, and stability, which allows long-term electrocardiographic (ECG) monitoring of the dynamically moving hearts of rats even with capillary bleeding. Because of the active data readout, the measured ECG signals exhibit a high signal-to-noise ratio of 52 dB. The novel stretchable MEA is carefully designed using state-of-the-art engineering techniques by combining extraordinarily high gain organic electrochemical transistors processed on microgrid substrates and a coating of poly(3-methoxypropyl acrylate), which exhibits significant antithrombotic properties while maintaining excellent ionic conductivity.

PEG-poly(L-lysine)-based polymeric micelle MRI contrast agent: Feasibility study of a Gd-micelle contrast agent for MR lymphography.

PURPOSE: To investigate the feasibility of polymeric micelle of poly(ethyleneglycol) (PEG)-b-poly(L-lysine-DOTA) (Gd-micelle) as a contrast agent for magnetic resonance lymphography (MRL). MATERIALS AND METHODS: Twenty-four female BALB/c mice were randomly divided into four groups of six mice each. Among them, mice of two groups were injected of complete Freund's adjuvant to obtain inflamed lymph nodes. We subcutaneously injected 0.5 µmol Gd per mouse of Gd-micelle or gadofluorine P in the right rear footpad. Identical 3D T1 -weighted gradient-echo imaging (1T MRI system) were subsequently obtained to create time-intensity curves of the right popliteal, sacral, and lumbar-aortic lymph nodes and to measure the contrast ratios (CRs). The peak CR, area under the curve (AUC), and elimination half-life (T1/2 ) of CR of the popliteal lymph node were assessed by two-way factorial analysis of variance. We also performed a qualitative assessment of normal and inflamed lymph node at three timepoints. RESULTS: The mean peak CR of Gd-micelle was 2.64 and 1.89 for gadofluorine P in normal mice, and 3.48 and 2.73 in the inflamed lymph node. Statistically, peak CR was higher for Gd-micelle (P = 0.004). In addition, the AUC was larger (P < 0.001) and T1/2 was longer (P < 0.001) for Gd-micelle. In qualitative assessment, Gd-micelle demonstrated the same or higher scores in every lymph node, and demonstrated a higher score in lumbar-aortic lymph node of a 360-minute image (P = 0.006) and in inflamed lymph node of a 360-minute image (P = 0.009). CONCLUSION: Compared to gadofluorine P, Gd-micelle showed higher and more prolonged enhancement in MRL imaging in normal and inflamed lymph nodes. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:238-245.

Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells.

Angiogenesis is essential for tumor development and metastasis. Among several angiogenic factors, vascular endothelial growth factor receptor (VEGF) is important for tumor-derived angiogenesis and commonly overexpressed in solid tumors. Thus, many antitumor strategies targeting VEGF have been developed to inhibit cancer angiogenesis, offering insights into the successful treatment of solid cancers. However, there are a number of issues such as harmful effects on normal vascularity in clinical trials. Taking this into consideration, we employed Cordyceps militaris as an antitumor approach due to its biological safety in vivo. The herbal medicinal mushroom Cordyceps militaris has been reported to show potential anticancer properties including anti-angiogenic capacity; however, its concrete properties have yet to be fully demonstrated. In this study, we aimed to elucidate the biological role of Cordyceps militaris extract in tumor cells, especially in regulating angiogenesis and tumor growth of a human malignant melanoma cell line. We demonstrated that Cordyceps militaris extract remarkably suppressed tumor growth via induction of apoptotic cell death in culture that links to the abrogation of VEGF production in melanoma cells. This was followed by mitigation of Akt1 and GSK-3ß activation, while p38α phosphorylation levels were increased. Extract treatment in mouse model xenografted with human melanoma cells resulted in a dramatic antitumor effect with down-regulation of VEGF expression. The results suggest that suppression of tumor growth by Cordyceps militaris extract is, at least, mediated by its anti-angiogenicity and apoptosis induction capacities. Cordyceps militaris extract may be a potent antitumor herbal drug for solid tumors.

Integrated lymphography using fluorescence imaging and magnetic resonance imaging in intact mice.

We assessed lymph drainage in living mice by an integrated imaging method using fluorescence imaging (FLI) and magnetic resonance imaging (MRI). Mice were subcutaneously injected with quantum dots and gadofluorine 8 into the right rear footpad. They were fixed on a transparent flat plate and underwent FLI and MRI successively. Small markers were attached to the mouse surface for spatial coregistration, and image fusion of FLIs and MRIs was performed. Two-dimensional fluorescence reflectance imaging was used for FLI. FLI and MRI provided generally consistent results and demonstrated lymphatic flow to the popliteal, sacral, and iliac lymph nodes in most mice and to the renal, inguinal, and lumbar-aortic lymph nodes in some mice. On the fusion images, the locations of the lymph nodes in the mouse trunk were in good agreement between FLI and MRI, indicating successful spatial registration even for the deep structures. The popliteal node tended to be visualized a little farther caudally in FLI than in MRI, presumably because the overlying tissues were thicker in the cranial portion. Integrated FLI/MRI lymphography with image fusion appears to be a useful tool for analysis of the murine lymphatic system.