TNFRSF1B A1466G genotype is predictive of clinical efficacy after treatment with a definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Currently definitive 5-fluorouracil (5-FU)/cisplatin (CDDP) -based chemotherapy is recognized as one of the most promising treatments for esophageal cancer. A series of studies performed found genetic polymorphisms and the plasma concentration of 5-FU to be predictive of acute severe toxicities and clinical response. Genetic polymorphisms of <it>tumor necrosis factor (TNF) -α </it>and its surface receptors, <it>TNFRSF1A </it>and <it>TNFRSF1B </it>have been examined in terms of susceptibility to various cancers. In this study, genetic polymorphisms of <it>TNFRSF1B </it>gene were evaluated Japanese esophageal squamous cell carcinoma (ESCC) patients treated with the definitive 5-FU/CDDP-based chemoradiotherapy and their predictive values of prognosis or severe acute toxicities were assessed.</p> <p>Methods</p> <p>Forty-six patients with ESCC were treated with the definitive 5-FU/CDDP-based chemoradiotherapy, one course of which consisted of the continuous infusion of 5-FU for days 1-5 and 8-12, the infusion of CDDP on days 1 and 8, and the radiation at 2 Gy/day on days 1-5, 8-12, and 15-19, with a second course repeated after 2-week interval. Genetic polymorphisms of a TNF-α receptor <it>TNFRSF1B </it>gene were determined by a TaqMan^®MGB probe-based polymerase chain reaction.</p> <p>Results</p> <p>The genotype of <it>TNFSR1B </it>A1466G, but not M196R/T587G or C1493T, was found to be predictive of clinical response, i.e., a complete response or not (p = 0.040). Clinical response was predicted by tumor size (p = 0,002), lymph node metastasis (p = 0.007), distant metastasis (p = 0.001) and disease stage (p < 0.001), but <it>TNFRSF1B </it>A1466G genotype was independent of these factors.</p> <p>Conclusions</p> <p>Genetic polymorphism of <it>TNFRSF1B </it>A1466G was found to be predictive response in Japanese ESCC patients with a definitive 5-FU/CDDP-based chemoradiotherapy. Further clinical investigation with a large number of patients or experiments in vitro should be performed to assess the predictive value of <it>TNFRSF1B </it>A1466G genotype after chemoradiotherapy.</p

PKR is required for P.gingivalis-induced NLRP3 expression in osteoblasts

The double-stranded RNA-dependent kinase (PKR), which is activated by double stranded RNA, induces inflammation by regulating NF-κB signaling. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome also modulates inflammation in response to infection. Porphyromonas gingivalis (P.gingivalis) is an oral bacterium which is implicated in the pathogenesis of periodontal diseases. We previously reported that PKR is a key modulator of bone metabolism and inflammation in the periodontal tissue. PKR was also reported to induce inflammation in response to microbes by regulating the NLRP3 inflammasome, suggesting that PKR could affect inflammation along with NLRP3 in periodontal diseases. In this study, we investigated the effects of PKR on NLRP3 expression and NF-κB activity in P. gingivalis infected osteoblasts. We first constructed a SNAP26b-tagged P.gingivalis (SNAP-P. g.) and traced its internalization into the cell. SNAP-P. g. increased the activity of PKR and NF-κB and also induced NLRP3 expression in osteoblasts. Inhibition of NF-κB attenuated SNAP-P. g.-induced NLRP3 expression. The knockdown of PKR using shRNA decreased both the activity of NF-κB and the expression of NLRP3 induced by SNAP-P.g.. We therefore concluded that in osteoblasts, P. gingivalis activated PKR, which in turn increased NLRP3 expression by activating NF-κB. Our results suggest that PKR modulates inflammation by regulating the expression of the NLRP3 inflammasome through the NF-κB pathway in periodontal diseases

IL-18 ; a cytokine translates a stress into medical science

Psychological/physical stresses have been reported to exacerbate auto-immune and inflammatory diseases. To clarify a mechanism by which non-inflammatory stresses disrupt host defenses, responses to immobilization stress in mice were investigated, focusing on the role of a multifunctional cytokine, interleukin-18 (IL-18). In the adrenal cortex, the stress induced IL-18 precursor proteins (pro-IL-18) via ACTH and a superoxide-mediated caspase-1 activation pathway, resulting in conversion of pro-IL-18 to the mature form which was released into plasma. Inhibitors of caspase-1, reactive oxygen species and P38 MAPK prevented stress-induced accumulation of plasma IL-18. These inhibitors also blocked stress-induced IL-6 expression. This, together with the observation that IL-6was not induced in stressed-IL-18 deficient mice, showed that IL-6 induction by stress is dependent on IL-18. In stressed organisms, IL-18 may influence pathological and physiological processes. Controlling the caspase-1 activating pathway to suppress IL-18 levels may provide preventative means against stress-related disruption of host defenses

Host selection of hematophagous leeches (Haemadipsa japonica): Implications for iDNA studies

The development of an efficient and cost‐effective method for monitoring animal populations or biodiversity is urgently needed, and invertebrate‐derived DNA (iDNA) may offer a promising tool for assessing the diversity and other ecological information of vertebrates. We studied the host species of a hematophagous leech (Haemadipsa japonica) in Yakushima by genetic barcoding and compared the results with those for mammal composition revealed by camera trapping. We analyzed 119 samples using two sets of primers by Sanger sequencing and one set of primer by next generation sequencing. The proportion of the samples that were successfully sequenced and identified to at least one species was 11.8–24.3%, depending on the three different methods. In all of these three methods, most of the samples were identified as sika deer (18/20, 6/15 and 16/29) or human (2/20, 7/15 and 21/29). The nonhuman mammal host species composition was significantly different from that estimated by camera trapping. Sika deer was the main host, which may be related with their high abundance, large body size and terrestriality. Ten samples included DNA derived from multiple species of vertebrates. This may be due to the contamination of human DNA, but we also found DNA from deer, Japanese macaque and a frog in the same samples, suggesting the mixture of the two meals in the gut of the leech. Using H. japonica‐derived iDNA would not be suitable to make an inventory of species, but it may be useful to collect genetic information on the targeted species, due to their high host selectivity

Optimization of prediction methods for risk assessment of pathogenic germline variants in the Japanese population

Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer-Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1, 995). Eleven breast cancer susceptibility genes were analyzed using target-capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third-degree relatives), triple-negative breast cancer patients under the age of 60, and ovarian cancer history (all P < .0001). In total, 816 patients (40.9%) satisfied the National Comprehensive Cancer Network (NCCN) guidelines for recommending multigene testing. The sensitivity and specificity of the NCCN criteria for discriminating PGV carriers from noncarriers were 71.3% and 60.7%, respectively. The TC model showed good discrimination for predicting BRCA PGVs (area under the curve, 0.75; 95% confidence interval, 0.69-0.81). Furthermore, use of the TC model with an optimized cutoff of TC score ≥0.16% in addition to the NCCN guidelines improved the predictive efficiency for high-risk groups (sensitivity, 77.2%; specificity, 54.8%; about 11 genes). Given the influence of ethnic differences on prediction, we consider that further studies are warranted to elucidate the role of environmental and genetic factors for realizing precise prediction

Prospective single-arm observational study of human chymase inhibitor Polygonum hydropiper L in subjects with hypertension

Background and Purpose: Human chymase (h-chymase) is a serine protease that forms local angiotensin II and has been proven to be related to onset of hypertension, arteriosclerosis, and post myocardial infarction cardiac remodeling. Since no chymase inhibitor was clinically available, an extensive screening for inhibition of h-chymase in three different extracts (water, hot water,  and ethanol) of approximately 800 food ingredients had been performed and we identified Polygonum hydropiper L (Polygonum). Using a dried and powdered Polygonum, we conducted a prospective, single-arm, pilot study to investigate its safety and antihypertensive effect in subjects with normal high blood pressure to moderate hypertension. Methods: First, a single oral dose of Polygonum powder (4000 mg) was administered to assess acute toxicity. Then, a pilot study was conducted in 11 subjects using the sequence of placebo and Polygonum for 2 weeks each. The dose of Polygonum was increased sequentially (200–2000 mg/day). Home blood pressure and pulse rate were monitored. Results: Oral administration of Polygonum (4000 mg) did not cause any adverse events. In the dose-escalation phase, evening systolic blood pressure was significantly decreased at 800 mg, 2000 mg doses post-treatment (p < 0.05, and p < 0.05, respectively). Depressor responders to Polygonum intake had significantly higher salt intake in spot urine (p < 0.05). No adverse events or reactions occurred. Conclusion: This was the first investigation that an h-chymase inhibitory Polygonum intake for safety and tolerability was proven and, in addition, chymase inhibitory Polygonum appeared to have depressor effect especially in a hypertensive subject with excessive salt intake

Selectivity of Ca2+ channel blockers for dilator actions on the isolated lower esophageal sphincter and aorta from rats

We compared dilator actions of representative four Ca2+ channel blockers on the isolated lower esophagus sphincter (LES) and thoracic aorta from rats. Verapamil, diltiazem, nifedipine and cilnidipine suppressed KCl-induced contractions of LES and thoracic aorta in a concentration-dependent manner. The order of selectivity for LES, which was calculated as ratio of IC50 value for thoracic aorta divided by that for LES, was diltiazem > verapamil > nifedipine > cilnidipine. These results suggest that diltiazem more preferentially dilates the LES whereas cilnidipine is expected to have lower potential risk of gastroesophageal dysfunction during the antihypertensive therapy. Keywords: Ca2+ channel blockers, Lower esophagus sphincter, Thoracic aort

Measurement of Lipid Hydroperoxides by the Ferric-Xylenol Orange Method (1) Characteristics of the Ferric-Xylenol Orange/Membrane Phosphatidylcholine Complex

The ferric-xylenol orange (FOX) method for measurement of hydroperoxides is based on a technique that employs reduction of peroxides in an acidic condition by Fe2+ and formation of the colored ferric-xylenol orange (XO/Fe3) product with a peak at 560 nm. The 560 nm absorbance peak of XO/Fe3+ shifts to a 610 nm peak with high absorption intensity in the presence of phosphatidylcholine. This is useful for quantification of peroxides such as phospholipid hydroperoxides. Based on this finding, we recently reported a modified FOX method. We now show by measurements of absorbance, broadening of the electron paramagnetic resonance spectrum, changes in the vesicle size and their zeta potentials, the effects of detergents, and manipulation of the membrane lipid composition that the XO/Fe3 -phosphatidylcholine complex forms only in the presence of intact phosphatidylcholine membranes. The phosphate group on the phospholipid plays a role in this interaction which may involve an electron transfer from the phosphate to the Fe3+. A positively charged quaternary amine on the phosphatidylcholine is also necessary to give a peak absorbance at 610 nm. Our observations are consistent with binding of one X0/Fe3+ COmplex to about 3 molecules of the egg yolk phosphatidylcholine carrying a zero net charge.6 page(s