Association Between Serum Levels of Carotenoids and Serum Asymmetric Dimethylarginine Levels in Japanese Subjects

Background

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelium nitric oxide synthase (NOS). ADMA binds to a substrate-binding site of NOS and then inhibits nitric oxide production from vascular endothelial cells. Elevated ADMA levels are a risk factor for cardiovascular disease. Recently, it was reported that plasma ADMA levels were negatively correlated with vegetable and fruit consumption. The purpose of this study was to examine the association between serum levels of carotenoids and serum ADMA levels in Japanese subjects.

Methods

We conducted a cross-sectional study of 470 subjects (203 men and 267 women) who attended a health examination in August 2011. Serum levels of several carotenoids were separately measured by high-performance liquid chromatography. Serum ADMA levels were determined by using an enzyme-linked immunosorbent assay kit.

Results

In women, the multivariate-adjusted odds ratios (ORs) of elevated serum ADMA levels were significantly decreased in the highest tertile for β-cryptoxanthin (OR 0.47, 95% CI 0.23–0.95), α-carotene (OR 0.39, 95% CI 0.18–0.79), and β-carotene (OR 0.36, 95% CI 0.17–0.73) compared to the lowest tertile. In men, significantly decreased ORs were observed in the highest tertiles of serum zeaxanthin/lutein (OR 0.23, 95% CI 0.06–0.69) and α-carotene (OR 0.26, 95% CI 0.07–0.82), and in the middle and the highest tertiles of serum β-carotene (OR 0.27, 95% CI 0.09–0.74 and OR 0.20, 95% CI 0.03–0.88, respectively) when the tertile cutoff points of women were extrapolated to men.

Conclusions

Higher serum levels of carotenoids, such as α-carotene and β-carotene, may help to prevent elevated serum ADMA levels in Japanese subjects.Key words: asymmetric dimethylarginine, carotenoids, cross-sectional study     

Novel Compounds Identified by Structure-Based Prion Disease Drug Discovery Using In Silico Screening Delay the Progression of an Illness in Prion-Infected Mice

The accumulation of abnormal prion protein (PrP^Sc) produced by the structure conversion of PrP (PrP^C) in the brain induces prion disease. Although the conversion process of the protein is still not fully elucidated, it has been known that the intramolecular chemical bridging in the most fragile pocket of PrP, known as the “hot spot,” stabilizes the structure of PrP^C and inhibits the conversion process. Using our original structure-based drug discovery algorithm, we identified the low molecular weight compounds that predicted binding to the hot spot. NPR-130 and NPR-162 strongly bound to recombinant PrP in vitro, and fragment molecular orbital (FMO) analysis indicated that the high affinity of those candidates to the PrP is largely dependent on nonpolar interactions, such as van der Waals interactions. Those NPRs showed not only significant reduction of the PrP^Sc levels but also remarkable decrease of the number of aggresomes in persistently prion-infected cells. Intriguingly, treatment with those candidate compounds significantly prolonged the survival period of prion-infected mice and suppressed prion disease-specific pathological damage, such as vacuole degeneration, PrP^Sc accumulation, microgliosis, and astrogliosis in the brain, suggesting their possible clinical use. Our results indicate that in silico drug discovery using NUDE/DEGIMA may be widely useful to identify candidate compounds that effectively stabilize the protein.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00903-9) contains supplementary material, which is available to authorized users.     

Japanese version of The Cancer Genome Atlas,JCGA, established using fresh frozen tumors obtained from 5143 cancer patients

This study aimed to establish the Japanese Cancer Genome Atlas (JCGA) using data from fresh frozen tumor tissues obtained from 5143 Japanese cancer patients, including those with colorectal cancer (31.6%), lung cancer (16.5%), gastric cancer (10.8%) and other cancers (41.1%). The results are part of a single‐center study called “High‐tech Omics‐based Patient Evaluation” or “Project HOPE” conducted at the Shizuoka Cancer Center, Japan. All DNA samples and most RNA samples were analyzed using whole‐exome sequencing, cancer gene panel sequencing, fusion gene panel sequencing and microarray gene expression profiling, and the results were annotated using an analysis pipeline termed “Shizuoka Multi‐omics Analysis Protocol” developed in‐house. Somatic driver alterations were identified in 72.2% of samples in 362 genes (average, 2.3 driver events per sample). Actionable information on drugs that is applicable in the current clinical setting was associated with 11.3% of samples. When including those drugs that are used for investigative purposes, actionable information was assigned to 55.0% of samples. Germline analysis revealed pathogenic mutations in hereditary cancer genes in 9.2% of samples, among which 12.2% were confirmed as pathogenic mutations by confirmatory test. Pathogenic mutations associated with non–cancerous hereditary diseases were detected in 0.4% of samples. Tumor mutation burden (TMB) analysis revealed 5.4% of samples as having the hypermutator phenotype (TMB ≥ 20). Clonal hematopoiesis was observed in 8.4% of samples. Thus, the JCGA dataset and the analytical procedures constitute a fundamental resource for genomic medicine for Japanese cancer patients.     

Risk of second malignancies in patients with gastric marginal zone lymphomas of mucosa associate lymphoid tissue (MALT)

Background

It is controversial whether patients with gastric marginal zone lymphomas of mucosa associated lymphoid tissue (MALT) have higher risk of second malignancies. The aim of this study was to define the risk of second malignancies in these patients.

Methods

We analyzed prospective follow-up data of 146 consecutive patients with gastric MALT lymphoma treated at Aichi Cancer Center Hospital and compared the incidence of second malignancies with that in the general population. We calculated the standardized incidence ratio (SIR), using age- and sex-specific incidence rates from the Aichi Cancer Registry.

Results

The median follow-up period was 74 months. A total of 27 tumors occurred in 22 patients (15.1 %), including 19 solid tumors. Of these, nine tumors were detected concomitantly with, and 18 tumors following, the diagnosis of gastric MALT lymphoma. Four patients had two second malignancies each. For the entire group, the SIR of an additional malignancy was 3.39 (95 % confidence interval [CI] 2.11–4.66). An increased incidence of solid tumors (SIR 2.91 [1.60–4.22]) and hematologic malignancies (SIR 5.54 [1.70–9.38]) were seen. In addition, there was increased risk for development of second malignancies during follow up (SIR 2.26 [1.21–3.30]). Chemotherapy for treatment of MALT was an independent risk factor for second malignancies (age–sex adjusted hazard ratio 3.98 [1.47–10.79].

Conclusions

Compared with the general population, patients with gastric MALT lymphoma are at increased risk for second malignancies, including gastric cancer.     

Soluble interleukin-2 receptor level on day 7 as a predictor of graft-versus-host disease after HLA-haploidentical stem cell transplantation using reduced-intensity conditioning

In the present study, we analyzed the kinetics of serum soluble interleukin-2 receptor (sIL-2R) using data from 77 patients undergoing HLA-haploidentical transplantation using reduced-intensity conditioning (RIC), who were at an advanced stage or at high risk for relapse, to clarify the usefulness of sIL-2R as a biomarker of acute graft-versus-host disease (GVHD). Anti-T-lymphocyte globulin and methylprednisolone were used as GVHD prophylaxis. While the median sIL-2R in 38 patients not developing GVHD was suppressed at levels <740 U/ml, sIL-2R in 25 patients developing severe GVHD peaked on day 11 (1,663 U/ml), and thereafter decreased to <1,000 U/ml after day 30. The occurrence of GVHD was not limited to times of high sIL-2R level, but occurred at any time point on the sIL-2R curve. Most patients developing GVHD, however, experienced a higher sIL-2R level early in their transplant course. The combination of RIC and glucocorticoids sufficiently suppressed sIL-2R levels after HLA-haploidentical transplantation. In a multivariate analysis to identify factors associated with GVHD, day 7 sIL-2R >810 U/ml was the only factor significantly associated with the occurrence of severe GVHD (p = 0.0101).     

Diagnostic yield of endoscopic retrograde cholangiography and of EUS-guided fine needle aspiration sampling in gallbladder carcinomas

Background

Obtaining histological evidence of gallbladder carcinoma (GBC) is difficult due to its extraductal nature, and pathological confirmation remains challenging. We compared the diagnostic value and safety of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) with endoscopic retrograde cholangiography (ERC) in patients with suspected GBC.

Patients

Eighty-three patients with GBC were evaluated. Prior to definitive management, pathological evidence of GBC was obtained through either ERC cytopathologic sampling (n?=?33), EUS-FNA (n?=?24) or both (n?=?26).

Results

Among the 83 patients, 59 (71.0%) with biliary obstruction were sampled using ERC with 47.4% (28/59) sensitivity. In 19 of the remaining 31 cases, EUS-FNA sampling had 100% diagnostic sensitivity. Likewise, 50 (60.2%) of the 83 patients with suspected GBC underwent EUS-FNA of regional lymph nodes or the gallbladder (GB) mass itself with 94.8% sensitivity. The overall diagnostic sensitivity rates of ERC and EUS-FNA were 47.4 and 96%, respectively (P?<?0.001). Post-procedural complications were seen in 6.7% of the ERC group (4/59, all were mild pancreatitis), and in none of the EUS-FNA group (P?=?0.10).

Conclusions

Gallbladder carcinoma sampling using ERC and EUS-FNA should be incorporated into the diagnostic workup of GB lesions as complementary tools, and EUS-FNA should be applied in the setting of failed or not indicated ERC.     

Effect of Low‐Density Lipoprotein Apheresis for Nephrotic Idiopathic Membranous Nephropathy as Initial Induction Therapy

Low‐density lipoprotein apheresis (LDL‐A) has been used for nephrotic syndrome (NS) caused by focal segmental glomerulosclerosis in Japan. Idiopathic membranous nephropathy (iMN) can also cause treatment‐resistant NS. Therefore, we investigated the effect of LDL‐A during initial induction for it. This retrospective, observational, and single‐center study enrolled consecutive iMN patients who received steroids from March 2000 to May 2015. We compared data between 11 patients treated with LDL‐A (LDL‐A group) and 27 patients without (non‐LDL‐A group) at baseline and 4 and 8 weeks later. Reduction rate of proteinuria and increase rate of serum albumin in LDL‐A group were significantly higher than the other after 4 weeks (P = 0.036 and 0.030) and 8 weeks (P = 0.030 and <0.001), respectively. There was no adverse event caused by LDL‐A and immunosuppressant dose was not significantly different. In conclusion, LDL‐A may be an effective choice for initial induction of nephrotic iMN.     

Axin2+ Peribiliary Glands in the Periampullary Region Generate Biliary Epithelial Stem Cells That Give Rise to Ampullary Carcinoma

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Primary staging of laryngeal and hypopharyngeal cancer: CT,MR imaging and dual-energy CT

Laryngeal and hypopharyngeal cancer, in particular T4a disease associated with cartilage invasion and extralaryngeal spread, needs to be evaluated accurately because treatment can impact heavily on a patient's quality of life. Reliable imaging tools are therefore indispensible. CT offers high spatial and temporal resolution and remains the preferred imaging modality. Although cartilage invasion can be diagnosed with acceptable accuracy by applying defined criteria for combinations of erosion, lysis and transmural extralaryngeal spread, iodine-enhanced tumors and non-ossified cartilage are sometimes difficult to distinguish. MR offers high contrast resolution for images without motion artifacts, although inflammatory changes in cartilage sometimes resemble cartilage invasion. With dual-energy CT, combined iodine overlay images and weighted average images can be used for evaluation of cartilage invasion, since iodine enhancement is evident in tumor tissue but not in cartilage. Extralaryngeal spread can be evaluated from CT, MR or dual-energy CT images and the routes of tumor spread into the extralaryngeal soft tissue must be considered; (1) via the thyrohyoid membrane along the superior laryngeal neurovascular bundle, (2) via the inferior pharyngeal constrictor muscle, and (3) via the cricothyroid membrane. Radiologists need to understand the advantages and limitations of each imaging modality for staging of laryngeal and hypopharyngeal cancer.     

Safety and Feasibility of Laparoscopic Intersphincteric Resection for Very Low Rectal Cancer

Background

Laparoscopic surgery has been reported to be one of the approaches for total mesorectal excision (TME) in rectal cancer surgery. Intersphincteric resection (ISR) has been reported as a promising method for sphincter-preserving operation in selected patients with very low rectal cancer.

Methods

From July 2005 to December 2008, 35 patients with very low rectal cancer underwent laparoscopic TME with ISR. The results were compared retrospectively with those of previous open TME with ISR.

Results

Conversion to open surgery was necessary in one (3%) patient. The median operation time was 293 min and median estimated blood loss was 40 ml. The pelvic plexus was completely preserved in 32 patients. There was no mortality. Postoperative complications occurred in three (9%) patients. The median length of postoperative hospital stay was 17 days. Macroscopic complete mesorectal excision was achieved in all cases. Complete resection (R0) was achieved in 34 patients. Clinical lymph node stage, operation time, and blood loss were significantly different between the laparoscopic group and open group, but the differences of other factors were not statistically significant.

Conclusions

Laparoscopic TME with ISR is technically feasible and a safe alternative to laparotomy with favorable short-term postoperative outcomes.