Impact of Oophorectomy on Survival and Improving Nutritional Status in Ovarian Metastasis from Colorectal Adenocarcinoma.

INTRODUCTION: Ovarian metastasis of colorectal cancer is known to have a poor prognosis. This study aimed to elucidate the characteristics of patients who underwent oophorectomy for ovarian metastasis from colorectal cancer. METHODS: This retrospective study included 16 patients who underwent oophorectomy for colorectal cancer metastasis to the ovary from January 2004 to December 2017. Improvement in patient's symptoms and pre- and postoperative changes in various nutritional and inflammatory indicators were assessed. Survival analysis and identification of prognostic factors were conducted with a median follow-up of 40.7 (5-109) months. RESULTS: Of 16 patients, 12 had (75%) synchronous and 4 (25%) had metachronous metastasis. Fourteen patients were symptomatic but symptoms resolved postoperatively. Thirteen patients (81.3%) had ascites and 5 (31.3%) had pleural effusion on preoperative computed tomography that disappeared after surgery in all cases. The median value of prognostic nutritional factor was significantly increased postoperatively (36.0 [preoperatively] vs. 47.5, p < 0.0001). The median (interquartile range) values for lymphocyte-C-reactive protein ratio were 715.2 (110-2,607) preoperatively and 6,095.2 (1,612.3-14,431.8) postoperatively (p = 0.0214). The median survival of the entire cohort was 60.4 months. The 3-year survival rates for R0 + R1 and R2 cases were 83% and 24% (p = 0.018), respectively. Univariate analysis showed that R2 resection and low postoperative lymphocyte-C-reactive protein ratio were associated with poor prognosis. CONCLUSIONS: Oophorectomy for ovarian metastasis from colorectal cancers was safely performed. It improved the patients' symptoms and nutritional status and may result in improved prognosis.

Short-term outcomes of laparoscopic and robotic distal gastrectomy for gastric cancer: Real-world evidence from a large-scale inpatient database in Japan.

BACKGROUND AND OBJECTIVES: Robotic distal gastrectomy (RDG) has been widely performed throughout Japan since it became insured in 2018. This study aimed to evaluate the short-term outcomes of RDG and laparoscopic distal gastrectomy (LDG) for gastric cancer using real-world data. METHODS: A total of 4161 patients who underwent LDG (n = 3173) or RDG (n = 988) for gastric cancer between April 2018 and October 2022 were identified through the Japanese Diagnosis Procedure Combination Database, which covers 42 national university hospitals. The primary outcome was postoperative in-hospital mortality rate. The secondary outcomes were postoperative complication rates, time to diet resumption, and postoperative length of stay (LOS). RESULTS: In-hospital mortality and postoperative complication rates in the RDG group were comparable with those in the LDG group (0.1% vs. 0.0%, p = 1.000, and 8.7% vs. 8.2%, p = 0.693, respectively). RDG was associated with a longer duration of anesthesia (325 vs. 262 min, p < 0.001), similar time to diet resumption (3 vs. 3 days, p < 0.001), and shorter postoperative LOS (10 vs. 11 days, p < 0.001) compared with LDG. CONCLUSIONS: RDG was performed safely and provided shorter postoperative LOS, since it became covered by insurance in Japan.

Increased mitochondria are responsible for the acquisition of gemcitabine resistance in pancreatic cancer cell lines.

Pancreatic ductal adenocarcinoma has a particularly poor prognosis as it is often detected at an advanced stage and acquires resistance to chemotherapy early during its course. Stress adaptations by mitochondria, such as metabolic plasticity and regulation of apoptosis, promote cancer cell survival; however, the relationship between mitochondrial dynamics and chemoresistance in pancreatic ductal adenocarcinoma remains unclear. We here established human pancreatic cancer cell lines resistant to gemcitabine from MIA PaCa-2 and Panc1 cells. We compared the cells before and after the acquisition of gemcitabine resistance to investigate the mitochondrial dynamics and protein expression that contribute to this resistance. The mitochondrial number increased in gemcitabine-resistant cells after resistance acquisition, accompanied by a decrease in mitochondrial fission 1 protein, which induces peripheral mitosis, leading to mitophagy. An increase in the number of mitochondria promoted oxidative phosphorylation and increased anti-apoptotic protein expression. Additionally, enhanced oxidative phosphorylation decreased the AMP/ATP ratio and suppressed AMPK activity, resulting in the activation of the HSF1-heat shock protein pathway, which is required for environmental stress tolerance. Synergistic effects observed with BCL2 family or HSF1 inhibition in combination with gemcitabine suggested that the upregulated expression of apoptosis-related proteins caused by the mitochondrial increase may contribute to gemcitabine resistance. The combination of gemcitabine with BCL2 or HSF1 inhibitors may represent a new therapeutic strategy for the treatment of acquired gemcitabine resistance in pancreatic ductal adenocarcinoma.

Glutamate-Sensing Genes Are Conserved among Populations Compared to Glutamate Metabolism Genes.

INTRODUCTION: Glutamate is a representative taste molecule with an umami flavor and is a major nutrient found abundantly in nature. Furthermore, it plays a significant role in the human body as a key metabolic intermediate and neurotransmitter. Therefore, the divergence of glutamate functions among populations during their evolution is of particular interest with a hypothesis that the genetic variation can lead to understanding divergence in taste perception. To elucidate variation in glutamate applications and to deepen our understanding of taste perception, we examined the nucleotide diversity of genes associated with glutamate sensing and metabolism among human populations. METHODS: We first established 67 genes related to glutamate sensing and metabolism based on the database and literature survey. Then, for those genes, we used a population genomics approach based on ten populations over 76,156 human genomes in the gnomAD database. RESULTS: Statistical tests of means and medians of the minor allele frequencies did not show any significant difference among populations. However, we observed substantial differences between two functional groups, glutamate sensing and glutamate metabolism, in populations of Latino/admixed American, Ashkenazi Jewish, and Others. Interestingly, we could find significant differences between the African population and the East Asian population at the single nucleotide polymorphism level of glutamate metabolism genes, but no clear differences were noted in glutamate-sensing genes. These suggest that glutamate-sensing genes are under the functional constraint compared to glutamate metabolism genes. CONCLUSION: Thus, glutamate-sensing genes and metabolism genes have a contrasting mode of the evolution, and glutamate-sensing genes are conservatively evolved, indicating its functional importance.

[A Case of Conversion Surgery after Nivolumab Monotherapy as Third-Line Therapy for Advanced Gastric Cancer].

A 79-year-old man with unresectable advanced gastric cancer due to invasion to the pancreas and positive lavage cytology( T4b, N+, M1, CY1, cStage ⅣB; Japanese classification of gastric carcinoma, 15th edition)received standard chemotherapy, including 6 courses of S-1 plus cisplatin as first-line therapy and 2 courses of paclitaxel plus ramucirumab followed by 6 courses of paclitaxel monotherapy as second-line therapy. The primary lesion became PD with these treatments. Subsequently, nivolumab monotherapy was introduced as third-line therapy. After 9 courses, the primary tumor shrunk, and lavage cytology turned to negative on diagnostic laparoscopy. We judged that the tumor was resectable, and the patient underwent radical total gastrectomy and D2 lymphadenectomy as conversion surgery. The pathological stage was ypT3(SS), N0, M0, CY0, and the therapeutic effect was Grade 1b. R0 resection was accomplished. He has been alive without recurrence for 18 months after resection without adjuvant chemotherapy.

The function of SARS-CoV-2 spike protein is impaired by disulfide-bond disruption with mutation at cysteine-488 and by thiol-reactive N-acetyl-cysteine and glutathione.

Viral spike proteins play important roles in the viral entry process, facilitating attachment to cellular receptors and fusion of the viral envelope with the cell membrane. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds to the cellular receptor angiotensin converting enzyme-2 (ACE2) via its receptor-binding domain (RBD). The cysteine residue at position 488, consisting of a disulfide bridge with cysteine 480 is located in an important structural loop at ACE2-binding surface of RBD, and is highly conserved among SARS-related coronaviruses. We showed that the substitution of Cys-488 with alanine impaired pseudotyped SARS-CoV-2 infection, syncytium formation, and cell-cell fusion triggered by SARS-CoV-2 spike expression. Consistently, in vitro binding of RBD and ACE2, spike-mediated cell-cell fusion, and pseudotyped viral infection of VeroE6/TMPRSS2 cells were inhibited by the thiol-reactive compounds N-acetylcysteine (NAC) and a reduced form of glutathione (GSH). Furthermore, we demonstrated that the activity of variant spikes from the SARS-CoV-2 alpha and delta strains were also suppressed by NAC and GSH. Taken together, these data indicate that Cys-488 in spike RBD is required for SARS-CoV-2 spike functions and infectivity, and could be a target of anti-SARS-CoV-2 therapeutics.

Cold-Restraint Stress-Induced Ultrasonic Vocalization as a Novel Tool to Measure Anxiety in Mice.

Ultrasonic vocalization (USVs) is a promising tool to measure behavioral anxiety in rodents as USV recording is noninvasive, behaviorally relevant, ethological, and reproducible. Studies reporting the effects of stress-induced USVs in adult mice remain limited and debated. We investigated the conditions under which mice emit aversive USVs and evaluated the effects of psychiatric drugs on stress-induced USVs. Male C57BL/6J mice were used. USVs during entire stress sessions were recorded according to their frequency. To investigate the effect of psychiatric drugs on USVs, the number of USVs under cold-restraint stress conditions before and after drug administration was compared. Immediately after stress exposure, blood samples were collected and plasma corticosterone levels were measured. The combination of cold and restraint stress conditions significantly increased the USV numbers and plasma corticosterone levels compared with each stress alone. A benzodiazepine anxiolytic (midazolam) and δ-opioid receptor agonist putative anxiolytic (KNT-127) significantly reduced the stress-induced USV number and plasma corticosterone levels; however, a monoaminergic antidepressant (duloxetine) and N-methyl-D-aspartic acid receptor antagonist antidepressant (ketamine) did not reduce the USV numbers. No changes were noted in the USV numbers after repeated exposure to cold-restraint stress on days 1 and 3. The suppressive effect of midazolam on day 3 was comparable to that on day 1. Stress-induced USV may be used as a quantitative measure of anxiety to systematically assess the effects of anxiolytics. Therefore, cold-restraint stress-induced USVs may be used as a novel tool to measure rodent anxiety and as a useful anxiolytic-screening system.

Direct Inhibition of SARS-CoV-2 Spike Protein by Peracetic Acid.

Peracetic acid (PAA) disinfectants are effective against a wide range of pathogenic microorganisms, including bacteria, fungi, and viruses. Several studies have shown the efficacy of PAA against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, its efficacy in SARS-CoV-2 variants and the molecular mechanism of action of PAA against SARS-CoV-2 have not been investigated. SARS-CoV-2 infection depends on the recognition and binding of the cell receptor angiotensin-converting enzyme 2 (ACE2) via the receptor-binding domain (RBD) of the spike protein. Here, we demonstrated that PAA effectively suppressed pseudotyped virus infection in the Wuhan type and variants, including Delta and Omicron. Similarly, PAA reduced the authentic viral load of SARS-CoV-2. Computational analysis suggested that the hydroxyl radicals produced by PAA cleave the disulfide bridges in the RBD. Additionally, the PAA treatment decreased the abundance of the Wuhan- and variant-type spike proteins. Enzyme-linked immunosorbent assay showed direct inhibition of RBD-ACE2 interactions by PAA. In conclusion, the PAA treatment suppressed SARS-CoV-2 infection, which was dependent on the inhibition of the interaction between the spike RBD and ACE2 by inducing spike protein destabilization. Our findings provide evidence of a potent disinfection strategy against SARS-CoV-2.

Selection of and Retention in Surgical Specialty during Early Career in Japan.

The number of surgeons is decreasing in Japan. We investigated the trend and factors influencing surgeons' selection of and retention in surgical specialty. In 2016, we obtained data of biennial surveys conducted by the government, and analyzed the annual data of doctors up to the latest available survey at that time (survey, 1994-2014; medical license acquisition, 1993-2014). The rate of selecting surgery by male and female doctors during early career (first three surveys after acquiring medical license) decreased from 28.1% in 1994 to 21.3% in 2010 (first to nineth survey). Female surgeons increased from 7.8% in 1993 to 12.4% in 2003, but decreased from 12.5% in 2006 to 10.7% in 2010. Total number of surgeons declined throughout the period. In females, the rate of selecting surgery tended to increase at the beginning of the new training system in 2004, but declined slightly thereafter. The retention rate in those who selected surgery at least once by the third survey (1998) after acquiring medical license in 1993 showed a downward trend. The retention rate in females declined continuously to 48.4% in 2002, stabilized thereafter, and then increased from 47.6% in 2006 to 50.8% in 2014. The retention rate after 10 years (1993-2003) was almost stable (72.4%) in males, but increased to 57.5% in females, and the gender difference tended to decrease. Younger doctors tend to value their private life, and may not choose or continue to practice surgery unless working conditions in surgery improve and income is commensurate with their work.

Efficacy and safety of concurrent anti-Cancer and anti-tuberculosis chemotherapy in Cancer patients with active Mycobacterium tuberculosis: a retrospective study.

BACKGROUND: In our previous study, colorectal cancer (CRC) patients with active Mycobacterium tuberculosis (MTB) tolerated concurrent anti-cancer chemotherapy (anti-CCT) and anti-MTB chemotherapy. In this study, we retrospectively confirmed the efficacy and safety of concurrent chemotherapy in a greater number of patients with different types of malignancies. METHODS: We enrolled 30 patients who were treated concurrently with anti-CCT and anti-MTB regimens between January 2006 and February 2016. Cancer and MTB treatments were administered according to the approved guidelines. RESULTS: Patient demographics included: men/woman: 24/6; median age: 66.5 years; Eastern Cooperative Oncology Group performance status 0-1/2/3-4: 24/4/2; Stage IIB-IIIC/IV/recurrence: 6/22/2; lung cancer (LC)/CRC/other: 15/10/5; and MTB diagnosis (before or during anti-CCT): 20/10 (LC: 8/7; CRC: 8/2; other: 4/1). For anti-CCT, 23 patients received two cytotoxic agents with or without targeted agents and 7 patients received a single cytotoxic or targeted agent. The overall response rate was 36.7%. Regarding anti-MTB chemotherapy, 22 patients received a daily drug combination containing isoniazid, rifampicin, and ethambutol, plus pyrazinamide in 15 of the 22 patients, followed by daily isoniazid and rifampicin; the remaining 8 patients received other combinations. Hematological adverse events of Grade ≥ 3 were observed in 19 (67.9%) of 28 patients; laboratory data were lost for the remaining 2. Grade 3 lymphopenia and higher were significantly more frequent in LC compared to other malignancies (P < 0.005). Non-hematological adverse events of Grade ≥ 3 were observed in 5 (16.7%) of 30 patients. One CRC patient experienced Grade 3 hemoptysis and another 2 experienced Grade 3 anaphylaxis. One patient with cholangiocellular carcinoma and gastric cancer experienced Grade 3 pseudomembranous colitis as a result of a Clostridium difficile infection. One patient (3.3%) died of pemetrexed-induced pneumonitis. The success of the anti-MTB chemotherapy was 70.0%. There were no MTB-related treatment failures. The median overall survival (months, 95.0% confidence interval) was 10.5 (8.7-36.7), 8.7 (4.7-10.0), 36.7 (minimum 2.2), and 14.4 (minimum 9.6) for all patients combined, LC, CRC, and Other malignancies, respectively. LC patients experienced delayed MTB diagnosis and shorter overall survival. CONCLUSIONS: Concurrent chemotherapy is effective and safe for treating cancer patients with active MTB.

MeSH ORA framework: R/Bioconductor packages to support MeSH over-representation analysis.

BACKGROUND: In genome-wide studies, over-representation analysis (ORA) against a set of genes is an essential step for biological interpretation. Many gene annotation resources and software platforms for ORA have been proposed. Recently, Medical Subject Headings (MeSH) terms, which are annotations of PubMed documents, have been used for ORA. MeSH enables the extraction of broader meaning from the gene lists and is expected to become an exhaustive annotation resource for ORA. However, the existing MeSH ORA software platforms are still not sufficient for several reasons. RESULTS: In this work, we developed an original MeSH ORA framework composed of six types of R packages, including MeSH.db, MeSH.AOR.db, MeSH.PCR.db, the org.MeSH.XXX.db-type packages, MeSHDbi, and meshr. CONCLUSIONS: Using our framework, users can easily conduct MeSH ORA. By utilizing the enriched MeSH terms, related PubMed documents can be retrieved and saved on local machines within this framework.

[A Case of Gastric Carcinoid Associated with Hypergastrinemia Treated with LATG].

A 67-year-old man had a gastric polyp diagnosed on screening. Atrophic changes in the upper gastric mucosa were seen on upper gastrointestinal endoscopy. In addition, endoscopy revealed in the middle area of the stomach wall a 10 mm polyp that was diagnosed as a carcinoid tumor through biopsy. Blood serum gastrin was elevated at 2,800 pg/mL.We diagnosed a Rindi Type 1 gastric carcinoid. The patient was planned to be treated with surgical laparoscopy assisted distal gastrectomy (LADG); however, the procedure was changed to intraoperative laparoscopy assisted total gastrectomy (LATG). Chromogranin-positive tumor pathological findings in the mucous membrane submucosa and in the muscularis mucosae endocrine cell micronest (ECM) were widespread. There was no obvious vascular invasion. After the surgery, the serum gastrin level normalized and the patient remains alive.

[A Case of Abdominal Wall Hernia Rupture during Bevacizumab Treatment].

A 78 -year-old man with rectal cancer underwent abdominoperineal resection of the rectum. In the postoperative period, the patient experienced wound infection, leading to an abdominal wall hernia. Two years following surgery, a rise in the serum CEA level was seen. A metastatic tumor was detected in the right lung on chest CT. VATS right lung inferior lobe segmental resection was performed. After lobectomy, the serum CEA level continued to increase. Another metastatic tumor was detected in the right lung on chest CT. Chemotherapy with capecitabine, oxaliplatin, and bevacizumab was commenced. The erosive part of the abdominal wall scar hernia extended during the nine weeks of chemotherapy. The chemotherapy was then discontinued. In the follow-up CT scan, a right pleural recurrence, local recurrence in the pelvis, and a liver metastasis were detected. Chemotherapy was re-introduced 3 years after surgery. The erosive part of the abdominal wall hernia again began to spread with chemotherapy recommencement. Four months after restarting chemotherapy, the hernia ruptured, with a loop of the small intestine protruding out of it. The patient covered this with a sheet of vinyl and was taken by the ambulance to our hospital. The erosive part of the abdominal wall hernia had split by 10 cm, and a loop of the small intestine was protruding. As ischemia of the small intestine was not observed, we replaced it into the abdominal cavity, and performed a temporary suture repair of the hernia sac. Following this, bevacizumab was discontinued, and the erosive part reduced. We performed a radical operation for abdominal wall scar hernia repair 11 weeks after the discontinuation of bevacizumab.

[Super-Elderly Patient with Recurrent Rectal Cancer with Liver Metastases Effectively Treated with Capecitabine plus Bevacizumab Chemotherapy--Report of a Case].

The safety and feasibility of chemotherapy for super-elderly patients (over 85 years old) has not been clarified yet. We report an extremely aged patient with recurrent rectal cancer that was successfully treated with capecitabine plus bevacizumab chemotherapy. An 85-year-old-woman underwent a Hartmann procedure for rectal cancer. Nine months after surgery, tumor markers were elevated. CT and MRI revealed liver metastases in S5 and S7. We administered capecitabine plus bevacizumab chemotherapy. Tumor makers were normalized after 2 courses, and the liver metastases disappeared after 6 courses. Although Grade 1 hypertension developed, no other adverse event occurred. Chemotherapy has been safely performed for 20 courses. The patient's PS score has been maintained at 0, and she has been under treatment as an outpatient. We suggest that capecitabine plus bevacizumab chemotherapy is an effective regimen for extremely aged patients with recurrent colorectal cancer.

[Clinical outcome of 13 patients with perforated colorectal cancer].

We investigated the clinicopathological findings of 13 patients with perforated colorectal cancer. In 6 patients, the primary region affected by the cancer was the sigmoid or rectosigmoid colon, and 9 out of 13 patients had perforations at the location of the tumor itself. The Hartmann operation was performed in 5 patients, and D2 or D3 lymph node dissection was performed in 6 patients. The final stages of the 13 patients were as follows: 1 patient with stage II cancer, 5 patients with stage III cancer, and 7 patients with stage IV cancer. Postoperative death occurred in 1 patient. Five out of 7 patients with curative operations had recurrences; 2 patients had peritoneal disseminations, 2 patients had lung metastases, and 1 patient had paraaortic lymph node metastases. Even if patients underwent a curative operation, a high frequency of recurrence, especially of peritoneal dissemination, was observed. Therefore, we conclude that a careful follow-up is required.

[A case of advanced rectal cancer with irinotecan (CPT-11)-induced delayed emesis].

A 64 -year-old woman was referred to our hospital with a diagnosis of advanced rectal cancer with metastases to the left supraclavicular lymph nodes and paraaortic lymph nodes. Alow anterior resection was performed because of the symptoms of ileus. Subsequently, chemotherapy consisting of XELOX with bevacizumab was initiated as the first-line regimen, over 6 courses. Asecond -line regimen of FOLFIRI with bevacizumab was selected due to multiple lung metastases and the progression to both left supraclavicular and paraaortic lymph nodes. During the first 3 courses, the patient had no harmful side effects. Although the patient received adequate prophylactic antiemetic therapy and supportive treatment, grade 4 delayed emesis induced by irinotecan (CPT-11) occurred at 7 days after the fourth course of FOLFIRI chemotherapy. The patient was given total parenteral nutrition, after which she recovered substantially from the emesis. Delayed emesis is occasionally seen with irinotecan therapy and can be efficiently managed with adequate prophylactic antiemetic therapy. However, delayed emesis occurring one week after administration is rarely observed. Delayed emesis and subsequent therapy affect the quality of life (QOL) of the patient and subsequent therapy therefore, adequate attention and prompt management are required for delayed emesis.

[A case of advanced HER2- positive gastric cancer with a partial response to molecular targeted chemotherapy (S-1+CDDP+Trastuzumab)].

A 61-year-old man was referred to our hospital because of gastric pain and weight loss.Upper gastrointestinal endoscopy revealed a superficial depressed (Type 3) tumor with pyloric stenosis.The tumor was diagnosed as tubular adenocarcinoma by pathological examination.Abdominal computed tomography showed enlarged paraaortic and No. 8a lymph nodes.The patient underwent distal gastrectomy (D0)and Roux-en-Y reconstruction.After surgery, chemotherapy combined with molecular targeted therapy (S-1+cisplatin[CDDP]+trastuzumab), based on overexpression of the HER2 protein in the primary tumor as assessed by immunostaining, was administered.After the molecular targeted chemotherapy, the carcinoembryonic antigen (CEA )levels decreased to the normal range and the enlarged lymph nodes were remarkably decreased in size. The patient is currently alive without progressive disease.

A Nationwide Survey on Medication Follow-up Care by Community Pharmacists: From The Japanese Nationwide Pharmacy Collaboration Survey in 2023.

In Japan, the Pharmaceutical and Medical Device Act was amended in December 2019, and now requires pharmacists to follow-up on patients during treatment. Although there have been some studies on the effectiveness of follow-ups by pharmacists, there are no reports on the status of implementation in clinical practice. We conducted a nationwide survey on follow-up care to investigate the actual situation. We randomly selected 10% of community pharmacies in each prefecture and conducted a survey. We built a web-based system for the collection of basic information on the pharmacies and follow-up cases. A total of 561 pharmacies were pre-entered. Of these, 110 pharmacies (19.6%) reported 326 follow-up cases. Information was provided to doctors in 129 cases (39.6%), of which prescription proposals were made in 10 (7.8%) instances. The follow-up implementation rate based on the number of prescriptions dispensed was estimated to be 0.84% (95% confidence interval: 0.76-0.94%). This study revealed the status of follow-ups in clinical practice. Pharmacists can contribute to the optimization of drug treatment by providing follow-up information to doctors and making prescription proposals.

Two-way AIC: detection of differentially expressed genes from large scale microarray meta-dataset.

BACKGROUND: Detection of significant differentially expressed genes (DEGs) from DNA microarray datasets is a common routine task conducted in biomedical research. For the detection of DEGs, numerous methods are proposed. By such conventional methods, generally, DEGs are detected from one dataset consisting of group of control and treatment. However, some DEGs are easily to be detected in any experimental condition. For the detection of much experiment condition specific DEGs, each measurement value of gene expression levels should be compared in two dimensional ways, or both with other genes and other datasets simultaneously. For this purpose, we retrieve the gene expression data from public database as possible and construct "meta-dataset" which summarize expression change of all genes in various experimental condition. Herein, we propose "two-way AIC" (Akaike Information Criteria), method for simultaneous detection of significance genes and experiments on meta-dataset. RESULTS: As a case study of the Pseudomonas aeruginosa, we evaluate whether two-way AIC method can detect test data which is the experiment condition specific DEGs. Operon genes are used as test data. Compared with other commonly used statistical methods (t-rank/F-test, RankProducts and SAM), two-way AIC shows the highest specificity of detection of operon genes. CONCLUSIONS: The two-way AIC performs high specificity for operon gene detection on the microarray meta-dataset. This method can also be applied to estimation of mutual gene interactions.

Optimal Administration of Glycyrrhizin Avoids Pharmacokinetic Interactions With High-dose Methotrexate and Exerts a Hepatoprotective Effect.

BACKGROUND/AIM: Glycyrrhizin (GZ) is widely used to treat high-dose methotrexate (MTX)-induced liver dysfunction. However, in a previous in vivo study, we showed that simultaneous administration of both drugs increased the plasma concentration of MTX and exacerbated hepatic injuries. In this study, we investigated the optimal dosing interval in rats to avoid the interaction between high-dose MTX and GZ and to demonstrate the inherent hepatoprotective effect of GZ. MATERIALS AND METHODS: Male Wistar rats were treated with high-dose MTX (2,000 mg/kg) alone, with concomitant administration of 100 mg/kg GZ or GZ administered 3, 6, and 24 h before MTX administration. Plasma concentrations of MTX, alanine aminotransferase, aspartate aminotransferase, and total bilirubin were measured. RESULTS: The plasma concentration and half-life of methotrexate were significantly increased after concomitant administration of GZ, or when GZ was administered 3 h before MTX administration, compared with MTX alone, increasing hepatic enzyme levels. However, when GZ was administered 6 and 24 h before MTX administration, the levels were not significantly different from those of MTX alone and showed a tendency to decrease MTX-induced liver injury. These results suggest that the pharmacokinetic interaction between GZ and MTX could be avoided and the hepatoprotective effect of GZ could be achieved by an optimal dosing regimen, using the half-life of GZ as an indicator. CONCLUSION: When using high-dose MTX in combination with GZ, the administration intervals should be considered to avoid unwanted interactions and to achieve the GZ hepatoprotective effect.