Evaluation of risk factors for chemotherapy-induced nausea and vomiting in cisplatin and gemcitabine treatment for biliary tract cancer: acid suppressants do not prevent nausea.

Chemotherapy-induced nausea and vomiting (CINV) is one of the most serious adverse effects of cancer therapy. Cancer patients frequently use acid suppressants (AS) for palliation of gastrointestinal symptoms associated with malignancy and/or anticancer therapy. AS are suggested as an additional option for CINV management in several antiemetic guidelines, although their efficacy remains unknown. The aim of this study was to determine whether AS administration affects CINV incidence in cisplatin and gemcitabine treatment for biliary tract cancer. The primary endpoint was to evaluate whether AS administration was associated with the incidence of all-grade nausea in the first administration by logistic analysis. The secondary endpoints were to assess factors associated with anorexia. Prophylactic antiemetics were based on current guidelines. Nausea occurred in 34.2% of patients (grade 1, 31.7%; grade 2, 2.5%). Patients exhibiting vomiting and anorexia represented 4.2% and 39.1%, respectively, without grade 3/4 symptoms. Multivariate analysis suggested that the independent risk factors for nausea as female sex, and no- or less-alcohol drinking habit and regular narcotics administration were associated with anorexia. In contrast, AS administration was not associated with nausea and anorexia incidence (odds ratio, 95% confidence interval: 1.43, 0.64-3.23; P =0.38 for nausea, 1.62, 0.71-3.68; P =0.25 for anorexia). In conclusion, we found that AS administration is not associated with CINV incidence, and female sex is a risk factor for nausea, and non-alcohol drinking habits and regular narcotic use are factors associated with anorexia in cisplatin and gemcitabine treatment for biliary tract cancer. We should correctly administer AS depending on the patient's situation. Successful CINV management needs effective monitoring and administration of prophylactic antiemetics and counter-measure medicines for patients at risk.

The CODATwins Project: The Current Status and Recent Findings of COllaborative Project of Development of Anthropometrical Measures in Twins.

The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural-geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.

Gene expression profiling of Escherichia coli in response to interactions with the lettuce rhizosphere.

AIMS: The objective of this study was to examine transcriptional changes in Escherichia coli when the bacterium was growing in the lettuce rhizoshpere. METHODS AND RESULTS: A combination of microarray analyses, colonization assays and confocal microscopy was used to gain a more complete understanding of bacterial genes involved in the colonization and growth of E. coli K12 in the lettuce root rhizosphere using a novel hydroponic assay system. After 3 days of interaction with lettuce roots, E. coli genes involved in protein synthesis, stress responses and attachment were up-regulated. Mutants in curli production (crl, csgA) and flagella synthesis (fliN) had a reduced capacity to attach to roots as determined by bacterial counts and by confocal laser scanning microscopy. CONCLUSIONS: This study indicates that E. coli K12 has the capability to colonize lettuce roots by using attachment genes and can readily adapt to the rhizosphere of lettuce plants. SIGNIFICANCE AND IMPACT OF THE STUDY: Results of this study show curli production and biofilm modulation genes are important for rhizosphere colonization and may provide useful targets to disrupt this process. Further studies using pathogenic strains will provide additional information about lettuce-E. coli interactions.

An isotype-specific trans-acting factor is defective in a mutant B cell line that expresses HLA-DQ, but not -DR or -DP.

The B lymphoblastoid cell line clone 13 (a subclone of the mutant cell line P3JHR-1) has been found to express high levels of HLA-DQ; by contrast, HLA-DR and -DP antigens are not expressed and cannot be induced by interferon gamma. Northern blot analysis using gene-specific probes indicated that the lack of surface expression of the DR and DP antigens is due to a marked decrease in the levels of steady-state RNA for both the alpha and beta chains. Southern blots demonstrated that none of the transcriptionally repressed genes are grossly deleted. Preparations of interspecific transient heterokaryons between clone 13 and the class II antigen-positive murine B cell lymphoma, A20, resulted in reactivation of the DRA gene and surface expression of both the DR and DP molecules. The efficiency of the DRA promoter relative to the DQB promoter is markedly and specifically diminished in clone 13 (P3JHR-1) as compared with the parental cell line, Jijoye, as assayed both by transient expression of appropriate chloramphenicol acetyltransferase gene (CAT) constructs and by in vitro transcription analysis. These data clearly demonstrate the existence of an isotype-specific trans-acting factor, and provide direct evidence that the highly homologous class II genes have distinct regulatory mechanisms.

Cooperativity between the J and S elements of class II major histocompatibility complex genes as enhancers in normal and class II-negative patient and mutant B cell lines.

The class II major histocompatibility complex genes all contain in their proximal promoters three cis-elements called S, X, and Y that are conserved in both sequence and position, and a fourth element, J, conserved in sequence but not in position. J, X, and Y and, to some extent, S, have been shown to be functionally important in regulation of expression of these genes. In the present study, a protein factor that binds cooperatively to the S plus J elements of the promoter of the class II major histocompatibility complex gene DPA has been detected. Moreover, functional cooperativity between S and J in activation of the enhancerless -40 interferon-beta (-40 IFN-beta) promoter has been demonstrated. Finally, the latter assay appears to subdivide complementation group A of class II negative human B cell lines that includes both mutants generated in vitro and cells from patients with the bare lymphocyte syndrome (type II). In three of these cell lines, the enhancerless -40 IFN-beta promoter containing the S plus J elements was functionally active, while in the others it was inactive.

Two cases of wheat-dependent anaphylaxis induced by aspirin administration but not by exercise.

BACKGROUND: Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to enhance the symptoms of wheat-dependent exercise-induced anaphylaxis (WDEIA). In contrast to many reports on WDEIA, there have been only a few reports of wheat-dependent aspirin-induced anaphylaxis not induced by the combination of wheat and exercise. METHODS: Two patients with wheat-dependent anaphylaxis underwent provocation tests to clarify the cause of their symptoms. Skin-prick testing (SPT) was also performed with and without administration of aspirin. Specific IgE antibody to wheat, gluten, and omega-5 gliadin were examined. RESULTS: In the provocation tests, anaphylactic reactions were not induced by wheat or aspirin alone or by the combination of wheat and exercise, but were induced by the combination of wheat and aspirin. An increase in the blood histamine level was detected after provocation in both patients. Pretreatment with aspirin enhanced the SPT reactions to wheat and gluten in both patients. Specific IgE antibodies to wheat and gluten were expressed in the serum of both patients, and specific omega-5 gliadin IgE antibody was detected in the serum of one patient. CONCLUSIONS: We present two cases of specific wheat-dependent anaphylaxis induced by aspirin but not by exercise. We suggest that pretreatment with aspirin under controlled conditions is useful to confirm the diagnosis of food allergy when a challenge test with food alone or with food and exercise fails to induce positive reactions.

Development of a method to control the water evaporation of hatching eggs during incubation.

Three experiments were conducted to develop methods to control the amount of water loss and to evaluate the metabolic effects of water condition in the White Leghorn breeder eggs during incubation. One hundred twenty, 54, and 90 Julia strain White Leghorn breeder eggs were incubated at 37.8 degrees C, 60% RH in experiments 1, 2, and 3. In experiment 1, eggs were drilled with various bore diameters of 0, 0.5, 1, 2, 3, 4, and 5 mm on the blunt end of the eggshell. In experiment 2, 4 x 4 mm(2) windows were cut into the eggs or the eggs were drilled with 5 holes of bore diameter 2 mm on the blunt end of eggshell. In experiment 3, eggs were drilled with 1, 3, 5, and 7 holes of diameter 2 mm on the blunt end of eggshell. Eggs were treated on d 3 of each experiment and the amount of water loss was recorded on d 19 of incubation. Embryo growth was evaluated in experiments 2 and 3. In addition, the livers of embryos were collected in the 0-, 1-, 3-, and 5-hole treatment groups after weighing eggs to determine 3-hydroxy acyl coenzyme A dehydrogenase activity. In experiment 1, although higher water loss was observed in all windowed eggs than in control, there were no differences in amount of water loss among all bore diameters. Accordingly, that was not successful to control amount of water loss. In experiment 2, higher water loss was observed in drilled eggs at the same levels in windowed eggs as in control. Drilling holes was a more useful treatment to control amount of water loss on incubated eggs than windowing. In experiment 3, amount of water loss increased linearly with increasing number of holes on the blunt end of eggshell. Hepatic 3-hydroxy acyl coenzyme A dehydrogenase activity increased with increasing the number of drilled holes.

Workspace analysis and design improvement of a carotid flow measurement system.

Heart and cerebrovascular diseases such as arteriosclerosis and myocardial ischemia dysfunction are currently among the main causes of death in developed countries. Recently, wave intensity (WI), which is an index used to obtain the force of cardiac contraction, has been investigated as a method for early-stage diagnosis of the above-mentioned diseases. Nevertheless, experimental tests have proven that the manual measurements of WI by means of commercial ultrasonic diagnostic systems require too much time and can be affected by the operator's skills. For this purpose, the introduction of robotic-assisted technology has advantages in terms of repetitiveness and accuracy of the measurement procedure. Therefore, at Waseda University, the development of a carotid blood flow measurement system has been proposed to support doctors while using ultrasound diagnostic equipment to measure the WI. This robotic system is composed of a serial robot with a wrist having a six-degree-of-freedom (6-DOF) parallel mechanism. The main focus is to obtain a suitable workspace performance of the 6-DOF parallel mechanism wrist. In this paper, a workspace analysis is carried out on a wrist prototype built for the Waseda-Tokyo Women's Medical Aloka Blood Flow Measurement System No.1 Refined (WTA-1R). Then, mechanical design enhancements are proposed and validated to provide a suitable workspace performance both as reachable workspace and dexterity, and a refined prototype WTA-1RII has been built.

A new quantum control scheme for multilevel systems based on effective decomposition by intense laser fields.

A new quantum control scheme for general multilevel systems using intense laser fields is proposed. In the present scheme, the target subspace consisting of several quantum levels is effectively isolated by applying intense cw lasers with specific conditions. The formulation is carried out using the Green function with the help of projection operator method. Dynamics of the isolated target subspace is governed by an effective Hamiltonian. The developed scheme is applied to the quantum control of dissipative four- and five-level systems. It is clarified that the present method makes it possible not only to manipulate the coherent population dynamics but also to suppress the dissipative dynamics.

[On-pump coronary artery bypass grafting is still useful for the complete revascularization of low risk patients].

Many clinical studies demonstrate that complete revascularization with total arterial grafts leads to the best late surgical results. Though off-pump coronary artery bypass grafting (CABG) is superior to on-pump CABG (ONCABG) in morbidity and mortality, some coronary surgeons feel it difficult to revascularise multi-vessel disease completely without cardiopulmonary bypass (CPB). Acute conversion from off-pump to on-pump results in increased major complications and high mortality. For the patients with high risk for CPB, coronary revascularization should be performed without CPB even if completeness is failed. It seems to be reasonable to adopt ONCABG for low risk patients who need many anastomoses in the posterior wall of the heart.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS): novel compound heterozygous mutations in the SACS gene.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder first described among French Canadians in Quebec. To date, 24 mutations have been reported in the SACS gene of ARSACS patients. The authors report a clinical and genetic analysis of a Japanese family with ARSACS with novel compound heterozygous mutations in the SACS gene (N161fsX175, L802P). The phenotype is similar to that of previously reported ARSACS patients.

Human corticotropin-releasing factor plus lysine vasopressin test during glucocorticoid therapy.

1.0 micrograms/kg body wt human corticotropin-releasing factor (hCRF) and 0.005 IU/kg body wt lysine vasopressin (LVP) were administered in a bolus dose to patients receiving daily or alternate-day glucocorticoid therapy. In normal subjects with this hCRF-LVP test, the plasma ACTH increment was significantly greater (approximately 2.5-fold) 15 min after injection than under the CRF test. In patients receiving daily glucocorticoid therapy (greater than 15 mg prednisolone or an equivalent daily dose), the plasma ACTH and cortisol responses to hCRF-LVP were suppressed 2 wk to 1 mo after the beginning of glucocorticoid administration but partially improved at 2-10 mo, and was markedly suppressed several years later. On the other hand, in patients receiving alternate-day glucocorticoid therapy, the plasma ACTH response was normal at 2 wk, normal or higher at 1-3 mo, and normal after 4 mo. A normal plasma cortisol response was observed throughout the test period in patients receiving alternate-day therapy after pulse therapy, whereas plasma cortisol response was gradually improved in patients receiving alternate-day therapy after several months of daily therapy.

A factor that regulates the class II major histocompatibility complex gene DPA is a member of a subfamily of zinc finger proteins that includes a Drosophila developmental control protein.

A novel DNA sequence element termed the J element involved in the regulated expression of class II major histocompatibility complex genes was recently described. To study this element and its role in class II gene regulation further, a cDNA library was screened with oligonucleotide probes containing both the S element and the nearby J element of the human DPA gene. Several DNA clones were obtained by this procedure, one of which, clone 18, is reported and characterized here. It encodes a protein predicted to contain 688 amino acid residues, including 11 zinc finger motifs of the C2H2 type in the C-terminal region, that are Krüppel-like in the conservation of the H/C link sequence connecting them. The 160 N-terminal amino acids in the nonfinger region of clone 18 are highly homologous with similar regions of several other human, mouse, and Drosophila sequences, defining a subfamily of Krüppel-like zinc finger proteins termed TAB (tramtrack [ttk]-associated box) here. One of the Drosophila sequences, ttk, is a developmental control gene, while a second does not contain a zinc finger region but encodes a structure important in oocyte development. An acidic activation domain is located between the N-terminal conserved region of clone 18 and its zinc fingers. This protein appears to require both the S and J elements, which are separated by 10 bp for optimal binding. Antisense cDNA to clone 18 inhibited the expression of a reporter construct containing the DPA promoter, indicating its functional importance in the expression of this class II gene.

Sp1-mediated transcription of the Werner helicase gene is modulated by Rb and p53.

The regulation of Werner's syndrome gene (WRN) expression was studied by characterizing the cis-regulatory elements in the promoter region and the trans-activating factors that bind to them. First, we defined the transcription initiation sites and the sequence of the 5' upstream region (2.8 kb) of WRN that contains a number of cis-regulatory elements, including 7 Sp1, 9 retinoblastoma control element (RCE), and 14 AP2 motifs. A region consisting of nucleotides -67 to +160 was identified as the principal promoter of WRN by reporter gene assays in HeLa cells, using a series of WRN promoter-luciferase reporter (WRN-Luc) plasmids that contained the 5'-truncated or mutated WRN upstream regions. In particular, two Sp1 elements proximal to the transcription initiation site are indispensable for WRN promoter activity and bind specifically to Sp1 proteins. The RCE enhances WRN promoter activity. Coexpression of the WRN-Luc plasmids with various dosages of plasmids expressing Rb or p53 in Saos2 cells lacking active Rb and p53 proteins showed that the introduced Rb upregulates WRN promoter activity a maximum of 2. 5-fold, while p53 downregulates it a maximum of 7-fold, both dose dependently. Consistently, the overexpressed Rb and p53 proteins also affected the endogenous WRN mRNA levels in Saos2 cells, resulting in an increase with Rb and a decrease with p53. These findings suggest that WRN expression, like that of other housekeeping genes, is directed mainly by the Sp1 transcriptional control system but is also further modulated by transcription factors, including Rb and p53, that are implicated in the cell cycle, cell senescence, and genomic instability.

Antitumor effect of actinomycin D entrapped in liposomes bearing subunits of tumor-specific monoclonal immunoglobulin M antibody.

Sonicated liposomes containing actinomycin D in the membranes were chemically coated with the subunits of monoclonal immunoglobulin M (IgM) antibody against a mouse mammary tumor-associated antigen (MM antigen) and examined for their in vitro and in vivo antitumor effects against MM46 (MM+) and MM48 (MM-) tumors of C3H/He mouse origin. The antibody-bearing, actinomycin D-containing liposomes (chemoimmunoliposomes) were selectively bound to MM+ tumor cells and showed much more in vitro cytotoxicity against the tumor cells than that shown by free actinomycin D. The in vivo antitumor effect of the chemoimmunoliposomes was tested on the mammary tumor cells (5 X 10(4) to 5 X 10(6) transplanted i.p. into syngeneic mice. A single i.p. injection of the chemoimmunoliposomes containing 0.3, 0.5, or 1 microgram of actinomycin D into MM46 tumor-bearing mice resulted in the cure of some mice and a prolonged survival time in the rest of the mice as compared to results in controls. In this test, free actinomycin D, anti-MM IgM antibody, and bovine serum albumin-coated liposomes containing actinomycin D were marginally effective or ineffective. To examine a systemic antitumor effect of chemoimmunoliposomes, mice were inoculated with MM46 tumor cells and then treated with a single i.v. injection of liposomes 4 days later. If the mice were pretreated with an i.v. injection of unmodified multilamellar liposomes, an injection of the chemoimmunoliposomes containing 1 microgram of actinomycin D resulted in a significant inhibition of tumor growth. Both free actinomycin D and bovine serum albumin-coated liposomes containing actinomycin D were ineffective against the s.c. tumor. These results indicate that an antitumor drug entrapped in the membranes of small sonicated liposomes bearing antitumor monoclonal antibodies can be delivered to antigenic tumor cells and exert more efficient antitumor activity than does the free drug.

Host-mediated therapeutic effects produced by appropriately timed administration of bleomycin on a rat fibrosarcoma.

The timing of bleomycin (BLM) administration after KMT-17 tumor inoculation was found to be important for optimizing its therapeutic effect on tumor-bearing rats. A remarkable therapeutic effect was observed when BLM (5 mg/kg/day) was administered i.p. for 5 days from the eighth day after tumor inoculation (Day 8 to Day 12) rather than when BLM was administered i.p. for 5 days during the days immediately following tumor inoculation (Day 1 and Day 5) (cured rats/treated rats: 10/21 and 2/16, respectively). By means of a Winn assay, stronger tumor-neutralizing activities were observed in spleen cells from BLM (Day 8 to Day 12)-treated tumor-bearing rats than were observed in spleen cells from BLM (Day 1 to Day 5)-treated tumor-bearing rats (% Inhibition: 70.9 and 49.3%, respectively). These therapeutic effects were thus found to be consistent with the antitumor immunity against KMT-17. The enhanced tumor-neutralizing activities of spleen cells from BLM-treated tumor-bearing rats were suppressed by adding spleen cells from nontreated tumor-bearing rats. In cell transfer experiments, an antitumor transplantation resistance in rats immunized with irradiated KMT-17 cells was abrogated by an adoptive transfer of spleen cells from untreated tumor-bearing rats or BLM (Day 1 to Day 5)-treated tumor-bearing rats but not from BLM (Day 8 to Day 12)-treated tumor-bearing rats. These results suggest that, when BLM is administered during a late stage of tumor growth, it is effective in eliminating suppressor cells and that this leads to an improvement in the therapeutic effects of the drug.

Positron emission tomography analysis of metastatic tumor cell trafficking.

Organ-specific colonization of metastatic tumor cells is regulated through complex interactions of specific adhesion molecules on the tumor cell surface with organ specific microvascular endothelium. The present paper shows the real time tumor cell trafficking under the actual blood flow, which became able to be determined using a new technology, positron emission tomography. This technology would be useful to evaluate the interaction of characteristic tumor cells with various organs in vivo. High and low metastatic rat mammary adenocarcinoma cell variants, MTLn3 and MTC, respectively, were labeled with [2-18F]2-fluoro-2-deoxy-D-glucose in vitro. The labeled cells preferentially accumulated in the lungs, in which the disposition was more intense for MTLn3 than for MTC cells especially for the first 2-10 min after injection, apparently reflecting the organ specific interaction of metastatic tumor cells which may lead to metastasis. Such a short time change of cell disposition is easily determined in a living animal by this new technique. Furthermore, sialidase treatment of MTLn3 cells suppressed the accumulation of these cells in lungs, suggesting that some sialyl glycoconjugates on the MTLn3 cell surface play an important role in cell adhesion to lung endothelium. Positron emission tomography scanning thus enables the noninvasive study of the interaction of characteristic tumor cells with specific endothelium in a living animal.

Abnormal telomere dynamics of B-lymphoblastoid cell strains from Werner's syndrome patients transformed by Epstein-Barr virus.

The characteristics of B-lymphoblastoid cell strains transformed by Epstein-Barr virus (EBV) from normal individuals and Werner's syndrome (WRN) patients were compared. We continuously passaged cell strains from 28 WRN patients and 20 normal individuals for about 2 years corresponding to over 160 population doubling levels (PDLs). First, the WRN mutation significantly suppressed the immortalization: all the 28 cell strains from WRN patients, as well as 15 out of 20 cell strains from normal individuals, died out before 160 PDLs mostly without developing a significant telomerase activity. The remaining five cell strains from normal individuals became moderately/strongly telomerase-positive and, three of them were apparently immortalized with an infinitively proliferating activity. Second, the monitoring of the telomere length of both normal and WRN cell strains during the culture period suggests that the WRN gene mutation causes abnormal dynamics of the telomere: (1) a significant proportion of WRN cell strains showed drastic shortening or lengthening of telomere lengths during cell passages compared with normal cell strains, and (2) WRN cell strains terminated their life-span at a wide range of telomere length (between 3.5 and 18.5 Kbp), whereas normal cell strains terminated within a narrow telomere length range (between 5.5 and 9 Kbp). The chromosomal aberration characteristic of WRN cells, including translocation was confirmed in our experiment. We discussed the correlation between the chromosomal instability, abnormal telomere dynamics and inability of immortalization of the WRN B-lymphobloastoid cell strains.