Tumor-to-tumor metastasis: lung cancer within a thymoma.

Tumor-to-tumor metastasis is a rare phenomenon. We present a rare case of an 83-year-old man with pulmonary squamous cell carcinoma and thymoma. Thymectomy and superior segmentectomy of the left lower lobe were successfully performed on the patient. This thymoma had a region of lung cancer. Metastasis from other tumors to thymoma is rare, and we found a report that described a pancreatic carcinoma metastasizing to thymoma. We report an extremely rare case of metastasis from lung cancer to a thymoma.

Quantitative Modeling and Simulation in PMDA: A Japanese Regulatory Perspective.

In Japan in October 2016, the Pharmaceuticals and Medical Devices Agency (PMDA) began to receive electronic data in new drug applications (NDAs). These electronic data are useful to conduct regulatory assessment of sponsors' submissions and contribute to the PMDA's research. In this article, we summarize the number of submissions of quantitative modeling and simulation (M&S) documents in NDAs in Japan, and we describe our current thinking and activities about quantitative M&S in PMDA.

Analysis of transcriptional control elements in the 5'-upstream region of ovine interferon-tau gene using feeder-independent caprine trophoblast cell line, HTS-1.

Interferon-tau (IFNtau) is a protein secreted from the embryonic trophectoderm of ruminant ungulates during peri-implantation period. This protein acts on the uterine endometrium, which indirectly maintains corpus luteum function, and is therefore considered essential for the process of maternal recognition of pregnancy. Transcriptional regulation of IFNtau genes had been examined using human choriocarcinoma cell lines, JEG-3 or JAR, however, molecular mechanisms by which cell and term specific IFNtau expression are regulated have not been elucidated. Recently, a feeder cell free-trophoblast cell line derived from Shiba-goat placenta, termed HTS-1, was established. In the present investigation, the 5'-upstream region of ovine IFNtau (oIFNtau) gene was analysed using this cell line, which would provide a more suitable system for studies of the ovine trophoblast specific gene than human choriocarcinoma cells. Variously modified 5'-upstream sequences of the oIFNtau gene fused to a luciferase reporter gene were transiently transfected into HTS-1 cells, and human JEG-3 cells were used as a control. These results and co-transfection with expression vectors revealed that Ets-2 binding site in the promoter region was important in HTS-1, whereas AP-1 that binds to the enhancer region was a major activator in JEG-3. By electrophoretic mobility shift assay, a nuclear protein from HTS-1 cells was confirmed to bind specifically to the Ets-2 site of oIFNtau promoter region. Differences in amounts of AP-1 and Ets-2 protein were demonstrated in nuclear extracts from HTS-1, JEG-3 and ovine conceptuses. Substantial differences on oIFNtau gene transcriptions found between caprine HTS-1 and human JEG-3 cells suggest that this cell line could be valuable in the elucidation of a molecular mechanism(s) by which oIFNtau gene expression is regulated in a cell specific manner.

Cdk2-dependent and -independent pathways in E2F-mediated S phase induction.

The transcription factor E2F plays an important role in G(1) to S phase transition in the higher eukaryotic cell cycle. Although a number of E2F-inducible genes have been identified, the biochemical cascades from E2F to the S phase entry remain to be investigated. In this study, we generated stably transfected mouse NIH3T3 cells that express exogenous human E2F-1 under the control of a heavy metal-inducible metallothionein promoter and analyzed the molecular mechanism of the E2F-1-mediated initiation of chromosomal DNA replication. Ectopic E2F-1 expression in cells arrested in G(0)/G(1) by serum deprivation enabled them to progress through G(1) and to enter S phase. During the G(1) progression, mouse cyclin E, but little of cyclin D1, was induced to express, which subsequently activated Cdk2. Experiments using the Cdk inhibitory proteins p27, p18, and p19 proved that the activity of Cdk2, but not of Cdk4, was required for S phase entry mediated by E2F-1. Minichromosome maintenance proteins (MCM) 4 and 7, the components of the DNA-replication initiation complex (RC), were constitutively expressed during the cell cycle, although the MCM genes are well known E2F-inducible genes. However, tight association of these two proteins with chromatin depended upon ectopic E2F-1 expression. In contrast, the Cdc45 protein, another RC component, which turned out to be a transcriptional target of E2Fs, was induced to express and subsequently bound to chromatin in response to E2F-1. Experiments utilizing a chemical Cdk-specific inhibitor, butyrolactone I, revealed that Cdk2 activity was required only for chromatin binding of the Cdc45 proteins, and not for the expression of Cdc45 or chromatin binding of MCM4 and -7. These results indicate that at least two separate pathways function downstream of E2F to initiate S phase; one depends upon the activity of Cdk2 and the other does not.

Time-course curves of enzyme reactions with dilute substrates can be determined from the reverse reactions.

We present a novel and useful principle that can be applied to enzyme reactions with dilute substrates and enables to obtain the desired time-course curve from the reverse reaction when the latter can be measured more easily. Let us imagine an enzyme mixture that can catalyze the interconversion between substances A, B, C,.... If one substance (sufficiently dilute) is added to the mixture as the substrate and the time-course curve of the concentration of another substance is followed, then, "the time-course curve of A-->B" (which is the time-course curve of the concentration of substance B when substance A is added as the substrate) and that of the reverse reaction B-->A will coincide when plotted at appropriate scales of magnitude. Similar relation holds on any pair of substances even if they are widely separated in any type of reaction scheme. The principle was proved mathematically and holds on any first-order reaction network and can be applied on an enzyme reaction with a dilute substrate because it is reduced to a first-order reaction network. An example of experimental application of this principle is also given.

[The biological activity of vitamin E].

The relative biopotency of alpha-(RRR(d)-, 2-ambo (dl)-and all-rac (dl)), beta-, gamma- and delta-tocopherol, tocotrienol homologues and tocopherol derivatives are summarized in the tables. The new United States Pharmacopoeia [USP] XXII-NFXVII (1990) does not mention the USP (International) Unit of the six different forms of alpha-tocopherol that has indicated the difference in biopotency between d-alpha-tocopherol and dl-(2- ambo)-alpha-tocopherol and been used for 40 years from 1950. Metabolic and bio-discrimination studies of tocopherols are necessary to determine the precise relative biopotency of d-(RRR)-and dl-(all-rac)-alpha tocopherol. The synergistic effect of all-rac-alpha- tocopherol with its 8 stereoisomers and the biotransformation from beta-, gamma-and delta-to alpha-tocopherol are also subjects for further study of the biological activity of tocopherols.

[Colorimetric studies on hiding effect of Cosmotech porcelain for laminate restoration].

The hiding effect on color tone of discolored teeth restored with ceramic laminate veneer crown was examined. Translucent (T1, T2), Enamel (E1, E2, E3), Dentin (DA2, DA3, DB2, DB3), Masking dentin (MDA2, MDA3, MDB2, MDB3) in 13 colors and Modifire (M61, M62, M65, M66, M67, M68, M69, M70, M79) in 7 colors of the ceramic materials (Cosmotech porcelain G C Co., Ltd) were examined in this experiments. The colorimetric examination of the color tone backing with the white or black color was carried out by testing for color difference (delta E*ab), value difference (delta L*), chrom and hue of the samples. The result obtained were as follows; 1. Color difference was higher in order of T2 greater than T1 in Translucent greater than E1 greater than E3 greater than E2 in Enamel greater than DB3 greater than DA2 greater than DA3 greater than DB2 in Dentin greater than MDB3 greater than MDA2 greater than MDB2 greater than MDA3 in Masking dentin, and M69 greater than M79 greater than M70 greater than M68 greater than M66 greater than M61 greater than M62 greater than M67 greater than M65 in Modifire. 2. Value difference was higher in order of T2 greater than T1 in Translucent greater than E1 greater than E3 greater than E2 in Enamel greater than DB3 greater than DA2 greater than DB2 greater than DA3 in Dentin greater than MDA2 greater than MDB3 greater than MDB2 greater than MDA3 in Masking dentin, and M69 greater than M70 greater than M79 greater than M68 greater than M66 greater than M61 greater than M67 greater than M65 greater than M62 in Modifire.(ABSTRACT TRUNCATED AT 250 WORDS)

Study of estimation of color recognition on the dentist. On the ability of subjects to discriminate color in terms of hue, value and chroma.

The tooth crown color space model was manufactured and the improvement of the color representation and communication on the dental clinic have been trying. The study of color discrimination by dentist and student viewing with the use of tooth crown color chips reported here in basic knowledge on the color sensitivity of human eye. The test card were 55 x 90 mm in size and the color chip, 5 x 10 mm. The paired color chips were placed on the test card to have a 2 mm distance between them. Color difference of two tooth crown color chips on the test cards was 3.5 (delta E*ab), the combination of hue, value and chroma was constant of all cards. The subjects were 22 people, 6 dentists and 16 dental school students with normal color sensibility. In proportion of method of comparison for surface color (JIS Z 8723), the subject observed the test card which were different of hue, value and chroma on the their naked-eye, were investigated to evaluate their judgement of the test cards. The following results were obtained. The standard of judgment for the color discrimination was made firstly in terms of hue, secondly in terms of value, and thirdly in terms of chroma.

Clinical evaluations of the tumor marker sialyl SSEA-1 antigen for clinical gynecological disease.

Sialyl SSEA-1 antigen (SLX) is a highly specific tumor marker composed of sugar chain antigens that have Lewis X at their terminals and bind to sialic acid. This antigen is rarely detected in normal tissues, and is present in adenocarcinoma and fetal tissues. We studied the clinical usefulness of SLX in gynecological patients and obtained the following results. (1) The antigen was frequently positive in patients with ovarian cancer with a mean of 89.5 +/- 48.3 U/ml (72.8%, 8/11) and in those with endometriosis with a mean of 39.8 +/- 10.3 U/ml (75.0%, 6/8). (2) Among the gynecological malignancies, the percent positivity was low in those with cervical cancer (20.0%, 5/25), endometrial cancer (33.3%, 1/3), and cancer of the fallopian tube (33.3%, 1/3). (3) The antigen was negative in 20 with myoma uteri, 20 normal pregnant women, and 9 nonpregnant healthy women during the follicular, luteal, or menstrual phase. It was negative in 8 of 9 patients with benign ovarian cyst. False negative results were rare. (4) The SLX level was higher in the ascites than in the serum in patients with ovarian cancer and in those with benign ovarian tumors. (5) The serum SLX in patients with ovarian cancer, which was positive before tumor resection, became negative 2 weeks postoperatively. These results suggest that SLX is a tumor marker with a high specificity to adenocarcinoma of the reproductive organs.

Differential diagnosis of ovarian cancer, benign ovarian tumor and endometriosis by a combination assay of serum sialyl SSEA-1 antigen and CA125 levels.

We used a combination assay of serum sialyl SSEA-1 antigen (SLX) and CA125 levels, and evaluated the clinical usefulness of this technique for a differential diagnosis of ovarian cancer, benign ovarian tumor and endometriosis. In 82 patients with ovarian tumors, the sera of 20 (64.5%) of 31 with ovarian cancer and 15 (48.4%) of the 31 with endometriosis (endometrial cyst) were positive for both SLX and CA125, but serum SLX level was 5 U/ml or less in these 14 SLX- and CA125-positive patients with endometriosis. The sera of 16 (80.0%) patients with benign ovarian tumor were negative for both tumor markers. The sera of 3 (9.7%) of 31 with ovarian cancer and the sera of 2 (6.5%) of 31 with endometriosis were negative for both markers. The diagnostic accuracy (true positive rate X true negative rate) of the combination assay for ovarian cancer was 49.0% when the cutoff value of the serum SLX was 38 U/ml but improved to 78.5% when the value was set at 50 U/ml. When the cutoff value of serum SLX was set at 50 U/ml and that of serum CA125 at 35 U/ml, 27 of 37 patients who were positive only for CA125 had endometriosis. From the above observations, a combination assay of serum SLX and CA125 is a promising method for the differential diagnosis of malignant and benign ovarian tumors. Our results also suggest that to improve the diagnostic accuracy, the cutoff value of the serum SLX level should be 50 U/ml for ovarian tumors alone.

[The cytoimmunological effect of concomitant use of sizofiran (SPG) on advanced uterine cervical cancer treated with radiation].

The immunological effect has been studied of the non-specific immunopotentiator sizofiran (SPG) on patients with advanced uterine cervical cancer treated with radiation. Ten cases (study group: SPG group) were administered weekly 40 mg of SPG throughout the course of radiation and two weekly 40 mg during 12 months after radiotherapy. Nineteen cases (control group) were treated with irradiation alone. The lymphocyte count, the PHA index and the ratio of CD4 cells/CD8 cells were significantly reduced by radiotherapy, being observed the most remarkable decrease at post-radiotherapy. But in SPG group, these decreasing values were significantly smaller than in control group and the values showed a more progressive rise during the 12 month respectively. There was no significant difference in peripheral T lymphocyte; CD3, CD4, CD8. The NK cytotoxic activity showed a progressive rise during the 12 month period following a minimal change after radiotherapy. These results suggest that the SPG have some enhancing effect on the function of the lymphocytes.

[Diagnosis and follow-up of ovarian cancer by a combination assay of serum sialyl SSEA-1 antigen and CA125 levels].

We used a combination assay of serum sialyl SSEA-1 antigen (SLX) and CA125 levels, and evaluated the clinical usefulness of this technique for a diagnosis of ovarian cancer and follow-up of the patient with ovarian cancer. In 28 patients with ovarian tumors, the sera of 8 (66.7%) of 12 with ovarian cancer and 5 (71.4%) of the 7 with endometriosis (endometrial cyst) were positive for both SLX and CA125, but serum SLX level was 50 U/ml or less in all these 5 SLX-and-CA125 positive patients with endometriosis. The sera of all 9 patients with benign ovarian tumor were negative for both tumor markers. No patient with endometriosis was negative for both markers. The diagnostic accuracy (true positive rate X true negative rate) of the combination assay for ovarian cancer was 50.3% when the cut-off value of the serum SLX was 38 U/ml but improved to 81.8% when the value was set at 50 U/ml. From the above observations, a combination assay of serum SLX and CA125 is promising method for the differential diagnosis of malignant and benign ovarian tumors. Our results also suggest that to improve the diagnostic accuracy, the cut-off value of the serum SLX level should be 50 U/ml for ovarian tumors alone. We found following-up two cases of ovarian cancer that the serum SLX level is not affected by the ascites and inflammation. We expect that this combination assay of serum SLX and serum CA125 will be beneficial for diagnosis and follow-up of ovarian cancer.

[Effects of nicotinate ethyl ester treatment on gingival blood circulation of experimental gingivitis in monkeys].

The effects of nicotinate ethyl ester treatment on the gingival blood circulation of plaque induced inflammation in monkeys were determined. The blood flow, amount of hemoglobin and oxyhemoglobin rate (oxyhemoglobin/total hemoglobin) in gingival blood circulation in addition to bacterial colony forming units (CFU), gingival index (GI), probing depth (PD), loss of attachment (LA) and amount of gingival crevicular fluid (GCF) were used as parameters. Besides 1% nicotinate ethyl ester paste (nicotinate paste), 0.5% chlorhexidine (CHX) paste as an antibacterial agent, a mixture of the two pastes and the base alone as a control were used. 1. The blood flow, amount of hemoglobin, CFU, GCF, PD and GI increased as inflammation developed, and these showed significant correlations. 2. The oxyhemoglobin rate showed no corresponding change with inflammation. 3. Nicotinate paste, CHX paste and the mixed paste seemed to reduce the inflammation of the gingiva as assessed by the blood flow, hemoglobin amount, CFU and GCF amount compared with the control paste.

Serum CA 125 as a marker for patients with external endometriosis.

Serum CA 125 levels were assayed in 75 healthy female controls and 34 patients with external endometriosis prior to treatment, during treatment, and after treatment. The results of the assay showed that the mean pretreatment serum CA 125 level of the patients with external endometriosis (80.7 U/mL) was significantly (P less than .001) higher than that of the controls (17.9 U/mL). This difference was even more pronounced for those patients with progressive (stage III or IV) endometriosis (mean = 114.0 U/mL). Thus, the assay of serum CA 125 may be useful as an auxiliary tool in the diagnosis of progressive endometriosis. Although the high pretreatment level of serum CA 125 decreased after danazol treatment of 400 mg/day to within the normal limits, usually within 4 to 12 weeks, laparoscopic examinations indicated that most of the endometriosis cases were not cured until 12-16 weeks of danazol treatment.

[Studies of intra-arterial hypertensive chemotherapy with cisplatin and peplomycin in advanced cancer of the uterine cervix--suitable dose of angiotensin II determined by intra-arterial digital subtraction angiography].

UNLABELLED: We have been treating advanced cancer of the cervix uteri with intra-arterial cisplatin (CDDP) and peplomycin (PEP) (injected into the bilateral internal iliac artery), combined with radiotherapy and hysterectomy. Concomitant angiotensin II (ATII) administered by intravenous drip infusion was found to double tumoral blood flow and thereby to enhance the efficiency of the intra-arterial chemotherapeutic regimen. In the present study, hypertensive intra-arterial chemotherapy utilizing ATII was administered to a small group of patients with advanced cancer of the cervix uteri while ascertaining the increase in intratumoral blood flow by intra-arterial digital subtraction angiography. The subjects were 10 patients with stage IIb or more advanced cancer of the cervix uteri. RESULTS: A 2-fold or greater increase in tumoral blood flow was attained in those patients who showed concurrently a 1.5 fold or greater increase in mean blood pressure and an increase in mean blood pressure to 150mmHg or higher. In 2 patients, ATII infusion failed to raise blood pressure to a therapeutically adequate level. At 1 week after the treatment in question histological evidence indicated unequivocal degenerative changes and necrotic changes in tumor cells. Many plasma cells, lymphocytes + and granulocytes appeared around necrosis changed carcinoma nests.

Ultrasonic evaluation of fallopian tube carcinoma.

Primary malignant neoplasms of the fallopian tube are the least common of all the gynecologic malignancies, and constitute only about 0.1-1% of all such malignancies. The actual 5-year survival is 64% in those with stage I, 60% in cases of stage II, and 18% and 25% for stages III and IV, respectively. Therefore, early detection of these neoplasm stages is most important to attain a cure. The preoperative diagnosis of this neoplasm has rarely been reported because these lesions are not common. We present herein the clinical and sonographic features in 4 Japanese women with fallopian tube carcinoma. While the sonographic features alone are not distinct enough to establish a definite preoperative diagnosis, the findings as seen in our patients suggest inclusion of tubal carcinoma in the differential diagnosis.

Clinical usefulness of determination of CA 125 levels in the serum and menstrual blood.

We measured CA 125 levels in sera and menstrual blood of subjects with a normal ovulatory cycle and in those with endometriosis. Serum CA 125 levels were higher in the latter, in each phase of the menstrual cycle. The CA 125 levels in patients with endometriosis, particularly those with adenomyosis, tend to be higher than in those with a normal ovulatory cycle. We propose that measurement of CA 125 in the menstrual blood may be able to help distinguishing adenomyosis from myoma uteri and may also help in assessing clinical endometriosis.

Statistical analysis of channel current from a membrane patch. I. Some stochastic properties of ion channels or molecular systems in equilibrium.

The stochastic behavior of single-channel current in a steady-state has been interpreted as the channel's state transitions between several open and shut states, and these transitions have been regarded as a homogeneous Markov process. When a channel is in equilibrium, the principle of detailed balance holds for every step in the state transition scheme. Here we show two stochastic properties of a channel, or any molecule obeying a reversible state transition scheme, under the constraint of detailed balance. First, the distribution functions and the probability density functions of shut or open dwell-time are expressed by the sum of exponential terms with positive coefficients. The same holds for the time-dependent open (or shut) frequency after the shut (or open) transition. Second, the time course of state transition from the state SI to SJ (PI,J(t] is proportional to its reverse transition time course (PJ,I(t], even if SI and SJ are widely separated. The same relation holds also for a transition scheme having transition pathways to the absorbing states. If analysis of a channel current record shows it to be incompatible with either of these two properties, the channel is not in equilibrium but in a steady-state with an energy-consuming cyclic flow. These two properties are also useful for the analysis of any molecular process obeying a homogeneous Markov process or a network of first-order chemical reactions.

Statistical analysis of channel current from a membrane patch. II. A stochastic theory of a multi-channel system in the steady-state.

A general stochastic theory is presented for analysis of current records of a patch containing an arbitrary number (N) of independent homologous channels in the steady-state. We give the "basic theorem" that at the instant of any open (or shut) transition of a channel, the other N-1 channels are located in each state with a probability equal to those in the steady-state, if enough transitions are observed. Using the "basic theorem", we derived: (a) the time-dependent open and shut frequencies after a definite type of transition, and (b) the probability density functions (pdf) of the duration of any period between two successive transitions. Briefly, the main results obtained were: (1) The time-dependent open (or shut) transition frequency after every shut (or open) transition at t = 0 in an N-channel patch, fJSh,Op(t)(N) (or fJOp,Sh(t)(N)), is the same as that of a one-channel patch except for the value of the constant. (2) In the all-shut (or all-open) period of a patch, the average duration of the period is 1/N, and the slowest exponential decay constant contained in the pdf is N times those of a single channel patch, respectively. (3) An example calculation for small N showed that the stochastic properties of a single channel can be obtained even when N is uncertain, if the channel open probability is small and exponential decay constants are separated. (4) When the channels are in equilibrium, the pdf of duration of every type of period in the patch is described by a sum of exponential terms with positive coefficients. This also holds for fJSh,Op(t)(N) and fJOp,Sh(t)(N).