X-ray microdiffraction, TEM characterization and texture analysis of human dentin and enamel.

Human tooth is a complex bioceramic composite, which consists of enamel, dentin and the interface, the dentin-enamel junction (DEJ). The crystal properties and ultrastructure of the inorganic phase through the thickness of healthy human molar teeth were investigated using X-ray microdiffraction (µXRD), electron diffraction and transmission electron microscopy (TEM) techniques. The XRD data were analysed using the Le Bail profile fitting approach. The size and the texture of the crystallites forming enamel and dentin in the crown part of teeth were measured using both techniques and then compared. Results showed that the thickness of dentin crystallites was found to decrease towards the DEJ, whereas the thickness of the enamel crystallites increased from the DEJ towards the outer layers. It was demonstrated that enamel exhibited an increase of texture in 002 lattice planes from the DEJ towards the outer layers. Texture was also detected in 102 lattice planes. The texture effect in 002 planes at the scale of less than 1 µm was also demonstrated in dentin. The variation of lattice parameters as a function of the position within the thickness of dentin and enamel was also observed. The values of the nonuniform microstrain in the dentin and enamel crystallites were from 1.40 × 10(-6) % to 4.44 × 10(-5) %. The good correlation between XRD and TEM indicated that µXRD is a useful technique to study crystallography and microstructure of heterogeneous enamel and dentin. The observed gradient characteristics of texture and crystallite size in enamel and dentin maybe an evolutionary outcome to resist wear and fracture, thereby contributing to the excellent mechanical properties of teeth.

Cyclic biological expression in mouse mammary tumors.

Biological characteristics were assessed in GR mouse mammary tumors during 22 serial transplantations. Although unidirectional progression from hormone dependency to independency was observed, other biological markers such as progesterone receptors, polyploid frequency and thymidine kinase activity demonstrated cyclic phenomena every fourth to sixth transplant generation, suggesting the continued presence of regulatory mechanisms among various cells subpopulations.

Elastic anomalies associated with transformation sequences in perovskites: II. The strontium zirconate-titanate Sr(Zr,Ti)O(3) solid solution series.

The sequence of phase transitions due to octahedral tilting across the Sr(Zr,Ti)O(3) solid solution series has been investigated by resonant ultrasound spectroscopy at high and low temperatures using ceramic samples. The elastic behaviour associated with phase transitions as a function of composition in Sr(Zr,Ti)O(3) at room temperature is proposed to be analogous to that as a function of temperature in SrZrO(3), with the [Formula: see text] transition at SrZr(0.57)Ti(0.43)O(3), [Formula: see text] at SrZr(0.35)Ti(0.65)O(3), and [Formula: see text] at SrZr(0.05)Ti(0.95)O(3). Changes in elastic constants and acoustic dissipation with temperature have been analysed for samples across the compositional range. The intermediate phases, I4/mcm and what is assumed to be Imma, appear to have stability fields across the full compositional range and both show large dissipation effects, most probably due to twin wall mobility. In contrast, the Zr-rich Pnma phase, which should contain transformation twin walls, is an unexpectedly stiff and non-dissipating material, similar to the high temperature and/or Ti-rich [Formula: see text] phase. In the case of Pnma, this is attributed to coupling between the two order parameters, which could impede relaxation responses to an applied stress. The [Formula: see text] structure is a classically stiff cubic perovskite and no transformation-related dissipation processes are expected.

Effect of structure and thermodynamic stability on the response of lanthanide stannate pyrochlores to ion beam irradiation.

The lanthanide stannates, Ln2Sn2O7, Ln=La-Lu and Y, have the isometric pyrochlore structure, A2B2O7, and their structural properties have been refined by Rietveld analysis of powder neutron and synchrotron X-ray diffraction data. In this study, the enthalpies of formation of selected stannate pyrochlores, Ln=La, Nd, Sm, Eu, Dy, and Yb, were measured by high-temperature oxide melt solution calorimetry. Their radiation response was determined by 1 MeV Kr2+ ion irradiation combined with in situ TEM observation over the temperature range of 25 to 1000 K. The enthalpy of formation from binary oxides of stannate pyrochlores became more endothermic (from -145 to -40 kJ/mol) as the size of the lanthanide in the A-site decreases. A more exothermic trend of the enthalpy of formation was observed in stannate pyrochlores with larger lanthanide ions, particularly La, possibly as a result of increased covalency in the Sn-O bond. In contrast to lanthanide titanate pyrochlores, Ln2Ti2O7, that are generally susceptible to radiation-induced amorphization and zirconate pyrochlores, Ln2Zr2O7, that are generally resistant to radiation-induced amorphization, the lanthanide stannate pyrochlores show a much greater variation in their response to ion irradiation. La, Nd, and Gd stannates experience the radiation-induced transformation to the aperiodic state, and the critical amorphization temperatures are approximately 960, 700, and 350 K, respectively. Y and Er stannate pyrochlores cannot be amorphized by ion beam irradiation, even at 25 K, and instead disorder to a defect fluorite structure. Comparison of the calorimetric and ion irradiation data for titanate, zirconate, and stannate pyrochlores reveals a strong correlation among subtle changes in crystal structure with changing composition, the energetics of the disordering process, and the temperature above which the material can no longer be amorphized. In summary, as the structure approaches the ideal, ordered pyrochlore structure, radiation-induced amorphization is more easily attained. This is consistent with an increasingly exothermic trend in the enthalpies of formation of pyrochlores from the oxides, that is, the greater the thermochemical stability of the pyrochlore structure, the more likely it will be amorphized upon radiation damage rather than recover to a disordered fluorite structure.

Up-regulation of estrogen receptors by nonsteroidal antiestrogens in human breast cancer.

Development of resistance to hormonal therapy in breast cancer is frequently associated with a decline or loss of cellular estrogen receptors. Agents which up-regulate the receptor may reduce the incidence of hormonal resistance. Antiestrogens at concentrations ranging from 0.1 to 1 microM produced a 2- to 4-fold increase of estrogen receptors in MCF-7 and T-47D breast cancer cells. This increase, which occurred as early as 3 h and was sustained throughout the 4 days of continuous exposure to tamoxifen, was primarily due to an enhancement in receptor synthesis.

Circadian stage dependence of cis-diamminedichloroplatinum lethal toxicity in rats.

Renal physiology is circadian rhythmic. The major toxicity of cis-diamminedichloroplatinum (cisplatin) is irreversible renal damage. A single dose of cisplatin (11 mg/kg) was given to groups of standardized female Fischer 344 rats at one of six equispaced circadian stages. A statistically significant effect of time of injection upon tolerance was found by chi 2 analysis. Differences of 3- to 8-fold in survival rate of 50% mortality and a nearly 3-fold difference in long-term survival depended on circadian timing of cisplatin administration. Cisplatin timing resulting in optimal tolerance was similar from study to study. Additional 0.9% NaCl solution was administered with cisplatin in three experiments and resulted in an increase in overall mean survival time. It also resulted in an amplification of the survival rhythm without changing its timing. The increase in survival resulting from 0.9% NaCl solution loading, when compared to controls receiving cisplatin alone, was also highly time dependent. A 52% improvement in mean survival time was achieved in those animals receiving cisplatin and 0.9% NaCl solution at the most favorable circadian stage, as compared to a 20% improvement when this regimen was administered at an inopportune circadian stage. The safest time for cisplatin administration is near the midactivity span, shortly after the maximum of the circadian rhythm in rectal temperature.

Binding characteristics of zearalenone analogs to estrogen receptors.

The estrogenic effect of zearalenone derivatives was investigated for their binding characteristics to cytosol and nuclear receptors in the uterus. Competition with 17beta-estradiol at the cytosol receptor sites was observed in four of the six derivatives tested, namely trans- and cis-zearalenone, zearalenol, and zearalanol. The other two, 8'-hydroxyzearalenone and 6'-aminozearalene, lacked the binding ability to receptors and were biologically inactive. trans-Zearalenone, like 17beta-estradiol, could elicit an immediate translocation of cytosol-receptor complexes into the uterine nuclei. However, it differs from either 17beta-estradiol or antiestrogens (tamoxifen) in three aspects: (a) a second wave of translocation occurred 6 to 12 hr following zearalenone injection; (b) there was a much longer nuclear retention (over 24 hr) than in the case of 17beta-estradiol; and (c) following a depletion of cytosol receptors, trans-zearalenone induced an overreplenishment by 24 hr, whereas tamoxifen is reported to suppress the replenishment.

Acute changes of alpha-fetoprotein and human chorionic gonadotropin during induction chemotherapy of germ cell tumors.

Thirty-seven consecutive patients with germ cell cancers (34 testicular, three extragonadal) and elevated serum levels of alpha-fetoprotein (AFP) and/or human chorionic gonadotropin (HCG) were treated with vinblastine, bleomycin, and cis-diamminedichloroplatinum induction chemotherapy. The AFP and/or HCG normalized in 36 patients. The AFP half-life was 7.9 days between Days 1 and 21 postchemotherapy but 6.0 days between Days 21 and 42 (p less than 0.05). The prolonged AFP half-life between Days 1 and 21 was related to a median increase of 57.5% (range, 22 to 219%) in the AFP level. This increase in the marker value occurred between Days 2 and 9 of therapy (median, Day 5). There was also a median increase of 181% (range, 27 to 600%) in the HCG level at a median of 5 days after the start of therapy. The increase in the AFP and HCG levels occurred in 63 and 70% of evaluable patients, respectively, and correlated with the presence of a large volume of metastatic disease (chi 2 = 8.87). Patients with relapsed or refractory disease had prolongation of the AFP half-life between Days 21 and 42 as compared to nonrelapsed patients. AFP and HCG half-life calculations should be used in the management of patients with germ cell cancers.

Reduction of cis-diamminedichloroplatinum nephrotoxicity in rats by optimal circadian drug timing.

A prominent circadian rhythm in the nephrotoxicity of a therapeutic dose of cis-diamminedichloroplatinum (cisplatin) is demonstrated in female Fischer rats. Rats were randomized to receive two doses of either cisplatin or 0.9% NaCl solution 14 days apart at the times of either high or low values in their circadian rhythm of urinary volume. Toxicity was assessed by measuring changes in body weight and changes in the 24-hr means of urinary volume, blood urea nitrogen, and urinary beta-N-acetylglucosaminidase (NAG) activity. Toxicity was least in rats which received the drug near the circadian maximum of urinary volume. Conversely, rats which received the same dose of drug near the circadian minimum of urinary volume lost more weight and exhibited a 2-fold increase in the 24-hr mean of urinary volume, a 3-fold rise in the 24-hr mean of blood urea nitrogen, and a 5-fold increase in the 24-hr mean of urinary NAG activity. A positive correlation between urinary NAG at the time of cisplatin administration and the extent of cisplatin nephrotoxicity was demonstrated (p less than 0.02). A correlation also was found between tissue NAG concentration and tissue uptake of cisplatin (p less than 0.001). A marked circadian rhythm of NAG activity in proximal tubular cells may contribute to the prominent circadian rhythm in murine renal tolerance for cisplatin.

Multivariate analysis of prognostic variables in patients with metastatic testicular cancer.

A majority of patients with metastatic testicular cancer achieve a complete remission as a result of current treatment programs. However, patients who fail to achieve a complete remission have a very poor prognosis, and nearly all die of their disease. A multivariate logistic regression analysis of several clinical variables associated with prognosis was performed using data from 171 patients treated for metastatic testicular cancer at Memorial Hospital between September 1975 and February 1981. A mathematical model was identified which correctly predicted 94% of complete remissions and 83% of all outcomes. The variables achieving statistical significance were the logarithm of the serum values of lactate dehydrogenase (p less than 0.001) and human chorionic gonadotropin (p less than 0.001) and the total number of sites of metastasis (p less than 0.001). The model was tested against 49 patients with metastatic testicular cancer treated at the University of Minnesota Hospitals, and it correctly predicted 86% of complete remissions and 84% of all outcomes. In a highly curable disease such as testicular cancer, mathematical modeling may enable the clinical investigator to anticipate those patients who are least likely to do well. Alternate treatment strategies would be appropriate for such patients.

Nb K-edge x-ray absorption investigation of the pressure induced amorphization in A-site deficient double perovskite La1/3NbO3.

Nb K-edge x-ray absorption spectroscopy is utilized to investigate the changes in the local structure of the A-site deficient double perovskite La1/3NbO3 which undergoes a pressure induced irreversible amorphization. EXAFS results show that with increasing pressure up to 7.5 GPa, the average Nb-O bond distance decreases in agreement with the expected compression and tilting of the NbO6 octahedra. On the contrary, above 7.5 GPa, the average Nb-O bond distance show a tendency to increase. Significant changes in the Nb K-edge XANES spectrum with evident low energy shift of the pre-peak and the absorption edge is found to happen in La1/3NbO3 above 6.3 GPa. These changes evidence a gradual reduction of the Nb cations from Nb(5+) towards Nb(4+) above 6.3 GPa. Such a valence change accompanied by the elongation of the average Nb-O bond distances in the octahedra, introduces repulsion forces between non-bonding adjacent oxygen anions in the unoccupied A-sites. Above a critical pressure, the Nb reduction mechanism can no longer be sustained by the changing local structure and amorphization occurs, apparently due to the build-up of local strain. EXAFS and XANES results indicate two distinct pressure regimes having different local and electronic response in the La1/3NbO3 system before the occurence of the pressure induced amorphization at ∼14.5 GPa.

Medical oncology manpower training: a position statement of the American Society of Clinical Oncology.

The evolution of Medical Oncology is facing its first major crisis, that of oversupply of trained oncologists. The tabulated number of certified medical oncologists does not constitute all of the physicians practicing Medical Oncology in the United States. Because of the adequate supply of medical oncologists in clinical practice, but a deficiency of academic oncologists dedicated to research careers, a reduction in training programs should emphasize those programs that lack research opportunities. These recommendations are in keeping with the report of the Long-Range Planning Committee of the American Society of Clinical Oncology of March 21, 1984. Plans to expedite these goals are being established.

Stage II nonseminomatous testicular cancer: a 10-year experience.

Between 1970 and 1980, 82 patients with pathologic stage II nonseminomatous germ cell testicular carcinoma were treated at the University of Minnesota. Of the 30 patients treated with a retroperitoneal lymph node dissection, 22 (77%) relapsed. Of the 18 patients treated with retroperitoneal lymph node dissection and adjuvant radiotherapy, 12 (63%) relapsed. Sixteen patients received adjuvant chemotherapy before 1976, and 14 (87.5%) relapsed. After 1976, 18 patients received adjuvant chemotherapy (11 with cisplatin) and 2 (11%) have relapsed. No patient treated with cisplatin-based adjuvant chemotherapy has relapsed. The toxicity has been modest. Cisplatin-based chemotherapy is an effective and a safe adjuvant therapy for stage II nonseminomatous germ cell testicular carcinoma.

Use of Truquant BR radioimmunoassay for early detection of breast cancer recurrence in patients with stage II and stage III disease.

PURPOSE: The Truquant BR radioimmunoassay (RIA) (Biomira Diagnostics Inc, Rexdale, Canada) uses the monoclonal antibody B27.29 to quantitate the MUC-1 gene product (CA 27.29 antigen) in serum. We evaluated CA 27.29 antigen in a controlled, prospective clinical trial for its ability to predict relapse in stage II and stage III breast cancer patients. PATIENTS AND METHODS: Over a 2-year period, 166 patients who had completed therapy for stage II (80.1%) or III (19.9%) breast cancer and were clinically free of disease were serially tested for CA 27.29 antigen levels. The study was double-masked and cancer recurrence was documented based on clinical findings. Patients with two consecutive CA 27.29 antigen test results above the upper limit of normal were considered positive. RESULTS: The Truquant BR RIA had a sensitivity of 57.7%, specificity of 97.9%, positive predictive value of 83.3%, and negative predictive value of 92.6%. The recurrence rate was 15.7%. A Cox regression analysis showed that the only variable to correlate with recurrent disease was the CA 27.29 antigen test result. Patients with a positive test result had increased odds of having a recurrence (odds ratio, 6.8; P < .00001). The test was effective in predicting recurrence in patients with both distant and locoregional disease. In a subgroup of patients with bone pain, CA 27.29 antigen level was found to identify reliably patients who would subsequently develop recurrent disease. CONCLUSION: These data demonstrate that the Truquant BR RIA can be used as an aid to predict recurrent breast cancer in patients with stage II and III disease.

Four-drug combination chemotherapy (methotrexate, cyclophosphamide, hexamethylmelamine, and CCNU) for non-small cell bronchogenic carcinoma: a Cancer and Leukemia Group B study.

Ninety-eight evaluable patients with nonresectable regional or metastatic non-small cell bronchogenic carcinoma were treated with a four-drug combination chemotherapy program of methotrexate, cyclophosphamide, hexamethylmelamine, and CCNU (MCHC). Fifteen partial or complete responses (15%) were obtained, all but one of which occurred in good performance status (0-1) patients. While "responders lived longer than non-responders", this was due more to initial performance status among responding patients than to achievement of partial (greater than 50%) or complete disease regression. Evaluation of those patients with good performance status (PS 0-1), indicated no statistically significant differences in median survival time for complete response and partial response patients compared to patients with "improved" or "stable" disease status in this group. This combination of modestly active single agents produced disappointing results in our lung cancer population. A search for more active single agents in lung cancer is necessary.

Long-term survival of patients with Hodgkin's disease. Treatment with cyclophosphamide, vinblastine, procarbazine, and prednisone.

Thirty-eight patients with advanced Hodgkin's disease were treated with a combination of cyclophosphamide, vinblastine, procarbazine, and prednisone (CVPP); the minimum period of observation for surviving patients was five years. Twenty-eight patients (74%) achieved complete remission; in 17 (61%), remissions lasted at least five years. Twenty-five (66%) of the 38 patients survived more than five years from the initiation of CVPP. There were no differences in either rates or duration of response when evaluation was performed for multiple pretreatment clinical features. However, survival was adversely influenced by advanced age, nodular sclerosis histologic subtype, and pretreatment bone marrow involvement. Two patients died, in remission, of overwhelming viral infections, and acute nonlymphocytic leukemia developed in one patient. In another patient, aseptic necrosis of the heads of both femora developed. Our data suggest that treatment with CVPP may result in long-term disease-free survival for patients with advanced Hodgkin's disease.

Mechanism of the hypocalcemic effect of mithramycin.

Mithramycin is effective in the treatment of hypercalcemia. The mechanism of its hypocalcemic effect was studied in six patients with hypercalcemia by serum 85Sr or 45Ca kinetic techniques. Mithramycin was given at two dosage levels (25 or 50 microgram/kg iv). Mithramycin at the low dosage had little effect on the rate of bone accretion. However, at both dosage levels, mithramycin caused an upward shift of the slope of the specific activity curve, indicating an inhibitory effect on bone resorption. This effect started 6-12 h after a 25-microgram/kg dose of mithramycin and lasted from 4-6 days. It appears that mithramycin has a preferential effect on bone resorption.

The evolution of hydroxyurea therapy in chronic myelogenous leukemia.

The evolution of hydroxyurea as a chemotherapeutic agent has been unique. Hydroxyurea inhibits synthesis of DNA, has antitumor activity, and is myelosuppressive. It has attained a significant role in the management of chronic myelogenous leukemia. A nonrandomized comparison of busulfan and hydroxyurea concluded that hydroxyurea was the preferable agent in the treatment of chronic myelogenous leukemia and was associated with less life-threatening toxicity. Because of its systemic effects, hydroxyurea is also used in the treatment of polycythemia and psoriasis.

Lack of age-dependent cisplatin nephrotoxicity.

Cisplatin nephrotoxicity was evaluated by serial pretreatment and post-treatment 24-hour creatinine clearance determinations in 43 patients who received 295 monthly infusions of 60 mg/m2 of this drug. An aggressive standard hydration protocol was used without diuretic administration. Fourteen of these patients had a single kidney. Older patients and patients with a single kidney had lower pretreatment creatinine clearances when compared with younger persons with two functioning kidneys. Older and younger patients with two kidneys had an equal, progressive, dose-related deterioration of renal function. Renal function did not decline in persons with a single kidney but did so markedly in those with two kidneys. When administered at 60 mg/m2, cisplatin dose or schedule modification is not indicated on the basis of advancing age or decreased renal function secondary to the surgical loss or total ureteral obstruction of one kidney.

VP-16-213 (etoposide): the mandrake root from Issyk-Kul.

VP-16-213 (etoposide) is an orally and parenterally active antineoplastic agent synthesized from podophyllum extracts of a common North American plant, the May apple or mandrake. The drug delays and kills cells in the G2 phase of the cell cycle and is active in a variety of animal tumors and leukemias. Major therapeutic activity for the drug has been found in small cell bronchogenic carcinoma, germ cell malignancies, acute non-lymphocytic leukemia, Hodgkin's disease and non-HOdgkin's lymphoma. Minor therapeutic activity of the drug occurs in non-small cell bronchogenic carcinoma, pediatric neoplasms, hepatocellular carcinoma and gastric cancer. Toxicity is primarily hematologic, with alopecia, nausea and vomiting occurring less frequently.