Abstracts of the 24th international isotope society (UK group) symposium: synthesis and applications of labelled compounds 2015.

The 24th annual symposium of the International Isotope Society's United Kingdom Group took place at the Møller Centre, Churchill College, Cambridge, UK on Friday 6th November 2015. The meeting was attended by 77 delegates from academia and industry, the life sciences, chemical, radiochemical and scientific instrument suppliers. Delegates were welcomed by Dr Ken Lawrie (GlaxoSmithKline, UK, chair of the IIS UK group). The subsequent scientific programme consisted of oral presentations, short 'flash' presentations in association with particular posters and poster presentations. The scientific areas covered included isotopic synthesis, regulatory issues, applications of labelled compounds in imaging, isotopic separation and novel chemistry with potential implications for isotopic synthesis. Both short-lived and long-lived isotopes were represented, as were stable isotopes. The symposium was divided into a morning session chaired by Dr Rebekka Hueting (University of Oxford, UK) and afternoon sessions chaired by Dr Sofia Pascu (University of Bath, UK) and by Dr Alan Dowling (Syngenta, UK). The UK meeting concluded with remarks from Dr Ken Lawrie (GlaxoSmithKline, UK).

Periodontal treatment and HbA1c levels in subjects with diabetes mellitus.

It has earlier been reported that individuals with poorly controlled diabetes have severe periodontal disease (PD) compared to well-controlled diabetes. This longitudinal interventional study compared periodontal treatment outcomes with HbA1c level changes in four groups of diabetic and non-diabetic patients with or without PD, respectively. HbA1c, bleeding on probing (BOP), plaque index and periodontal pocket depth (PPD) 4 < 6 mm and ≥6 mm were recorded at baseline to 3 months after non-surgical treatment and 3-6 months for surgical treatment in subjects with or without T2D, and with or without PD. A total of 129 patients were followed from baseline to 6 months. Diabetics with PD and without PD showed reductions in HbA1c levels with a mean value of 0·3% after 3 months and mean values of 1% and 0·8%, respectively, after 6 months. Diabetics with PD showed higher levels of BOP versus non-diabetics without PD (P < 0·01) and versus diabetics without PD (P < 0·05) at baseline. After 6 months, diabetics with PD showed higher number of PPD 4 < 6 mm versus diabetics without PD (P < 0·01) and non-diabetics with PD (P < 0·01). Diabetics without PD showed higher levels of PPD 4 < 6 mm versus non-diabetics without PD (P < 0·01). Surgical and non-surgical periodontal treatment in all groups improved periodontal inflammatory conditions with a decrease in HbA1c levels in a period of three and 6 months. No change was seen in the number of pockets PPD 4 < 6 mm in diabetic subjects with PD after non-surgical and surgical treatment.

Intra-cavitary dosimetry for IMRT head and neck treatment using thermoluminescent dosimeters in a naso-oesophageal tube.

Complex intensity-modulated radiation therapy (IMRT) treatment plans require rigorous quality assurance tests. The aim of this study was to independently verify the delivered dose inside the patient in the region of the treatment site. A flexible naso-gastric tube containing thermoluminescent dosimeters (TLDs) was inserted into the oesophagus via the sinus cavity before the patient's first treatment. Lead markers were also inserted into the tube in order that the TLD positions could be accurately determined from the lateral and anterior-posterior electronic portal images taken prior to treatment. The measured dose was corrected for both daily linac output variations and the estimated dose received from the portal images. The predicted dose for each TLD was determined from the treatment planning system and compared to the measured TLD doses. The results comprise 431 TLD measurements on 43 patients. The mean measured-to-predicted dose ratio was 0.988 +/- 0.011 (95% confidence interval) for measured doses above 0.2 Gy. There was a variation in this ratio when the measurements were separated into low dose (0.2-1.0 Gy), medium dose (1.0-1.8 Gy) and high dose (>1.8 Gy) measurements. The TLD-loaded, naso-oesophageal tube for in vivo dose verification is straightforward to implement, and well tolerated by patients. It provides independent reassurance of the delivered dose for head and neck IMRT.

Self-perceived oral health and salivary proteins in children with type 1 diabetes.

The aim was to validate self-perceived oral health with salivary IgG as an inflammatory parameter in children with type 1 diabetes. Unstimulated whole saliva samples were collected from 36 children with well controlled and 12 with poorly controlled type 1 diabetes and 40 non-diabetic children (Controls). Salivary flow rate, random blood glucose level, salivary protein concentration and immunoglobulin A and G levels were recorded using standard techniques. Data concerning oral health and diabetes status were collected. Self-perceived gingival bleeding (bleeding gums), bad breath and dry mouth were higher in diabetic children when compared with those in controls (P < 0.05). Gingival bleeding was frequently perceived by children with poorly controlled compared to well-controlled type 1 diabetes (P < 0.05) and controls (P < 0.001). Bad breath was common perceived by children with poorly controlled compared to well-controlled type 1 diabetes (P < 0.05) and controls (P < 0.0001). Salivary flow rate was lower in the diabetic children compared to controls (P < 0.01) with no difference between children with poorly controlled and well-controlled type 1 diabetes. Salivary IgG per mg protein concentration was higher in the diabetics when compared with the control group (P < 0.0001). IgG per mg protein levels were also higher in children with poorly controlled when compared with well-controlled type 1 diabetes (P < 0.05). There was no difference in IgA per mg protein and total protein concentrations between children with poorly controlled and well-controlled type 1 diabetes. Self-perceived gingival bleeding and salivary IgG per mg protein concentration were increased in children with type 1 diabetes compared with controls. These variables were also increased in children with poorly controlled compared with well-controlled type 1 diabetes.

Copepods drive large-scale trait-mediated effects in marine plankton.

Fear of predation may influence food webs more than actual predation. However, the mechanisms and magnitude of nonconsumptive predator effects are largely unknown in unicellular-dominated food webs such as marine plankton. We report a general mechanism of chemically induced predator effects in marine plankton. Copepods, the most abundant zooplankton in the oceans, imprint seawater with unique polar lipids-copepodamides-which trigger toxin production and bioluminescence in harmful dinoflagellates. We show that copepodamides also elicit defensive traits in other phytoplankton, inducing the harmful algal bloom-forming diatom Pseudo-nitzschia seriata to produce 10 times more toxins, and colony-forming diatoms to decrease colony size by half. A 1-year study in the northeast Atlantic revealed that natural copepodamide concentrations are high enough to induce harmful algal toxins and size reduction in dominant primary producers when copepods are abundant. We conclude that copepodamides will structure marine plankton toward smaller, more defended life forms on basin-wide scales.

Modulation of gene expression in subjects at risk for colorectal cancer by the chemopreventive dithiolethione oltipraz.

Prolonged exposure to mutagenic substances is strongly associated with an individual's risk of developing colorectal cancer. Clinical investigation of oltipraz as a chemopreventive agent is supported by its induction of the expression of detoxication enzymes in various tissues, and its protective activity against the formation of chemically induced colorectal tumors in animals. The goals of the present study were: to determine if oltipraz could induce detoxicating gene expression in human tissues; to identify effective non-toxic doses for more extensive clinical testing; and to establish a relationship between effects in the colon mucosa and those in a more readily available tissue, the peripheral mononuclear cell. 24 evaluable patients at high risk for colorectal cancer were treated in a dose-finding study with oltipraz 125, 250, 500, or 1,000 mg/m2 as a single oral dose. Biochemical analysis of sequential blood samples and colon mucosal biopsies revealed increases in glutathione transferase activity at the lower dose levels. These effects were not observed at the higher doses. More pronounced changes were observed in detoxicating enzyme gene expression in both tissues at all doses. Peripheral mononuclear cell and colon mRNA content for gamma-glutamylcysteine synthetase (gamma-GCS) and DT-diaphorase increased after dosing to reach a peak on day 2-4 after treatment, and declined to baseline in the subsequent 7-10 d. The extent of induction of gene expression in colon mucosa reached a peak of 5.75-fold for gamma-GCS, and a peak of 4.14-fold for DT-diaphorase at 250 mg/m2 ; higher doses were not more effective. Levels of gamma-GCS and DT-diaphorase correlated closely (P < or = 0.001) between peripheral mononuclear cells and colon mucosa both at baseline and at peak. These findings demonstrate that the administration of minimally toxic agents at low doses may modulate the expression of detoxicating genes in the tissues of individuals at high risk for cancer. Furthermore, peripheral mononuclear cells may be used as a noninvasive surrogate endpoint biomarker for the transcriptional response of normal colon mucosa to drug administration.

Mammography adherence and psychological distress among women at risk for breast cancer.

BACKGROUND: Previous studies estimate that first-degree relatives of women with breast cancer have a twofold to 10-fold increased risk of developing breast cancer. Recently, attention has focused on the mammography screening practices of women who are at high risk for breast cancer. PURPOSE: Our purpose was to characterize mammography screening practices in a sample of first-degree relatives of breast cancer patients and to identify variables that may serve as barriers to or facilitators of adherence to mammography. METHODS: Cross-sectional (rather than prospective) data were collected by telephone interviews with 140 women aged 35-79 years who had a family history of breast cancer in at least one first-degree relative (mother, sister, or daughter). Data were recorded on mammography screening patterns, depression, stress impact, and breast cancer worries. RESULTS: Women whose mammography history adhered to age-specific recommendations varied by age: 76% of first-degree relatives aged 35-39 years, 86% aged 40-49 years, and 63% aged 50 years or more. In bivariate analyses, level of education (P = .001), employment (P = .046), and time since diagnosis of the index patient (P = .044) were significantly and positively associated with mammography adherence. Variables associated negatively with adherence included age (P = .019), intrusive thoughts about breast cancer (P = .042), and breast cancer worries that interfered with daily functioning (P = .004). Multivariate analysis by logistic regression indicated that only breast cancer worries (odds ratio [OR] = 2.5; 95% confidence interval [CI] = 1.09-5.9) and education (OR = 4.8; CI = 1.6-14.3) were significant independent predictors of mammography adherence. CONCLUSIONS: This study suggests that most women at high risk for breast cancer adhere to the recommended mammography screening guidelines of the National Cancer Institute. However, rates of adherence among high-risk women aged 50 years and older are suboptimal; only 63% of these women received annual screening mammograms, and 13% had never been screened. Breast cancer worries may pose a barrier to mammography adherence among high-risk women, particularly those with less formal education. IMPLICATIONS: Prospective longitudinal studies are needed to validate the present findings and to evaluate the impact of psychoeducational interventions for women with affected first-degree relatives.

Phase I/pharmacokinetic reevaluation of thioTEPA.

Because the initial evaluation of N,N',N''-triethylenethiophosphoramide (thioTEPA) preceded the standardized approach to the Phase I trials, uncertainty surrounds the recommended dose. Since it has recently been demonstrated that an almost 100-fold increase in dose can be administered in bone marrow transplant regimens, we conducted a Phase I reevaluation of thioTEPA. ThioTEPA was administered i.v. in 50 ml 5% dextrose in water over 10 min. Twenty-seven patients were entered at doses ranging from 30 to 75 mg/m2. The major toxic effect was myelosuppression; thrombocytopenia greater than or equal to grade 3 occurred in four of seven patients, and leukopenia greater than or equal to grade 3 in two of seven patients at 75 mg/m2. Among eight patients at 65 mg/m2 only two had greater than or equal to grade 3 myelosuppression making this the recommended new phase II dose for the majority of patients. Moderate (grade 2) easily controlled nausea and vomiting was the only other major side effect. There was no alopecia or mucosal or neurological toxicity. Three partial remissions were observed among nine previously treated ovarian cancer patients. Plasma concentrations of thioTEPA and its major active metabolite triethylenephosphoramide (TEPA) were measured by gas chromatography. The half-life of thioTEPA ranged from 51.6 to 211.8 min, and its pharmacokinetics was dose dependent; total body thioTEPA clearance decreased with increasing dose. The half-life of TEPA was considerably longer than that of the parent compound (3.0 to 21.1 h); as a result, the area under the plasma concentration-time curve (AUC) of TEPA was severalfold greater than that of the parent compound. The ratio of TEPA AUC to thioTEPA AUC decreased with increasing dose, suggesting that formation of TEPA is a saturable step in elimination. The AUC and total body clearance of thioTEPA, but not of TEPA, were closely correlated with neutrophil but not platelet toxicity.

Glutathione S-transferase activity and glutathione S-transferase mu expression in subjects with risk for colorectal cancer.

The glutathione S-transferases (alpha, mu, and pi), a family of Phase II detoxication enzymes, play a critical role in protecting the colon mucosa by catalyzing the conjugation of dietary carcinogens with glutathione. We investigated the efficacy of using the glutathione S-transferase (GST) activity of blood lymphocytes and GST-mu expression as biomarkers of risk for colorectal cancer. GST activity was measured in the blood lymphocytes of control individuals (n = 67) and in the blood lymphocytes (n = 60) and colon tissue (n = 34) of individuals at increased risk for colon cancer. Total GST activity was determined spectrophotometrically with the use of 1-chloro-2,4-dinitrobenzene as a substrate. The ability to express the um subclass of GST was determined with the use of an ELISA. Although interindividual variability in the GST activity of blood lymphocytes was greater than 8-fold (range, 16.7-146.8 nmol/min/mg), the GST activity of blood lymphocytes and colon tissue within an individual was constant over time and was unrelated to sex, age, or race. The GST activity of blood lymphocytes from high-risk individuals was significantly lower than that of blood lymphocytes from control individuals (P < or = 0.004). No association was observed between the frequency of GST-mu phenotype and risk for colorectal cancer. Blood lymphocytes from high-risk individuals unable to express GST-mu had lower levels of GST activity than did those from control subjects with the GST-mu null phenotype; however, this difference was significant in male subjects only (P < or = 0.006). Analysis of paired samples of blood lymphocytes and colon tissue indicated a strong correlation between the GST activity of the two tissue types (Spearman's rank correlation, r = 0.87; P < or = 0.0001). The GST activity of blood lymphocytes may be used to identify high-risk individuals with decreased protection from this Phase II detoxication enzyme who may benefit from clinical trials evaluating GST modulators as chemopreventive agents for colorectal cancer. The GST activity of blood lymphocytes may also be used in colorectal cancer chemoprevention trials to monitor the responsiveness of colon tissue to regimens that modify Phase II detoxication enzymes.

Methyl-accepting chemotaxis proteins are distributed in the membrane independently from basal ends of bacterial flagella.

Chemotactic behavior of Escherichia coli involves communication between methyl-accepting chemotaxis proteins and basal ends, the rotary motors of bacterial flagella. Both the proteins and the basal ends are embedded in the cytoplasmic membrane, but the spatial relationship between the two has not been determined. This communication describes a procedure for obtaining a preparation of membrane vesicles enriched in basal ends and thus in the regions of membrane immediately surrounding them. Methyl-accepting chemotaxis proteins were neither enriched nor depleted in this membrane fraction but instead were distributed throughout the membrane. Thus functional linkages between these proteins and flagellar motors must be mediated by processes other than direct physical interaction.

Studies of in vivo electropermeabilization by gamma camera measurements of (99m)Tc-DTPA.

A protocol was developed to study the drug uptake from in vivo electropermeabilization at different settings of parameters influencing the uptake efficiency. Radiolabelled diethylenetriaminepentaacetic acid (DTPA) was used to trace the distribution and internalization of a hydrophilic drug after in vivo electropermeabilization. Skeletal muscle tissue in rat was treated with permeabilizing electric pulses before or after intravenous administration of (99m)Tc-DTPA. The drug accumulation in the treated volume was subsequently evaluated with a scintillation camera. The dependence of uptake on field strength and duration of the applied electric pulses was investigated for exponentially decaying pulses and square wave pulses. Further, the uptake dependence on time interval between injection and pulsation was studied as well as the uptake dependence on the number of pulses applied in a single electropermeabilization treatment. Dynamic gamma camera studies were performed to quantify the time scale of the drug uptake in electropermeabilized tissue.

Cancer risk notification: psychosocial and ethical implications.

Basic and medical science investigations have identified a growing number of risk factors important in carcinogenesis. By communicating cancer risk information in medical practice, we have the potential to motivate high-risk individuals to adhere to cancer prevention and surveillance protocols. However, cancer screening and risk notification might have adverse psychologic and social consequences as well. In this review, we address the psychosocial and ethical implications of cancer risk notification. The literature on the psychosocial impact of cancer screening programs and programs for notifying workers exposed to occupational carcinogens is reviewed critically. In addition, we examine new concerns and responsibilities raised by the emerging field of cancer genetics. Suggestions for future research and for patient education are addressed.

Nonsurgical management of esophageal cancer: report of a study of combined radiotherapy and chemotherapy.

Between October 1980 and December 1985, 50 patients with esophageal cancer were treated with combined radiotherapy and chemotherapy (5-fluorouracil [5-FU] and mitomycin C). Thirty patients with stage I or II disease received definitive treatment consisting of 6,000 cGy in 6 to 7 weeks and 5-FU (1,000 mg/m2/24 h) as a continuous intravenous (IV) infusion for 96 hours, starting on days 2 and 29. Mitomycin C (10 mg/m2) was administered as a bolus injection on day 2. Twenty patients received palliative treatment (5,000 cGy plus chemotherapy) for stage III or IV disease (extraesophageal spread or distant metastases). All patients treated in this program had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Of the 30 definitively treated patients, 23 had squamous cell cancer, while seven had adenocarcinoma. Follow-up ranged from 6 months to 63 months. The complete response rate at 1 to 3 months following completion of treatment was 87% (26 of 30) documented by barium swallow and endoscopy (+/- biopsy). The actuarially determined local relapse-free rate at 1 year and beyond was 73%, and the actuarial survivals at 1, 2, and 5 years were 68%, 47%, and 32%, respectively. Of the 20 palliatively treated patients, ten had squamous cell carcinoma, eight had adenocarcinoma, and two had undifferentiated carcinoma. Seventeen patients were evaluable for freedom from dysphagia 1 or more months following completion of treatment. Eighty-two percent of evaluable patients (14 of 17) had no dysphagia posttreatment, while 64% (11 of 17) remained free of dysphagia until death or last follow-up, emphasizing the significant local control of those patients. The median survival for this group was 8 months. Treatment was well tolerated, and acute toxicity included esophagitis, stomatitis, oral candidiasis, and hematologic toxicities of thrombocytopenia and neutropenia. Late toxicities were predominantly manifested as a mild to moderate benign stricture, which required dilatation in four patients. One patient developed a perforation into the mediastinum in the absence of tumor, while two patients with persistent local disease developed tracheoesophageal fistula, and radiation pneumonitis was observed in two patients. This combination of radiation therapy with infusional 5-FU and mitomycin C is an effective and relatively well-tolerated regimen in the treatment of esophageal cancer. Surgical resection may not be necessary when high-dose radiation and chemotherapy are used.

Telephone counseling improves adherence to colposcopy among lower-income minority women.

PURPOSE: A randomized trial was conducted to evaluate the impact of a telephone counseling intervention to improve patient adherence to colposcopic examination for suspected cervical intraepithelial neoplasia (CIN). METHODS: Subjects were lower-income, minority women who missed a scheduled initial appointment for colposcopy at an urban medical clinic. Patients were randomly assigned to either a control condition (n = 42) or a telephone counseling condition (n = 48). The 15-minute, structured telephone counseling intervention protocol addressed educational, psychosocial, and practical barriers to colposcopy adherence. RESULTS: The most common patient-reported barriers to colposcopy adherence included a lack of understanding of the purpose of colposcopy (50%), worry about or fear of cancer (25%), and forgetting (23%). Telephone counseling was found to be highly effective in addressing these barriers and improving adherence to diagnostic follow-up and treatment. Of patients in the control condition, 43% complied with a rescheduled colposcopy appointment, compared with 67% in the telephone counseling condition. Logistic regression analysis indicated that the effect of telephone counseling was independent of sociodemographic confounder variables (odds ratio = 2.6; P less than .003). Additionally, 74% of patients who received the initial telephone counseling adhered to recommended treatment, compared with 53% of patients in the control condition. CONCLUSION: Brief, structured telephone contact may be a cost-effective mechanism for improving adherence to diagnostic follow-up and treatment for a variety of cancer screening tests.

Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor.

EST 5275 is a phase II and III study of fluorouracil plus streptozocin (5-FU plus STZ) or doxorubicin in patients with measurable progressive carcinoid tumor. Among one hundred seventy-two cases with no prior chemotherapy and no heart disease, the response rate was 22% for 5-FU plus STZ and 21% for doxorubicin, while the median response duration and median survival were 31 weeks and 64 weeks for the combination and 26 weeks and 48 weeks for doxorubicin. Thirty-three patients who failed 5-FU plus STZ crossed over to doxorubicin and achieved an 18% response. Of the thirty-five patients who failed on doxorubicin, 29% responded to 5-FU plus STZ. Hematologic toxicity was similar for both treatments; however, the 5-FU plus STZ patients experienced more vomiting but acceptable renal toxicity. Both chemotherapy regimens have antitumor activity in carcinoid tumors.

Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil--an Eastern Cooperative Oncology Group study.

One hundred ninety-one patients with pathologically confirmed, locally unresectable adenocarcinoma of the stomach (57 patients) and pancreas (91 patients), were randomly allocated to therapy with 5-fluorouracil (5-FU) alone, 600 mg/m2 intravenously (IV) once weekly, or radiation therapy, 4,000 rad, plus adjuvant 5-FU, 600 mg/m2 IV, the first three days of radiotherapy, then follow-up maintenance 5-FU, 600 mg/m2, weekly. Forty-three patients (22%) could not be analyzed because of ineligibility or cancellation, thus 148 patients were evaluable. The median survival time was similar for both treatment programs and for both types of primary carcinoma, and was as follows: gastric primary carcinoma, 5-FU, 9.3 months; 5-FU plus radiotherapy, 8.2 months; pancreatic primary carcinoma, 5-FU, 8.2 months; 5-FU plus radiotherapy, 8.3 months. Substantially more toxicity was experienced by patients treated with the combined modality arm than by those patients receiving 5-FU alone. Severe or worse toxicity experienced by patients with gastric primary carcinoma treated by 5-FU was 19%, and the combined modality arm was 31%. The toxicity experienced by patients with pancreatic primary carcinoma treated with 5-FU was 27%, and the combined modality arm was 51%. Significant prognostic variables included: weight loss in stomach-cancer patients; and performance status, degree of anaplasia, and reduced appetite in pancreas-cancer patients.

Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival analysis.

PURPOSE: To determine the activity and toxicity of combination paclitaxel (24 hours) and carboplatin in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligibility required measurable disease (stage IV or stage IIIB with malignant pleural effusion), Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, absolute neutrophil count > or = 2,000/microL, platelet count > or = 100,000/microL serum creatinine concentration < or = 1.5 mg/dL, and bilirubin level < or = 2 mg/dL. Paclitaxel was initially administered at a dose of 135 mg/m2/d, followed by carboplatin on day 2 at a targeted area under the concentration-time curve (AUC) of 7.5 using the Calvert formula. Granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg subcutaneously (SC) on days 3 to 17 was introduced during the second and subsequent cycles. In patients who sustained less than grade 4 myelosuppression, the paclitaxel dose was sequentially escalated 40 mg/m2 per cycle to a maximum of 215 mg/m2. Treatment was repeated at 3-week intervals for six cycles. RESULTS: From June 1993 through February 1994, 54 patients were enrolled; 53 are assessable for toxicity and response. The median age was 62 years (range, 34 to 84). Sixty-nine percent were male, 65% had adenocarcinoma, and 93% had stage IV disease. Two hundred sixty-eight cycles were administered; 32 patients (59%) completed all six cycles. Twenty-five unanticipated hospitalizations occurred during treatment (9.3% of cycles) in 20 patients (37%). Myelosuppression was the principal toxicity; grade 3 or 4 granulocytopenia occurred in 57% of patients after the first cycle, but decreased to 35% during the second cycle after introduction of G-CSF and consistently remained < or = 22% during subsequent cycles. Seven episodes of neutropenic fever occurred, all during the first cycle. Grade 3 or 4 thrombocytopenia and anemia occurred in 47% and 33% of patients, respectively. Eight patients (15%) required platelet transfusions and 16 (30%) required packed RBC support. Neuropathy, myalgias/arthralgias, and thrombocytopenia, although generally mild, were cumulative. The paclitaxel dose was boosted to 215 mg/m2 in > or = 70% of patients who received three or more cycles. At an AUC of 7.5, the median first-cycle carboplatin dose was 424 mg/m2 (range, 273 to 709 mg/m2). The objective response rate was 62%, with five (9%) complete responses and 28 (53%) partial responses. The median progression-free survival time was 28 weeks and the median survival time 53 weeks. The 1-year survival rate is 54%. CONCLUSION: The paclitaxel-carboplatin combination is active in advanced NSCLC and may enhance survival; it merits further investigation in phase III trials.

Characterization of Agrobacterium tumefaciens virulence proteins induced by the plant factor acetosyringone.

The Ti plasmid virulence (vir) loci encode functions essential for the transfer of the T-DNA element from Agrobacterium tumefaciens to plant cells. The expression of these loci is specifically signaled by plant phenolics such as acetosyringone. Here, we characterize the protein products that are induced in Agrobacterium grown in the presence of acetosyringone. More than 10 to 15 proteins are induced in strains harboring different Ti plasmids. Two general classes of acetosyringone-induced proteins are observed, encoded either within or outside the vir region. Synthesis of both classes of proteins requires acetosyringone and the products of the vir regulatory genes A and G. Those proteins encoded outside the vir region define a novel category of proteins, the virulence-related proteins, which are both chromosomally and Ti plasmid-encoded. The molecular weight and subcellular localization of several pTiA6 vir-induced proteins are identified. The most abundant induced protein has a molecular weight of 65,000, and is the single product of the virE locus; this protein distributes into both cell envelope and soluble fractions. Three proteins with molecular weights of approximately 33,000, 80,000 and 25,000 fractionate with the cell envelope and are encoded by genes within the 5' half of the virB locus. The envelope localization of the virB proteins suggests that they play a role in directing T-DNA transfer events that occur at the bacterial surface.

Preclinical and clinical evaluation of broccoli supplements as inducers of glutathione S-transferase activity.

Previous studies suggest that cruciferous vegetables may provide protection against carcinogen exposure by inducing detoxification enzymes. ICR(Ha) mice were gavaged with broccoli tablets (1 g/kg), and colon tissues were collected after treatment. Glutathione S-transferase (GST) activity was assayed and peaked on days 1 and 2 after treatment, respectively (P = 0.03). Elevations in GST activity were attributed to the increased expression of mu and pi. These data supported a clinical assessment of broccoli supplements. Twenty-nine subjects at increased risk for colorectal cancer were randomized to group 1 (no cruciferous vegetables) or group 2 (broccoli supplements, 3 g/day) for 14 days. Blood samples and colon biopsies were obtained pre- and postintervention. No significant difference was observed between the GST activities of the control and broccoli supplementation groups posttreatment. Mean lymphocyte GST activity was 107% of baseline in the broccoli supplementation group (range, 79-158%) and 102% of baseline in the control group (range, 75-158 percent;). Correlation of the GST activities of blood lymphocytes and colon mucosa taken simultaneously suggested that the GST activity of blood lymphocytes may be used as a biomarker of the responsiveness of colon tissue to chemopreventive regimens. Future clinical studies evaluating cruciferous vegetables should consider using concentrated dietary supplements in subjects with a previous history of colorectal cancer.

The LAMB1 gene from the clubmoss, Lycopodium annotinum, is a divergent MADS-box gene, expressed specifically in sporogenic structures.

Transcription factors encoded by the large MADS-box gene family have important developmental functions in angiosperms, the flowering plants. Mutations in certain MADS-box genes are known to cause homeotic alterations in floral organ identity, and the establishment of floral organ identity is the most well-studied developmental process in which MADS-box genes are known to function. Our interest is in the potential connection between the duplication history of this gene family and the evolutionary origin of the structures that the different MADS-box genes developmentally regulate in plants. Previous studies have demonstrated that the origin of the MADS-box genes that control floral organ identity predate the evolutionary origin of the flower itself, since gymnosperms have genes that are orthologous to angiosperm floral homeotic MADS-box genes, whereas ferns appear to lack such genes. Here we report on the isolation of a MADS-box gene from Lycopodium annotinum, which belongs to the clubmosses, the phylogenetic sister group to other vascular plants. The gene, LAMB1, in the sporophyte is expressed exclusively in the reproductive structure, the strobilus, during sporogenesis. LAMB1 is similar to other plant MADS-box genes in that it contains a MADS-box as well as a second conserved element, a K-box. However, it differs in length and in exon/intron structure in the region between the MADS- and K-box, and also in the length and structure of the C-terminal region. A phylogenetic analysis indicates that LAMB1 is not closely related to other plant-type MADS-box genes, and may represent one of the basal branches in the phylogenetic tree of plant MADS-box genes.