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D Francis

Publications and source records attributed to D Francis.

At least 19 recordsLinked to original sources
PubMed2006

Sequencing of chemotherapy and radiation therapy for early breast cancer.

BACKGROUND: After surgery for localised breast cancer, adjuvant radiotherapy improves both local control and breast cancer specific survival. In patients at risk of harbouring micro-metastatic disease, adjuvant chemotherapy improves 15-year survival. However, the best sequence of administering these two types of adjuvant therapy for early stage breast cancer is not clear. OBJECTIVES: To determine the effects of different sequencing of chemotherapy and radiotherapy for women with early breast cancer. SEARCH STRATEGY: We searched the Cochrane Breast Cancer Group Specialized Register (10 March 2005). Details of the search strategy and methods of coding are described in the Group's module in The Cochrane Library. We extracted studies that had been coded as 'early', 'chemotherapy' and 'radiotherapy'. SELECTION CRITERIA: Randomised controlled trials evaluating different sequencing of chemotherapy and radiotherapy were included. DATA COLLECTION AND ANALYSIS: We assessed the eligibility and quality of the identified studies and extracted data from the published reports of the included studies. We derived odds ratios (OR) and risk ratios from the available numerical data. Hazard ratios were extracted directly from text. Toxicity data were extracted, where reported. We used a fixed-effect model for meta-analysis and conducted analyses on the basis of the method of sequencing of the two treatments. MAIN RESULTS: Three trials reporting two different sequencing comparisons were identified. There were no significant differences between the various methods of sequencing adjuvant therapy for survival, distant metastases or local recurrence, based on 853 randomised patients in two trials. One of these two trials (647 women) provided data on toxicity. Haematological toxicity (OR 1.43, confidence interval (CI) 1.01 to 2.03) and oesophageal toxicity (OR 1.44, CI 1.03 to 2.02) were significantly increased with concurrent therapy, and nausea and vomiting were significantly decreased (OR 0.70, CI 0.50 to 0.98). Other measures of toxicity did not differ between the two types of sequencing. On the basis of one trial (244 women), radiotherapy before chemotherapy was associated with a significantly increased risk of neutropenic sepsis (OR 2.96, 95% CI 1.26 to 6.98) compared with chemotherapy before radiotherapy, but other measures of toxicity were not significantly different. AUTHORS' CONCLUSIONS: The data included in this review, from three well conducted randomised trials, suggest that different methods of sequencing chemotherapy and radiotherapy do not appear to have a major effect on survival or recurrence for women with breast cancer if radiation therapy is commenced within 7 months after surgery.

Breast Neoplasms↗
PubMed2006

Maternal separation alters serotonergic transporter densities and serotonergic 1A receptors in rat brain.

RATIONALE: The basic mechanisms underlying the association between early life maternal separation and adulthood psychiatric disorders are largely unknown. One possible candidate is the central serotonergic system, which is also abnormal in psychiatric illnesses. Neuroadaptational changes in serotonergic transporter and serotonergic 1A receptors may underlie links between early life stress and adulthood psychiatric disorders. OBJECTIVE: The aim of this study was to investigate the consequences of a rat model of maternal separation on serotonergic transporter and serotonergic 1A receptor densities and function in adult rat forebrain. METHODS: Rat pups were separated from dams from postnatal day 2 to postnatal day 14, each day, for zero time, 15 min and 180 min to determine the time-course of effects. A non-handled group was added to control for the effects of handling by an experimenter compared with the animal facility-reared group. Quantitative [(125)I]3beta-(4-iodophenyl)tropan-2beta-carboxylic acid methyl ester and [(125)I]-mPPI autoradiography was used to determine serotonergic transporter and serotonergic 1A densities, respectively. Adult rats were challenged with saline or serotonergic 1A agonist (+) 8-hydroxy-2-(di-n-propylamino)tetralin, 0.4 mg/kg, s.c.) and plasma adrenocorticotropic hormone and corticosterone were determined. RESULTS: serotonergic transporter and serotonergic 1A densities were significantly lower in the non-handled group in the paraventricular, arcuate, dorsomedial and ventromedial nuclei of the hypothalamus. The non-handled group also displayed lower serotonergic transporter and serotonergic 1A densities in the basolateral anterior, basolateral ventral and basomedial amygdaloid nuclei. Serotonergic transporter densities were also decreased in the CA3 area of the hippocampus in the non-handled group. In contrast, the maternal separation 15 min group displayed the highest serotonergic transporter and serotonergic 1A densities in the basomedial nucleus of amygdala, basolateral anterior nucleus of amygdala, basolateral ventral nucleus of amygdala and basomedial nucleus of amygdala amygdaloid nuclei. CONCLUSIONS: Early life maternal separation and the extent of handling can alter adult brain serotonergic transporter and serotonergic 1A levels and function in the forebrain. Alterations in these serotonergic systems by early rearing conditions might increase vulnerability for behavioral disorders in adulthood.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2005

Photodynamic therapy with topical methyl aminolaevulinate for 'difficult-to-treat' basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) may be difficult to treat by conventional means, particularly if the lesions are large or located in the mid-face (H-zone). Photodynamic therapy (PDT) using topical methyl aminolaevulinate (MAL) may be a good noninvasive option for these patients. OBJECTIVES: To investigate the efficacy and safety of PDT using MAL for BCCs defined as 'difficult to treat', i.e. large lesions, in the H-zone, or in patients at high risk of surgical complications. METHODS: This was a prospective, multicentre, noncomparative study. Patients were assessed 3, 12 and 24 months after the last PDT treatment. One hundred and two patients with 'difficult-to-treat' BCC were treated with MAL PDT, using 160 mg g(-1) cream and 75 J cm(-2) red light (570-670 nm), after lesion preparation and 3 h of cream exposure. Results Ninety-five patients with 148 lesions were included in the per protocol analysis. The histologically confirmed lesion complete response rate at 3 months was 89% (131 of 148). At 12 months, 10 lesions had reappeared, and therefore the cumulative treatment failure rate was 18% (27 of 148). At 24 months, an additional nine lesions had reappeared, resulting in a cumulative treatment failure rate of 24% (36 of 148). The estimated sustained lesion complete response rate (assessed using a time-to-event approach) was 90% at 3 months, 84% at 12 months and 78% at 24 months. Overall cosmetic outcome was judged as excellent or good in 79% and 84% of the patients at 12 and 24 months, respectively. Follow-up is continuing for up to 5 years. CONCLUSIONS: MAL PDT is an attractive option for 'difficult-to-treat' BCC. Because of the excellent cosmetic results, the treatment is particularly well suited for lesions that would otherwise require extensive surgical procedures.

Administration, Topical↗
PubMed2005

The Arabidopsis CDC25 induces a short cell length when overexpressed in fission yeast: evidence for cell cycle function.

The putative mitotic inducer gene, Arath;CDC25 cloned in Arabidopsis thaliana, was screened for cell cycle function by overexpressing it in Schizosaccharomyces pombe (fission yeast). The expression pattern of Arath;CDC25 was also examined in different tissues of A. thaliana. Fission yeast was transformed with plasmids pREP1 and pREP81 with the Arath;CDC25 gene under the control of the thiamine-repressible nmt promoter. Using reverse transcription-polymerase chain reaction (RT-PCR), the expression of Arath;CDC25 was examined in seedlings, flower buds, mature leaves and stems of A. thaliana; actin (ACT2) was used as a control. In three independent transformants of fission yeast, cultured in the absence of thiamine (T), pREP1::Arath;CDC25 induced a highly significant reduction in mitotic cell length compared with wild type, pREP::Arath;CDC25 +T, and empty vector (pREP1 +/- T). The extent of cell shortening was greater using the stronger pREP1 compared with the weaker pREP81. However, Arath;CDC25 was expressed at low levels in all tissues examined. The data indicate that Arath;CDC25 can function as a mitotic accelerator in fission yeast. However, unlike other plant cell cycle genes, expression of Arath;CDC25 was not enhanced in rapidly dividing compared with non-proliferative Arabidopsis tissues.

Arabidopsis↗
PubMed2005

Expression of fission yeast cdc25 driven by the wheat ADP-glucose pyrophosphorylase large subunit promoter reduces pollen viability and prevents transmission of the transgene in wheat.

Cell number was to be measured in wheat (Triticum aestivum) endosperm expressing Spcdc25 (a fission yeast cell-cycle regulator) controlled by a supposedly endosperm-specific promoter, AGP2 (from the large subunit of ADP glucose pyrophosphorylase). Wheat was transformed by biolistics either with AGP2::GUS or AGP2::Spcdc25. PCR and RT-PCR checked integration and expression of the transgene, respectively. In cv. Chinese Spring, AGP2::GUS was unexpectedly expressed in carpels and pollen, as well as endosperm. In cv. Cadenza, three AGP2::Spcdc25 plants, AGP2::Spcdc25.1, .2 and .3, were generated. Spcdc25 expression was detected in mature leaves of AGP2::Spcdc25.1/.3 which exhibited abnormal spikes, 50% pollen viability and low seed set per plant; both were small compared with the nonexpressing and normal AGP2::Spcdc25.2. Spcdc25 was not transmitted to the T(1) in AGP2::Spcdc25.1 or .3, which developed normally. Spcdc25 was PCR-positive in AGP2::Spcdc25.2, using primers for a central portion, but not with primers for the 5' end, of the ORF, indicating a rearrangement; Spcdc25 was not expressed in either T(0) or T(1). The AGP2 promoter is not tissue-specific and Spcdc25 expression disrupted reproduction.

Gene Expression Regulation, Plant↗
PubMed2005

In closely monitored patients, adherence in the first month predicts completion of therapy for latent tuberculosis infection.

BACKGROUND: Current therapy for latent TB infection (LTBI) is long, and requires close follow-up. This results in sub-optimal adherence-the major reason for failure of therapy. METHODS: In an open label randomised trial comparing 4 months of rifampicin with 9 months of isoniazid, the proportion and regularity of doses taken, measured with an electronic monitoring system (MEMS), and provider estimates of adherence in the first month of therapy, were assessed as predictors of treatment completion. RESULTS: Of 104 patients analysed, 86 took more than 80% of doses within the expected interval, 11 took more than 80% of doses but over a longer time interval than usually allowed, and seven did not complete treatment. Treatment completion was associated with the number of doses taken, and the variability of intervals between doses during the first month of treatment. CONCLUSIONS: Adherence in the first month, based on the number of doses and variability of times when taken, could be useful to predict completion of LTBI therapy. Interventions could be targeted to patients with suboptimal adherence in the first month.

Adult↗
PubMed2004

Differential expression of putative floral genes in Pharbitis nil shoot apices cultured on glucose compared with sucrose.

If, following an inductive treatment of 2 d of continuous darkness, shoot apices of Pharbitis nil are cultured 1 d later on White's medium supplemented with 2% sucrose, they cannot form carpels, but they can if they are cultured on 2% glucose. It was hypothesized that the differential effect of these sugars was because of differential expression of carpel-specific genes. Partial cDNA homologues to the Arabidopsis genes, LEAFY (PnLFY), AGAMOUS (PnAG1/2), and CRABS CLAWS (PnCRC1/2) were cloned. PnLFY was expressed in the shoot apex 1 d following the start of induction and remained higher than in non-induced apices for a further 6 d before exhibiting a major peak of expression on day 7. Peaks of expression of PnAG1 and PnAG2 spanned days 7-11, coinciding with the appearance of stamens and then carpels. The Pharbitis 'PnCRC2' showed greatest homology to Arabidopsis YABBY2 (PnYABBY). Its expression peaked on day 8 when the carpels first appeared. 'PnCRC1' showed greatest homology to Arabidopsis FILAMENTOUS (PnFIL). Its expression was approximately the same in inductive and non-inductive treatments. Apart from PnFIL these partial cDNAs could be used as markers to test the hypothesis concerning differential effects of sucrose and glucose. Cultured shoot apices from induced plants were sampled at weekly intervals. All four genes were expressed more strongly in the glucose compared with the sucrose treatment, most notably at day 17. A more intensive sampling (days 15-19) indicated that PnLFY and PnYABBY exhibited much higher expression on glucose compared with sucrose, most notably on days 15-16 and days 18-19.

Arabidopsis↗
PubMed2004

Comparison of methodologies for the in vivo assessment of 18FLT utilisation in colorectal cancer.

Fluorine-18 3'-deoxy-3'-fluorothymidine (18FLT) is a tissue proliferation marker which has been suggested as a new tumour-specific imaging tracer in positron emission tomography (PET). The objectives of this study were to investigate the pharmacokinetics of 18FLT in patients with colorectal cancer, defining methodologies for the quantitative analysis of the in vivo 18FLT uptake and subsequently assessing the accuracy of semi-quantitative measures. Dynamic acquisitions over a single field of view of interest identified by computed tomography were carried out for up to 60 min following injection of 18FLT (360 +/- 25 MBq). Dynamic arterial blood sampling was carried out in order to provide a blood input function. Simultaneous venous samples were also taken in order to investigate their potential utilisation in deriving a hybrid input function. Arterial and venous blood samples at 5, 15, 30, 60 and 90 min p.i. were used for metabolite analysis. Eleven patients with primary and/or metastatic colorectal cancer were studied on a lesion by lesion basis (n = 21). All acquired images were reconstructed using ordered subsets expectation maximisation and segmented attenuation correction. Time-activity curves were derived by image region of interest (ROI) analysis and image-based input functions were obtained using abdominal or thoracic aorta ROIs. Standardised uptake values (SUVs) were calculated to provide semi-quantitative indices of uptake, while non-linear regression (NLR) methodology in association with a three-compartment model and Patlak analysis were carried out to derive the net influx constant Ki. The metabolite analysis revealed two radioactive metabolites, with the parent compound representing approximately 80% of the total radioactivity in the 30-min plasma sample. In the case of NLR, better fits were obtained with a 3k model (i.e. k4 = 0) for both lesion and bone marrow time-activity curves. For the same lesions, a high correlation was observed between the Ki derived from either Patlak analysis or NLR(3k) and the corresponding SUVs. Our results also suggest that the quantitative behaviour of 18FLT in vivo (up to 60 min p.i.) may be characterised using a 3k model or Patlak analysis in combination with image-derived input functions. The good correlation found between the SUVs (at 60 min) and Ki values supports the use of semi-quantitative indices to assess the proliferation rate of colorectal cancer lesions in vivo with 18FLT.

Aged↗
PubMed2003

A comparison of photodynamic therapy using topical methyl aminolevulinate (Metvix) with single cycle cryotherapy in patients with actinic keratosis: a prospective, randomized study.

BACKGROUND: Actinic keratosis (AK) is a very common condition, which has the potential of progressing to squamous cell carcinoma. The present study is a prospective, randomized study comparing the lesion response, cosmetic outcome, patient satisfaction and tolerability of a new treatment modality, photodynamic therapy (PDT), using topical methyl aminolevulinate (Metvix), with the most commonly used standard therapy for AK, cryotherapy. METHODS: A total of 204 patients with clinically diagnosed AK were randomized to either cryotherapy or PDT. The PDT patients were further assigned to an active or placebo group in a random, double-blind manner. Cryotherapy was performed using liquid nitrogen spray in a single freeze-thaw cycle. PDT was performed using 160 mg/g methyl aminolevulinate cream or placebo, a 3-hour application time, red light (570-670 nm) and a total light dose of 75 J/cm(2). PDT was repeated after 7 days. Two sessions of PDT were undertaken, as a previous study had shown a single session had similar efficacy to cryotherapy. Lesion response was assessed clinically after 3 months (complete response or non-complete response). RESULTS: The lesion response rate was 91% in the methyl aminolevulinate PDT group, 68% in the cryotherapy group and 30% in the placebo PDT group. Methyl aminolevulinate PDT was statistically significantly better than both cryotherapy and placebo PDT in terms of response rates and cosmetic outcome. Most patients preferred PDT to other treatments. CONCLUSIONS: PDT with methyl aminolevulinate is an excellent treatment option, particularly for patients with widespread damage or AK lesions in cosmetically sensitive areas.

Administration, Cutaneous↗
PubMed2002

Tissue Doppler analysis of age-dependency in diastolic ventricular behaviour and filling: a cross-sectional study of healthy hearts (the Umeå General Population Heart Study).

BACKGROUND: Much in the diagnosis of diastolic ventricular dysfunction is dependent upon the filling pattern, and most patients diagnosed with diastolic heart failure are elderly. Data from healthy asymptomatic individuals across a range of ages are rare. We sought to find an age-related variation in normal diastolic physiology, specifically the filling pattern and segmental myocardial longitudinal velocities. METHODS AND RESULTS: To assess the effect of normal ageing on left ventricular longitudinal function, we studied myocardial shortening and lengthening velocities using the tissue Doppler technique in 60 healthy subjects who were randomly selected from the Umeå (Sweden) General Population Register, which represents a wide range of ages (23-88 years). Myocardial velocities were documented at four left ventricular sites (anterior, left, posterior and septal) and at three levels (basal, mid-cavity and apical). Transmitral, transtricuspid and pulmonary venous flow velocities were recorded using pulsed-wave Doppler. While systolic myocardial velocities were conserved across ages, there was a marked decrease in early diastolic velocities with age (from 16 cm. s(-1)at 30 years to 9 cm. s(-1)at 80 years at the basal segment) and a corresponding significant increase in late diastolic velocities (from 10 to 16 cm. s(-1)). Although these findings were most marked at the basal level, they were also clearly manifested at the apical level. Myocardial lengthening velocities were related to transmitral flow velocities, showing a correlation of 0.64 (P<0.0001) in early diastole and 0.68 (P<0.0001) in late diastole. Finally, diastolic pulmonary venous flow velocity was found to correlate with early diastolic myocardial velocities (at the basal level, r=0.53, P<0.0001). CONCLUSIONS: Normal ageing causes a decrease in early diastolic and a substantial increase in late diastolic myocardial lengthening velocities. These changes explain the known trends in the transmitral flow pattern with age. In contrast, systolic myocardial velocities do not change significantly with age. These findings should be considered when evaluating diastolic function, especially in the elderly.

Adult↗
PubMed2001

Recombinant HIV-1 glycoprotein 120 induces distinct types of delayed hypersensitivity in persons with or without pre-existing immunologic memory.

Induction of T cell help is critical in HIV-1 control and potentially in prevention by immunization. A practical approach is needed to identify HIV-1-specific helper activities in vivo. We explored the feasibility of measuring delayed-type hypersensitivity (DTH) following intradermal injection of recombinant soluble HIV-1(MN) glycoprotein 120 in HIV-1-infected, vaccinated, and exposed individuals. DTH reactions were elicited within 48 h in 16 of 29 untreated, infected patients and in 24 of 30 uninfected vaccinees. Concomitant envelope-specific lymphoproliferation in vitro was undetectable among 9 infected patients tested with positive envelope-specific DTH. By contrast, no 48-h DTH reactions occurred among 25 high risk and 32 low risk, uninfected volunteers. However, 7--12 days after injection, 10 (40%) high risk and 11 (34%) low risk individuals developed induration resembling DTH, and the cellular infiltrates contained monocytes and T cells. Five of 18 examined also developed anti-gp120 Abs. The very delayed time course and lack of correlation with previous Ag exposure clearly distinguish this reaction from DTH. Thus, HIV-1 skin testing can identify persons with HIV-specific recall responses resulting from infection, in the absence of in vitro lymphoproliferation, and from vaccination. In contrast, very late reactivities may signify chemotactic properties of the envelope protein and/or herald the induction of primary HIV-specific Th1-type immunity.

AIDS Vaccines↗
PubMed2001

QS-21 promotes an adjuvant effect allowing for reduced antigen dose during HIV-1 envelope subunit immunization in humans.

Three separate studies were undertaken in HIV-1 uninfected persons to determine if the adjuvant QS-21 improves the magnitude or kinetics of immune responses induced by recombinant soluble gp120 HIV-1(MN) protein (rsgp120) immunization. The QS-21 was administered at two doses (50 and 100 microg), either alone or in combination with aluminum hydroxide (600 microg). At the highest doses of rsgp120 (100, 300, and 600 microg), QS-21 exerted no significant effect on either binding or neutralizing antibody titers. Antibody binding and neutralizing responses fell dramatically when rsgp120, formulated with alum alone, was given at low doses (3 and 30 microg). In contrast, antibody responses similar in titer to those in the high dose antigen groups were induced with the low dose rsgp120 formulated with QS-21. In addition, the lymphocyte proliferation and delayed type hypersensitivity skin testing were superior in the QS-21 recipients compared with the alum recipients at the low antigen doses. Moderate to severe pain was observed in majority of the volunteers receiving QS-21 formulations, and vasovagal episodes and hypertension were not infrequent. Thus, the use of QS-21 may provide a means to reduce the dose of a soluble protein immunogen.

AIDS Vaccines↗
PubMed2001

Safety of 2 recombinant human immunodeficiency virus type 1 (HIV-1) envelope vaccines in neonates born to HIV-1-infected women.

To determine the safety of 2 candidate vaccines against human immunodeficiency virus type 1 (HIV-1), a randomized, placebo-controlled, multicenter trial compared low, medium, and high doses of the vaccines or an adjuvant among infants born to HIV-infected women. No local or systemic reactions of grade 2 or greater were reported 48 h after the subjects underwent immunization. Grade 3 or 4 chemistry toxicities occurred in 5 (3%) and grade 3 or 4 hematologic toxicities in 17 (11%) of 154 vaccinated subjects (not significantly different from 29 adjuvant recipients). CD4(+) cell percentages of < or = 20% occurred at least once in 9 vaccinated subjects and 1 control subject. Sustained CD4(+) cell percentages of < or = 20% occurred in 4 HIV-infected children. Fourteen infants (8%) were confirmed to be HIV-infected; median CD4(+) cell counts among these children were 2074, 1674, 1584, and 821 cells/mm(3) at birth and weeks 24, 52, and 104, respectively. Thus, both vaccines were safe and well tolerated in neonates, and there was no evidence of accelerated immunologic decline in HIV-infected infants.

AIDS Vaccines↗
PubMed2001

Replication origins in Xenopus egg extract Are 5-15 kilobases apart and are activated in clusters that fire at different times.

When Xenopus eggs and egg extracts replicate DNA, replication origins are positioned randomly with respect to DNA sequence. However, a completely random distribution of origins would generate some unacceptably large interorigin distances. We have investigated the distribution of replication origins in Xenopus sperm nuclei replicating in Xenopus egg extract. Replicating DNA was labeled with [(3)H]thymidine or bromodeoxyuridine and the geometry of labeled sites on spread DNA was examined. Most origins were spaced 5-15 kb apart. This regular distribution provides an explanation for how complete chromosome replication can be ensured although origins are positioned randomly with respect to DNA sequence. Origins were grouped into small clusters (typically containing 5-10 replicons) that fired at approximately the same time, with different clusters being activated at different times in S phase. This suggests that a temporal program of origin firing similar to that seen in somatic cells also exists in the Xenopus embryo. When the quantity of origin recognition complexes (ORCs) on the chromatin was restricted, the average interorigin distance increased, and the number of origins in each cluster decreased. This suggests that the binding of ORCs to chromatin determines the regular spacing of origins in this system.

Animals↗
PubMed2001

Beta-blocking in heart failure patients. Balancing the evidence.

Evidence for the effectiveness of beta-blockers in the management of patients with heart failure is now compelling with a database of over 13000 patients enrolled in randomised prospective placebo-controlled clinical trials. However this therapy remains vastly underused in clinical practice. The different points challenging the widespread use beta blockade agents in the routine treatment in heart failure are presented and discussed. After a review of the potential mechanism hypothesised behind the benefits of beta-blockers in heart failure, the controversial effects on the haemodynamics, exercise tolerance, hospitalisation and mortality are underlined.

Adrenergic beta-Antagonists↗