Thermal performance curves identify seasonal and site-specific variation in the development of Ecklonia radiata (Phaeophyceae) gametophytes and sporophytes.

Rapid ocean warming is affecting kelp forests globally. While the sporophyte life stage has been well studied for many species, the microscopic life stages of laminarian kelps have been understudied, particularly regarding spatial and temporal variations in thermal tolerance and their interaction. We investigated the thermal tolerance of growth, survival, development, and fertilization of Ecklonia radiata gametophytes, derived from zoospores sampled from two sites in Tasmania, Australia, throughout a year, over a temperature gradient (3-30°C). For growth we found a relatively stable thermal optimum at ~20.5°C and stable thermal maxima (25.3-27.7°C). The magnitude of growth was highly variable and depended on season and site, with no consistent spatial pattern for growth and gametophyte size. Survival also had a relatively stable thermal optimum of ~17°C, 3°C below the optimum for growth. Gametophytes grew to single cells between 5 and 25°C, but sporophytes were only observed between 10 and 20°C, indicating reproductive failure outside this range. The results reveal complex effects of source population and season of collection on gametophyte performance in E. radiata, with implications when comparing results from material collected at different localities and times. In Tasmania, gametophytes grow considerably below the estimated thermal maxima and thermal optima that are currently only reached during summer heatwaves, whereas optima for survival (~17°C) are frequently reached and surpassed during heatwaves, which may affect the persistence and recruitment of E. radiata in a warmer climate.

Primary production of the kelp Lessonia corrugata varies with season and water motion: Implications for coastal carbon cycling.

Kelp forests provide vital ecosystem services such as carbon storage and cycling, and understanding primary production dynamics regarding seasonal and spatial variations is essential. We conducted surveys at three sites in southeast Tasmania, Australia, that had different levels of water motion, across four seasons to determine seasonal primary production and carbon storage as living biomass for kelp beds of Lessonia corrugata (Order Laminariales). We quantified blade growth, erosion rates, and the variation in population density and estimated both the net biomass accumulation (NBA) per square meter and the carbon standing stock. We observed a significant difference in blade growth and erosion rates between seasons and sites. Spring had the highest growth rate (0.02 g C · blade-1 · d-1 ) and NBA (1.62 g C · m-2 · d-1 ), while summer had the highest blade erosion (0.01 g C · blade-1 · d-1 ), with a negative NBA (-1.18 g C · m-2 · d-1 ). Sites exhibiting lower blade erosion rates demonstrated notably greater NBA than sites with elevated erosion rates. The sites with the highest water motion had the slowest erosion rates. Moreover, the most wave-exposed site had the densest populations, resulting in the highest NBA and a greater standing stock. Our results reveal a strong seasonal and water motion influence on carbon dynamics in L. corrugata populations. This knowledge is important for understanding the dynamics of the carbon cycle in coastal regions.

Autophagy inhibition improves the chemotherapeutic efficacy of cruciferous vegetable-derived diindolymethane in a murine prostate cancer xenograft model.

Prostate cancer is the second leading cause of cancer-related deaths in men in North America and there is an urgent need for development of more effective therapeutic treatments against this disease. We have recently shown that diindolylmethane (DIM) and several of its halogenated derivatives (ring-DIMs) induce death and protective autophagy in human prostate cancer cells. However, the in vivo efficacy of ring-DIMs and the use of autophagy inhibitors as adjuvant therapy have not yet been studied in vivo. The objective of this study was to determine these effects on tumor growth in nude CD-1 mice bearing bioluminescent androgen-independent PC-3 human prostate cancer cells. We found that chloroquine (CQ) significantly sensitized PC-3 cells to death in the presence of sub-toxic concentrations of DIM or 4,4'-Br2DIM in vitro. Moreover, a combination of DIM (10 mg/kg) and CQ (60 mg/kg), 3× per week, significantly decreased PC-3 tumor growth in vivo after 3 and 4 weeks of treatment. Furthermore, 4,4'-Br2DIM at 10 mg/kg (3× per week) significantly inhibited tumour growth after 4 weeks of treatment. Tissues microarray analysis showed that DIM alone or combined with CQ induced apoptosis marker TUNEL; the combination also significantly inhibited the cell proliferation marker Ki67. In conclusion, we have confirmed that DIM and 4,4'-Br2DIM are effective agents against prostate cancer in vivo and shown that inhibition of autophagy with CQ enhances the anticancer efficacy of DIM. Our results suggest that including selective autophagy inhibitors as adjuvants may improve the efficacy of existing and novel drug therapies against prostate cancer.

Effects of selective serotonin-reuptake inhibitors (SSRIs) on human villous trophoblasts syncytialization.

Selective serotonin-reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants during pregnancy. The human placenta is a highly specialized organ supporting normal growth and development of the fetus. Therefore, this study aims to analyze the effects of SSRIs on villous cytotrophoblasts cells, using BeWo cells and human placental trophoblast cells in primary culture. The SSRIs fluoxetine and its metabolite norfluoxetine, sertraline and venlafaxine did not affect BeWo cell proliferation and viability, nor the percentage of M30-positive (apoptotic) primary trophoblast cells. None of the SSRIs affected basal or forskolin-stimulated BeWo cell fusion, whereas sertraline and venlafaxine increased the fusion of primary villous trophoblasts. Sertraline and venlafaxine also modified human chorionic gonadotropin beta (ß-hCG) secretion by BeWo cells, whereas none of the SSRIs affected ß-hCG secretion in primary trophoblasts. Norfluoxetine increased CGB (chorionic gonadotropin beta) and GJA1 (gap junction protein alpha 1) levels of gene expression (biomarkers of syncytialization) in BeWo cells, whereas in primary trophoblasts none of the SSRIs tested affected the expression of these genes. This study shows that SSRIs affect villous trophoblast syncytialization in a structure- and concentration-dependent manner and suggests that certain SSRIs may compromise placental health. In addition, it highlights the importance of using primary trophoblast cells instead of "trophoblast -like" cell lines to assess the effects of medications on human villous trophoblast function.

The impact of immunoglobulin in acute HIV infection on the HIV reservoir: a randomized controlled trial.

OBJECTIVES: Antiretroviral therapy (ART) during acute HIV infection (AHI) restricts the HIV reservoir, but additional interventions are necessary to induce a cure. Intravenous immunoglobulin (IVIG) is not HIV-specific but is safe and temporarily reduces the HIV reservoir in chronic HIV infection. We present a randomized controlled trial to investigate whether IVIG plus ART in AHI reduces the HIV reservoir and immune activation compared with ART alone. METHODS: Ten men with AHI (Fiebig II-IV) initiated ART (tenofovir, entricitabine, ritonavir boosted darunavir and raltegravir) at HIV-1 diagnosis and were randomized to ART alone or ART plus 5 days of IVIG, once virally suppressed (week 19). Blood samples were evaluated for viral reservoir, immune activation, immune exhaustion and microbial translocation. Flexible sigmoidoscopy was performed at weeks 19, 24 and 48, and gut proviral DNA and cell numbers determined. RESULTS: IVIG was well tolerated and no viral blips (> 50 HIV-1 RNA copies/mL) occurred during IVIG therapy. From baseline to week 48, total HIV DNA in peripheral blood mononuclear cells (PBMCs) (cases: -3.7 log10 copies/106 CD4 cells; controls: -3.87 log10 copies/106 CD4 cells) declined with no differences observed between the groups (P = 0.49). Declines were observed in both groups from week 19 to week 48 in total HIV DNA in PBMCs (P = 0.38), serum low copy RNA (P = 0.57) and gut total HIV DNA (P = 0.55), but again there were no significant differences between arms. Biomarkers of immune activation, immune exhaustion and microbial translocation and the CD4:CD8 ratio were similar between arms for all comparisons. CONCLUSIONS: Although safe, IVIG in AHI did not impact total HIV DNA, immune function or microbial translocation in peripheral blood or gut tissue.

The use of a unique co-culture model of fetoplacental steroidogenesis as a screening tool for endocrine disruptors: The effects of neonicotinoids on aromatase activity and hormone production.

Estrogen biosynthesis during pregnancy is dependent on the collaboration between the fetus producing the androgen precursors, and the placenta expressing the enzyme aromatase (CYP19). Disruption of estrogen production by contaminants may result in serious pregnancy outcomes. We used our recently developed in vitro co-culture model of fetoplacental steroidogenesis to screen the effects of three neonicotinoid insecticides on the catalytic activity of aromatase and the production of steroid hormones. A co-culture of H295R human adrenocortical carcinoma cells with fetal characteristics and BeWo human choriocarcinoma cells which display characteristics of the villous cytotrophoblast was exposed for 24h to various concentrations of three neonicotinoids: thiacloprid, thiamethoxam and imidacloprid. Aromatase catalytic activity was determined in both cell lines using the tritiated water-release assay. Hormone production was measured by ELISA. The three neonicotinoids induced aromatase activity in our fetoplacental co-culture and concordingly, estradiol and estrone production were increased. In contrast, estriol production was strongly inhibited by the neonicotinoids. All three pesticides induced the expression of CYP3A7 in H295R cells, and this induction was reversed by co-treatment of H295R cells with exogenous estriol. CYP3A7 is normally expressed in fetal liver and is a key enzyme involved in estriol synthesis. We suggest that neonicotinoids are metabolized by CYP3A7, thus impeding the 16α-hydroxylation of fetal DHEA(-sulfate), which is normally converted to estriol by placental aromatase. We successfully used the fetoplacental co-culture as a physiologically relevant tool to highlight the potential effects of neonicotinoids on estrogen production, aromatase activity and CYP3A7 expression during pregnancy.

Azathioprine is effective for oral involvement in Crohn's disease but not for orofacial granulomatosis alone.

BACKGROUND: There have been no previous reports assessing the effectiveness of azathioprine (AZA) in the treatment of orofacial granulomatosis (OFG). This report is a review of patients receiving AZA for active OFG with or without concomitant gut Crohn's disease (CD) in a specialist tertiary referral centre. METHODS: Clinical response was defined by Global Physician Assessment at 4-, 12- and 24-month follow-up and a standardised oral disease activity score (ODAS). RESULTS: Sixty of 215 patients seen with OFG in our clinic over a 12-year period were treated with AZA. Of these, 22 had concomitant CD. The proportion of patients responding to AZA with a diagnosis of CD/OFG vs. OFG only at 4, 12 and 24 months were 54% vs. 21% (P = 0.03), 59% vs. 21% (P = 0.003) and 41% vs. 24% (P = 0.16), respectively. A statistically significant difference was seen between starting and follow-up ODAS scores at 4 months in the CD/OFG group which was not observed in the OFG only group. Factors predicting a need for AZA included a diagnosis of intestinal CD, sulcal swelling, sulcal ulcers and upper lip involvement. The factor predicting response to treatment was a diagnosis of CD at 12 months of follow-up. No difference in the number of adverse effects was observed between the two groups of patients. CONCLUSIONS: AZA is significantly more effective in the treatment of oral disease with a concurrent diagnosis of CD rather than in the treatment of OFG alone.

Elevated glucocorticoid concentrations during gestation predict reduced reproductive success in subordinate female banded mongooses.

Dominant females in social species have been hypothesized to reduce the reproductive success of their subordinates by inducing elevated circulating glucocorticoid (GC) concentrations. However, this 'stress-related suppression' hypothesis has received little support in cooperatively breeding species, despite evident reproductive skews among females. We tested this hypothesis in the banded mongoose (Mungos mungo), a cooperative mammal in which multiple females conceive and carry to term in each communal breeding attempt. As predicted, lower ranked females had lower reproductive success, even among females that carried to term. While there were no rank-related differences in faecal glucocorticoid (fGC) concentrations prior to gestation or in the first trimester, lower ranked females had significantly higher fGC concentrations than higher ranked females in the second and third trimesters. Finally, females with higher fGC concentrations during the third trimester lost a greater proportion of their gestated young prior to their emergence from the burrow. Together, our results are consistent with a role for rank-related maternal stress in generating reproductive skew among females in this cooperative breeder. While studies of reproductive skew frequently consider the possibility that rank-related stress reduces the conception rates of subordinates, our findings highlight the possibility of detrimental effects on reproductive outcomes even after pregnancies have become established.

A practical guide to the use of thiopurines in oral medicine.

Thiopurines are widely used as first-line immunosuppressive therapies in the management of chronic inflammatory oral disease. However, despite over half a century of clinical experience, the evidence base for their use is limited. The aims of this paper were to review the evidence for the use of thiopurines in oral medicine and provide a contemporary model of thiopurine metabolism and mechanism of action and a rationale for clinical use and safe practice.

Defective macrophage handling of Escherichia coli in Crohn's disease.

BACKGROUND AND AIM: Escherichia coli can be isolated from lamina propria macrophages in Crohn's disease (CD), and their intramacrophage persistence may provide a stimulus for inflammation. To further determine the contributions of macrophage dysfunction and E. coli pathogenicity to this, we aimed to compare in vitro functioning of macrophages from patients with CD and healthy controls (HC) in response to infection with CD-derived adherent-invasive E. coli (AIEC) and less pathogenic E. coli strains. METHODS: Monocyte-derived macrophages were cultured from patients with CD and HC. Intramacrophage survival of E. coli strains (CD-derived adherent-invasive [AI] and non-AI strains and laboratory strain K-12) was compared. Macrophage cytokine release (tumor necrosis factor alpha [TNFα], interleukin [IL]-23, IL-8 and IL-10) and monocyte phagoctyosis and respiratory burst function were measured after E. coli infection. For CD patients, laboratory data were correlated with clinical phenotype, use of immunomodulation, and CD risk alleles (NOD2, IL-23R, ATG16L1 and IRGM). RESULTS: Attenuated TNFα and IL-23 release from CD macrophages was found after infection with all E. coli strains. There was prolonged survival of CD-derived AIEC, CD-derived non-AIEC and E. coli K-12 in macrophages from CD patients compared to within those from HC. No abnormality of monocyte phagocytosis or respiratory burst function was detected in CD. Macrophage dysfunction in CD was not influenced by phenotype, use of immunomodulation or genotype. CONCLUSIONS: CD macrophage responses to infection with E. coli are deficient, regardless of clinical phenotype, CD genotype or E. coli pathogenicity. This suggests host immunodeficiency is an important contributor to intramacrophage E. coli persistence in CD.

THE PITTING TEST; AN INVESTIGATION OF AN UNSTANDARDIZED ASSESSMENT OF LYMPHEDEMA.

Soft tissue pitting is the occurrence of a temporary indentation on the body surface after the release of sustained thumb or finger pressure. In the management of lymphedema, presence or absence of pitting can contribute to clinical reasoning and guide healthcare management. However, the pitting test and its application has not been described consistently nor is it a standardized part of assessment. Therefore investigations are needed to assess the outcome measures of pitting identification and characterization of lymphedematous tissue. To determine valid testing parameters for a future study, we evaluated six therapists of varying lymphedema experience who assessed a range of locations on six patients with lymphedema representing the breadth of pitting assessment techniques used clinically. The consequence of an unstandardized assessment is demonstrated by the large variation in techniques observed for test duration (1.1 to 76.0 seconds), pressure (1.3 to 14.4 N/cm2) and contact area (0.2 to 6.8 cm2). Experienced therapists performed the pitting test with a significantly different technique from their inexperienced counterparts, involving a longer duration (p < 0.001), higher pressure (p < 0.001) and a larger contact area (p < 0.001). The results of this pilot study support the need for evaluation of the underlying tissue response to sustained pressure and release, in order to inform the development of a standardized procedure.

Pharmacogenetics of pemetrexed combination therapy in lung cancer: pathway analysis reveals novel toxicity associations.

Identification of polymorphisms that influence pemetrexed tolerability could lead to individualised treatment regimens and improve quality of life. Twenty-eight polymorphisms within eleven candidate genes were genotyped using the Illumina Human Exome v1.1 BeadChip and tested for their association with the clinical outcomes of non-small cell lung cancer and mesothelioma patients receiving pemetrexed/platinum doublet chemotherapy (n=136). GGH rs11545078 was associated with a reduced incidence of grade ⩾3 toxicity within the first four cycles of therapy (odds ratio (OR) 0.25, P=0.018), as well as reduced grade ⩾3 haematological toxicity (OR 0.13, P=0.048). DHFR rs1650697 conferred an increased risk of grade ⩾3 toxicity (OR 2.14, P=0.034). Furthermore, FOLR3 rs61734430 was associated with an increased likelihood of disease progression at mid-treatment radiological evaluation (OR 4.05, P=0.023). Polymorphisms within SLC19A1 (rs3788189, rs1051298 and rs914232) were associated with overall survival. This study confirms previous pharmacogenetic associations and identifies novel markers of pemetrexed toxicity.

Ring-substituted analogs of 3,3'-diindolylmethane (DIM) induce apoptosis and necrosis in androgen-dependent and -independent prostate cancer cells.

We recently reported that novel ring-substituted analogs of 3,3'-diindolylmethane (ring-DIMs) have anti-androgenic and growth inhibitory effects in androgen-dependent prostate cancer cells. The objectives of this study were to confirm the ability of 4,4'- and 7,7'-dibromo- and dichloro-substituted ring-DIMs to inhibit androgen-stimulated proliferation of androgen-dependent LNCaP human prostate cancer cells using a non-invasive, real-time monitoring technique. In addition, their ability to induce apoptotic and necrotic cell death in androgen-dependent as well as -independent (PC-3) prostate cancer cells was studied. Prostate cancer cells were treated with increasing concentrations of DIM and ring-DIMs (0.3-30 µM) and effects on cell proliferation were measured in real-time using an xCELLigence cellular analysis system. Chromatin condensation and loss of membrane integrity were determined by Hoechst and propidium iodide staining, respectively. Apoptotic protein markers were measured by immunoblotting and activation of caspases determined using selective fluorogenic substrates. Intra- and extracellular concentrations of DIM and ring-DIMs were assessed by electrospray ionization tandem mass spectrometry. Ring-DIMs inhibited androgen-stimulated LNCaP cell proliferation and induced apoptosis and necrosis in LNCaP and PC-3 cells with 2-4 fold greater potencies than DIM. DIM and the ring-DIMs increased caspases -3, -8 and -9 activity, elevated expression of Fas, FasL, DR4 and DR5 protein, and induced PARP cleavage in both cell lines. The cytotoxicity of the most potent ring-DIM, 4,4'-dibromoDIM, but not the other compounds was decreased by an inhibitor of caspase -3. The 4,4'-dibromoDIM was primarily found in the extracellular medium, whereas all other compounds were present to a much larger extent in the cell. In conclusion, ring-DIMs inhibited prostate cancer cell growth and induced cell death in LNCaP and PC-3 cells with greater potencies than DIM; they also structure-dependently activated different cell death pathways suggesting that these compounds have clinical potential as chemopreventive and chemotherapeutic agents in prostate cancer, regardless of hormone-dependency.

Evidence for frequent incest in a cooperatively breeding mammal.

As breeding between relatives often results in inbreeding depression, inbreeding avoidance is widespread in the animal kingdom. However, inbreeding avoidance may entail fitness costs. For example, dispersal away from relatives may reduce survival. How these conflicting selection pressures are resolved is challenging to investigate, but theoretical models predict that inbreeding should occur frequently in some systems. Despite this, few studies have found evidence of regular incest in mammals, even in social species where relatives are spatio-temporally clustered and opportunities for inbreeding frequently arise. We used genetic parentage assignments together with relatedness data to quantify inbreeding rates in a wild population of banded mongooses, a cooperatively breeding carnivore. We show that females regularly conceive to close relatives, including fathers and brothers. We suggest that the costs of inbreeding avoidance may sometimes outweigh the benefits, even in cooperatively breeding species where strong within-group incest avoidance is considered to be the norm.

Pathogenicity of conidia-based preparations of entomopathogenic fungi against the greenhouse pest aphids Myzus persicae, Aphis gossypii, and Aulacorthum solani (Hemiptera: Aphididae).

Seeking new isolates of entomopathogenic fungi with greater virulence against greenhouse aphid pests than those currently registered in North America for control of these insects, single-dose screening assays of 44 selected fungal isolates and 4 commercially available strains were conducted against first-instar nymphs of Myzus persicae and Aphis gossypii. The assays identified a number of Beauveria and Metarhizium isolates with virulence equal to or greater than that of the commercial strains against the nymphal aphids, but none exhibited exceptionally high virulence. Virulence of Isaria isolates was unexpectedly low (<31% mortality at doses>1000conidia/mm(2)). In dose-response assays, Beauveria ARSEF 5493 proved most virulent against M. persicae and A. gossypii; however, LC50s of this isolate did not differ significantly from those of B. bassiana commercial strain JW-1. Dose-response assays were also conducted with Aulacorthum solani, the first reported evaluations of Beauveria and Metarhizium against this pest. The novel isolate Metarhizium 5471 showed virulence⩾that of Beauveria 5493 in terms of LC25 and LC50, but 5493 produced a steeper dose response (slope). Additional tests showed that adult aphids are more susceptible than nymphs to fungal infection but confirmed that infection has a limited pre-mortem effect on aphid reproduction. Effects of assay techniques and the potential of fungal pathogens as aphid-control agents are discussed.

Within-plant distribution of Aulacorthum solani (Hemiptera: Aphididae), on various greenhouse plants with implications for control.

Foxglove aphid, Aulacorthum solani (Kaltenbach) (Hemiptera: Aphididae), has recently undergone a status change from an occasional pest to a serious pest in greenhouses of North America and the United Kingdom. Little nonanecdotal information exists on the ecology of this insect in greenhouse crops. To help improve integrated pest management decisions for A. solani, the within-plant distribution of this pest was explored on a variety of common greenhouse plants in both the vegetative and flowering stage. This aphid generally was found on lower leaves of vegetative plants, but was found higher in the canopy on reproductive plants (on flowers, flower buds, or upper leaves). Aphid numbers were not consistently positively correlated with total leaf surface areas within plant strata across plant species. Thus, the observed differences in preferred feeding sites on vegetative versus flowering plants are possibly a response to differences in nutritional quality of the various host-plant tissues. Despite being anecdotally described as a "stem-feeding aphid," A. solani was rarely found feeding on stems at the population densities established in our tests, with the exception of racemes of scarlet sage (Salvia splendans). Although some previous reports suggested that A. solani prefers to feed on new growth of plants, our results indicate that mature leaves are preferred over growing tips and young leaves. The implications of the within-plant feeding preferences of A. solani populations with respect to both biological and chemical control are discussed.

Biomechanical factors associated with patellofemoral pain in children and adolescents.

To investigate the biomechanical factors associated with patellofemoral pain in children and adolescents. A cross-sectional, population-based study conducted in Brazil from 2019 to 2023, involving students from public schools. Adjusted prevalence ratios and their respective 95% confidence intervals for the outcome in relation to independent variables were calculated for association analysis, adopting a significance level of 5%. Out of the total of 283 students, 152 were female and 182 were aged between 16 and 18 years old. A positive association was observed between the presence of patellofemoral pain and a poor movement quality in both lower limbs (right side: p = 0.04 and left side: p = 0.04) as well as with dynamic valgus of the left lower limb (p < 0.01). Patellofemoral pain in children and adolescents is associated with poor movement quality in the lower limbs and dynamic valgus of the left lower limb. Actions targeting these biomechanical factors may be crucial for early diagnosis and clinical treatment of this disfunction.

Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity.

BACKGROUND: Fluoropyrimidine drugs are extensively used for the treatment of solid cancers. However, adverse drug reactions are a major clinical problem, often necessitating treatment discontinuation. The aim of this study was to identify pharmacogenetic markers predicting fluoropyrimidine toxicity. METHODS: Toxicity in the first four cycles of 5-fluorouracil or capecitabine-based chemotherapy were recorded for a series of 430 patients. The association between demographic variables, DPYD, DPYS, TYMS, MTHFR, CDA genotypes, and toxicity were analysed using logistic regression models. RESULTS: Four DPYD sequence variants (c.1905+1G>A, c.2846A>T, c.1601G>A and c.1679T>G) were found in 6% of the cohort and were significantly associated with grade 3-4 toxicity (P<0.0001). The TYMS 3'-untranslated region del/del genotype substantially increased the risk of severe toxicity (P=0.0123, odds ratio (OR)=3.08, 95% confidence interval (CI): 1.38-6.87). For patients treated with capecitabine, a MTHFR c.1298CC homozygous variant genotype predicted hand-foot syndrome (P=4.1 × 10⁻6, OR=9.99, 95% CI: 3.84-27.8). The linked CDA c.-92A>G and CDA c.-451C>T variants predicted grade 2-4 diarrhoea (P=0.0055, OR=2.3, 95% CI: 1.3-4.2 and P=0.0082, OR=2.3, 95% CI: 1.3-4.2, respectively). CONCLUSION: We have identified a panel of clinically useful pharmacogenetic markers predicting toxicity to fluoropyrimidine therapy. Dose reduction should be considered in patients carrying these sequence variants.

Antiproliferative, antiandrogenic and cytotoxic effects of novel caffeic acid derivatives in LNCaP human androgen-dependent prostate cancer cells.

Caffeic acid and its naturally occurring derivative caffeic acid phenethyl ester (CAPE) have antiproliferative and cytotoxic properties in a variety of cancer cell lines without displaying significant toxicity toward healthy cells, and are considered to be potential anticancer agents. However, little is known about their effects on prostate cancer cells. We synthesized and evaluated the effects of caffeic acid, CAPE (2) and 18 synthetic derivatives on cell viability and androgen-dependent cell proliferation, subcellular localisation and expression of androgen receptor (AR) and secretion of prostate-specific antigen (PSA) in LNCaP human hormone-dependent prostate cancer cells. Several synthetic derivatives of CAPE were strong, concentration-dependent cytotoxic agents in LNCaP cells with IC50 values in the 6.8-26.6 µM range, potencies that were up to five-fold greater than that of CAPE (33.7±4.0 µM). A number of caffeic acid derivatives were inhibitors of androgen-stimulated LNCaP cell proliferation with concomitant inhibition of DHT-stimulated PSA secretion. Compound 24 was the most cytotoxic and antiproliferative caffeic acid derivative (IC50 values of 6.8±0.3 and 2.4±0.8 µM, respectively) inhibiting DHT-stimulated cell proliferation and PSA secretion statistically significantly at concentrations as low as 0.3 µM. Exposure to DHT increased cytoplasmic and nuclear AR levels and co-treatment with increasing concentrations of compound 24 or CAPE (2), notably, further increased these levels. In conclusion, a number of synthetic derivatives of caffeic acid are potent inhibitors of androgen-dependent prostate cancer cell proliferation and viability, acting, at least in part, via an antiandrogenic mechanism that involves increased nuclear accumulation of (presumably inactive) AR.

Dietary intervention for oral allergy syndrome as a treatment in orofacial granulomatosis: a new approach?

BACKGROUND: Orofacial granulomatosis (OFG) is a chronic granulomatous condition of the mouth, face and lips. Recent work demonstrates a high rate of atopy and silver birch sensitisation from skin prick testing (SPT). Oral allergy syndrome (OAS) is an acute oro-pharyngeal IgE mediated reaction, triggered by foods that cross react with pollens, most commonly silver birch. The aim of this study was to determine if patients with OFG and positive SPT to common OAS associated pollens responded to avoidance of cross reactive foods. METHODS: Patients with OFG and positive SPT to silver birch, grass, mugwort, ragweed and latex were required to avoid cross reacting foods, for 6 weeks and, in those who responded, for a total of 12 weeks. All had standardized oral examinations and were given severity scores (SS) at each appointment. RESULTS: Twenty two of 47 (47%) patients had one or more positive SPT and 13/22 completed 6 weeks on the diet. No difference was seen in SS between weeks 0 (14.62 ± 11.16) and 6 (13.31 ± 10.33; P = 0.656). Six of 14 (43%) had significantly improved SS (week 0; 19.17 ± 12.95, week 6; 10.83 ± 4.99, P = 0.027). Five completed 12 weeks and no further improvement was seen (week 6; 11 ± 5.57, week 12; 10.4 ± 9.94; P = 0.068). Two patients required no further treatments. CONCLUSIONS: On an intention to treat basis, only 2/14 patients improved and required no further intervention. Whilst this diet cannot be recommended routinely, the improvement seen in some patients raises questions about the role of OAS in patients with OFG.