Epilactose as a Promising Butyrate-Promoter Prebiotic via Microbiota Modulation.

Epilactose is a disaccharide composed of galactose and mannose, and it is currently considered an "under development" prebiotic. In this study, we described the prebiotic potential of epilactose by in vitro fermentation using human fecal inocula from individuals following a Mediterranean diet (DM) or a Vegan diet (DV). The prebiotic effect of epilactose was also compared with lactulose and raffinose, and interesting correlations were established between metabolites and microbiota modulation. The production of several metabolites (lactate, short-chain fatty acids, and gases) confirmed the prebiotic properties of epilactose. For both donors, the microbiota analysis showed that epilactose significantly stimulated the butyrate-producing bacteria, suggesting that its prebiotic effect could be independent of the donor diet. Butyrate is one of the current golden metabolites due to its benefits for the gut and systemic health. In the presence of epilactose, the production of butyrate was 70- and 63-fold higher for the DM donor, when compared to lactulose and raffinose, respectively. For the DV donor, an increase of 29- and 89-fold in the butyrate production was obtained when compared to lactulose and raffinose, respectively. In conclusion, this study suggests that epilactose holds potential functional properties for human health, especially towards the modulation of butyrate-producing strains.

Impact of Ultrasound-Guided Foam Sclerotherapy for Pain Control in Patients with Chronic Venous Disease and Great Saphenous Vein Reflux.

Chronic venous disease (CVD) associated with great saphenous vein (GSV) reflux has a higher prevalence of pain in the lower limbs. This study evaluates the impact of ultrasound-guided foam sclerotherapy (UGFS) for GSV and symptom control, accessed by the visual analogue scale (VAS). Patients with CVD who underwent GSV-UGFS were included in this retrospective cohort (417 limbs). The pain was measured before and after the treatment. The scale alteration was assessed as a function of age, sex, Clinical Etiologic Anatomic Pathophysiologic (CEAP) classes, total of sclerotherapy sessions, GSV occlusion patterns, and ulcer healing. Majority of patients were female (59.2%), and the mean age was 56 ± 11.5 years. In the total sample, 78.2% of the GSVs were fully occluded, 19.7% had partial occlusion, 2.2% remained open, and 3.2 ± 1.9 (median = 3.0) sessions were performed. The reduction of symptoms occurred in 88.3% of participants (VAS drop median = 4.8). Patients younger than 50 years and females had the greatest VAS decreases. When comparing the outcomes of complete occlusion versus partial occlusion, there was no significant difference in VAS pain reduction ( p = 0.14). The comparison between CEAP clinical classes also did not show statistically significant differences in delta VAS ( p = 0.71). GSV-UGFS was effective for pain control. However, this improvement does not appear to be related to the pattern of occlusion, indicating that in the short term, the outcomes of total and partial occlusion suggest successful management of symptoms. Other aspects such as gender, age, pretreatment pain intensity, and CEAP classes seem to play a role in the clinical outcome.

Tailoring fructooligosaccharides composition with engineered Zymomonas mobilis ZM4.

Zymomonas mobilis ZM4 is an attractive host for the development of microbial cell factories to synthesize high-value compounds, including prebiotics. In this study, a straightforward process to produce fructooligosaccharides (FOS) from sucrose was established. To control the relative FOS composition, recombinant Z. mobilis strains secreting a native levansucrase (encoded by sacB) or a mutated ß-fructofuranosidase (Ffase-Leu196) from Schwanniomyces occidentalis were constructed. Both strains were able to produce a FOS mixture with high concentration of 6-kestose. The best results were obtained with Z. mobilis ZM4 pB1-sacB that was able to produce 73.4 ± 1.6 g L-1 of FOS, with a productivity of 1.53 ± 0.03 g L-1 h-1 and a yield of 0.31 ± 0.03 gFOS gsucrose-1. This is the first report on the FOS production using a mutant Z. mobilis ZM4 strain in a one-step process. KEY POINTS: • Zymomonas mobilis was engineered to produce FOS in a one-step fermentation process. • Mutant strains produced FOS mixtures with high concentration of 6-kestose. • A new route to produce tailor-made FOS mixtures was presented.

Hydrolysates containing xylooligosaccharides produced by different strategies: Structural characterization, antioxidant and prebiotic activities.

This study explores the structural characterization, antioxidant and prebiotic activities of hydrolysates containing xylooligosaccharides (XOS) produced by different strategies: direct fermentation of beechwood xylan (FermBX) and enzymatic treatment of beechwood (EnzBX) and rice husk (EnzRH) xylans. EnzBX and EnzRH showed XOS with a backbone of (1 â†’ 4)-linked-xylopyranosyl residues and branches of arabinose, galactose, and uronic acids. FermBX presented the highest content of total phenolic compounds (14 mg GAE/g) and flavonoids (0.6 mg QE/g), which may contribute to its antioxidant capacity -39.1 µmol TE/g (DPPH), 45.7 µmol TE/g (ABTS), and 79.9 µmol Fe II/g (FRAP). The fermentation of hydrolysates decreased the abundance of microorganisms associated with intestinal diseases from Eubacteriales, Desulfovibrionales and Methanobacteriales orders, while stimulating the growth of organisms belonging to Bacteroides, Megamonas and Limosilactobacillus genera. The production of short-chain fatty acids, ammonia, and CO2 suggested the prebiotic potential. In conclusion, hydrolysates without previous purification and obtained from non-chemical approaches demonstrated promising biological activities for further food applications.

Radiofrequency Ablation for Axial Reflux Associated with Foam Sclerotherapy for Varicosities in One-Step Approach: A Prospective Cohort Study Comprising Large Diameters Saphenous Veins.

OBJECTIVE: This study assessed the outcomes and impact on the quality of life following one-step outpatient radiofrequency ablation (RFA) and ultrasound guided foam sclerotherapy (USGFS) for large reflux with varicosities in the great saphenous vein (GSV). DESIGN: Prospective, single-centre, analytical cohort. MATERIALS AND METHODS: Thirty symptomatic patients having reflux in the GSV and varicosities (CEAP C3 to C6) were treated with RFA and USGFS simultaneously, in a single-step procedure, from March 2016 to December 2016. They were followed up at 1 week, 6 months, 1 and 3 years. Clinical outcomes, changes in the Quality of Life (QOL) questionnaires SF-36™, VCSS and AVVQ, evolutive vein occlusion rates were assessed by duplex ultrasound, and ulcer closure was checked. RESULTS: The sample was divided into two groups: (Group 1) GSV diameter ≥13.0 mm (median 19.0 [14-24]), 17 subjects, and (Group 2) GSV diameter ≤12.9 mm (median 10.3 [10-12]), 16 subjects. No major adverse event was observed, and the postoperative minor adverse event rates were similar between the two groups. A significant improvement was observed in VCSS and AVVQ from the preoperative levels to the sixth month and the third-year follow-up. Twelve of 13 ulcers had healed at 1 year and remained closed until 3 years. The entire sample had a significant increase in all short form 36 domains, except for mental health in the Group 2 (GSV ≥ 13.0 mm). Overall first week occlusion rate for the whole sample was 90.9% and 69.7% at the 3-year follow-up. No difference in occlusion rate was observed between the two groups at any time. CONCLUSION: Exclusively outpatient combined techniques were safe and feasible in this study with no major adverse events, despite the large diameters of the GSV or ulcer presence. Within 3 years, both diameter groups showed equivalent improvement in all QOL parameters, satisfactory axial occlusion, and maintained ulcer closure.

Survival predictors and outcomes of patients with recurrent and/or metastatic head and neck cancer treated with chemotherapy plus cetuximab as first-line therapy: A real-world retrospective study.

BACKGROUND: In patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) the estimated prognosis is usually poor. Patient-specific factors that affect prognosis should be considered when choosing therapy. We conducted a retrospective, single-center analysis in patients treated with first line platinum and antiEGFR antibody-containing regimen. The objective was to generate real-world data considering treatment outcomes and to identify predictors of survival. PATIENTS/METHODS: Clinical charts of patients treated with cetuximab and platinum-based chemotherapy (CT) for R/M HNSCC in first-line setting, between January-2009 and December-2018 were assessed. In these 103 patients, the prognostic value of site of the primary tumor, age at diagnosis, gender, Cetuximab induced skin toxicity and prior treatments were studied multivariately. To evaluate progression free survival (PFS) and overall survival (OS), Kaplan-Meier curves and the log-rank test were used. The Coxregression model was used to investigate the effect of these variables on OS. RESULTS: Longer OS was associated with oral cavity tumor location (p = 0,003), European Cooperative Oncology Group-Performance Status 0 (ECOG-PS) (p = 0,01), complete/partial response (p<0,0001), cetuximab monotherapy until disease progression or unacceptable toxicity (p = 0,037) and Grade 2-4 cetuximab induced skin toxicity (p = 0,037). The median follow-up period was 11,7 months. The mortality rate was 90,3% during this retrospective cohort assessment. The PFS was 7,1 months (95% confidence interval (CI), 5,6-8.6). The OS was 11,7 months (95%CI, 10,5-12,8). CONCLUSIONS: The present study demonstrates that the combination of cetuximab with platinum-based CT was effective in R/M HNSCC. Among patients with R/M HSCC treated with platinum plus cetuximab as first-line therapy, primary site, ECOG-PS, grade 2-4 cetuximab induced toxicity, and weekly cetuximab monotherapy have a marked impact on OS.

Novel and emerging prebiotics: Advances and opportunities.

Consumers are conscientiously changing their eating preferences toward healthier options, such as functional foods enriched with pre- and probiotics. Prebiotics are attractive bioactive compounds with multidimensional beneficial action on both human and animal health, namely on the gastrointestinal tract, cardiometabolism, bones or mental health. Conventionally, prebiotics are non-digestible carbohydrates which generally present favorable organoleptic properties, temperature and acidic stability, and are considered interesting food ingredients. However, according to the current definition of prebiotics, application categories other than food are accepted, as well as non-carbohydrate substrates and bioactivity at extra-intestinal sites. Regulatory issues are considered a major concern for prebiotics since a clear understanding and application of these compounds among the consumers, regulators, scientists, suppliers or manufacturers, health-care providers and standards or recommendation-setting organizations are of utmost importance. Prebiotics can be divided in several categories according to their development and regulatory status. Inulin, galactooligosaccharides, fructooligosaccharides and lactulose are generally classified as well established prebiotics. Xylooligosaccharides, isomaltooligosaccharides, chitooligosaccharides and lactosucrose are classified as "emerging" prebiotics, while raffinose, neoagaro-oligosaccharides and epilactose are "under development." Other substances, such as human milk oligosaccharides, polyphenols, polyunsaturated fatty acids, proteins, protein hydrolysates and peptides are considered "new candidates." This chapter will encompass actual information about the non-established prebiotics, mainly their physicochemical properties, market, legislation, biological activity and possible applications. Generally, there is a lack of clear demonstrations about the effective health benefits associated with all the non-established prebiotics. Overcoming this limitation will undoubtedly increase the demand for these compounds and their market size will follow the consumer's trend.

Zymomonas mobilis as an emerging biotechnological chassis for the production of industrially relevant compounds.

Zymomonas mobilis is a well-recognized ethanologenic bacterium with outstanding characteristics which make it a promising platform for the biotechnological production of relevant building blocks and fine chemicals compounds. In the last years, research has been focused on the physiological, genetic, and metabolic engineering strategies aiming at expanding Z. mobilis ability to metabolize lignocellulosic substrates toward biofuel production. With the expansion of the Z. mobilis molecular and computational modeling toolbox, the potential of this bacterium as a cell factory has been thoroughly explored. The number of genomic, transcriptomic, proteomic, and fluxomic data that is becoming available for this bacterium has increased. For this reason, in the forthcoming years, systems biology is expected to continue driving the improvement of Z. mobilis for current and emergent biotechnological applications. While the existing molecular toolbox allowed the creation of stable Z. mobilis strains with improved traits for pinpointed biotechnological applications, the development of new and more flexible tools is crucial to boost the engineering capabilities of this bacterium. Novel genetic toolkits based on the CRISPR-Cas9 system and recombineering have been recently used for the metabolic engineering of Z. mobilis. However, they are mostly at the proof-of-concept stage and need to be further improved.

Mulheres negras e construção de sentidos de identidade na transição capilar / Mujeres negras y construcción de significados de identidad en la transición capilar / Black women and construction of meanings of identity in hair transition

Resumo Transição capilar é o processo de abdicação de alisamentos químicos ou físicos dos cabelos, reassumindo suas texturas naturais. A presente pesquisa, de natureza qualitativa, visou a investigar a construção dos sentidos de identidade em mulheres negras que passaram pela transição capilar. Participaram do estudo 12 mulheres negras com idades compreendidas entre 18 e 34 anos. Para a coleta de dados foram utilizadas entrevistas semiestruturadas que foram analisadas através da análise de posicionamento. A transição capilar mudou a forma de posicionamento em relação a si, ao cabelo, à sociedade e à construção da autoimagem. Além de elucidar o processo de reafirmação identitária das interlocutoras, o estudo fomenta a discussão do racismo na sociedade brasileira, ao tratar da desvalorização da estética negra e, por conseguinte, do enaltecimento da branquitude.

Abstract Hair transition is the process of abdicating chemical or physical hair straightening, resuming its natural textures. This qualitative research aimed at investigating the construction of the meanings of identity in black women who went through the hair transition. Twelve black women between the ages of 18 and 34 participated in the study. For the data collection, semi-structured interviews were used and analyzed through the positioning analysis. Hair transition has changed the way of positioning towards itself, hair, society and the construction of self-image. In addition to elucidating the identity affirmation process of the interviewees, the study instigates the discussion of racism in Brazilian society, by dealing with the devaluation of black aesthetics and, therefore, the praise of whiteness.

Resumen La transición capilar es el proceso de abdicar del alisado químico o físico del cabello, retomando sus texturas naturales. La presente investigación, de carácter cualitativo, tuvo como objetivo investigar la construcción de los significados de la identidad en mujeres negras que atravesaron la transición capilar. Participaron del estudio doce mujeres negras de entre 18 y 34 años. Para la recolección de datos se utilizaron entrevistas semiestructuradas, las cuales fueron analizadas mediante análisis de posicionamiento. La transición capilar cambió la forma de posicionamiento en relación con una misma, el cabello, la sociedad y la construcción de la autoimagen. Además de dilucidar el proceso de afirmación identitaria de las interlocutoras, el estudio fomenta la discusión del racismo en la sociedad brasileña, al abordar la devaluación de la estética negra y, por tanto, el elogio de la blancura.

In vitro assessment of prebiotic properties of xylooligosaccharides produced by Bacillus subtilis 3610.

Xylooligosaccharides (XOS) are emergent prebiotics exhibiting high potential as food ingredients. In this work, in vitro studies were performed using human fecal inocula from two healthy donors (D 1 and D2) to evaluate the prebiotic effect of commercial lactulose and XOS produced in a single-step by recombinant Bacillus subtilis 3610. The fermentation of lactulose led to the highest production of lactate (D1: 33.7 ±â€¯0.5 mM; D2:19.7 ±â€¯0.3 mM) and acetate (D1: 77.5 ±â€¯0.6 mM; D2: 81.0 ±â€¯0.7 mM), while XOS led to the highest production of butyrate (D1: 9.0 ±â€¯0.6 mM; D2: 10.5 ±â€¯0.8 mM) and CO2 (D1: 8.92 ±â€¯0.02 mM; D2: 11.4 ±â€¯0.3 mM). Microbiota analysis showed a significant decrease in the relative abundance of Proteobacteria for both substrates and an increase in Bifidobacterium and Lactobacillus for lactulose, and Bacteroides for XOS.

From lignocellulosic residues to market: Production and commercial potential of xylooligosaccharides.

The updated definition of prebiotic expands the range of potential applications in which emerging xylooligosaccharides (XOS) can be used. It has been demonstrated that XOS exhibit prebiotic effects at lower amounts compared to others, making them competitively priced prebiotics. As a result, the industry is focused on developing alternative approaches to improve processes efficiency that can meet the increasing demand while reducing costs. Recent advances have been made towards greener and more efficient processes, by applying process integration strategies to produce XOS from costless lignocellulosic residues and using genetic engineering to create microorganisms that convert these residues to XOS. In addition, collecting more in vivo data on their performance will be key to achieve regulatory claims, greatly increasing XOS commercial value.

Fraudes no mel de abelha comercializado no mercado público de Maceió - AL / Frauds in bee honey comercialized in the public market of Maceió - AL

O mel é um produto alimentício produzido pelas abelhas melíferas, a partir do néctar das flores ou das secreções procedentes de partes vivas das plantas ou de excreções de insetos sugadores que ficam sobre partes vivas de plantas, que as abelhas recolhem, transformam, combinam com substâncias específicas próprias, armazenam e deixam madurar nos favos da colmeia. Além de saboroso, possui alta aceitabilidade pelos consumidores, principalmente por ser benéfico à saúde, quando consumido na quantidade adequada, e dispor de inúmeros efeitos terapêuticos e de alto valor nutritivo. Porém, por ser de fácil adulteração por meio do acréscimo de aditivos proibidos, para que o produto seja comercializado de forma segura, do ponto de vista higiênico, sanitário e de identidade, é necessário que os méis disponibilizados para a população advenham de origem confiável e sejam analisados quanto aos requisitos mínimos exigidos para a sua qualidade. A pesquisa objetivou analisar a qualidade de méis comercializados no mercado público de Maceió - AL, por meio da detecção de fraudes pela adição de amido e/ou açúcar comercial. Foram analisadas 40 amostras de mel in natura, adquiridas no mercado da produção do município alagoano, por meio do teste de Reação de Lugol. Das 40 amostras analisadas, 85% (34 amostras) apresentaram Reação de Lugol positiva, indicando a presença de adulteração, e 15% (6 amostras) apresentaram reação negativa. Tais resultados demonstram a necessidade de uma maior fiscalização do mel destinado à comercialização no município de Maceió – AL, a fim de que a saúde da população consumidora seja protegida dos riscos inerentes ao consumo de mel fraudado.

Downscale fermentation for xylooligosaccharides production by recombinant Bacillus subtilis 3610.

The global demand of prebiotics such as xylooligosaccharides (XOS) has been growing over the years, motivating the search for different production processes with increased efficiency. In this study, a cloned Bacillus subtilis 3610, containing the xylanase gene xyn2 of Trichoderma reesei coupled with an endogenous secretion tag, was selected for XOS production through direct fermentation of beechwood xylan. A mixture of XOS with a degree of polymerization ranging from 4 to 6 was obtained, presenting high stability after a static in vitro digestion (98.5 ± 0.2%). The maximum production yield expressed as total XOS per amount of xylan (306 ± 4 mg/g) was achieved after 8 h of fermentation operating under one-time impulse fed-batch. The optimal conditions found were pH 6.0 and 42.5 °C, using 2.5 g/L of initial concentration of xylan increased up to 5.0 g/L at 3 h. Xylopentaose was the major oligosaccharide produced, representing 47% of the total production yield.

One-step process for producing prebiotic arabino-xylooligosaccharides from brewer's spent grain employing Trichoderma species.

Xylooligosaccharides (XOS) are prebiotic nutraceuticals that can be sourced from lignocellulosic biomass, such as agro-residues. This study reports for the first time an optimization study of XOS production from agro-residues by direct fermentation using two Trichoderma species. A total of 13 residues were evaluated as potential substrates for single-step production. The best results were found for Trichoderma reesei using brewers' spent grain (BSG) as substrate. Under optimal conditions (3 days, pH 7.0, 30 °C and 20 g/L of BSG), a production yield of 38.3 ±â€¯1.8 mg/g (xylose equivalents/g of BSG) was achieved. The obtained oligosaccharides were identified as arabino-xylooligosacharides (AXOS) with degree of polymerization from 2 to 5. One-step fermentation proved to be a promising strategy for AXOS production from BSG, presenting a performance comparable with the use of commercial enzymes. This study provides new insights towards the bioprocess integration, enabling further developments of low-cost bioprocesses for the production of these valuable compounds.

Single-step production of arabino-xylooligosaccharides by recombinant Bacillus subtilis 3610 cultivated in brewers' spent grain.

Brewers' spent grain (BSG) is an inexpensive and abundant brewery by-product that can be used to produce prebiotic arabino-xylooligosaccharides (AXOS). In this study, Bacillus subtilis 3610 was used, for the first time, to produce AXOS through direct fermentation of BSG. Additionally, the microorganism was genetically modified to improve the AXOS production. The xylanase gene xyn2 from Trichoderma reesei coupled with a secretion tag endogenous to B. subtilis was cloned in pDR111 and integrated into its chromosome. After optimization by experimental design, AXOS with a degree of polymerization ranging from 2 to 6 were obtained. The maximum production yield expressed in xylose equivalents per amount of BSG (54.2 ± 1.1 mg/g) represents an increase of 33% comparing to the wild type. When compared with the enzymatic hydrolysis process, single-step fermentation with B. subtilis proved to be a very promising low-cost strategy for the simultaneous production of AXOS and valorization of BSG.

New blocking antibodies impede adhesion, migration and survival of ovarian cancer cells, highlighting MFGE8 as a potential therapeutic target of human ovarian carcinoma.

Milk Fat Globule--EGF--factor VIII (MFGE8), also called lactadherin, is a secreted protein, which binds extracellularly to phosphatidylserine and to αvß3 and αvß5 integrins. On human and mouse cells expressing these integrins, such as endothelial cells, phagocytes and some tumors, MFGE8/lactadherin has been shown to promote survival, epithelial to mesenchymal transition and phagocytosis. A protumoral function of MFGE8 has consequently been documented for a few types of human cancers, including melanoma, a subtype of breast cancers, and bladder carcinoma. Inhibiting the functions of MFGE8 could thus represent a new type of therapy for human cancers. Here, we show by immunohistochemistry on a collection of human ovarian cancers that MFGE8 is overexpressed in 45% of these tumors, and we confirm that it is specifically overexpressed in the triple-negative subtype of human breast cancers. We have established new in vitro assays to measure the effect of MFGE8 on survival, adhesion and migration of human ovarian and triple-negative breast cancer cell lines. Using these assays, we could identify new MFGE8-specific monoclonal antibodies, which efficiently blocked these three tumor-promoting effects of MFGE8. Our results suggest future use of MFGE8-blocking antibodies as new anti-cancer therapeutics in subgroups of ovarian carcinoma, and triple-negative breast carcinoma patients.

Catalytic hydrodechlorination of chloroaromatic gas streams promoted by Pd and Ni: the role of hydrogen spillover.

Catalytic hydrodechlorination (HDC) is an effective means of detoxifying chlorinated waste. Involvement of spillover hydrogen is examined in gas phase dechlorination of chlorobenzene (CB) and 1,3-dichlorobenzene (1,3-DCB) over Pd and Ni. The catalytic action of single component Pd and Ni, Pd/Al(2)O(3), Ni/Al(2)O(3) and physical mixtures with Al(2)O(3) has been considered. Catalyst activation is characterized in terms of temperature programmed reduction, the supported nano-scale metal phase by transmission electron microscopy and hydrogen/surface interactions by chemisorption/temperature programmed desorption. Pd/Al(2)O(3) generated significantly greater amounts of spillover hydrogen (by a factor of over 40) compared with Ni/Al(2)O(3). Hydrogen spillover on Pd/Al(2)O(3) far exceeded the chemisorbed component, whereas chemisorbed and spillover content was equivalent for Ni/Al(2)O(3). Inclusion of Al(2)O(3) with Ni and Ni/Al(2)O(3) increased spillover with an associated increase in specific HDC rate (up to a factor of 10) and enhanced selectivity to benzene from 1,3-DCB. HDC rate delivered by Pd and Pd/Al(2)O(3) was largely unaffected by the addition of Al(2)O(3). This can be attributed to the higher intrinsic HDC performance of Pd that results in appreciable HDC activity under conditions where Ni/Al(2)O(3) was inactive. Spillover was partially recovered (post TPD) for the Ni samples but the loss was irreversible in the case of Pd.

Superior antitumor activity of SAR3419 to rituximab in xenograft models for non-Hodgkin's lymphoma.

PURPOSE: To investigate the activity of SAR3419, a novel humanized anti-CD19 antibody (huB4), conjugated to a cytotoxic maytansine derivative N(2)'-deacetyl-N(2)'-(4-mercapto-4-methyl-1-oxopentyl) maytansine, in preclinical xenograft models for non-Hodgkin's lymphoma. EXPERIMENTAL DESIGN: Antitumor activity of SAR3419 was assessed as a single agent and in comparison with conventional therapies using a subcutaneous model for diffuse large B-cell lymphoma (WSU-DLCL2) and a systemic model for follicular small cleaved cell lymphoma (WSU-FSCCL) in mice with severe combined immune deficiency. RESULTS: Our results showed that in these chemotherapy-resistant models, SAR3419 was more effective than CHOP (cyclophosphamide-Adriamycin-vincristine-prednisone) regimen or rituximab. Only treatment with SAR3419 led to survival of the whole group of animals to the end of the experiment (150-155 days) in both models. Higher doses of SAR3419 (15 and 30 mg/kg) were more effective than lower dose of 7.5 mg/kg. The immunoconjugation was necessary because neither huB4 nor DM4 alone had significant activity. Treatment with rituximab resulted in antitumor activity in both models comparable with the low dose of SAR3419. Cyclophosphamide-Adriamycin-vincristine-prednisone alone showed modest activity in both models. Necropsy and tissue staining in the WSU-FSCCL systemic model revealed that all deaths featured leptomeningeal lymphoma in the control and treated groups. Interestingly, some of the animals that survived to the end of the experiment and seemed healthy at time of euthanasia did show microscopic evidence of lymphoma. CONCLUSIONS: Overall, SAR3419 is a very active immunotoxin in preclinical models for human B-cell lymphoma and holds promise as a novel and well-tolerated therapy in B-cell non-Hodgkin's lymphoma.

P-gp activity is a critical resistance factor against AVE9633 and DM4 cytotoxicity in leukaemia cell lines, but not a major mechanism of chemoresistance in cells from acute myeloid leukaemia patients.

BACKGROUND: AVE9633 is a new immunoconjugate comprising a humanized monoclonal antibody, anti-CD33 antigen, linked through a disulfide bond to the maytansine derivative DM4, a cytotoxic agent and potent tubulin inhibitor. It is undergoing a phase I clinical trial. Chemoresistance to anti-mitotic agents has been shown to be related, in part, to overexpression of ABC proteins. The aim of the present study was to investigate the potential roles of P-gp, MRP1 and BCRP in cytotoxicity in AVE9633-induced acute myeloid leukaemia (AML). METHODS: This study used AML cell lines expressing different levels of P-gp, MRP1 or BCRP proteins and twenty-five samples from AML patients. Expression and functionality of the transporter protein were analyzed by flow cytometry. The cytotoxicity of the drug was evaluated by MTT and apoptosis assays. RESULTS: P-gp activity, but not MRP1 and BCRP, attenuated AVE9633 and DM4 cytotoxicity in myeloid cell lines. Zosuquidar, a potent specific P-gp inhibitor, restored the sensitivity of cells expressing P-gp to both AVE9633 and DM4. However, the data from AML patients show that 10/25 samples of AML cells (40%) were resistant to AVE9633 or DM4 (IC(50) > 500 nM), and this was not related to P-gp activity (p-Value: 0.7). Zosuquidar also failed to re-establish drug sensitivity. Furthermore, this resistance was not correlated with CD33 expression (p-Value: 0.6) in those cells. CONCLUSION: P-gp activity is not a crucial mechanism of chemoresistance to AVE9633. For patients whose resistance to conventional anthracycline AML regimens is related to ABC protein expression, a combination with AVE9633 could be beneficial. Other mechanisms such as microtubule alteration could play an important role in chemoresistance to AVE9633.

Palladium supported on structured and nonstructured carbon: a consideration of Pd particle size and the nature of reactive hydrogen.

This study sets out a comprehensive characterization of bulk Pd and Pd (ca. 8% w/w) supported on activated carbon (AC), graphite and graphitic nanofibers (GNF). Catalyst activation has been examined by temperature programmed reduction (TPR) analysis and the activated catalysts analyzed in terms of BET area, TEM, H2 chemisorption/TPD, and XRD measurements. While H2 chemisorption and TEM delivered the same sequence of increasing (surface area weighted) average Pd particle sizes, a significant difference (by up to a factor of 3) in the values obtained from both techniques has been recorded and is attributed to an unwarranted (but widely adopted) assumption of an exclusive H2/Pd adsorption stoichiometry=1/2. It is demonstrated that TEM analysis provides a valid mean particle size once it is established that the associated standard deviation is small and insensitive to additional particle counting. XRD line broadening yielded an essentially equivalent Pd size (20-25 nm) for each supported catalyst. The nature of the hydrogen associated with the supported catalysts has been probed and is shown to comprise of chemisorbed (on Pd), spillover (on the carbon support), and hydride (associated with Pd) species. Physical mixtures of bulk Pd + support (AC, graphite, and GNF) were also considered in order to assess hydrogen spillover by H2 TPD analysis. Generation of spillover hydrogen at room temperature is established where temperatures in excess of 740 K are required for effective desorption from the supported Pd catalysts, i.e., 280 K higher than that required for the desorption of chemisorbed hydrogen. Pd hydride formation (at room temperature) is shown to be reversible with decomposition occurring at ca. 380 K. Taking the hydrodechlorination of chlorobenzene as a test reaction, the capability of Pd hydride to promote a hydrogen scission of C-Cl in the absence of an external supply of H2 is demonstrated with a consequent consumption of the hydride. This catalytic response was entirely recoverable once the Pd hydride was replenished during a subsequent reactivation step.