Autologous stem cell transplantation for untreated transformed indolent B-cell lymphoma in first remission: an international, multi-centre propensity-score-matched study.

High-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) are used as consolidation in first remission (CR1) in some centres for untreated, transformed indolent B-cell lymphoma (Tr-iNHL) but the evidence base is weak. A total of 319 patients with untreated Tr-iNHL meeting prespecified transplant eligibility criteria [age <75, LVEF ≥45%, no severe lung disease, CR by positron emission tomography or computed tomography ≥3 months after at least standard cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab (R-CHOP) intensity front-line chemotherapy] were retrospectively identified. Non-diffuse large B-cell lymphoma transformations were excluded. About 283 (89%) patients had follicular lymphoma, 30 (9%) marginal-zone lymphoma and six (2%) other subtypes. Forty-nine patients underwent HDC/ASCT in CR1, and a 1:2 propensity-score-matched cohort of 98 patients based on age, stage and high-grade B-cell lymphoma with MYC, BCL2 and/or BCL6 rearrangements (HGBL-DH) was generated. After a median follow-up of 3·7 (range 0·1-18·3) years, ASCT was associated with significantly superior progression-free survival [hazard ratio (HR) 0·51, 0·27-0·98; P = 0·043] with a trend towards inferior overall survival (OS; HR 2·36;0·87-6·42; P = 0·1) due to more deaths from progressive disease (8% vs. 4%). Forty (41%) patients experienced relapse in the non-ASCT cohort - 15 underwent HDC/ASCT with seven (47%) ongoing complete remission (CR); 10 chimeric antigen receptor-modified T-cell (CAR-T) therapy with 6 (60%) ongoing CR; 3 allogeneic SCT with 2 (67%) ongoing CR. Although ASCT in CR1 improves initial duration of disease control in untreated Tr-iNHL, the impact on OS is less clear with effective salvage therapies in this era of CAR-T.

Polyphasic approach to the identification and characterization of aflatoxigenic strains of Aspergillus section Flavi isolated from peanuts and peanut-based products marketed in Malaysia.

Peanuts are widely consumed as the main ingredient in many local dishes in Malaysia. However, the tropical climate in Malaysia (high temperature and humidity) favours the growth of fungi from Aspergillus section Flavi, especially during storage. Most of the species from this section, such as A. flavus, A. parasiticus and A. nomius, are natural producers of aflatoxins. Precise identification of local isolates and information regarding their ability to produce aflatoxins are very important to evaluate the safety of food marketed in Malaysia. Therefore, this study aimed to identify and characterize the aflatoxigenic and non-aflatoxigenic strains of Aspergillus section Flavi in peanuts and peanut-based products. A polyphasic approach, consisting of morphological and chemical characterizations was applied to 128 isolates originating from raw peanuts and peanut-based products. On the basis of morphological characters, 127 positively identified as Aspergillus flavus, and the other as A. nomius. Chemical characterization revealed six chemotype profiles which indicates diversity of toxigenic potential. About 58.6%, 68.5%, and 100% of the isolates are positive for aflatoxins, cyclopiazonic acid and aspergillic acid productions respectively. The majority of the isolates originating from raw peanut samples (64.8%) were aflatoxigenic, while those from peanut-based products were less toxigenic (39.1%). The precise identification of these species may help in developing control strategies for aflatoxigenic fungi and aflatoxin contamination in peanuts, especially during storage. These findings also highlight the possibility of the co-occurrence of other toxins, which could increase the potential toxic effects of peanuts.

Dietary intake of aflatoxins in the adult Malaysian population - an assessment of risk.

Exposure to aflatoxins in the adult Malaysian diet was estimated by analysing aflatoxins in 236 food composites prepared as "ready for consumption". Dietary exposure to aflatoxin B1 (AFB1) ranged from 24.3 to 34.00 ng/kg b.w./day (lower to upper bound), with peanuts being the main contributor. Estimated liver cancer risk from this exposure was 0.61-0.85 cancers/100,000 population/year, contributing 12.4%-17.3% of the liver cancer cases. Excluding AFB1 occurrence data higher than 15 µg/kg reduced exposure by 65%-91% to 2.27-11.99 ng/kg b.w./day, reducing the cancer risk to 0.06-0.30 cancers/100,000 population/year (contributing 1.2%-6.1% liver cancer cases). Reducing further the ML of AFB1 from 15 to 5 µg/kg yielded 3%-7% greater drop in the exposure to 0.47-10.26 ng/kg b.w./day with an estimated risk of 0.01-0.26 cancers/100,000 population/year (0.2%-5.1% liver cancer cases attributed to dietary AFB1). These findings indicate that current MLs are adequate in protecting Malaysians' health.

Lupus nephritis in children in Malaysia.

OBJECTIVES: To determine the pattern of renal histology, clinical outcome of children with lupus nephritis and to identify any associated risk factors predicting renal failure in these children. METHODS: Retrospectively, 27 children under 16 years of age with lupus nephritis who had renal biopsies done at Sultanah Aminah Hospital Johor, Malaysia from 1994 to 2002 were studied. The renal histology was graded according to WHO classification system (1982). The medical records, laboratory data and the clinical outcome of the patients were studied. RESULTS: There were 24 cases of WHO Class IV, two cases of WHO Class II and a case of WHO Class V. Twenty children were in the good renal outcome group while six children progressed into the poor renal outcome group and required renal replacement. One child was lost to follow-up. All six children in the poor renal outcome group had WHO Class IV histology. The 5-year patient and renal survival rates were 84% and 75%, respectively. Age, sex, activity and chronicity indices in the renal histology, anaemia, elevated serum creatinine, depressed levels of C3 and C4, heavy proteinuria or presence of urinary active sediments were not associated with progression to renal failure. CONCLUSIONS: Presently, children with lupus nephritis appeared to have better patient and renal survival rates. Assessment of renal histology in these children was important for diagnosis, treatment and probably prognosis. In this study, there was a 25% incidence of loss of renal function over 5 years in children with WHO Class IV renal histology.

Biopsy-proven childhood glomerulonephritis in Johor.

BACKGROUND: There has been no published study of biopsy-proven childhood glomerulonephritis in Malaysia. OBJECTIVES: To determine the pattern of childhood glomerulonephritis in Johor, Malaysia from a histopathological perspective and the various indications used for renal biopsy in children. MATERIALS AND METHODS: Retrospective study was done of all renal biopsies from children under 16 years of age, received in Sultanah Aminah Hospital, Johor between 1994 and 2001. The histopathological findings were reviewed to determine the pattern of biopsy-proven glomerulonephritis. The indications for biopsy, mode of therapy given after biopsy and the clinical outcome were studied. RESULTS: 122 adequate biopsies were received, 9 children had repeat biopsies. Of the 113 biopsies, minimal change disease formed the most common histopathological diagnosis (40.7%) while lupus nephritis formed the most common secondary glomerulonephritis (23.0%). The main indications for biopsy were nephrotic syndrome (50.8%), lupus nephritis (25.4%) and renal impairment (13.1%). The mode of therapy was changed in 59.8% of the children. Of 106 patients followed-up, 84 children were found to have normal renal function in remission or on treatment. 4 patients developed chronic renal impairment and 16 reached end stage renal disease. Five of the 16 children with end stage disease had since died while 11 were on renal replacement therapy. Another 2 patients died of other complications. CONCLUSIONS: The pattern of childhood GN in our study tended to reflect the more severe renal parenchymal diseases in children and those requiring more aggressive treatment. This was because of our criteria of selection (indication) for renal biopsy. Renal biopsy where performed appropriately in selected children may not only be a useful investigative tool for histological diagnosis and prognosis but may help clinicians plan the optimal therapy for these children.

Bioactive aromatic compounds from leaves and stems of Vanilla fragrans.

Alcoholic extracts of leaves and stems of Vanilla fragrans were fractionated with ethyl acetate and aqueous butanol. All three fractions of ethyl acetate, butanol, and water were screened for toxic bioactivity against mosquito larvae. The results of these experiments showed that the fractions from the ethyl acetate and butanol phases were both active in the bioassay. Bioactivity of the ethyl acetate fraction was found to be much greater than that from the butanol fraction in mosquito larvae toxicity. The water phase appeared to contain no substances that impaired mosquito larval growth. Repeated column chromatography of the ethyl acetate fraction on silica gel led to the isolation of 4-ethoxymethylphenol (1), 4-butoxymethylphenol (2), vanillin (3), 4-hydroxy-2-methoxycinnamaldehyde (4), and 3,4-dihydroxyphenylacetic acid (5). Compounds 4 and 5 were isolated from Vanilla species for the first time and 2 has not been reported to have been found in a natural form. 4-Ethoxymethylphenol (1) was the predominant compound, but 4-butoxymethylphenol (2) showed the strongest toxicity to mosquito larvae. The structures of the compounds were determined on the basis of their mass spectra and (1)H or (13)C NMR data.

Modification of fatty acids changes the flavor volatiles in tomato leaves.

Expression of the yeast Delta9 desaturase gene in tomato (Lycopersicon esculentum Mill.) resulted in changes in the profiles of fatty acids in tomato leaves. Transgenic leaves displayed a dramatic increase in cis-Delta9 16:1, which only existed in a small quantity in control leaves. Also higher, but not as dramatic, were 18:1 and 16:3 fatty acids. Several fatty acids, viz. 16:0, 18:0, and 18:3 declined in transgenic leaves. Changes in fatty acids were accompanied by changes in certain volatile compounds derived from fatty acids. On a percentage basis, most notable increases (>3-fold) were 1-hydroxy-2-butanone, 1-penten-3-ol, heptanal, 3-hexen-1-ol, 2-octanol,cis-3-hexenal, hexanal and 2-nonenal. Several flavor compounds not known to be biochemically derived from fatty acids, viz. 2-ethyl-furan, 5-ethyl-2-[5H]-furanone, eugenol, and 2-ethylthiophene also showed sharp increases in transgenic leaves.

Bioactive constituents from gum guggul (Commiphora wightii).

Bioactivity-directed fractionation and purification afforded cytotoxic components of Commiphora wightii. The exudates of C. wightii were extracted with EtOAc and the extract was subjected to repeated column chromatography. A fraction showing cytotoxic activity was characterized as a mixture of two ferulates with an unusual skeleton by spectral and chemical methods, including by NMR, GC-MS and chemical derivatization. This fraction also showed moderate scavenging effect against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals.

Effect of urea on volatile generation from Maillard reaction of cysteine and ribose.

Urea occurs naturally in many food products, and its presence affects food quality. However, little is known about its impact on flavor generation in food production. In this study, the urea contents in beef, pork, and chicken were determined. The effects of urea and pH on thermal flavor generation were investigated using the model system of cysteine with ribose, which was heated to the roasting temperature of 180 degrees C for 2 h at pH 5 and pH 8.5. The results revealed relatively large amounts of urea in these meats and demonstrated that pH affects aroma generation. Volatiles identified from the reaction system of ribose and cysteine showed that sulfur-containing compounds such as thiophenes, thiazoles, and thiophenethiols were the most abundant compounds. The addition of urea into the reaction mixture caused the disappearance or reduction in content of some sulfur-containing compounds but resulted in the generation of several important nitrogen-containing volatiles, like pyrazine, methylpyrazine, 2,5- (and 2,6-)dimethylpyrazine and other alkylpyrazines, which are known to elicit roasty, nutty flavor notes. A plausible explanation for this phenomenon is that ammonia can be released from urea upon heating and the formed ammonia competes with hydrogen sulfide to react with Maillard reaction precursors to produce nitrogen-containing compounds such as alkylpyrazines.

Production and elicitation of benzalacetone and the raspberry ketone in cell suspension cultures of Rubus idaeus.

Production levels of p-coumaric acid (p-CA), p-hydroxyphenylbut-3-ene-2-one (benzalacetone), and p-hydroxyphenyl-2-butanone (raspberry ketone) were measured in raspberry cell suspension cultures to investigate metabolite dynamics in a short (two-step) pathway. Intracellular concentrations of benzalacetone and the raspberry ketone fluctuated during the time course of a normal batch culture cycle but showed higher levels during periods of rapid growth. Cells elicited with the signal coupler methyl jasmonate yielded a 2- to 3-fold increase in metabolite concentrations after 24 h. The results suggest that raspberry ketone production is rapidly inducible during periods of high carbohydrate utilization. It is not an end product, however, and undergoes conversion to subsequent metabolites.

Inhibitory activity of boswellic acids from Boswellia serrata against human leukemia HL-60 cells in culture.

Four major triterpene acids including beta-boswellic acid (1), 3-O-acetyl-beta-boswellic acid (2), 11-keto-beta-boswellic acid (3), and 3-O-acetyl-11-keto-beta-boswellic acid (4) were isolated from the gum resin of Boswellia serrata and examined for their in vitro antitumor activity. They inhibited the synthesis of DNA, RNA and protein in human leukemia HL-60 cells in a dose dependent manner with IC50 values ranging from 0.6 to 7.1 microM. Among them, compound 4 induced the most pronounced inhibitory effects on DNA, RNA and protein synthesis with IC50 values of 0.6, 0.5, and 4.1 microM, respectively. The effect of 4 on DNA synthesis was found to be irreversible. Compound 4 significantly inhibited the cellular growth of HL-60 cells, but did not affect cell viability.

Asterlingulatosides C and D, cytotoxic triterpenoid saponins from Aster lingulatus.

A further investigation of Aster lingulatus has led to the isolation of two additional novel triterpene saponins, asterlingulatoside C [3-O-beta-D-glucopyranosyl-3 beta, 16 alpha-dihydroxyolean-12-en-28-oic acid 28-O-beta-D-xylopyranosyl-(1-->4)-alpha-L-rhamnopyranosyl-(1-->2)-alpha- L- arabinopyranoside] (1) and asterlingulatoside D [3-O-beta-D-glucopyranosyl-3 beta,16 alpha-dihydroxyolean-12-en-28-oic acid 28-O-beta-D-xylopyranosyl-(1-->3)-beta-D-xylopyranosyl-(1-->4)-alpha-L- rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranoside] (2). Elucidation of the structures of 1 and 2 was mainly based on FABMS and 1D and 2D homonuclear and heteronuclear NMR techniques. Compounds 1 and 2 showed good inhibitory activity against DNA synthesis in human leukemia HL-60 cells with IC50 values of 8.8 and 6.1 microM, respectively.

Steroidal saponins from Asparagus officinalis and their cytotoxic activity.

Two oligofurostanosides were isolated from the seeds of Asparagus officinalis L and their structures characterized as 3-O-[alpha-L-rhamnopyranosyl-(1-->2)-(alpha-L-rhamnopyranosyl- (1-->4))-beta-D-glucopyranosyl]-26-O-[beta-D-glucopyranosyl]-(25R) -22 alpha-methoxyfurost-5-ene-3 beta,26-diol(methyl protodioscin) and its corresponding 22 alpha-hydroxy analogue (protodioscin). The structural identification was performed using detailed analysis of 1H- and 13C-NMR spectra including two-dimensional NMR spectroscopy (COSY, HMQC, NOESY and HMBC), and chemical conversions. These two compounds have been shown to inhibit the growth of human leukemia HL-60 cells in culture and macromolecular synthesis in a dose-dependent manner. The inhibitory effect on DNA synthesis was found to be irreversible.

Triterpenoid saponins from Aster lingulatus.

Two new triterpenoid saponins named asterlingulatosides A and B were isolated from the whole plants of Aster lingulatus. Their structures were determined by spectroscopic data and chemical transformations to be 3-O-beta-D-glucopyranosyl-3 beta,16 alpha-dihydroxyolean-12-en-28-oic acid-28-O-alpha-L-O-arabinopyranoside and 3-O-beta-D-glucopyranosyl-3 beta,16 alpha-dihydroxyolean-12-en-28-oic acid-28-O-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranoside++ +. They showed inhibitory activity on DNA synthesis in human leukaemia HL-60 cells.

First Report of Powdery Mildew in Greenhouse-Grown Tomatoes in New Jersey.

Powdery mildew of tomatoes caused by an Erysiphe sp. has been reported to occur in greenhouses in New York (2). In March and April of 1996, outbreaks of this disease were found in greenhouse-grown tomato plants of cv. PSR55809 at the Cook College campus in New Brunswick, NJ, and in cv. Match in commercial greenhouses in Burlington County, NJ. Identification of an Erysiphe sp. was made by comparative morphology of the conidial state since the perfect stage was not observed. Symptoms included development of patches of white mycelium predominantly on upper surfaces of older leaves followed by chlorosis of tissues colonized by the fungus. Microscopic examination of mycelium revealed the presence of typical Oidium conidiogenous cells and conidia. Conidiogenous cells were short and cylindrical and produce conidia in chains apically. Conidia were hyaline, cylindrical to ellipsoidal, and measured 36 + 4.9 × 16.7 + 2.2 µm (n = 20). Both conidia and symptoms of this powdery mildew are comparable to those previously given for the Erysiphe sp. described in New York (2). Another powdery mildew of tomato, caused by Oidiopsis sicula Scalia, occurs in the western U.S., Mediterranean Basin, Africa, and Asia. However, the conidia of O. sicula are of two types, pyriform and cylindrical, and they are larger than those of an Erysiphe sp. (1). To verify pathogenicity of this Erysiphe sp. to tomatoes, conidia washed from leaves were misted onto uninfected leaves of young tomato plants. After 1 week in a growth chamber (25°C; 80% relative humidity; 12 h of light), typical powdery mildew symptoms were evident on inoculated plants, while unmisted plants remained free of symptoms. Microscopic examination of the fungus on surfaces of leaves confirmed it to be an Erysiphe sp. References: (1) R. N. Campbell and R. W. Scheuerman. Plant Dis. Rep. 63:1087, 1979. (2) D. M. Karasevicz and T. A. Zitter. Plant Dis. 80:709, 1996.

Inhibitory effect of caffeic acid phenethyl ester on human leukemia HL-60 cells.

Caffeic acid phenethyl ester (CAPE) was synthesized from caffeic acid and phenethyl alcohol (ratio 1:5) at room temperature with dicyclohexyl carbodiimide (DCC) as a condensing reagent. The yield was about 38%. CAPE was found to arrest the growth of human leukemia HL-60 cells. It also inhibits DNA, RNA and protein synthesis in HL-60 cells with IC50 of 1.0 microM, 5.0 microM and 1.5 microM, respectively.

An echinocystic acid saponin derivative from Kalimeris shimadae.

A new triterpene saponin, shimadoside A, has been isolated from Kalimeris shimadae and its structure deduced as 3-O-beta-D-glucopyranosiduronic acid-3 beta, 16 alpha-dihydroxyolean-12-en-28-oic acid-28-O-beta-D-xylopyranosyl-(1-->3)-beta-D-xylopyranosyl-(1--> 4)-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-xylopyranoside by means of spectral data, especially NMR, including COSY, HMQC, HOHAHA and ROESY techniques, and chemical degradation.

Anti-tumor activity of the crude saponins obtained from asparagus.

The crude saponins from the shoots (edible part of asparagus) of asparagus (asparagus crude saponins; ACS) were found to have antitumor activity. The ACS inhibited the growth of human leukemia HL-60 cells in culture and macromolecular synthesis in a dose and time dependent manner. The ACS at 75-100 micrograms/ml range was cytostatic. ACS concentrations greater than 200 micrograms/ml were cytocidal to HL-60 cells. The ACS at 6 and 50 micrograms/ml inhibited the synthesis of DNA, RNA and protein in HL-60 cells by 41, 5, and 4, respectively, or by 84, 68 and 59%, respectively. The inhibitory effect of ACS on DNA synthesis was irreversible.