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BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma.

The poorly differentiated carcinoma with t(15;19)(q13, p13.1) is characterized by its highly aggressive, invariably lethal clinical course. The chromosome 19 translocation breakpoint targets the BRD4 double bromodomain-containing gene, which functions in regulation of cell cycle progression. Herein we demonstrate that BRD4 is fused with nearly the entire transcript of the novel 15q13 gene, NUT (nuclear protein in testis), forming a 6.4-kb fusion oncogene, BRD4-NUT. NUT, like BRD4, is predicted to encode a nuclear protein but, unlike the ubiquitous BRD4 transcript, is expressed only in testis. These findings establish a model to elucidate the oncogenic consequences of unscheduled NUT expression and altered BRD4 function. Very few fusion oncogenes have been identified in epithelial tumors, and BRD4-NUT is the first fusion oncogene mechanism identified in a highly lethal form of carcinoma.

Amino Acid Sequence↗

Betel-nut chewing may aggravate asthma.

A questionnaire survey on the relationship between chewing betel nut and asthma was carried out in 61 asthmatic patients who regularly attend a follow-up clinic at Port Moresby General Hospital. 54 of these had once chewed or were still chewing betel nut; 20 patients had already given it up, while 34 were still regular or occasional chewers. 7 patients had never chewed. 11 of the 20 patients who used to chew but had given up reported having stopped because of aggravation of their asthma. 22 of the 34 patients who still chewed also reported aggravation of their asthma by betel nut. Anecdotal reports were given directly linking specified methods of chewing the nut with asthma aggravation, in some cases indicating dose-response (toxicity) relationships. While more elaborate and objective studies are being undertaken, it is hereby suggested that patients with asthma be cautioned against chewing betel nut.

Adult↗

Action of an RNA site at a distance: role of the nut genetic signal in transcription antitermination by phage-lambda N gene product.

The N gene product of Escherichia coli phage lambda is a transcriptional activator that captures the host RNA polymerase and modifies it to a termination-resistant form, permitting gene expression in two large polycistronic operons of the phage genome. Antitermination in vitro requires at least one host factor called NusA, which directly binds the N protein as well as RNA polymerase, and also a transcribed cis-acting site known as nut, within which lies the hypothesized N-recognition signal, boxB. BoxB is an interrupted palindrome capable of forming a hairpin in the mRNA. Inhibition studies with complementary DNA oligonucleotides provide evidence for a direct role of the boxB hairpin in antitermination. Kinetic studies of transcript elongation reveal that the boxB hairpin does not induce an appreciable pause to hold polymerase captive for engagement by N and NusA. Moreover, the efficiency of antitermination remains virtually the same whether N and NusA are added early, prior to nut site transcription, or added later, after the polymerase has already transcribed past the nut site. After transcription of the nut site, RNA polymerase remains susceptible to modification by N and NusA for an appreciable amount of time and distance, and the nut site DNA becomes dispensable for this modification. These results lead to the hypothesis that the boxB RNA hairpin acts in a manner analogous to the DNA enhancers, binding N and mediating a productive polymerase-NusA-N interaction by mRNA looping.

Bacterial Proteins↗

Cytotoxic and genotoxic effects of areca nut-related compounds in cultured human buccal epithelial cells.

Because betel quid chewing has been linked to the development of oral cancer, pathobiological effects of an aqueous areca nut extract, four areca nut alkaloids (arecoline, guvacoline, guvacine, and arecaidine), and four nitrosated derivatives [N-nitrosoguvacoline, N-nitrosoguvacine, 3-(N-nitrosomethylamino)propionaldehyde and 3-(N-nitrosomethylamino)propionitrile] have been investigated using cultured human buccal epithelial cells. Areca nut extract in a dose-dependent manner decreases cell survival, vital dye accumulation, and membrane integrity, and it causes formation of both DNA single strand breaks and DNA protein cross-links. Depletion of cellular free low-molecular-weight thiols also occurs, albeit at quite toxic concentrations. Comparisons of the areca nut-related N-nitroso compounds and their precursor alkaloids, at concentrations up to 5 mM, indicate that 3-(N-nitrosomethylamino)propionaldehyde is the most potent on a molar basis to decrease both survival and thiol content and to cause significant formation of DNA single strand breaks. Arecoline, guvacoline, or N-nitrosoguvacoline decreases survival and cellular thiols, whereas arecaidine, guvacine, N-nitrosoguvacine, and 3-(N-nitrosomethylamino)propionitrile have only minor effects on these variables. Taken together, the present studies indicate that aqueous extract and, in particular, one N-nitroso compound related to areca nut, i.e., 3-(N-nitrosomethylamino)propionaldehyde, are highly cytotoxic and genotoxic to cultured human buccal epithelial cells, of potential importance in the induction of tumors in betel quid chewers.

Arecoline↗

Purification and partial characterization of acyl carrier proteins from developing oil seeds of pisa (Actinodaphne hookeri) and ground nut (Arachis hypogaea).

Acyl carrier proteins (ACP) were purified to homogeneity in the active form from developing seeds of pisa (Actinodaphne hookeri) which synthesizes exclusively trilaurin and from ground nut (Arachis hypogaea) which synthesizes triacylglycerols containing long chain fatty acids. Two major isoforms of ACPs were purified from developing pisa seeds using DEAE-cellulose, Superose-6 FPLC and C4 reversed phase HPLC chromatographic methods. In contrast, only a single form of ACP was present in ground nut seeds which was purified by anion-exchange and activated thiol-Sepharose 4B affinity chromatography. The two isoforms of ACPs from pisa showed nearly the same specific activity of 6,706 and 7,175 pmol per min per mg protein while ground nut ACP showed a specific activity of 3,893 pmol per min per mg protein when assayed using E. coli acyl-ACP synthetase and [1-14C]palmitic acid. When compared with E. coli ACP, the purified ACPs from both the seeds showed considerable difference in their mobility in native PAGE, but showed similar mobility in SDS-PAGE under reducing conditions. In the absence of reducing agents formation of dimers was quite prominent. The ACPs from both the seed sources were acid- and heat-stable. The major isoform of pisa seed ACP and the ground nut ACP contain 91 amino acids with M(r) 11,616 and 1,228 respectively. However, there is significant variation in their amino acid composition. A comparison of the amino acid sequence in the N-terminal region of pisa and ground nut seed ACPs showed considerable homology between themselves and with other plant ACPs but not with E. coli ACP.

Amino Acid Sequence↗

The areca nut chewing habit and oral squamous cell carcinoma in South African Indians. A retrospective study.

A retrospective study (1983-1989) of oral squamous carcinomas and concomitant oral habits was undertaken in South African Indians from Natal. Information came from hospital records and interviews with patients, families and friends. There were 143 oral squamous carcinomas; these occurred in a ratio of 1:1,6 for men and women respectively. Squamous carcinomas of the cheek (buccal mucosa, alveolar sulcus and gingiva) occurred most frequently, especially in women (57/89--64%), while in men tongue cancer predominated (22/54--41%). Ninety-three per cent of women (83/87) and 17% of men (9/54) habitually chewed the areca nut. Thirty-nine of 57 women (68%) with cheek cancer and 21/25 (84%) with tongue cancer only chewed the nut (no tobacco, snuff or smoking). Analyses confirmed an association between nut chewing and cheek cancer. The odds ratio (OR) for oral cancer in women 25 years and older who only chewed the nut was 43,9 and the attributable risk (AR) 0,89 (89%). With tobacco the OR increases to 47,42 and the AR to 0,91 (91%). The data showed that the areca nut habit with or without tobacco use is important in the development of oral squamous carcinoma. Elimination of this habit can reduce the risk in these women substantially (89-91%) if all other factors remain the same.

Adolescent↗

Comparison of enterococci and coliform microorganisms in commercially produced pecan nut meats.

Pecan nut meats in the unbroken shell are sterile for enteric microorganisms. Recovery of coliform microorganisms or enterococci from finished pecan nut meats indicated contact contamination, assuming the tempering procedures to be satisfactory. Results of specific studies, designed toward developing background data on the sanitary significance of enterococci and coliform microorganisms in the production of pecan meats are reported. Unbroken pecan nuts or nut meats from various stages of shelling operations were diluted with a phosphate-buffered diluent. Serial dilutions were inoculated into Lactose Broth and Azide Dextrose Broth. The lactose fermentors were carried through indole, methyl red, Voges-Proskauer, and citrate reactions; the positive Azide Dextrose cultures were confirmed in Ethyl Violet Azide Broth and microscopically. Viable plate counts were obtained. Enterococci were found resistant to many deterrent factors affecting coliforms. Recoveries of enterococci were detected long after pollution had occurred. Little correlation was found between enterococcal recovery and observed insanitary practices in commercial shelling operations. Using the coliaerogenes group and, specifically, Escherichia coli as a sanitation index, microorganisms allowed accurate appraisal of tempering, personnel practices, and contact surface contaminating factors. It is felt this was due, in part, to the more delicate growth characteristics of E. coli. The fact that other pathogenic microorganisms, capable of causing gastrointestinal upsets, are associated with the presence of E. coli introduces a health factor which is important to regulatory agencies concerned with consumer protection.

Carya↗

Passive transfer of nut allergy after liver transplantation.

An anaphylactic reaction to cashew nut developed in a nonatopic 60-year-old man 25 days after receiving a liver allograft from a 15-year-old atopic boy who died of anaphylaxis after peanut ingestion. The liver recipient had no history of nut allergy. Posttransplantation skin prick test results were positive for peanut, cashew nut, and sesame seed, and the donor had allergen-specific IgE antibodies to the same 3 allergens. Contact tracing of the recipients of other solid organs from the same donor disclosed no other development of allergic symptoms after ingestion of peanut or cashew nut. Results of molecular HLA typing did not detect any donor-origin leukocytes in the recipient after transplantation, which excluded peripheral microchimerism. The patient inadvertently ingested peanut-contaminated food and suffered a second anaphylactic reaction 32 weeks after the transplantation. This case illustrates that transfer of IgE-mediated hypersensitivity can occur after liver transplantation and have potentially serious consequences. We therefore recommend that organ donors undergo screening for allergies, and that recipients be advised regarding allergen avoidance.

Anaphylaxis↗

Widespread tannin intake via stimulants and masticatories, especially guarana, kola nut, betel vine, and accessories.

Tannins are increasingly recognized as dietary carcinogens and as antinutrients interfering with the system's full use of protein. Nevertheless, certain tannin-rich beverages, masticatories, and folk remedies, long utilized in African, Asiatic, Pacific, and Latin American countries, are now appearing in North American sundry shops and grocery stores. These include guarana (Paullinia cupana HBK.) from Brazil, kola nut (Cola nitida Schott & Endl. and C. acuminata Schott & Endl.) from West Africa, and betel nut (Areca catechu L.) from Malaya. The betel nut, or arecanut, has long been associated with oral and esophageal cancer because of its tannin content and the tannin contributed by the highly astringent cutch from Acacia catechu L. and Uncaria gambir Roxb. and the aromatic, astringent 'pan' (leaves of Piper betel L.) chewed with it. In addition to the constant recreational/social ingestion of these plant materials, they are much consumed as aphrodisiacs and medications. Guarana and kola nut enjoy great popularity in their native lands because they are also rich in caffeine, which serves as a stimulant. Research and popular education on the deleterious effects of excessive tannin intake could do much to reduce the heavy burden of early mortality and health care, especially in developing countries.

Animals↗

In vitro genotoxic effects of areca nut extract and arecoline.

The genotoxic potential of the aqueous extract of areca nut as well as arecoline, the major alkaloid of the areca nut, was tested with the help of cytogenetic markers such as sister-chromatid exchanges and chromosome aberrations, utilizing Chinese hamster ovary (CHO) cells. The continuous-treatment and pulse-treatment schedules yielded dose-dependent elevations in the frequencies of sister-chromatid exchange and chromosomal aberration in CHO cells, indicating a genotoxic effect of both the extract and arecoline. The results also imply that, besides arecoline, there may be some other water-extractable substances in the areca nut that make the extract more genotoxic. The chromosome damage was found to be more severe on treating the cells with low concentrations and for longer duration, which mimic the effects of chronic areca nut consumption.

Animals↗

In vitro availability of iron from selected nuts and oilseeds.

Availability of iron from sixteen varieties of selected nuts and oilseeds was assessed by in vitro method. Wide and significant variations were recorded in the contents of total and ionisable iron and in the bioavailability of iron of the nuts and oilseeds. The total iron content was the highest in nigre seeds and the lowest in linseed seeds. Bioavailability of iron was significantly high from pistachio nut and almond and markedly low from groundnut. Most of the nuts and oilseeds were found to have less than 10 percent of bioavailability of iron, hence, they were not considered as good sources of iron among plant foods.

Analysis of Variance↗

Characterization of Chilean hazel nut sweet cookies.

A series of studies were carried out to test the effect of the incorporation of Chilean hazel nut flour in sweet cookies at the levels of 0%, 5%, 10%, 15% and 20%. The proximate chemical analysis of the different flour mixtures showed a regular increase from 7.2 to 12.2%, 14.5% to 18.8% and 1% to 2.2%, respectively, decreasing at the same time with the percentages of water and carbohydrates. Chemical amino acid scores of leucine and threonine in wheat flour improved with the incorporation of Chilean hazel nut flour. The farinographic evaluation made to the different blends showed several changes occurred with the incorporation of Chilean hazel nut flour to wheat flour. These included increase in water absorption, decrease in dough developing time and weakening of the dough. Sensory characteristics such as appearance, texture, flavor and also acceptability improved with the incorporation of Chilean hazel nut flour into the cookie formulas.

Amino Acids↗

Tree nut allergy.

Tree nuts are clinically associated with severe immunoglobulin E-mediated systemic allergic reactions independent of pollen allergy and with reactions that are usually confined to the oral mucosa in patients with immunoglobulin E directed toward cross-reacting pollen allergens. The latter reactions can progress to severe and life-threatening episodes in some patients. Many patients with severe tree nut allergy are co-sensitized to peanut. Clinical studies on cross-reactivity between the tree nuts are few in number, but based on reports to date, avoidance of the other tree nuts once sensitivity is diagnosed appears prudent unless specific challenges are performed to ensure clinical tolerance. Even then, great care must be taken to avoid cross-contamination. As with other severe food allergies, a recurrent problem in clinical management is the failure of physicians to prescribe self-injectable epinephrine to patients who are at risk of anaphylaxis.

Clinical Trials as Topic↗

The impact of nuts on diabetes and diabetes risk.

Nuts have many nutritional benefits: they are high in monounsaturated and polyunsaturated fats, fiber, vitamin, minerals, and phytonutrients. Population studies indicate that individuals who regularly consume nuts have reduced risk for cardiovascular disease and diabetes. In clinical trials, nuts appear to have a neutral effect on glucose and insulin, and a beneficial effect on lipid profile. Thus, nuts can be a healthy dietary component for individuals with diabetes or those at risk for diabetes, providing overall caloric intake is regulated to maintain a healthy body weight.

Body Weight↗

Modulatory effect of Areca nut on the action of mace (Myristica fragrans, Houtt) on the hepatic detoxification system in mice.

The present paper reports the modifying potential of areca nut (Areca catechu), an ingredient of the habitual masticatory betel quid, on the induction of the hepatic detoxification system in mice by mace (the aril of nutmeg, Myristica fragrans) a known chemopreventor of chemically induced carcinogenesis. The modulatory effect of areca nut was assessed by determining the levels of enzymes of the hepatic detoxification system, such as glutathione S-transferase (GST), cytochrome b5 and cytochrome P-450, and the content of acid-soluble sulphhydryl (-SH). Mice were fed either control diet or diet containing 0.25, 0.5 or 1% areca nut for 45 days. During the last 10 days the diet was supplemented with 0.5 or 1% mace. At 0.5 and 1% in the diet, areca nut decreased mace-induced increases in hepatic GST and -SH levels and elevated further increases in the levels of cytochrome b5 and cytochrome P-450.

Animals↗

Modulation of baroreflex sensitivity by walnuts versus cashew nuts in subjects with metabolic syndrome.

BACKGROUND: Impaired baroreflex sensitivity (BRS) is associated with cardiovascular diseases and the metabolic syndrome. Because lipid abnormalities have been associated with impaired BRS, this study aimed to determine whether diets known to improve the lipid profile, namely a diet high in polyunsaturated fatty acids (walnuts) or monounsaturated fatty acids (cashew nuts), would improve BRS in subjects with metabolic syndrome (MS). METHODS: A controlled feeding trial with a randomized, controlled, parallel study design was undertaken, which involved 62 subjects with MS. Subjects were stratified according to gender and age and were randomized into three groups receiving a control diet, or a diet high (20% energy) in walnuts or unsalted cashew nuts for 8 weeks while maintaining body weight. The BRS, C-reactive protein (CRP), and MS components were measured before and after the intervention. RESULTS: After the intervention, BRS in the walnut-fed study group decreased (P = .038) and that in the cashew-fed study group increased (P = .036), but the BRS in the control group did not change (P = .56). The percent change of the walnut versus cashew group differed (P = .019). Body mass index, waist circumference, blood pressure, high-density lipoprotein cholesterol, and triacylglycerol did not change. The fasting glucose concentrations of the cashew group increased (P = .03). CONCLUSIONS: The significant improvements in BRS obtained by a diet rich in cashew nuts underline the beneficial cardiovascular effects of nuts. However, the opposite result was obtained with a diet rich in walnuts. These significant changes observed might indicate that BRS is particularly sensitive and influenced by changes in diet without changes in obesity.

Adult↗

Study of unscheduled DNA synthesis following exposure of human cells to arecoline and extracts of betel nut in vitro.

Aqueous, acetic acid, hydrochloric acid and ethanol extracts of betel nut (Areca catechu L.) have been found to induce unscheduled DNA synthesis in Hep 2 cells obtained from human larynx carcinoma, in vitro. Different concentrations of extracts of betel nut induced dose-dependent unscheduled DNA synthesis in Hep 2 cells. Together with the viability of the Hep 2 cells, our results indicate that the aqueous and acetic acid extracts of betel nut induce relatively more unscheduled DNA synthesis than the hydrochloric acid and ethanol extracts and arecoline. The carcinogenic potency of raw and unprocessed betel nut of North-East India used in this study is discussed.

Arecoline↗

Fatty acid composition of nuts--implications for cardiovascular health.

It is well established that, due to their high content of saturated fatty acids (SFA), the intake of meat and meat products is strongly associated with elevated blood cholesterol concentrations and an increased risk of hypertension, diabetes and cardiovascular diseases. Conversely, the intake of foods rich in unsaturated fatty acids, such as those contained in most vegetable fats and oils and oily fish, is associated with improved lipid profiles, a lower potency of intermediate biomarkers of atherosclerosis and lesser incidence of cardiovascular diseases. There are persuasive evidences that dietary substitution of monounsaturated fatty acids (MUFA) or n-6 polyunsaturated fatty acids (PUFA) for SFA lowers blood cholesterol and may have beneficial effects on inflammation, thrombosis, and vascular reactivity. MUFA may have an advantage over PUFA because enrichment of lipoprotein lipids with MUFA increases their resistance to oxidation. Marine n-3 PUFA have a number of anti-atherosclerotic effects, including anti-arrhythmic properties and, at relatively high doses, reduce serum triglycerides. These effects appear to be shared in part by vegetable n-3 PUFA. Nuts are natural foods rich in unsaturated fatty acids; most nuts contain substantial amounts of MUFA, while walnuts are especially rich in both n-6 and n-3 PUFA. Healthy fats in nuts contribute to the beneficial effects of frequent nut intake observed in epidemiological studies (prevention of coronary heart disease, diabetes, and sudden death) and in short-term feeding trials (cholesterol lowering, LDL resistance to oxidation, and improved endothelial function).

Animals↗