Radiological complexity of nuclear facilities: an information complexity approach to workplace monitoring.

Nuclear energy is crucial for achieving net-zero carbon emissions. A big challenge in the nuclear sector is ensuring the safety of radiation workers and the environment, while being cost-effective. Workplace monitoring is key to protecting workers from risks of ionising radiation. Traditional monitoring involves radiological surveillance via installed radiation monitors, continuously recording measurements like radiation fields and airborne particulate radioactivity concentrations, especially where sudden radiation changes could significantly impact workers. However, this approach struggles to detect incremental changes over a long period of time in the radiological measurements of the facility. To address this limitation, we propose abstracting a nuclear facility as a complex system. We then quantify the information complexity of the facility's radiological measurements using an entropic metric. Our findings indicate that the inferences and interpretations from our abstraction have a firm basis for interpretation and can enhance current workplace monitoring systems. We suggest the implementation of a radiological complexity-based alarm system to complement existing radiation level-based systems. The abstraction synthesized here is independent of the type of nuclear facility, and hence is a general approach to workplace monitoring at a nuclear facility.

Microwave assisted synthesis of guar gum based biopolymeric macromolecule optimized as a flocculant for mineral ore processing.

The research endeavour to synthesize a novel, non-toxic, eco-friendly guar gum based biopolymeric macromolecule, [2-(methacryloyloxy) ethyl] trimethyl ammonium chloride grafted guar gum (GG-g-P (MAETMAC)) that has been optimized as a flocculant for mineral ore processing. The synthesis was performed using non-radiation and microwave assisted technique to compare and ensure the superiority of the latter. The intended grafting of monomer[2-(methacryloyloxy) ethyl] trimethyl ammonium chloride on to the biological macromolecule (guar gum) was confirmed through standard physico-chemical characterization techniques namely X-ray diffraction (XRD), scanning electron microscopy (SEM), thermal gravimetric analysis (TGA), Fourier transform infrared (FTIR) spectroscopy, ultraviolet-visible (UV-visible) spectroscopy, intrinsic viscosity study, etc. The flocculation efficacy of the synthesized novel graft copolymer was thoroughly investigated in kaolin, coal fine, and iron ore suspensions. We have explored a graft copolymer, [2-(methacryloyloxy) ethyl] trimethyl ammonium chloride grafted guar gum that has not been studied yet to the best of our knowledge. To establish the superiority of the synthesized biomaterial, the flocculation study revealed that the best grade of the synthesized novel graft copolymer showed flocculation efficacy of 90 % in kaolin, 69 % in Iron ore, and 29 % in coal fine suspensions which was significantly higher than using alum as a coagulant which provided 36 % efficacy in kaolin, 29 % in iron ore and 10 % in coal fine suspensions.

Infants later diagnosed with autism have lower canonical babbling ratios in the first year of life.

BACKGROUND: Canonical babbling-producing syllables with a mature consonant, full vowel, and smooth transition-is an important developmental milestone that typically occurs in the first year of life. Some studies indicate delayed or reduced canonical babbling in infants at high familial likelihood for autism spectrum disorder (ASD) or who later receive an ASD diagnosis, but evidence is mixed. More refined characterization of babbling in the first year of life in infants with high likelihood for ASD is needed. METHODS: Vocalizations produced at 6 and 12 months by infants (n = 267) taking part in a longitudinal study were coded for canonical and non-canonical syllables. Infants were categorized as low familial likelihood (LL), high familial likelihood diagnosed with ASD at 24 months (HL-ASD) or not diagnosed (HL-Neg). Language delay was assessed based on 24-month expressive and receptive language scores. Canonical babble ratio (CBR) was calculated by dividing the number of canonical syllables by the number of total syllables. Generalized linear (mixed) models were used to assess the relationship between group membership and CBR, controlling for site, sex, and maternal education. Logistic regression was used to assess whether canonical babbling ratios at 6 and 12 months predict 24-month diagnostic outcome. RESULTS: No diagnostic group differences in CBR were detected at 6 months, but HL-ASD infants produced significantly lower CBR than both the HL-Neg and LL groups at 12 months. HL-Neg infants with language delay also showed reduced CBR at 12 months. Neither 6- nor 12-month CBR was significant predictors of 24-month diagnostic outcome (ASD versus no ASD) in logistic regression. LIMITATIONS: Small numbers of vocalizations produced by infants at 6 months may limit the reliability of CBR estimates. It is not known if results generalize to infants who are not at high familial likelihood, or infants from more diverse racial and socioeconomic backgrounds. CONCLUSIONS: Lower canonical babbling ratios are apparent by the end of the first year of life in ASD regardless of later language delay, but are also observed for infants with later language delay without ASD. Canonical babbling may lack specificity as an early marker when used on its own.

Selection of ACC deaminase positive, thermohalotolerant and drought tolerance enhancing plant growth-promoting bacteria from rhizospheres of Cyamopsis tetragonoloba grown in arid regions.

Plant growth-promoting bacteria (PGPB) expressing 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase activity are widely acknowledged to have a role in mitigation of abiotic stress caused by extreme environmental conditions. Consequently, several studies have focused on the isolation of ACC deaminase positive PGPBs. However, the application of such strains in drought-prone arid regions has remained grossly under-exploited. In order to be used in arid agroecosystems, PGPBs need to have the dual capability: to express ACC deaminase and to have the ability to tolerate increased temperature and salt concentration. Conspicuously, to date, very few studies have reported about isolation and characterization of PGPBs with this kind of dual capability. Here we report the isolation of bacterial strains from rhizosphere(s) of Cyamopsis tetragonoloba, a commercial crop from arid regions of Rajasthan, India, and their characterization for ACC deaminase activity and thermohalotolerance. Isolates found positive for desired traits were subsequently assessed for plant growth promotion under simulated drought conditions. Our finding showed that although the bacterial diversity within the rhizosphere of C. tetragonoloba grown in the arid region is quite poor, multiple isolates are ACC deaminase positive. Four isolates were found to be ACC deaminase positive, thermohalotolerant, and successfully enhanced drought tolerance. These isolates were identified as strains belonging to genera Pseudomonas, Enterobacter, and Stenotrophomonas based on 16S rRNA sequence homology.

Prevalence and Associated Factors of Cesarean Section in Dhulikhel Hospital, Kathmandu University Hospital.

Background The Cesarean Section (CS) is a major obstetric life-saving procedure used to avoid pregnancy and childbirth complications. Cesarean sections are becoming more popular across the world, as well as in Nepal. Objective To assess the prevalence of cesarean section and its associated factors among women in Dhulikhel, Nepal. Method A cross-sectional study was conducted where 1246 pregnant women of age 15-45 years, admitted and delivered in hospital, were selected through purposive sampling technique and interviewed using structured questionnaires in Dhulikhel Hospital, Kathmandu University Hospital, Kavre, Nepal. Result The prevalence of cesarean section among women was 39.7% where the most common indication was previous cesarean section with scar tenderness, 27.9%. Half of the participants, i.e. 50.6%, were primigravida. Majority of women, 97.5% had done their antenatal checkup and among them 74.8% had their checkup in Dhulikhel Hospital, Kathmandu University Hospital. Most of them, i.e.76.2% had emergency cesarean section and 69.5% had primary cesarean section. Women of the age group 30-45 years (AOR=2.23) and women with higher secondary education level (AOR=2.03) were two times more likely to perform cesarean section. Women involved in service (AOR=1.37) and business (AOR=1.23) had greater odds of performing cesarean section than homemakers. Women giving birth to infants weighing 3.51- 5.00 kg were more likely to perform cesarean section (AOR=1.33). Conclusion The prevalence of cesarean section is noticeably high where the educated, employed and higher aged women are more inclined to cesarean section. More obstetric factors could be explored to determine the rise in cesarean section in Nepal which can help in decision making for clinicians.

Pyrolysis of sewage sludge for sustainable biofuels and value-added biochar production.

The study deals with the pyrolysis of sewage sludge to produce eco-friendly and sustainable fuels along with value-added biochar products. The experiments were conducted in a fixed-bed cylindrical glass reactor in the temperature range of 250-700 °C and achieved the product yield of 22.4 wt% bio-oil, 18.9 wt % pyrolysis gases, and 58.7 wt% biochar at 500 °C optimum temperature. The chemical composition of bio-oil was investigated by gas chromatograph-mass spectroscopy and fourier transformation infrared techniques. The ASTM standard procedures were used to assess the fuel qualities of bio-oil, and they were found to be satisfactory. Bio-oil has a greater H/C ratio (3.49) and a lower O/C ratio (1.10), indicating that it is suitable for engine use. The gas chromatographic analysis of pyrolysis gases confirmed the presence of 41.16 wt % combustible gases, making it suitable for use in spark-ignition engines. X-ray fluorescence analysis of biochar showed that it had a good amount of carbon, nitrogen, phosphorus, and potassium along with some micro-and macro-nutrient which proves its potential to utilize as organic manure in the agriculture sector. In addition, the data obtained from the TGA analysis during the pyrolysis of sewage sludge was applied to calculate kinetic parameters via the Coats-Redfern method.

Excitation Density Dependent Photoluminescence Studies on Homo-Epitaxial GaN Nanowall Networks Grown by Laser Assisted Molecular Beam Epitaxy.

The optical properties of laser-assisted molecular beam epitaxy grown homo-epitaxialGaN nanowall networks (NWNs) were investigated using power dependent photoluminescence (PL) spectroscopy and compared with homo-epitaxial GaN thin film. The pore size and tip width of GaN NWN sample is ˜120-180 nm and 10-15 nm, respectively. The ultraviolet-visible spectroscopy study shows that the GaN NWNs have low optical light reflection and minimum Fabry-Perot cavity effect than GaN film. The room temperature PL spectroscopy reveals that the GaN NWNs possesses enhanced band gap of 3.51 eV with blue shift of 90 meV than the GaN film (3.42 eV). The excitation density dependent PL spectroscopy measurements reveal that the GaN NWNs nanowall and near band emission (NBE) peak position and its linewidth invariant. The intensity of NBE peak for GaN film and nanowalls varies linearly whereas NBE to defect related yellow luminescence peak intensity ratio shows a non-linear variation on the excitation density. The excitation density in PL measurements plays a key role when the sample quality compared on the basis of PL data.

Effectiveness of pectoralis major myocutaneous flap in the surgical management of oral cancer: A retrospective study.

INTRODUCTION: Over 80,000 oral cancer cases get diagnosed each year in India, majority undergoing extensive resections owing to their late presentation. Pectoralis major myocutaneous (PMMC) flap is a pedicled axial pattern flap which is based on thoracoacromical artery. It is readily available as a viable alternative to free flap reconstruction, especially for the economically poor and malnourished patients. Its proximity to head and neck structures gives added advantage to reconstruct complex and large volume oral and maxillofacial defects. It provides a relatively good possibility of functional and aesthetic restoration providing both mucosal lining and skin cover. MATERIALS AND METHODS: This was a prospective observational study of 29 PMMC flap reconstructions, conducted between 2013-2016. The reconstruction outcomes assessed in this study were divided into two categories namely "success" and "failure" based on certain functional parameters observed during follow-up of 1 year. The complications were broadly classified as major/minor and flap related/non-flap related. We assessed the feasibility of using a PMMC flap for reconstructing various subsites of oral cavity cancer. Further, the association of patient variables with complication rates and outcome of reconstruction were analysed. RESULTS: Out of 29 patients overall complications were noted in 15 (51.7%) cases with a female preponderance. Flap-related complications were noted in 9 whereas non-flap-related complications were seen in 6 patients. Major and minor complications were noted in 2 (both flap related) and 13 cases respectively. Complete full thickness flap necrosis was not encountered in any patient. Patients with flap skin paddle size ≤ 36 cm2 (n = 12) had significantly increased overall complication rates. Despite complications a high success rate (93.1%, n = 27) was achieved with this mode of reconstruction. CONCLUSION: The PMMC flap reconstruction is a versatile, reliable and an affordable single staged procedure with a high success rate in terms of achieving treatment goals. Although it has moderately high complication rates, but PMMC flap proved to be a workhorse in locally advanced cases of head and neck cancer at the end of 1 year follow-up.

Free radical scavenging potential of sericin obtained from various ecoraces of tasar cocoons and its cosmeceuticals implication.

Tropical tasar silkworm Antheraea mylitta is a wild sericigenous insect which is distributed in different geographical regions and named as different ecoraces. In the present study, we investigated the molecular characterisation and cosmeceutical properties of sericin extracted from different ecoraces of tasar cocoons. The surface morphology and molecular weight of cocoons were determined by scanning electron microscope (SEM) and SDS-PAGE, respectively. Characterisation of sericin was performed by various methods such as FTIR, CHNS, TGA and amino acid analyzer. The anti-tyrosinase, anti-elastase, glutathione-S-transferase inhibition, free radical scavenging potential and inhibition of oxidative damages were measured in tasar ecoraces sericin. SEM images have revealed the removal of sericin from the surface of cocoons. SDS-PAGE of sericin depicted the presence of diverse molecular weight of proteins. Structural determination by FTIR revealed the presence of both α-helical and ß-sheet structures. Thermal properties of sericin were studied by TGA which showed a 50% weight loss at temperature 410 °C-430 °C. Additionally, ecoraces sericin contains 17 amino acids in which serine, aspartic acid and glycine are predominantly present (55.68-59.61%). Further, anti-tyrosinase, anti-elastase, inhibition of glutathione-S-transferase activity, free radical scavenging potential and inhibition of lipid peroxidation were also observed in ecoraces sericin. Our findings suggest that the present study appear to be helpful in exploiting sericin as potential biomaterial in cosmeceutical and allied field.

Tasar silk fiber waste sericin: New source for anti-elastase, anti-tyrosinase and anti-oxidant compounds.

The present study investigates the properties of sericin extracted from tasar silk fiber waste (TSFW). The surface morphology of TSFW was observed by scanning electron microscope (SEM). SEM images revealed the removal of residual sericin over the surface of TSFW. The molecular weight distribution of sericin was examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The results suggested that TSFW sericin represented a family of proteins with wide-ranging molecular weight distribution (11-245 kDa). Structural determination by FTIR revealed the presence of both α-helical and ß-sheet structures. The colour was studied by colorimeter indicating less brightness, more red and yellow colour intensities. The carbon: nitrogen ratio (C:N) was studied by CHNS element analyzer and the ratio is 5.15-7.85. Thermal properties of TSFW sericin have been studied by thermogravimetric analysis (TGA) method. TGA curve showed higher thermal stability and variable degradation profiles. Furthermore, TSFW sericin contains 17 amino acids where serine, aspartic acid and glycine are the more significant compounds (54.34-60.49%). In addition, sericin was found to inhibit tyrosinase, elastase and glutathione-S-transferase activity, and had apparent radical scavenging impacts on 2.2­diphenyl­1­picryl­hydrazil (DPPH), hydrogen peroxide and inhibition of lipid peroxidation. Result suggested that TSFW sericins might be a valuable ingredient for cosmoceutical products.

Comparative studies of Al3+ ions and Al2O3 nanoparticles on growth and metabolism of cabbage seedlings.

In the present study, we compared the effects of Al3+ ions and alumina (Al2O3) nanoparticles (NPs) on growth and biochemical parameters of cabbage seedlings. The seedlings were treated with A=698.8µM Al3+ions and A1=101.8µM, A2=253.8µM, A3=507.7µM, A4=1.02mM, A5=2.17mM NPs of Al2O3 in 700mL Hoagland solution. The untreated seedlings were taken as control. It was observed that aluminium ions were phytotoxic and adversely affected seedling growth and biochemical parameters of the test crop with stunting of the stem growth, while lower doses of alumina NPs enhanced seedling growth, pigments, sugar and protein contents of cabbage (Brassica oleracea var. capitata) seedlings. Higher doses of alumina NPs adversely affected biochemical parameters and nitrate reductase activities of the treated seedlings. Alumina NPs induced activities of antioxidant enzymes viz. SOD, CAT and POX. Antioxidant enzyme activities increased under all treatments with maximum increase in the seedlings treated with aluminium ions and higher concentrations of alumina NPs. The lower amount of alumina NPs buttressed the metabolic processes of the test crop and appeared to mitigate the phytotoxic effects of aluminium ions.

Determination and optimization of Vitamin B complex in xylanase enzyme treated polished rice by response surface methodology.

The present study provides information about the concentrations of Vitamin B (thiamine, riboflavin, pyridoxine and niacin) in polished brown rice treated with xylanase. Xylanase enzyme was produced from Aspergillus awamori MTCC 9166. Brown rice was treated with 60-100% enzyme (40 ml of buffer -undiluted) for 30 to 150 min (with variation of 30 min) at 30 degrees C to 50 degrees C (with variation of 5 degrees C) to attain a saturated moisture level of 35.5 g100(-1)g .The enzyme acted upon selective degradation (polishing time 10-50 sec) of bran layer facilitating retention of more vital nutrients along with the vitamins. Vitamin B content, detected through HPLC and optimized by response surface methodology (RSM) with central composite design (CCRD), demonstrated that selective degradation of bran layers for polished rice facilitated increase of thiamine (57%), riboflavin (48%), pyridoxine (90%) and niacin (55%) concentration in bio polished rice over normally milled rice.Enzyme treated bio-polished rice was considered to be better source of vitamin B complex than mechanically milled rice, hence more nutritionally efficacious.

Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults.

VRC-HIVMAB060-00-AB (VRC01) is a broadly neutralizing HIV-1 monoclonal antibody (mAb) isolated from the B cells of an HIV-infected patient. It is directed against the HIV-1 CD4 binding site and is capable of potently neutralizing the majority of diverse HIV-1 strains. This Phase I dose-escalation study in healthy adults was conducted at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Primary objectives were the safety, tolerability and pharmacokinetics (PK) of VRC01 intravenous (i.v.) infusion at 5, 20 or 40 mg/kg, given either once (20 mg/kg) or twice 28 days apart (all doses), and of subcutaneous (s.c.) delivery at 5 mg/kg compared to s.c. placebo given twice, 28 days apart. Cumulatively, 28 subjects received 43 VRC01 and nine received placebo administrations. There were no serious adverse events or dose-limiting toxicities. Mean 28-day serum trough concentrations after the first infusion were 35 and 57 µg/ml for groups infused with 20 mg/kg (n = 8) and 40 mg/kg (n = 5) doses, respectively. Mean 28-day trough concentrations after the second infusion were 56 and 89 µg/ml for the same two doses. Over the 5-40 mg/kg i.v. dose range (n = 18), the clearance was 0.016 l/h and terminal half-life was 15 days. After infusion VRC01 retained expected neutralizing activity in serum, and anti-VRC01 antibody responses were not detected. The human monoclonal antibody (mAb) VRC01 was well tolerated when delivered i.v. or s.c. The mAb demonstrated expected half-life and pharmacokinetics for a human immunoglobulin G. The safety and PK results support and inform VRC01 dosing schedules for planning HIV-1 prevention efficacy studies.

Fructose-induced ROS generation impairs glucose utilization in L6 skeletal muscle cells.

High fructose consumption has implicated in insulin resistance and metabolic syndrome. Fructose is a highly lipogenic sugar that has intense metabolic effects in liver. Recent evidences suggest that fructose exposure to other tissues has substantial and profound metabolic consequences predisposing toward chronic conditions such as type 2 diabetes. Since skeletal muscle is the major site for glucose utilization, in the present study we define the effects of fructose exposure on glucose utilization in skeletal muscle cells. Upon fructose exposure, the L6 skeletal muscle cells displayed diminished glucose uptake, glucose transporter type 4 (GLUT4) translocation, and impaired insulin signaling. The exposure to fructose elevated reactive oxygen species (ROS) production in L6 myotubes, accompanied by activation of the stress/inflammation markers c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2), and degradation of inhibitor of NF-κB (IκBα). We found that fructose caused impairment of glucose utilization and insulin signaling through ROS-mediated activation of JNK and ERK1/2 pathways, which was prevented in the presence of antioxidants. In conclusion, our data demonstrate that exposure to fructose induces cell-autonomous oxidative response through ROS production leading to impaired insulin signaling and attenuated glucose utilization in skeletal muscle cells.

Higher levels of antibodies to the tumour-associated antigen cyclin B1 in cancer-free individuals than in patients with breast cancer.

Cyclin B1 is a checkpoint protein that regulates cell division from G2 to the M phase. Studies in mice have shown that cyclin B1 vaccine-induced immunity significantly delayed or prevented the spontaneous cancer development later in life. We hypothesized that if these results showing a protective effect of anti-cyclin B1 antibodies could be extrapolated to the human condition, cancer-free individuals should have higher levels of endogenous antibodies than patients with cancers characterized by the over-expression of this tumour-associated antigen. To test this hypothesis, we characterized a large (1739 subjects) number of multi-ethnic patients with breast cancer (which over-expresses cyclin B1) and matched controls for anti-cyclin B1 immunoglobulin (Ig)G antibodies. Multivariate analyses, after adjusting for the covariates, showed that cancer-free individuals had significantly higher levels of naturally occurring IgG antibodies to cyclin B1 than patients with breast cancer (mean ± standard deviation: 148·0 ± 73·6 versus 126·1 ± 67·8 arbitrary units per ml; P < 0·0001). These findings may have important implications for cyclin B1-based immunotherapy against breast cancer and many other cyclin B1-over-expressing malignancies.

Genetic variants of immunoglobulin γ and κ chains influence humoral immunity to the cancer-testis antigen XAGE-1b (GAGED2a) in patients with non-small cell lung cancer.

GM (γ marker) allotypes, genetic variants of immunoglobulin γ chains, have been reported to be associated strongly with susceptibility to lung cancer, but the mechanism(s) underlying this association is not known. One mechanism could involve their contribution to humoral immunity to lung tumour-associated antigens. In this study, we aimed to determine whether particular GM and KM (κ marker) allotypes were associated with antibody responsiveness to XAGE-1b, a highly immunogenic lung tumour-associated cancer-testis antigen. Sera from 89 patients with non-small cell lung cancer (NSCLC) were allotyped for eight GM and two KM determinants and characterized for antibodies to a synthetic XAGE-1b protein. The distribution of various GM phenotypes was significantly different between XAGE-1b antibody-positive and -negative patients (P = 0·023), as well as in the subgroup of XAGE-1b antigen-positive advanced NSCLC (P = 0·007). None of the patients with the GM 1,17 21 phenotype was positive for the XAGE-1b antibody. In patients with antigen-positive advanced disease, the prevalence of GM 1,2,17 21 was significantly higher in the antibody-positive group than in those who lacked the XAGE-1b antibody (P = 0·026). This phenotype also interacted with a particular KM phenotype: subjects with GM 1,2,17 21 and KM 3,3 phenotypes were almost four times (odds ratio = 3·8) as likely to be positive for the XAGE-1b antibody as the subjects who lacked these phenotypes. This is the first report presenting evidence for the involvement of immunoglobulin allotypes in immunity to a cancer-testis antigen, which has important implications for XAGE-1b-based immunotherapeutic interventions in lung adenocarcinoma.

Expression and subcellular localization of organophosphate hydrolase in acephate-degrading Pseudomonas sp. strain Ind01 and its use as a potential biocatalyst for elimination of organophosphate insecticides.

UNLABELLED: Organophosphate hydrolase (OPH), the product of an organophosphate-degrading (opd) gene cloned from Brevundimonas diminuta, hydrolyses the triester linkage found in neurotoxic organophosphate (OP) insecticides and nerve agents. Despite the fact that OPHs have a broad substrate range, OP compounds with a P-S linkage, such as insecticides like acephate, are poor substrates for the enzyme. Expression of OPH in acephate-utilizing Pseudomonas sp. Ind01 generated a live biocatalyst capable of degrading a wide range of OP insecticides. The heterologously expressed OPH, which is a substrate of twin arginine transport (Tat) pathway, successfully targeted to the membrane of Pseudomonas sp. Ind01. The membrane-associated OPH had a size that coincided with the mature form of OPH (mOPH), suggesting successful processing and targeting of the expressed OPH to the membrane. Pseudomonas sp. Ind01 expressing OPH degraded a variety of OP insecticides besides using acephate as sole carbon source. SIGNIFICANCE AND IMPACT OF THE STUDY: A biocatalyst capable of degrading a wide range of organophosphate (OP) insecticides was generated by expressing an organophosphate degradation gene in Pseudomonas sp. Ind01 involved in mineralization of acephate. The biocatalyst can be used to eliminate a wide range of OP insecticide residues from the environment.

Racially restricted contribution of immunoglobulin Fcγ and Fcγ receptor genotypes to humoral immunity to human epidermal growth factor receptor 2 in breast cancer.

Tumour-associated antigen human epidermal growth factor receptor 2 (HER2) is over-expressed in 25-30% of breast cancer patients and is associated with poor prognosis. Naturally occurring anti-HER2 antibody responses have been described in patients with HER2 over-expressing tumours. There is significant interindividual variability in antibody responsiveness, but the host genetic factors responsible for this variability are poorly understood. The aim of the present investigation was to determine whether immunoglobulin genetic markers [GM (genetic determinants of γ chains)] and Fcγ receptor (FcγR) alleles contribute to the magnitude of natural antibody responsiveness to HER2 in patients with breast cancer. A total of 855 breast cancer patients from Japan and Brazil were genotyped for several GM and FcγR alleles. They were also characterized for immunoglobulin (Ig)G antibodies to HER2. In white subjects (n = 263), GM 23-carriers had higher levels of anti-HER2 antibodies than non-carriers of this allele (p = 0·004). At the GM 5/21 locus, the homozygotes for the GM 5 allele had higher levels of anti-HER2 antibodies than the other two genotypes (P = 0·0067). In black subjects (n = 42), FcγRIIa-histidine/histidine homozygotes and FcγRIIIa-phenylalanine/valine heterozygotes were associated with high antibody responses (P = 0·0071 and 0·0275, respectively). FcγR genotypes in white subjects and GM genotypes in black subjects were not associated with anti-HER2 antibody responses. No significant associations were found in other study groups. These racially restricted contributions of GM and FcγR genotypes to humoral immunity to HER2 have potential implications for immunotherapy of breast cancer.

Differential inhibition of trastuzumab- and cetuximab-induced cytotoxicity of cancer cells by immunoglobulin G1 expressing different GM allotypes.

Antibody-dependent cell-mediated cytotoxicity (ADCC), which links the innate and the adaptive arms of immunity, is a major host immunosurveillance mechanism against tumours, as well as the leading mechanism underlying the clinical efficacy of therapeutic antibodies such as cetuximab and trastuzumab, which target tumour antigens, human epidermal growth factor receptor (HER)1 and HER2, respectively. Immunoglobulin (Ig)G antibody-mediated ADCC is triggered upon ligation of Fcγ receptor (FcγR) to the Fc region of IgG molecules. It follows that genetic variation in FcγR and Fc could contribute to the differences in the magnitude of ADCC. Genetic variation in FcγR is known to contribute to the differences in the magnitude of ADCC, but the contribution of natural genetic variation in Fc, GM allotypes, in this interaction has hitherto not been investigated. Using an ADCC inhibition assay, we show that IgG1 expressing the GM 3+, 1-, 2- allotypes was equally effective in inhibiting cetuximab- and trastuzumab-mediated ADCC of respective target cells, in the presence of natural killer (NK) cells expressing either valine or phenylalanine allele of FcγRIIIa. In contrast, IgG1 expressing the allelic GM 17+, 1+, 2+ allotypes was significantly more effective in inhibiting the ADCC - mediated by both monoclonal antibodies - when NK cells expressed the valine, rather than the phenylalanine, allele of FcγRIIIa. These findings have important implications for engineering antibodies (with human γ1 constant region) against malignancies characterized by the over-expression of tumour antigens HER1 and HER2 - especially for patients who, because of their FcγRIIIa genotype, are unlikely to benefit from the currently available therapeutics.

Fluoride contamination and fluorosis in rural community in the vicinity of a phosphate fertilizer factory in India.

We studied chronic fluoride intoxication in 10 villages of Udaipur receiving F emissions from phosphate fertilizer factories. Although fluoride remained below permissible limit in most of the drinking water samples, the incidence of fluorosis in adults as well as in children was surprisingly high. Khemli appeared to be the most affected village (with >48% cases) where, about 93% of 2 h air samples contained fluoride above 2.0 µg m(-3) and crops and vegetable F ranged from 27.5 to 143.4 µg g(-1). Concentrations of fluoride and inorganic P in urine showed asynchrony and were well linked with prevalence of fluorosis. The study indicated that air-borne fluoride was the major factor for higher prevalence of fluorosis in these rural areas.