Preservation of deep epigastric perforators during anterior component separation technique (ACST) results in equivalent wound complications compared to transversus abdominis release (TAR).

PURPOSE: The use of component separation results in myofascial release and increased rates of fascial closure in abdominal wall reconstruction(AWR). These complex dissections have been associated with increased rates of wound complications with anterior component separation having the greatest wound morbidity. The aim of this paper was to compare the wound complication rate between perforator sparing anterior component separation(PS-ACST) and transversus abdominus release(TAR). METHODS: Patients were identified from a prospective, single institution hernia center database who underwent PS-ACST and TAR from 2015 to 2021. The primary outcome was wound complication rate. Standard statistical methods were used, univariate analysis and multivariable logistic regression were performed. RESULTS: A total of 172 patients met criteria, 39 had PS-ACST and 133 had TAR performed. The PS-ACST and TAR groups were similar in terms of diabetes (15.4% vs 28.6%, p = 0.097), but the PS-ACST group had a greater percentage of smokers (46.2% vs 14.3%, p < 0.001). The PS-ACST group had a larger hernia defect size (375.2 ± 156.7 vs 234.4 ± 126.9cm2, p < 0.001) and more patients who underwent preoperative Botulinum toxin A (BTA) injections (43.6% vs 6.0%, p < 0.001). The overall wound complication rate was not significantly different (23.1% vs 36.1%, p = 0.129) nor was the mesh infection rate (0% vs 1.6%, p = 0.438). Using logistic regression, none of the factors that were significantly different in the univariate analysis were associated with wound complication rate (all p > 0.05). CONCLUSION: PS-ACST and TAR are comparable in terms of wound complication rates. PS-ACST can be used for large hernia defects and promote fascial closure with low overall wound morbidity and perioperative complications.

NICO Phase II clinical trial - focus on an emerging immunotherapy strategy for the adjuvant treatment of locally-advanced oral cancers.

Outcomes remain poor for patients presenting with locally-advanced oral cancers and it remains imperative to re-evaluate adjuvant therapies to provide improved outcomes, ideally without compromising on long-term quality of life. We present current available evidence that supports the use of immune checkpoint inhibitors (ICI) in squamous cell carcinoma (SCC) of the head and neck and discuss trials examining the integration of ICI into the locoregional management of such lesions that are resectable. We focus particularly on the Neoadjuvant and adjuvant nivolumab as Immune Checkpoint inhibition in Oral cavity cancer (NICO) trial which is investigating the integration of neoadjuvant and adjuvant ICI into the treatment of resectable locally-advanced oral cavity cancers.

Adjuvant management of locally advanced oral squamous cell carcinoma - real-world challenges and opportunities.

Patients with locally advanced oral squamous cell cancer (LAOSCC) are treated with adjuvant radiotherapy (RT) or chemoradiotherapy (CRT) following surgical ablation. This depends on the pathological risk factors and aims to reduce the risk of local recurrence and improve survival. Delivery of these aggressive treatments is, however, challenging particularly following major surgery. To inform the adaptations necessary to deliver gold-standard therapy, we aimed to describe real-world delivery of multimodality treatment in LAOSCC, in a UK population with high levels of disease incidence and low socioeconomic status. Patients with LAOSCC (T1-4 N1-3/T3-4 N0) who were treated between October 2014 and October 2016 and had a minimum follow up of 24 months were included. They were identified using the Somerset Cancer Register and data were collected through retrospective case note review. Approval was obtained from the audit departments at the relevant NHS institutions, and data were analysed using IBM SPSS Statistics for Windows version 24 (IBM Corp). The analysis included 129 patients with 82% having an initial performance status (PS) of 0-1. The most frequent change in PS was a one point drop (46%). Twenty of the 93 eligible patients (22%) underwent adjuvant CRT. A total of 37 (40%) began adjuvant CRT/RT within 42 days, and 79 (85%) within 56 days. A delay in initiating adjuvant therapy was associated with higher rates of complications and a longer postoperative hospital stay. Concordance between imaging and pathological nodal staging was poor (cK 0.223). PS frequently declines after complex surgical procedures and long postoperative recovery periods, leading to difficulties providing adjuvant treatments within the national guidance of 42 days. Frequent deviation from planned adjuvant therapies highlights the need for improved treatment strategies.

Altered Nuclear Expression of the Deubiquitylase BAP1 Cannot be Used as a Prognostic Marker for Canine Melanoma.

BRCA1-associated protein-1 (BAP1) is a nuclear localized deubiquitylating enzyme that belongs to the ubiquitin c-terminal hydrolase subfamily. The encoded protein is highly homologous between man and dogs, suggesting a functional significance preserved by evolution. BAP1 has multiple properties, including tumour suppressor activity. Loss of BAP1 function is implicated in the oncogenesis of several types of cancers including uveal, mucosal and some cutaneous melanomas in humans, as well as in mesothelioma. In this study we investigate the significance of BAP1 in canine melanoma. Nuclear BAP1 protein was detected in five canine oral melanoma cell lines using an antibody commonly used for analysis of human tissues. BAP1 loss of function mutations often lead to loss of nuclear BAP1 (nBAP1) expression in humans; this is associated with a poorer prognosis in uveal and mucosal melanoma. Therefore, as a prelude to a study evaluating the prognostic significance of nBAP1 expression in dogs, immunohistochemistry (IHC) was used to assess cases of canine melanoma for nBAP1 expression. In 89 cases where tumour cells were identified by melan-A labelling, 100% of tumour cells were positive for nBAP1 expression, including eight uveal tract and 29 oral mucosal melanomas. This finding indicates that BAP1 IHC cannot be used as a prognostic marker in canine uveal and mucosal melanoma. Moreover, this observation suggests that either BAP1 has a different functional significance in canine melanoma or that loss of BAP1 function is achieved by a different route. This is a novel finding that warrants further investigation to determine the comparative biological relevance.

A 6-bp Deletion Variant in a Novel Canine Glutathione-S-Transferase Gene (GSTT5) Leads to Loss of Enzyme Function.

OBJECTIVES: Glutathione-S-transferases (GSTs) detoxify reactive xenobiotics, and defective GST gene polymorphisms increase cancer risk in humans. A low activity GST-theta variant was previously found in research beagles. The purpose of our study was to determine the molecular basis for this phenotype and its allele frequency in pet dogs. METHODS: Banked livers from 45 dogs of various breeds were screened for low GST-theta activity by the substrate 1,2-dichloro-4-nitrobenzene (DCNB), and were genotyped for variants in a novel canine GST gene, GSTT5. Whole-genome sequences from 266 dogs were genotyped at one discovered variant GSTT5 locus. RESULTS: Canine livers ranged 190-fold in GST-theta activities, and a GSTT5 exon coding variant 385_390delGACCAG (Asp129_Gln130del) was significantly associated with low activity (P < 0.0001) and a marked decrease in hepatic protein expression (P = 0.0026). Recombinant expression of variant GSTT5 led to a 92% decrease in Vmax for DCNB (P = 0.0095). The minor allele frequency (MAF) for 385_390delGACCAG was 0.144 in 45 dog livers, but was significantly higher in beagles (0.444) versus nonbeagles (0.007; P = 0.0004). The homozygous genotype was significantly over-represented in Pembroke Welsh corgis (P < 0.0001) based on available whole-genome sequence data. CONCLUSIONS: An Asp129_Gln130del variant in canine GSTT5 is responsible for marked loss of GST-theta enzyme activity. This variant is significantly over-represented in purpose-bred laboratory beagles and in Pembroke Welsh corgis. Additional work will determine the prevalence of this variant among other purebred dogs, and will establish the substrate range of this polymorphic canine enzyme with respect to common environmental carcinogens.

Modulating the DNA Damage Response to Improve Treatment Response in Cervical Cancer.

Cervical cancer is the fourth most common cause of cancer-related death in women worldwide and new therapeutic approaches are needed to improve clinical outcomes for this group of patients. Current treatment protocols for locally advanced and metastatic disease consist of ionising radiation and chemotherapy. Chemoradiation induces cytotoxic levels of DNA double-strand breaks, which activates programmed cell death via the DNA damage response (DDR). Cervical cancers are unique given an almost exclusive association with human papillomavirus (HPV) infection; a potent manipulator of the DDR, with the potential to alter tumour sensitivity to DNA-damaging agents and influence treatment response. This review highlights the wide range of therapeutic strategies in development that have the potential to modulate DDR and sensitise cervical tumours to DNA-damaging agents in the context of HPV oncogenesis.

A randomized trial testing the efficacy of modifications to the nutrition facts table on comprehension and use of nutrition information by adolescents and young adults in Canada.

INTRODUCTION: Given the proposed changes to nutrition labelling in Canada and the dearth of research examining comprehension and use of nutrition facts tables (NFts) by adolescents and young adults, our objective was to experimentally test the efficacy of modifications to NFts on young Canadians' ability to interpret, compare and mathematically manipulate nutrition information in NFts on prepackaged food. METHODS: An online survey was conducted among 2010 Canadians aged 16 to 24 years drawn from a consumer sample. Participants were randomized to view two NFts according to one of six experimental conditions, using a between-groups 2 x 3 factorial design: serving size (current NFt vs. standardized serving-sizes across similar products) x percent daily value (% DV) (current NFt vs. "low/med/high" descriptors vs. colour coding). The survey included seven performance tasks requiring participants to interpret, compare and mathematically manipulate nutrition information on NFts. Separate modified Poisson regression models were conducted for each of the three outcomes. RESULTS: The ability to compare two similar products was significantly enhanced in NFt conditions that included standardized serving-sizes (p ≤ .001 for all). Adding descriptors or colour coding of % DV next to calories and nutrients on NFts significantly improved participants' ability to correctly interpret % DV information (p ≤ .001 for all). Providing both standardized serving-sizes and descriptors of % DV had a modest effect on participants' ability to mathematically manipulate nutrition information to calculate the nutrient content of multiple servings of a product (relative ratio = 1.19; 95% confidence limit: 1.04-1.37). CONCLUSION: Standardizing serving-sizes and adding interpretive % DV information on NFts improved young Canadians' comprehension and use of nutrition information. Some caution should be exercised in generalizing these findings to all Canadian youth due to the sampling issues associated with the study population. Further research is needed to replicate this study in a more heterogeneous sample in Canada and across a range of food products and categories.

TITRE: Essai randomisé mesurant l'efficacité des modifications apportées au tableau de la valeur nutritive sur la compréhension et l'utilisation de l'information nutritionnelle par les adolescents et les jeunes adultes au Canada. INTRODUCTION: Compte tenu des changements proposés à l'étiquetage nutritionnel au Canada et de la rareté des travaux de recherche portant sur la compréhension et l'utilisation des tableaux de la valeur nutritive (tVN) chez les adolescents et les jeunes adultes, notre objectif consistait à réaliser un essai expérimental pour déterminer si les modifications apportées au tVN permettaient d'améliorer efficacement la façon dont les jeunes Canadiens interprètent, comparent et manipulent, sur le plan mathématique, l'information nutritionnelle figurant dans le tVN de denrées préemballées. MÉTHODOLOGIE: Une enquête en ligne a été menée auprès d'un échantillon de consommateurs composé de 2 010 Canadiens âgés de 16 à 24 ans. Nous avons réparti les participants de façon aléatoire en six groupes d'étude, et nous avons présenté à chacun des groupes deux des six tVN définis comme conditions expérimentales, selon un plan factoriel 2 x 3 : portion de référence (tVN actuel et portions de référence normalisées pour tous les produits similaires) x pourcentage de la valeur quotidienne (% VQ) (tVN actuel, ajout des descripteurs « faible/moyen/élevé ¼ et ajout d'un code de couleurs). L'enquête comprenait sept tâches consistant à interpréter, comparer et manipuler, sur le plan mathématique, l'information nutritionnelle figurant dans les tVN. Des modèles de régression de Poisson modifiés ont été élaborés pour chacun des trois résultats. RÉSULTATS: La capacité à comparer deux produits similaires s'est révélée significativement meilleure quand le tVN incluait une portion de référence normalisée (p ≤ 0,001 dans tous les cas). L'ajout de descripteurs ou d'un code de couleurs indiquant, sur le tVN, le % VQ pour les calories et les nutriments a amélioré de façon significative la capacité des participants à interpréter correctement l'information à propos de ce % VQ (p ≤ 0,001 dans tous les cas). Le fait de présenter aux participants des portions de référence normalisées et des descripteurs du % VQ a eu un effet modeste sur leur capacité à manipuler, sur le plan mathématique, l'information nutritionnelle pour calculer la valeur nutritive de plusieurs portions d'un produit (ratio relatif = 1,19; intervalle de confiance à 95 % : 1,04 à 1,37). CONCLUSION: La normalisation des portions de référence et l'ajout d'information sur l'interprétation du % VQ dans le tVN ont permis aux jeunes Canadiens de mieux comprendre et utiliser l'information nutritionnelle. Il faut néanmoins faire preuve de prudence avant de généraliser les résultats de l'enquête à l'ensemble des jeunes Canadiens en raison de l'échantillonnage de la population à l'étude. D'autres travaux de recherche sont nécessaires afin de reproduire cette étude au Canada avec un échantillon plus hétérogène, et en utilisant un éventail de produits alimentaires et de catégories d'aliments.

Positive association between a glutathione-S-transferase polymorphism and lymphoma in dogs.

Glutathione-S-transferase enzymes (GSTs) play an important role in the detoxification of environmental carcinogens. Defective GST genotypes are over-represented in human cancers; in particular, low activity GSTT1 genotypes are risk factors for non-Hodgkin lymphoma. We hypothesized that defective GSTT1 genotypes would be associated with lymphoma risk in dogs. To address this, we resequenced the exons, splice junctions, and 3'-UTR of canine GSTT1 in dogs with lymphoma (n = 93) and age-matched unaffected dogs (n = 86). Of 27 canine GSTT1 variants identified, the I2+28 G>A was significantly associated with lymphoma [odds ratio (OR) 6.26, 95% confidence interval (CI), 1.77-22.2], with the AA genotype found in 18.3% of affected dogs but only 3.5% of controls (P = 0.002). This intronic variant was predicted to perturb GSTT1 mRNA splicing, and may increase lymphoma risk by impairing detoxification of environmental chemicals. Confirmation of this finding in a larger population of dogs may support the inclusion of GSTT1 genotyping in epidemiologic studies of canine lymphoma risk.

The deubiquitylase Ataxin-3 restricts PTEN transcription in lung cancer cells.

The phosphatidylinositol-3-kinase (PI3K) pathway is commonly hyperactivated in cancer. One mechanism by which this occurs is by silencing of the phosphatase and tensin homolog (PTEN), a tumor suppressor and major antagonist of the pathway, through genetic, epigenetic or posttranscriptional mechanisms. Here, we used an unbiased siRNA screen in non-small-cell lung cancer cells to identify deubiquitylases (DUBs) that have an impact on PI3K signaling by regulating the abundance of PTEN. We found that PTEN expression was induced by depleting any of three members of the Josephin family DUBs: ataxin 3 (ATXN3), ataxin 3-like (ATXN3L) and Josephin domain containing 1 (JOSD1). However, this effect is not mediated through altered PTEN protein stability. Instead, depletion of each DUB increases expression of both the PTEN transcript and its competing endogenous RNA, PTENP1. In ATXN3-depleted cells, under conditions of transcriptional inhibition, PTEN and PTENP1 mRNAs rapidly decay, suggesting that ATXN3 acts primarily by repressing their transcription. Importantly, the PTEN induction observed in response to ATXN3 siRNA is sufficient to downregulate Akt phosphorylation and hence PI3K signaling. Histone deacetylase inhibitors (HDACi) have been suggested as potential mediators of PTEN transcriptional reactivation in non-small-cell lung cancer. Although PTEN exhibits a very limited response to the broad-spectrum HDACi Vorinostat (SAHA) in A549 cells, we find that combination with ATXN3 depletion enhances PTEN induction in an additive manner. Similarly, these interventions additively decrease cell viability. Thus, ATXN3 provides an autonomous, complementary therapeutic target in cancers with epigenetic downregulation of PTEN.

Voluntary food fortification in the United States: potential for excessive intakes.

BACKGROUND: Historically, the voluntary addition of micronutrients to foods in the United States has been regarded as an important means to lessen problems of nutrient inadequacy. With expanding voluntary food fortification and widespread supplement use, it is important to understand how voluntary food fortification has an impact on the likelihood of excessive usual intakes. Our objective was to investigate whether individuals in the United States with greater frequency of exposure to micronutrients from voluntarily fortified foods (vFF) are more likely to have usual intakes approaching or exceeding the respective tolerable upper intake levels (UL). SUBJECTS/METHODS: The National Cancer Institute method was applied to data from the 2007-2008 National Health and Nutrition Examination Survey (NHANES) to estimate the joint distribution of usual intake from both vFF and non-vFF sources for 12 nutrients and determine the probability of consuming these nutrients from vFF on a given day. For each nutrient, we estimated the distribution of usual intake from all food sources by quintile of probability of consuming vFF and compared the distributions with ULs. RESULTS: An increased probability of consuming zinc, retinol, folic acid, selenium and copper from vFF was associated with a greater risk of intakes above the UL among children. Among adults, increased probability of consuming calcium and iron from vFF was associated with a greater risk of intakes above the UL among some age/sex groups. CONCLUSION: The high nutrient exposures associated with vFF consumption in some population subgroups suggest a need for more careful weighing of the risks and benefits of uncontrolled food fortification.

Evaluation of polymorphisms in the sulfonamide detoxification genes CYB5A and CYB5R3 in dogs with sulfonamide hypersensitivity.

BACKGROUND: Delayed hypersensitivity (HS) reactions to potentiated sulfonamide antimicrobials occur in both dogs and humans, and involve an intermediate hydroxylamine metabolite that is detoxified by cytochrome b(5) and NADH cytochrome b(5) reductase. HYPOTHESIS/OBJECTIVES: We hypothesized that polymorphisms in the genes (CYB5A and CYB5R3) encoding these 2 enzymes would be associated with risk of sulfonamide HS in dogs. ANIMALS: A total of 18 dogs with delayed HS to potentiated sulfonamide antimicrobials and 16 dogs that tolerated (TOL) a therapeutic course of these drugs without adverse effect. METHODS: CYB5A and CYB5R3 were sequenced from canine liver, and the promoter, exons, and 3' untranslated regions of both genes were resequenced from genomic DNA obtained from all dogs. RESULTS: Multiple polymorphisms were found in both genes. When controlled for multiple comparisons, the 729GG variant in CYB5R3 was significantly overrepresented in dogs with sulfonamide HS (78% of dogs), compared to TOL dogs (31%; P = .003). CONCLUSIONS AND CLINICAL IMPORTANCE: The CYB5R3 729GG variant may contribute to the risk of sulfonamide HS in dogs. Functional characterization of this polymorphism, as well as genotyping in a larger number of HS and TOL dogs, is warranted.

Discretionary addition of vitamins and minerals to foods: implications for healthy eating.

OBJECTIVES: Health Canada proposes to allow manufacturers to add vitamins and minerals to a wide variety of foods at their discretion, a practice that has long been permitted in the United States and Europe. With Health Canada's proposed exclusion of staple and standardized foods from discretionary fortification, questions arise about the nutritional quality of the foods that remain eligible for fortification. To better understand the implications of this policy for healthy eating, this study examined the contribution of foods eligible to be fortified to the dietary quality of Canadians. METHODS: Using 24-h dietary recall data from the 2004 Canadian Community Health Survey, the relationship between intake of fortifiable foods and indicators of dietary quality was assessed. RESULTS: The mean percentage contribution of fortifiable foods to usual energy intake ranged from 19% among men over the age of 70 years to 36% for girls aged 14-18 years. Fortifiable food (as a percentage of total energy) was inversely associated with intake of vegetables and fruit, meat and alternatives, milk products, fiber, vitamins A, B6, B12 and D, magnesium, potassium and zinc. Fortifiable food was positively associated with dietary energy density, total energy intake and grain products. Few relationships were found for folate, vitamin C, iron, calcium, sodium and saturated fat. CONCLUSIONS: Consumption of foods slated for discretionary fortification is associated with lower nutrient intakes and suboptimal food intake patterns. Insofar as adding nutrients to these foods reinforces their consumption, discretionary fortification might function to discourage healthier eating patterns.

Resveratrol induces Fas signalling-independent apoptosis in THP-1 human monocytic leukaemia cells.

Resveratrol, a natural product present in wine, has recently been shown to inhibit the growth of a number of cancer cell lines in vitro. In the current study, we have demonstrated that resveratrol inhibits the growth of THP-1 human monocytic leukaemia cells in a dose-dependent manner with a median effective dose of 12 microM. It did not induce differentiation of THP-1 cells and had no toxic effect on THP-1 cells that had been induced to differentiate into monocytes/macrophages by phorbol myristate acetate. A significant fraction of resveratrol-treated cells underwent apoptosis as judged by flow cytometric analysis of DNA content, DNA fragmentation and caspase-specific cleavage of poly(ADP-ribosyl) polymerase. Resveratrol treatment had no effect on the expression of Fas receptor or Fas ligand (FasL) in THP-1 cells, nor did it induce clustering of Fas receptors. In addition, THP-1 cells were resistant to activating anti-Fas antibody, and neutralizing anti-Fas and/or anti-FasL antibodies had no protective effect against resveratrol-induced inhibition of THP-1 cell growth. The effect of resveratrol on THP-1 cells was reversible after its removal from the culture medium. These results suggest that (1) resveratrol inhibits the growth of THP-1 cells, at least in part, by inducing apoptosis, (2) resveratrol-induced apoptosis of THP-1 cells is independent of the Fas/FasL signalling pathway and (3) resveratrol does not induce differentation of THP-1 cells and has no toxic effect on differentiated THP-1 cells. Thus, resveratrol may be a potential chemotherapeutic agent for the control of acute monocytic leukaemia.

Applicant self-selection: correlates of withdrawal from a multiple hurdle process.

The authors examined applicant self-selection from a multiple hurdle hiring process. The relationships of the selection status of 3,550 police applicants (self-selected out prior to 1 of the hurdles, passing, or failing) and perceptions of the organization, commitment to a law enforcement job, expectations regarding the job, employment status, the need to relocate, the opinions of family and friends, and perceptions of the hiring process were examined. Differences between those who stayed in the process and those who self-selected out were observed in most areas, and those who self-selected out at early stages differed from those self-selecting out at later stages. African Americans' and women's perceptions also differed from the majority group, indicating some of the difficulties an organization faces in attempting to diversify.

Parental employment, school climate, and children's academic and social development.

Longitudinal data were used to examine the effects of parental employment status and school climate on children's academic and social development. Hierarchical regression, analyses of covariance, and latent growth modeling were used to assess various aspects of change as a function of work status and school climate with family income and education as control variables. Parental employment was associated with positive changes in social and academic progress even after controlling for prior developmental level, climate, and family income although effects were small and complex. School climate had minimal effect on the outcome variables. Income and education were related to various school outcomes.

Pertussis toxin-induced lung edema. Role of manganese superoxide dismutase and protein kinase C.

The mechanism by which pertussis toxin (Ptx) causes lung edema is not clear. We investigated the role of pulmonary manganese superoxide dismutase (MnSOD) and protein kinase C (PKC) in Ptx-induced lung edema. We demonstrated that intraperitoneal injection of Ptx at a concentration of 5 microg/100 g body weight caused a similar degree of lung edema in 2 d, as measured by lung wet weight/dry weight ratio, in heterozygous MnSOD gene (Sod2)-knockout mice (Sod2(+/-)) and in their wild-type littermates (Sod2(+/+)). The level of lung MnSOD activity in Sod2(+/-) mice was approximately half that of Sod2(+/-) mice. Ptx had no effect on levels of lung MnSOD messenger RNA, immunoreactive protein, or enzyme activity in either Sod2(+/+) or Sod2(+/-) mice. Ptx also had no effect on lung copper-zinc SOD, catalase, and glutathione peroxidase activities in these mice. On the other hand, Ptx caused the activation of lung PKC, for example, by translocation of a 72-kD PKC isoform from the cytosolic fraction to the membrane fraction. Pretreatment of mice with bisindolylmaleimide, a PKC inhibitor, prevented both the Ptx-induced activation of PKC and lung edema. These data suggest that Ptx-induced lung edema in mice is, at least in part, due to the activation of lung PKC.

Induction of Mn SOD in human monocytes without inflammatory cytokine production by a mutant endotoxin.

Endotoxin selectively induces monocyte Mn superoxide dismutase (SOD) without affecting levels of Cu,Zn SOD, catalase, or glutathione peroxidase. However, little is known about the structure-activity relationship and the mechanism by which endotoxin induces Mn SOD. In this study we demonstrated that a mutant Escherichia coli endotoxin lacking myristoyl fatty acid at the 3' R-3-hydroxymyristate position of the lipid A moiety retained its full capacity to coagulate Limulus amoebocyte lysate compared with the wild-type E. coli endotoxin and markedly stimulated the activation of human monocyte nuclear factor-kappaB and the induction of Mn SOD mRNA and enzyme activity. However, in contrast to the wild-type endotoxin, it failed to induce significant production of tumor necrosis factor-alpha and macrophage inflammatory protein-1alpha by monocytes and did not induce the phosphorylation and nuclear translocation of mitogen-activated protein kinase. These results suggest that 1) lipid A myristoyl fatty acid, although it is important for the induction of inflammatory cytokine production by human monocytes, is not necessary for the induction of Mn SOD, 2) endotoxin-mediated induction of Mn SOD and inflammatory cytokines are regulated, at least in part, through different signal transduction pathways, and 3) failure of the mutant endotoxin to induce tumor necrosis factor-alpha production is, at least in part, due to its inability to activate mitogen-activated protein kinase.