Perspectives on shorter durations of anti-HER2 therapy in early-stage HER2-positive breast cancer: a patient survey.

PURPOSE: Despite previous studies proposing shorter durations of anti-HER2 therapy for selected patients with HER2-positive early breast cancer (EBC), 12-months remains standard of care. A survey was performed to assess patient perspectives and willingness to participate in studies evaluating shorter durations of anti-HER2 therapy. METHODS: Patients with HER2-positive EBC completing or having previously completed anti-HER2 therapy, were recruited by healthcare professionals at The Ottawa Hospital Cancer Centre to participate in an anonymous online survey. The primary objective was to learn about patients' perspectives on shorter durations (less than 12-months) of anti-HER2 therapy. Secondary objectives were to explore patients' interest in clinical trials of shorter durations of anti-HER2 therapy and the degree of increased breast cancer risk they would accept with a shorter treatment duration. RESULTS: Responses were received from 94 eligible patients. Most patients received Trastuzumab alone (78%, 73/94), while 13% (12/94) received trastuzumab and pertuzumab. Side effects were experienced by 52% (46/89), the most common being; fatigue (61%, 28/46), myalgia (37%, 17/46), and diarrhea (24%, 11/46). Most patients (88%, 78/89) did not find treatment bothersome. Regarding perspectives on shorter durations of anti-HER2 therapy, most (79%, 74/94) respondents stated they would agree to less treatment if it were possible to receive fewer treatments with the same cancer benefits. 56% of patients were interested in clinical trials, however, about half stated they would not be accepting of any increase in breast cancer recurrence risk. CONCLUSION: Trials to investigate who can safely and effectively be treated with shorter durations of anti-HER2 therapy are needed. This study provides important insights to patients' perspectives on shorter durations of anti-HER2 treatment, and their concerns regarding potential increased cancer risk with less treatment.

A network approach to developing immuno-oncology combinations in Canada.

Immune checkpoint inhibitors have revolutionized care for many cancer indications, with considerable effort now being focused on increasing the rate, depth, and duration of patient response. One strategy is to combine immune strategies (for example, ctla-4 and PD-1/L1-directed agents) to harness additive or synergistic efficacy while minimizing toxicity. Despite encouraging results with such combinations in multiple tumour types, numerous clinical challenges remain, including a lack of biomarkers that reliably predict outcome, the emergence of therapeutic resistance, and optimal management of immune-related toxicities. Furthermore, the selection of ideal combinations from the myriad of immune, systemic, and locoregional therapies has yet to be determined. A longitudinal network-based approach could offer advantages in addressing those critical questions, including long-term follow-up of patients beyond individual trials. The molecular cancer registry Personalize My Treatment, managed by the Networks of Centres of Excellence nonprofit organization Exactis Innovation, is uniquely positioned to accelerate Canadian immuno-oncology (io) research efforts throughout its national network of cancer sites. To gain deeper insight into how a pan-Canadian network could advance research in io combinations, Exactis invited preeminent clinical and scientific advisors from across Canada to a roundtable event in November 2017. The present white paper captures the expert advice provided: leverage longitudinal patient data collection; facilitate network collaboration and assay harmonization; synergize with existing initiatives, networks, and biobanks; and develop an io combination trial based on Canadian discoveries.

Quantum Hall effect in hydrogenated graphene.

The quantum Hall effect is observed in a two-dimensional electron gas formed in millimeter-scale hydrogenated graphene, with a mobility less than 10 cm2/V·s and corresponding Ioffe-Regel disorder parameter (k(F)λ)(-1) ≫ 1. In a zero magnetic field and low temperatures, the hydrogenated graphene is insulating with a two-point resistance of the order of 250h/e2. The application of a strong magnetic field generates a negative colossal magnetoresistance, with the two-point resistance saturating within 0.5% of h/2e2 at 45 T. Our observations are consistent with the opening of an impurity-induced gap in the density of states of graphene. The interplay between electron localization by defect scattering and magnetic confinement in two-dimensional atomic crystals is discussed.

Neural heterogeneities influence envelope and temporal coding at the sensory periphery.

Peripheral sensory neurons respond to stimuli containing a wide range of spatio-temporal frequencies. We investigated electroreceptor neuron coding in the gymnotiform wave-type weakly electric fish Apteronotus leptorhynchus. Previous studies used low to mid temporal frequencies (<256 Hz) and showed that electroreceptor neuron responses to sensory stimuli could be almost exclusively accounted for by linear models, thereby implying a rate code. We instead used temporal frequencies up to 425 Hz, which is in the upper behaviorally relevant range for this species. We show that electroreceptors can: (A) respond up to the highest frequencies tested and (B) display strong nonlinearities in their responses to such stimuli. These nonlinearities were manifested by the fact that the responses to repeated presentations of the same stimulus were coherent at temporal frequencies outside of those contained in the stimulus waveform. Specifically, these consisted of low frequencies corresponding to the time varying contrast or envelope of the stimulus as well as higher harmonics of the frequencies contained in the stimulus. Heterogeneities in the afferent population influenced nonlinear coding as afferents with the lowest baseline firing rates tended to display the strongest nonlinear responses. To understand the link between afferent heterogeneity and nonlinear responsiveness, we used a phenomenological mathematical model of electrosensory afferents. Varying a single parameter in the model was sufficient to account for the variability seen in our experimental data and yielded a prediction: nonlinear responses to the envelope and at higher harmonics are both due to afferents with lower baseline firing rates displaying greater degrees of rectification in their responses. This prediction was verified experimentally as we found that the coherence between the half-wave rectified stimulus and the response resembled the coherence between the responses to repeated presentations of the stimulus in our dataset. This result shows that rectification cannot only give rise to responses to low frequency envelopes but also at frequencies that are higher than those contained in the stimulus. The latter result implies that information is contained in the fine temporal structure of electroreceptor afferent spike trains. Our results show that heterogeneities in peripheral neuronal populations can have dramatic consequences on the nature of the neural code.

Hydrodynamics of superfluid helium in a single nanohole.

The flow of liquid helium through a single nanohole with radius smaller than 25 nm was studied. Mass flow was induced by applying a pressure difference of up to 1.4 bar across a 50 nm thick Si(3)N(4) membrane and was measured directly by means of mass spectrometry. In liquid He I, we experimentally show that the fluid is not clamped by the short pipe with diameter-to-length ratio D/L≃1, despite the small diameter of the nanohole. This viscous flow is quantitatively understood by making use of a model of flow in short pipes. In liquid He II, a two-fluid model for mass flow is used to extract the superfluid velocity in the nanohole for different pressure heads at temperatures close to the superfluid transition. These velocities compare well to existing data for the critical superflow of liquid helium in other confined systems.

Flow conductance of a single nanohole.

The mass flow conductance of single nanoholes with a diameter ranging from 75 to 100 nm was measured using mass spectrometry. For all nanoholes, a smooth crossover is observed between single-particle statistical flow (effusion) and the collective viscous flow emanating from the formation of a continuum. This crossover is shown to occur when the gas mean free path matches the size of the nanohole diameter. As a consequence of the pinhole geometry, the breakdown of the Poiseuille approximation is observed in the power-law temperature exponent of the measured conductance.

Predictors of poor neurologic outcome after induced mild hypothermia following cardiac arrest.

BACKGROUND: Several predictors of poor neurologic outcome after cardiac arrest (CA) were proven to be valid. However, these studies preceded the advent of therapeutic induced mild hypothermia (TIMH), which may alter their validity. The objective of this study is to reassess the validity of these predictors in post-CA patients treated with TIMH. METHODS: Retrospective chart review of 37 consecutive adults who were comatose after resuscitation from CA and treated with TIMH. RESULTS: None of six patients without pupillary reactivity, six without corneal reflexes on day 3, or eight with myoclonus status epilepticus recovered awareness. Two of 14 patients with motor responses no better than extension at day 3 recovered motor responses only after 6 days post-arrest (one at 5 and one at 6 days post-rewarming) and regained awareness. CONCLUSIONS: Loss of motor responses better than extension on day 3 was not prognostically reliable after therapeutic induced mild hypothermia for comatose cardiac arrest survivors. None of the patients who lost pupillary or corneal reflexes on day 3 or developed myoclonus status epilepticus recovered awareness.

Nitrogen fertilizer impact on the Wilmot watershed aquifer in Prince Edward Island, Canada.

The objective of this study is to estimate the soil N flux from the vadose zone to the aquifer of the Wilmot watershed (Prince Edward Island, Canada) for a typical three-year cropping rotation (barley-red clover-potato). A conceptual model estimates that 199-221 tons of N were yearly available for leaching at the watershed scale. A significant portion of this N amount was available for leaching at the end of the crop season representing 80-90% of the annual N balance. Drainage water nitrate concentrations were significantly higher after the potato-rotation year than during the crop season. Low nitrate concentrations were measured at spring thaw indicating that most of the nitrate available from the preceding potato crop season was likely leached at the end of fall or during winter. Early spring ionic exchange membrane sampling show a large availability of nitrate in soil possibly throughout winter as well, resulting from soil N mineralization and nitrification over the winter period. These findings are corroborated by the isotope natural abundance analysis of nitrate in groundwater implying that nitrifiers are significantly active during winter, as well as during the crop season, and that leaching of soil nitrates with seasonal signals takes place whenever recharge is occurring.

Analysis of Fusarium graminearum mycotoxins in different biological matrices by LC/MS.

The purpose of this study was to develop an LC/MS assay to accurately detect three mycotoxins produced by Fusarium graminearum in various matrices. Using different LC conditions, deoxynivalenol (DON), 15-acetyldeoxynivalenol (15-ADON), and zearalenone (ZEN) were detected in four different matrices (fungal liquid cultures, maize grain, insect larvae and pig serum). The sensitivity of MS detection allowed us to detect concentrations as low as 8 ppb of DON and 12 ppb of ZEN. A very small quantity of matrix was therefore necessary for successful analysis of these toxins and a variety of experimental situations were successfully investigated using this technique. Production of 15-ADON and butenolide was monitored in a liquid culture of F. graminearum under controlled conditions. Using simple extraction procedures, the differential accumulation of DON and 15-ADON was followed in inoculated maize genotypes varying in susceptibility to F. graminearum. Toxicokinetic studies were carried out with maize insect pests reared continually on artificial diets containing ZEN and suggested that larvae may possess the ability to degrade ZEN. Finally, persistence of DON was assessed in pigs fed diet supplemented with DON, results indicated that DON accumulates quickly in pig blood and then levels decline progressively for 12 hours thereafter. The LC/MS study reported here is very useful and flexible for the detection of these mycotoxins in different media and at very low concentrations.

Fusarium Head Blight and Deoxynivalenol Accumulation of Barley in Eastern Canada: Cultivar Response and Correlation Analysis.

Fusarium head blight of barley (Hordeum vulgare) is a devastating disease in many countries. We undertook a study to identify barley cultivars, if any, that are resistant to Fusarium head blight and deoxynivalenol (DON) accumulation and to determine if DON concentration is correlated with other plant traits in Eastern Canada and China. Barley cultivars were grown in the field under artificial inoculation conditions at two locations (Charlottetown and Ottawa) in Canada during two summers and at Hangzhou in China during two winters. Seed samples were collected for DON analysis from the barley performance trial at five locations in Ontario. None of the 64 barley cultivars were immune to Fusarium head blight infection. Two-row cultivars, however, were significantly more resistant to Fusarium head blight infection and DON accumulation than six-row cultivars. Three cultivars (Island, AC Alberte, and Chevron) were found to be most resistant, as they were consistently low in Fusarium head blight incidence and DON concentration in both Eastern Canada and China. In six-row barley, DON concentration was correlated positively with Fusarium head blight incidence at both Charlottetown and Ottawa, and it was negatively correlated with plant height at Ottawa. DON concentration and heading date were not consistently correlated. Barley yellow dwarf and powdery mildew appeared to have very little effect on Fusarium head blight infection. Susceptibility to DON accumulation did not result in low yield under natural infection conditions in Ontario. Cultivar × location interactions for DON concentration, Fusarium head blight incidence, and heading date were significant.

A new 1-hydroxy-2,6-pyrazinedione associated with hypovirulent isolates of Sclerotinia minor.

A new 1-hydroxy-2,6-pyrazinedione, sclerominol (1), was isolated from cultures of hypovirulent isolates of Sclerotinia minor, a fungal plant pathogen associated with lettuce drop and other plant diseases. This compound was characterized by NMR, mass spectrometry, and X-ray crystallography. One other 1-hydroxy-2,6-pyrazinedione, flutimide, has been reported. Flutimide has activity as an inhibitor of influenza virus endonuclease, and therefore, sclerominol was evaluated for related biological activity. Sclerominol (1) displayed some activity against cancer cell lines but little activity against three influenza virus strains. The role of 1 in the physiology of hypovirulent isolates of S. minor has not been determined, but 1 has also been recovered from debilitated isolates of S. sclerotiorum.

Epstein-Barr virus primes human polymorphonuclear leucocytes for the biosynthesis of leukotriene B4.

In the present study, we have investigated the effect of the short-term incubation of polymorphonuclear leucocytes (PMN) with infectious Epstein-Barr virus (EBV) on leukotriene B(4) (LTB(4)) biosynthesis. Pre-exposure of PMN to EBV led to an increased production of LTB(4) upon stimulation with either the ionophore A23187, the chemotactic peptide fMLP, or phagocytic particles (zymosan). Experiments performed with viral particles pretreated with a neutralizing antibody raised against the gp350 of the viral envelope revealed that a specific interaction between the PMN surface and the viral glycoprotein gp350 is required for the priming effect of EBV. Preincubation of PMN with EBV resulted in an increased release of arachidonic acid upon stimulation with a second agonist. Moreover, LTB(4) biosynthesis in EBV/A23187-treated PMN was greatly diminished in the presence of an inhibitor of the cytosolic phospholipase A2 (cPLA(2)), suggesting that cPLA(2) plays a critical role in the priming effect of EBV. Accordingly, EBV by itself promoted Ser-505 phosphorylation of cPLA(2) and strongly enhanced fMLP-induced phosphorylation of p38 MAP kinase, an enzyme known to phosphorylate cPLA(2) in human PMN. Furthermore, fMLP-induced translocation of cPLA(2) was strongly enhanced when PMN were previously exposed to EBV. These data indicate that binding of EBV to human PMN results in the activation of intracellular events involved in the release of pro-inflammatory lipid mediators.

Sinorhizobium meliloti cells require biotin and either cobalt or methionine for growth.

Sinorhizobium meliloti is usually cultured in rich media containing yeast extract. It has been suggested that some components of yeast extract are also required for growth in minimal medium. We tested 27 strains of this bacterium and found that none were able to grow in minimal medium when methods to limit carryover of yeast extract were used during inoculation. By fractionation of yeast extract, two required growth factors were identified. Biotin was found to be absolutely required for growth, whereas previously the need for this vitamin was considered to be strain specific. All strains also required supplementation with cobalt or methionine, consistent with the requirement for a vitamin B(12)-dependent homocysteine methyltransferase for methionine biosynthesis.

Pre-harvest accumulation of deoxynivalenol in sweet corn ears inoculated with Fusarium graminearum.

Three types of commercial sweet corn hybrids [surgary (su1), shrunken or 'supersweet' (sh2) and surgary enhancer (se1)] were silk channel inoculated in 1996 and 1997 with a macroconidial suspension of Fusarium graminearum to determine how early the mycotoxin deoxynivalenol accumulates in kernels. Disease symptoms rapidly developed on all hybrids and were apparent 4 days after inoculation. Symptoms stabilized by 28 days after inoculation. Toxin levels were greater than 1 microgram/g in kernels as early as 2 weeks after silk emergence and rapidly increased to extremely high levels. Susceptibility in all hybrids decreased as the silk dried out. Deoxynivalenol concentrations were correlated to disease severity. There was some indication that the sh2 genotype was more susceptible than the su1 or se1 genotypes. These results suggest that improvement needs to be made in sweet corn with respect to resistance to gibberella ear rot.

A comparison of clinical, histopathological and cell-cycle markers in rats receiving the fungal toxins fumonisin B1 or fumonisin B2 by intraperitoneal injection.

Fumonisins B1 and B2 (FB1 and FB2) are fungal secondary metabolites produced by members of the genus Fusarium. Although FB1 is usually detected in greater quantities, FB2 frequently co-occurs in contaminated feeds and foods and contributes to the total toxin load. In the present study, the comparative toxicity of FB1 and FB2 was examined in male Sprague-Dawley rats administered toxin (0.75 mg/kg body weight) or vehicle control intraperitoneally (ip) for 2, 4 or 6 consecutive days. Clinical changes, including elevated serum cholesterol, alanine aminotransferase (ALT), creatinine and protein, were slightly more pronounced in FB1-treated rats. The most consistent hematological change was an increase in vacuolated bone marrow cells, which was more pronounced in FB1-treated rats. Histopathological changes were similar in FB1- and FB2-treated rats and included single cell necrosis in kidneys and liver, cytoplasmic vacuolation in adrenal cortex and lymphocytolysis in thymus. In the liver mRNA expression for the cyclin kinase inhibitor p21 gene was significantly increased in FB1- and FB2-treated rats, compared to controls. Expression of mRNA for the cyclin D1 gene was significantly depressed in FB2-treated rats. Hepatic cyclin E mRNA was elevated in response to FB1 and FB2 compared to controls. In FB2-treated animals this corresponded with decreased liver p27 mRNA expression. Hepatic proliferating cell nuclear antigen (PCNA) transcription was elevated in FB1- but not FB2- treated rats. Changes in liver microsomal protein levels of p27, cyclin E and PCNA were similar to changes in gene expression. In contrast, cyclin D1 protein levels were elevated in rats treated with FB1 and, to a lesser extent, FB2. The data indicate that FB1 and FB2 can alter the expression of genes associated with the cell cycle, and indicate a need for a further understanding of the mechanistic basis of FB1 and FB2 toxicity.

EBV suppresses prostaglandin E2 biosynthesis in human monocytes.

It is well known that EBV has developed strategies to evade immune surveillance. Previously, EBV was shown to bind specifically to monocytes and regulate expression of proinflammatory mediators such as IL-1, IL-6, TNF-alpha, and leukotrienes. EBV was also found to affect phagocytosis of monocytes. In this study, we show that in addition to these effects, EBV suppresses the biosynthesis of PGE2, a pleiotropic immunomodulatory molecule that is synthesized by the dioxygenation of arachidonic acid via the cyclooxygenase (COX) pathway. This down-regulation of PGE2 formation involved the inhibition of the inducible COX-2 isoform expression both at the transcriptional and translational levels, whereas expression of the constitutive COX-1 isoform was unaltered. Furthermore, exposure of monocytes to EBV was found to impact on the NF-kappaB activation pathway, which plays an essential role in the induction of COX-2 in monocytes. The inhibition of PGE2 biosynthesis was relieved when the experiments were conducted in presence of phosphonoacetic acid, an inhibitor of herpesviruses DNA polymerase, indicating that viral replication and/or neosynthesized viral proteins were involved in this process. Thus, inhibition of PGE2 biosynthesis in monocytes may represent an additional mechanism underlying EBV pathogenicity.

Infection of primary human monocytes by Epstein-Barr virus.

Previous studies have reported that infection of monocytes by viruses such as cytomegalovirus and human immunodeficiency virus weakens host natural immunity. In the present study, we demonstrated the capability of Epstein-Barr virus (EBV) to infect and replicate in freshly isolated human monocytes. Using electron microscopy analysis, we observed the presence of EBV virions in the cytoplasm and nuclei of approximately 20% of monocytes. This was confirmed by Southern blot analysis of EBV genomic DNA sequences in isolated nuclei from monocytes. Infection of monocytes by EBV leads to the activation of the replicative cycle. This was supported by the detection of immediate-early lytic mRNA BZLF-1 transcripts, and by the presence of two early lytic transcripts (BALF-2, which appears to function in DNA replication, and BHRF-1, also associated with the replicative cycle). The late lytic BcLF-1 transcripts, which code for the major nucleocapsid protein, were also detected, as well as EBNA-1 transcripts. However, attempts to detect EBNA-2 transcripts have yielded negative results. Viral replication was also confirmed by the release of newly synthesized infectious viral particles in supernatants of EBV-infected monocytes. EBV-infected monocytes were found to have significantly reduced phagocytic activity, as evaluated by the quantification of ingested carboxylated fluoresceinated latex beads. Taken together, our results suggest that EBV infection of monocytes and alteration of their biological functions might represent a new mechanism to disrupt the immune response and promote viral propagation during the early stages of infection.

Oxidative deamination of hydrolyzed fumonisin B(1) (AP(1)) by cultures of Exophiala spinifera.

Fumonisins are mycotoxins of world-wide distribution in maize infected by the fungus Fusarium verticillioides. They are highly toxic to certain livestock and are potential carcinogens. Exophiala spinifera, a black yeast fungus found on moldy maize kernels, was identified previously as capable of growing on fumonisin B1 as a sole carbon source and thus is a potential source for fumonisin detoxifying enzymes. Pure cultures of E. spinifera transform fumonisin B(1) to the amino polyol AP(1) plus free tricarballylic acid through the activity of a soluble extracellular esterase, and further transformation is evidenced by accumulation in culture supernatant of a less polar compound(s) lacking a fluorescamine-reactive amino group. A free amine is thought to be critical for biological activity of FB(1) or AP(1). As a first step towards characterizing this amine-modifying activity, we investigated the biotransformation of AP(1) by E. spinifera liquid cultures that had been previously grown in liquid medium containing AP(1) as a sole carbon source. Accumulation of AP(1)-derived metabolites was monitored by thin-layer chromatography of culture supernatants, and product metabolites were purified and evaluated by mass spectrometry and nuclear magnetic resonance. Two products of treatment of purified AP(1) with cultures of E. spinifera are shown to be N-acetyl AP(1) and a new compound, 2-oxo-12,16-dimethyl-3,5,10, 14,15-icosanepentol hemiketal (or 2-OP(1) hemiketal).

Interaction of Fusarium graminearum and F. moniliforme in Maize Ears: Disease Progress, Fungal Biomass, and Mycotoxin Accumulation.

ABSTRACT To investigate the interaction between two major ear-rotting pathogens, maize ears were inoculated with either Fusarium graminearum, F. moniliforme, or an equal mixture of the two. Silk and kernel tissues were periodically harvested throughout the growing season so that a time course of the experimental variables (disease severity, ergosterol content, fungal DNA content, and mycotoxin concentration) could be recorded. Over the 3 years tested (1992 to 1994), the highest levels of disease and ergosterol were found in the F. graminearum treatment, followed by the mixture treatment (F. graminearum plus F. moniliforme) and, finally, the F. moniliforme treatment. Kernel ergosterol content and disease rating were correlated for both pathogens, but the highest correlation coefficients were obtained in the F. graminearum treatment. The DNA analysis revealed that, in the mixed inoculum, F. moniliforme had a greater growth rate than did F. graminearum. In 1994, appreciable F. moniliforme from natural inoculum was found in the F. graminearum treatment. Fumonisin B(1) levels did not differ between the F. moniliforme treatment and the mixed inoculum treatment. The effect of temperature on the growth rate of the two species explained some of the field results, with temperatures in the silks being more favorable to F. moniliforme. Data on the growth rate on silks obtained by the incorporation of radiolabeled precursor to ergosterol demonstrated that F. graminearum was able to grow well at 26 to 28 degrees C, whereas F. moniliforme grew well over a broader range, including at higher temperatures.

Gavage administration of the fungal toxin fumonisin B1 to female Sprague-Dawley rats.

The fungal toxin fumonisin B1 (FB1) is a contaminant of corn-based foods and feeds produced by members of the genus Fusarium. Fumonisin B1 toxicity was examined using gavage administration of purified toxin to female Sprague-Dawley rats. For 11 consecutive days each rat received a single dose of FB1 at the following concentrations: control (saline), 1, 5, 15, 35, or 75 mg FB1/kg body weight/d. Significantly depressed body weight and food consumption occurred at 35 and 75 mg FB1/kg/d. By the end of the dosing period there were no significant changes in food consumption. Kidneys and bone marrow were most sensitive to FB1 exposure. Changes in renal morphology were observed from 5 to 75 mg FB1/kg/d, accompanied by transient changes in urine osmolality and urine enzyme levels. Increased cellular vacuolation was the primary change associated with bone-marrow toxicity, starting at doses of 5 mg FB1/kg/d. Hepatotoxicity was indicated by reduced liver weight, elevated serum alanine amonitransferase (ALT), and mild histopathological changes occurring at doses of 15 mg FB1/kg/d and higher. Increased cytoplasmic vacuolation of adrenal cortex cells occurred in rats treated with 15 mg FB1/kg/d and higher, indicating that the adrenals are also potential targets of FB1. Elevated serum cholesterol, which is a consistent response to FB1 was observed at 5 mg FB1/kg/d and higher. Based on responses in this study, gavage is an appropriate substitute for longer feeding studies. Compared to previous work with male rats, gender-related difference in FB1 responses lacked consistency but indicated that males may be marginally more sensitive than female Sprague-Dawley rats.