Social evaluative stress enhances central detail memory, reduces false memory, and results in intrusive memories that last for days.

Few studies have quantified what an individual remembers about a laboratory-controlled stressor. Here, we aimed to replicate previous work by using a modified version of the Trier Social Stress Test (TSST) to quantify participant memory for a stressful experience. We also aimed to extend this work by quantifying false and intrusive memories that ensued. One hundred and seven participants were exposed to the TSST (stress) or the friendly TSST (f-TSST; no stress). The TSST required participants to deliver a ten-minute speech in front of two laboratory panel members as part of a mock job interview; the f-TSST required participants to casually converse with the panel members about their interests. In both conditions, the panel members interacted with (central) or did not interact with (peripheral) several objects sitting on a desk in front of them. The next day, participants' memory for the objects was assessed with recall and recognition tests. We also quantified participants' intrusive memories on Days 2, 4, 6, and 8. Stressed participants recalled more central objects and exhibited greater recognition memory, particularly for central objects, than controls. Stress also led to less false recall and more intrusive memories on Days 2 and 4. Consistent with previous work, these findings suggest that participants exhibit enhanced memory for the central details of a stressful experience; they also extend prior work by showing that participants exposed to a stressor have less false memories and experience intrusive memories for several days following the event. The modified TSST paradigm used here may be useful for researchers studying not only what participants remember about a stressful event but also their susceptibility to intrusive memory formation.

Pre-Learning Stress That Is Temporally Removed from Acquisition Impairs Fear Learning.

Few studies have examined the time-dependent effects of stress on fear learning. Previously, we found that stress immediately before fear conditioning enhanced fear learning. Here, we aimed to extend these findings by assessing the effects of stress 30 min prior to fear conditioning on fear learning and fear generalization. Two hundred and twenty-one healthy adults underwent stress (socially evaluated cold pressor test) or a control manipulation 30 min before completing differential fear conditioning in a fear-potentiated startle paradigm. One visual stimulus (CS+), but not another (CS-), was associated with an aversive airblast to the throat (US) during acquisition. The next day, participants were tested for their fear responses to the CS+, CS-, and several generalization stimuli. Stress impaired the acquisition of fear on Day 1 but had no significant impact on fear generalization. The stress-induced impairment of fear learning was particularly evident in participants who exhibited a robust cortisol response to the stressor. These findings are consistent with the notion that stress administered 30 min before learning impairs memory formation via corticosteroid-related mechanisms and may help us understand how fear memories are altered in stress-related psychological disorders.

Childhood Maltreatment in Females Is Associated with Enhanced Fear Acquisition and an Overgeneralization of Fear.

Childhood maltreatment may alter fear neurocircuitry, which results in pathological anxiety and depression. One alteration of fear-related behaviors that has been observed in several psychiatric populations is an overgeneralization of fear. Thus, we examined the association between childhood maltreatment and fear generalization in a non-clinical sample of young adults. Two hundred and ninety-one participants underwent differential fear conditioning in a fear-potentiated startle paradigm. One visual stimulus (CS+), but not another (CS-), was associated with an aversive airblast to the throat (US) during acquisition. The next day, participants were tested for their fear responses to the CS+, CS-, and several generalization stimuli (GS) without the presence of the US. Participants also completed questionnaires that assessed symptoms of childhood maltreatment, anxiety, depression, and post-traumatic stress disorder (PTSD). Participants reporting high childhood maltreatment (n = 71; 23 males, 48 females) exhibited significantly greater anxiety, depression, and symptoms of PTSD than participants reporting low childhood maltreatment (n = 220; 133 males, 87 females). Females reporting high childhood maltreatment demonstrated significantly enhanced fear learning and greater fear generalization, based on their fear-potentiated startle responses. Our findings suggest that childhood maltreatment may sex-dependently influence the development of fear neurocircuitry and result in greater fear generalization in maltreated females.

TNF blockade uncouples toxicity from antitumor efficacy induced with CD40 chemoimmunotherapy.

Agonist CD40 antibodies are under clinical development in combination with chemotherapy as an approach to prime for antitumor T cell immunity. However, treatment with anti-CD40 is commonly accompanied by both systemic cytokine release and liver transaminase elevations, which together account for the most common dose-limiting toxicities. Moreover, anti-CD40 treatment increases the potential for chemotherapy-induced hepatotoxicity. Here, we report a mechanistic link between cytokine release and hepatotoxicity induced by anti-CD40 when combined with chemotherapy and show that toxicity can be suppressed without impairing therapeutic efficacy. We demonstrate in mice and humans that anti-CD40 triggers transient hepatotoxicity marked by increased serum transaminase levels. In doing so, anti-CD40 sensitizes the liver to drug-induced toxicity. Unexpectedly, this biology is not blocked by the depletion of multiple myeloid cell subsets, including macrophages, inflammatory monocytes, and granulocytes. Transcriptional profiling of the liver after anti-CD40 revealed activation of multiple cytokine pathways including TNF and IL-6. Neutralization of TNF, but not IL-6, prevented sensitization of the liver to hepatotoxicity induced with anti-CD40 in combination with chemotherapy without impacting antitumor efficacy. Our findings reveal a clinically feasible approach to mitigate toxicity without impairing efficacy in the use of agonist CD40 antibodies for cancer immunotherapy.

Macrophages: Key orchestrators of a tumor microenvironment defined by therapeutic resistance.

Macrophages have emerged as promising therapeutic targets in cancer. Within tumor tissue, macrophages foster tumor development, invasion, and metastasis. As the phenotype of macrophages is inherently pliable and dependent on cues received from the surrounding microenvironment, macrophages co-evolve with malignant and other non-malignant cells during cancer progression. In doing so, they establish a microenvironment that is therapeutically resistant and thwarts the productivity of T cell immunosuveillance. Strategies designed to deplete, inhibit, or redirect macrophages with anti-tumor activity are being explored to reverse the pro-tumor properties of macrophages that are commonly observed in cancer. In this review, we discuss our current understanding of the mechanisms that regulate macrophage recruitment to tumors, their impact on the tumor microenvironment, and their promise as therapeutic targets for improving the efficacy of cytotoxic- and immune-based therapies.

CAR T Cell Therapy of Non-hematopoietic Malignancies: Detours on the Road to Clinical Success.

Chimeric antigen receptor (CAR)-engineered T cells represent a breakthrough in personalized medicine. In this strategy, a patient's own T lymphocytes are genetically reprogrammed to encode a synthetic receptor that binds a tumor antigen, allowing T cells to recognize and kill antigen-expressing cancer cells. As a result of complete and durable responses in individuals who are refractory to standard of care therapy, CAR T cells directed against the CD19 protein have been granted United States Food and Drug Administration (FDA) approval as a therapy for treatment of pediatric and young adult acute lymphoblastic leukemia and diffuse large B cell lymphoma. Human trials of CAR T cells targeting CD19 or B cell maturation antigen in multiple myeloma have also reported early successes. However, a clear and consistently reproducible demonstration of the clinical efficacy of CAR T cells in the setting of solid tumors has not been reported to date. Here, we review the history and status of CAR T cell therapy for solid tumors, potential T cell-intrinsic determinants of response and resistance as well as extrinsic obstacles to the success of this approach for much more prevalent non-hematopoietic malignancies. In addition, we summarize recent strategies and innovations that aim to augment the potency of CAR T cells in the face of multiple immunosuppressive barriers operative within the solid tumor microenvironment. Advances in the field of CAR T cell biology over the coming years in the areas of safety, reliability and efficacy against non-hematopoietic cancers will ultimately determine how transformative adoptive T cell therapy will be in the broader battle against cancer.

IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma.

Inflammation mediated by activation of JAK/STAT signaling is a major cause of chemotherapy resistance in cancer. We studied the impact of selectively blocking the IL6 receptor (IL6R) as a strategy to inhibit IL6-induced STAT activation and to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC). To do this, STAT activation was investigated in tumors arising spontaneously in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1Cre (KPC) mice. Plasma from patients with PDAC was assessed for its ability to activate STAT3/SOCS3 in human monocytes using immunofluorescence microscopy and quantitative gene expression assays. KPC mice and syngeneic mice (wild type and IL6-/-) implanted with KPC-derived cell lines were treated with an IL6R-blocking antibody (anti-IL6R). The impact of treatment on tumor growth in KPC mice and mice with KPC-derived tumor implants was monitored using ultrasonography and calipers, respectively. Tumors were analyzed by IHC to detect changes in STAT activation, tumor viability, and proliferation. We found that STAT3 was the most activated STAT protein in PDAC tumors from KPC mice. Plasma from patients with advanced PDAC stimulated STAT3/SOCS3 activation in human monocytes. In mice, anti-IL6R antibodies targeted Ly6Chi monocytes, inhibited STAT3 activation in tumor cells, and decreased tumor cell proliferation in vivo IL6R blockade in combination with chemotherapy induced tumor cell apoptosis, tumor regressions, and improved overall survival. Overall, we show that IL6 signaling drives STAT3 activation in tumor cells and mediates chemoresistance in PDAC. Thus, disrupting IL6 signaling using anti-IL6R antibodies holds promise for improving chemotherapy efficacy in PDAC. Mol Cancer Ther; 16(9); 1898-908. ©2017 AACR.

Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists.

INTRODUCTION: CD40 is a promising therapeutic target for cancer immunotherapy. In patients with advanced solid malignancies, CD40 agonists have demonstrated some anti-tumor activity and a manageable toxicity profile. A 2nd generation of CD40 agonists has now been designed with optimized Fc receptor (FcR) binding based on preclinical evidence suggesting a critical role for FcR engagement in defining the potency of CD40 agonists in vivo. Areas covered: We provide a comprehensive review using PubMed and Google Patent databases on the current clinical status of CD40 agonists, strategies for applying CD40 agonists in cancer therapy, and the preclinical data that supports and is guiding the future development of CD40 agonists. Expert commentary: There is a wealth of preclinical data that provide rationale on several distinct approaches for using CD40 agonists in cancer immunotherapy. This data illustrates the need to strategically combine CD40 agonists with other clinically active treatment regimens in order to realize the full potential of activating CD40 in vivo. Thus, critical to the success of this class of immune-oncology drugs, which have the potential to restore both innate and adaptive immunosurveillance, will be the identification of biomarkers for monitoring and predicting responses as well as informing mechanisms of treatment resistance.

Economic and clinical impact of routine weekend catheterization services.

OBJECTIVES: To assess the impact of weekend cardiac catheterization (cath) services for nonemergent inpatients. STUDY DESIGN: Retrospective cohort study of patients undergoing cath before and after Saturday cath service availability (CSA). METHODS: Cohorts included Friday and Saturday admissions with cath (with or without revascularization) on the subsequent Monday from January 1, 2007, to December 31, 2008 (pre-CSA events), and Friday or Saturday admissions undergoing cath the subsequent or same Saturday from January 1, 2009, to December 31, 2010 (post-CSA events). Administrative and registry data provided demographics, comorbidities, percutaneous coronary intervention (PCI) details, adverse events, hospital length of stay (LOS), and inpatient expenditures. We used generalized linear modeling to predict LOS and costs, and logistic regression to estimate the likelihood of adverse events during follow-up. RESULTS: We identified 331 pre-CSA cases (327 patients) and 244 post-CSA cases (243 patients). Cohorts were similar in age (66 years), sex (59% male), and level of comorbidity. PCI use was higher following CSA (42% vs 26%; P <.001), with procedural success accomplished in 95% and 94% of pre- and post-CSA patients, respectively. Adjusted clinical outcomes were similar (odds ratio [OR] for in-hospital mortality, 0.67 post-CSA vs pre-CSA; P = .55; OR for 30-day revascularization, 1.14; P = .68). Models predict an average LOS reduction of 1.7 days following CSA (5.7 vs 4.0 days; P <.001) yet inpatient costs were similar ($24,817 vs $24,753; 95% CI of difference, -$3611 to $3576). CONCLUSIONS: Weekend CSA for routine inpatients was clinically safe and effective, and reduced hospital LOS. Similar inpatient costs likely reflect a shift in case mix in this nonrandomized study.

Identification of Optimal Mouse Models of Systemic Sclerosis by Interspecies Comparative Genomics.

OBJECTIVE: Understanding the pathogenesis of systemic sclerosis (SSc) is confounded by considerable disease heterogeneity. Animal models of SSc that recapitulate distinct subsets of disease at the molecular level have not been delineated. We applied interspecies comparative analysis of genomic data from multiple mouse models of SSc and patients with SSc to determine which animal models best reflect the SSc intrinsic molecular subsets. METHODS: Gene expression measured in skin from mice with sclerodermatous graft-versus-host disease (GVHD), bleomycin-induced fibrosis, Tsk1/+ or Tsk2/+ mice was mapped to human orthologs and compared to SSc skin biopsy-derived gene expression. Transforming growth factor ß (TGFß) activation was assessed using a responsive signature in mice, and tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) expression was measured in SSc patient and mouse skin. RESULTS: Gene expression in skin from mice with sclerodermatous GVHD and bleomycin-induced fibrosis corresponded to that in SSc patients in the inflammatory molecular subset. In contrast, Tsk2/+ mice showed gene expression corresponding to the fibroproliferative SSc subset. Enrichment of a TGFß-responsive signature was observed in both Tsk2/+ mice and mice with bleomycin-induced skin fibrosis. Expression of TNFRSF12A (the TWEAK receptor/fibroblast growth factor-inducible 14) was elevated in skin from patients with fibroproliferative SSc and the skin of Tsk2/+ mice. CONCLUSION: This study reveals similarities in cutaneous gene expression between distinct mouse models of SSc and specific molecular subsets of the disease. Different pathways underlie the intrinsic subsets including TGFß, interleukin-13 (IL-13), and IL-4. We identify a novel target, Tnfrsf12a, with elevated expression in skin from patients with fibroproliferative SSc and Tsk2/+ mice. These findings will inform mechanistic and translational preclinical studies in SSc.

IFNγ and CCL2 Cooperate to Redirect Tumor-Infiltrating Monocytes to Degrade Fibrosis and Enhance Chemotherapy Efficacy in Pancreatic Carcinoma.

UNLABELLED: Dense fibrosis and a robust macrophage infiltrate are key therapeutic barriers in pancreatic ductal adenocarcinoma (PDAC). CD40 activation can circumvent these barriers by inducing macrophages, originating from peripheral blood monocytes, to deplete fibrosis. The precise mechanism and therapeutic implications of this antifibrotic activity, though, remain unclear. Here, we report that IFNγ and CCL2 released systemically in response to a CD40 agonist cooperate to redirect a subset of Ly6C(+)CCR2(+)monocytes/macrophages to infiltrate tumors and deplete fibrosis. Whereas CCL2 is required for Ly6C(+)monocyte/macrophage infiltration, IFNγ is necessary for tumor-infiltrating monocytes/macrophages to shift the profile of matrix metalloproteinases (MMP) in tumors, leading to MMP-dependent fibrosis degradation. In addition, MMP13-dependent loss of extracellular matrix components induced by a CD40 agonist increased PDAC sensitivity to chemotherapy. Our findings demonstrate that fibrosis in PDAC is a bidirectional process that can be rapidly altered by manipulating a subset of tumor-infiltrating monocytes, leading to enhanced chemotherapy efficacy. SIGNIFICANCE: We report that CD40 agonists improve chemotherapy efficacy in pancreatic carcinoma by redirecting tumor-infiltrating monocytes/macrophages to induce fibrosis degradation that is dependent on MMPs. These findings provide novel insight into the plasticity of monocytes/macrophages in cancer and their capacity to regulate fibrosis and modulate chemotherapy efficacy in pancreatic carcinoma.

Exclusion of T Cells From Pancreatic Carcinomas in Mice Is Regulated by Ly6C(low) F4/80(+) Extratumoral Macrophages.

BACKGROUND & AIMS: Immunotherapies that induce T-cell responses have shown efficacy against some solid malignancies in patients and mice, but these have little effect on pancreatic ductal adenocarcinoma (PDAC). We investigated whether the ability of PDAC to evade T-cell responses induced by immunotherapies results from the low level of immunogenicity of tumor cells, the tumor's immunosuppressive mechanisms, or both. METHODS: Kras(G12D/+);Trp53(R172H/+);Pdx-1-Cre (KPC) mice, which develop spontaneous PDAC, or their littermates (controls) were given subcutaneous injections of a syngeneic KPC-derived PDAC cell line. Mice were then given gemcitabine and an agonist of CD40 to induce tumor-specific immunity mediated by T cells. Some mice were also given clodronate-encapsulated liposomes to deplete macrophages. Tumor growth was monitored. Tumor and spleen tissues were collected and analyzed by histology, flow cytometry, and immunohistochemistry. RESULTS: Gemcitabine in combination with a CD40 agonist induced T-cell-dependent regression of subcutaneous PDAC in KPC and control mice. In KPC mice given gemcitabine and a CD40 agonist, CD4(+) and CD8(+) T cells infiltrated subcutaneous tumors, but only CD4(+) T cells infiltrated spontaneous pancreatic tumors (not CD8(+) T cells). In mice depleted of Ly6C(low) F4/80(+) extratumoral macrophages, the combination of gemcitabine and a CD40 agonist stimulated infiltration of spontaneous tumors by CD8(+) T cells and induced tumor regression, mediated by CD8(+) T cells. CONCLUSIONS: Ly6C(low) F4/80(+) macrophages that reside outside of the tumor microenvironment regulate infiltration of T cells into PDAC and establish a site of immune privilege. Strategies to reverse the immune privilege of PDAC, which is regulated by extratumoral macrophages, might increase the efficacy of T-cell immunotherapy for patients with PDAC.

The Tsk2/+ mouse fibrotic phenotype is due to a gain-of-function mutation in the PIIINP segment of the Col3a1 gene.

Systemic sclerosis (SSc) is a polygenic, autoimmune disorder of unknown etiology, characterized by the excessive accumulation of extracellular matrix (ECM) proteins, vascular alterations, and autoantibodies. The tight skin (Tsk)2/+ mouse model of SSc demonstrates signs similar to SSc including tight skin and excessive deposition of dermal ECM proteins. By linkage analysis, we mapped the Tsk2 gene mutation to <3 megabases on chromosome 1. We performed both RNA sequencing of skin transcripts and genome capture DNA sequencing of the region spanning this interval in Tsk2/+ and wild-type littermates. A missense point mutation in the procollagen III amino terminal propeptide segment (PIIINP) of collagen, type III, alpha 1 (Col3a1) was found to be the best candidate for Tsk2; hence, both in vivo and in vitro genetic complementation tests were used to prove that this Col3a1 mutation is the Tsk2 gene. All previously documented mutations in the human Col3a1 gene are associated with the Ehlers-Danlos syndrome, a connective tissue disorder that leads to a defect in type III collagen synthesis. To our knowledge, the Tsk2 point mutation is the first documented gain-of-function mutation associated with Col3a1, which leads instead to fibrosis. This discovery provides insight into the mechanism of skin fibrosis manifested by Tsk2/+ mice.

Tight Skin 2 Mice Exhibit Delayed Wound Healing Caused by Increased Elastic Fibers in Fibrotic Skin.

Rationale: The Tight Skin 2 (Tsk2) mouse model of systemic sclerosis (SSc) has many features of human disease, including tight skin, excessive collagen deposition, alterations in the extracellular matrix (ECM), increased elastic fibers, and occurrence of antinuclear antibodies with age. A tight skin phenotype is observed by 2 weeks of age, but measurable skin fibrosis is only apparent at 10 weeks. We completed a series of wound healing experiments to determine how fibrosis affects wound healing in Tsk2/+ mice compared with their wild-type (WT) littermates. Method: We performed these experiments by introducing four 4 mm biopsy punched wounds on the back of each mouse, ventral of the midline, and observed wound healing over 10 days. Tsk2/+ mice showed significantly delayed wound healing and increased wound size compared with the WT littermates at both 5 and 10 weeks of age. We explored the potential sources of this response by wounding Tsk2/+ mice that were genetically deficient either for the NLRP3 inflammasome (a known fibrosis mediator), or for elastic fibers in the skin, using a fibulin-5 knockout. Conclusion: We found that the loss of elastic fibers restores normal wound healing in the Tsk2/+ mouse and that the loss of the NLRP3 inflammasome had no effect. We conclude that elastic fiber dysregulation is the primary cause of delayed wound healing in the Tsk2/+ mouse and therapies that promote collagen deposition in the tissue matrix in the absence of elastin deposition might be beneficial in promoting wound healing in SSc and other diseases.

Tight skin 2 mice exhibit a novel time line of events leading to increased extracellular matrix deposition and dermal fibrosis.

The tight skin 2 (Tsk2) mouse model of systemic sclerosis (SSc) has many features of the human disease including tight skin, fibrosis, extracellular matrix abnormalities, and reported antinuclear antibodies (ANA). Here we report that Tsk2/+ mice develop excess dermal fibrosis with age, as skin is not significantly fibrotic until 10 weeks, a full eight weeks after the development of the physical tight skin phenotype. Concomitantly with the tight skin phenotype at two weeks of age, Tsk2/+ mice demonstrate increased levels of total transforming growth factor beta 1 (TGF-ß1) and excessive accumulation of dermal elastic fibers. The increase in elastic fibers is not responsible for tight skin, however, because Tsk2/+ mice genetically engineered to lack skin elastic fibers nevertheless have tight skin and fibrosis. Finally, about two months after the first measurable increases of total collagen, a portion of Tsk2/+ mice produce ANAs, but at a similar level to wild-type littermates. The timeline of disease development in the Tsk2/+ mouse shows that fibrosis is progressive, with elastic fiber alterations and TGF-ß1 over-production occurring at least two months before bona fide fibrosis, that is not dependent on ANA production.

Harnessing the antitumor potential of macrophages for cancer immunotherapy.

Macrophages constitute a dominant fraction of the population of immune cells that infiltrate developing tumors. Recruited by tumor-derived signals, tumor-infiltrating macrophages are key orchestrators of a microenvironment that supports tumor progression. However, the phenotype of macrophages is pliable and, if instructed properly, macrophages can mediate robust antitumor functions through their ability to eliminate malignant cells, inhibit angiogenesis, and deplete fibrosis. While much effort has focused on strategies to block the tumor-supporting activity of macrophages, emerging approaches designed to instruct macrophages with antitumor properties are demonstrating promise and may offer a novel strategy for cancer immunotherapy.

What every dentist should know about bisphenol A.

Bisphenol A (BPA) is a common industrial chemical that has been associated with a variety of biological disorders. From the unborn to the elderly, BPA affects every demographic of the population; however, its potential long-term effects on prenatal and prepubescent development have led to concern about its use in the field of pediatrics. Because BPA is omnipresent in modern society, the use of BPA derivatives (such as Bis-GMA and Bis-DMA) in dental materials in general, and acrylic resins in particular, will be increasingly examined as research continues to implicate BPA in a number of biological disorders.

Phase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies.

PURPOSE: ABI-007 is a novel solvent-free, albumin-bound, 130-nm particle formulation of paclitaxel designed to avoid solvent-related toxicities and to deliver paclitaxel to tumors via molecular pathways involving an endothelial cell-surface albumin receptor (gp60) and an albumin-binding protein expressed by tumor cells and secreted into the tumor interstitium (secreted protein acid rich in cysteine). This study determined the maximum-tolerated dose (MTD) of ABI-007 monotherapy administered weekly (three weekly doses, repeated every 4 weeks) and assessed the pharmacokinetics of paclitaxel administered as ABI-007. PATIENTS AND METHODS: Patients with advanced nonhematologic malignancies received ABI-007 without premedication at dose levels from 80 to 200 mg/m(2) as a 30-minute intravenous infusion once a week for 3 weeks, followed by 1 week of rest (one cycle). RESULTS: Thirty-nine patients were treated with an average of five cycles of ABI-007; 33% of patients received > or = six cycles of treatment. MTDs for heavily and lightly pretreated patients were 100 and 150 mg/m(2), respectively; and the dose-limiting toxicities were grade 4 neutropenia and grade 3 peripheral neuropathy, respectively. Maximum paclitaxel concentration and area under the curve increased linearly with dose. Dose-dependent changes in plasma clearance did not occur. Partial responses were observed in five patients with breast, lung, and ovarian cancers, all of whom had previously been treated with paclitaxel containing polyoxyethylated castor oil in the formulation. CONCLUSION: This study demonstrated that weekly ABI-007 can be administered at doses exceeding those typically used for paclitaxel containing polyoxyethylated castor oil. Pharmacokinetics were linear over the dose range studied. Antitumor responses occurred in patients previously treated with paclitaxel containing polyoxyethylated castor oil.

The effects of low hardness and pH on copper toxicity to Daphnia magna.

The majority of metal toxicity data available for freshwater organisms have been generated in laboratory water at pH > 6.5 and hardness > 50 mg/L as CaCO3. Extrapolation of these results to soft surface waters (i.e., hardness < or = 40 mg/L as CaCO3), similar to predominant conditions in the southeastern United States, may prove challenging. For example, South Carolina has surface waters that average 20 mg/L as CaCO3, and exist at extremes of 1 and 600 mg/L as CaCO3. This research characterized the acute toxicity of Cu to Daphnia magna in waters with low hardness and low pH. The 48-h total Cu median lethal concentrations were related to water hardness over a hardness range of 8 to 51 mg/L as CaCO3. Although toxicological differences existed between water hardness of 7 and 20 mg/L as CaCO3 (p = 0.0001), differences in pH (range 5.5-8.5) did not influence acute Cu toxicity. Results of these laboratory studies will provide the data needed to more accurately predict organism response to Cu in waters with low pH and low hardness.