Leveraging a natural murine meiotic drive to suppress invasive populations.

Invasive rodents are a major cause of environmental damage and biodiversity loss, particularly on islands. Unlike insects, genetic biocontrol strategies including population-suppressing gene drives with biased inheritance have not been developed in mice. Here, we demonstrate a gene drive strategy (tCRISPR) that leverages super-Mendelian transmission of the t haplotype to spread inactivating mutations in a haplosufficient female fertility gene (Prl). Using spatially explicit individual-based in silico modeling, we show that tCRISPR can eradicate island populations under a range of realistic field-based parameter values. We also engineer transgenic tCRISPR mice that, crucially, exhibit biased transmission of the modified t haplotype and Prl mutations at levels our modeling predicts would be sufficient for eradication. This is an example of a feasible gene drive system for invasive alien rodent population control.

A phase 1 study of triple-targeted therapy with BRAF, MEK, and AKT inhibitors for patients with BRAF-mutated cancers.

BACKGROUND: Aberrant PI3K/AKT signaling in BRAF-mutant cancers contributes to resistance to BRAF inhibitors. The authors examined dual MAPK and PI3K pathway inhibition in patients who had BRAF-mutated solid tumors (ClinicalTrials.gov identifier NCT01902173). METHODS: Patients with BRAF V600E/V600K-mutant solid tumors received oral dabrafenib at 150 mg twice daily with dose escalation of oral uprosertib starting at 50 mg daily, or, in the triplet cohorts, with dose escalation of both oral trametinib starting at 1.5 mg daily and oral uprosertib starting at 25 mg daily. Dose-limiting toxicities (DLTs) were assessed within the first 56 days of treatment. Radiographic responses were assessed at 8-week intervals. RESULTS: Twenty-seven patients (22 evaluable) were enrolled in parallel doublet and triplet cohorts. No DLTs were observed in the doublet cohorts (N = 7). One patient had a DLT at the maximum administered dose of triplet therapy (dabrafenib 150 mg twice daily and trametinib 2 mg daily plus uprosertib 75 mg daily). Three patients in the doublet cohorts had partial responses (including one who had BRAF inhibitor-resistant melanoma). Two patients in the triplet cohorts had a partial response, and one patient had an unconfirmed partial response. Pharmacokinetic data suggested reduced dabrafenib and dabrafenib metabolite exposure in patients who were also exposed to both trametinib and uprosertib, but not in whose who were exposed to uprosertib without trametinib. CONCLUSIONS: Concomitant inhibition of both the MAPK and PI3K-AKT pathways for the treatment of BRAF-mutated cancers was well tolerated, leading to objective responses, but higher level drug-drug interactions affected exposure to dabrafenib and its metabolites.

Estrogenic influences on agonistic behavior in teleost fishes.

Teleost fishes show an extraordinary diversity of sexual patterns, social structures, and sociosexual behaviors. Sex steroid hormones are key modulators of social behaviors in teleosts as in other vertebrates and act on sex steroid receptor-containing brain nuclei that form the evolutionarily conserved vertebrate social behavior network (SBN). Fishes also display important differences relative to tetrapod vertebrates that make them particularly well-suited to study the physiological mechanisms modulating social behavior. Specifically, fishes exhibit high levels of brain aromatization and have what has been proposed to be a lifelong, steroid hormone dependent plasticity in the neural substrates mediating sociosexual behavior. In this review, we examine how estrogenic signaling modulates sociosexual behaviors in teleosts with a particular focus on agonistic behavior. Estrogens have been shown to mediate agonistic behaviors in a broad range of fishes, from sexually monomorphic gonochoristic species to highly dimorphic sex changers with alternate reproductive phenotypes. These similarities across such diverse taxa contribute to a growing body of evidence that estrogens play a crucial role in the modulation of aggression in vertebrates. As analytical techniques and genomic tools rapidly advance, methods such as LC-MS/MS, snRNAseq, and CRISPR-based mutagenesis show great promise to further elucidate the mechanistic basis of estrogenic effects on social behavior in the diverse teleost lineage.

Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia.

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956.

Improved outcomes with "7+3" induction chemotherapy for acute myeloid leukemia over the past four decades: analysis of SWOG trial data.

We have previously shown that complete response (CR) rates and overall survival of patients with acute myeloid leukemia have improved since the 1980s. However, we have not previously evaluated how the length of first CR (CR1) has changed over this time period. To address this, we analyzed 1,247 patients aged 65 or younger randomized to "7+3" arms from five SWOG studies: S8600 (n=530), S9031 (n=98), S9333 (n=57), S0106 (n=301), and S1203 (n=261). We evaluated length of CR1 and survival after relapse from CR1 over the four decades that these studies represent. Both length of CR1 and survival after relapse from CR1 have improved over the last four decades. The relative benefit associated with CR1 and the relative detriment associated with relapse have decreased over this period; while achieving CR1 and relapse from CR1 still have strong prognostic associations with outcomes, the magnitude of the association has decreased over time. Possible explanations for these patterns include higher CR rates with salvage therapies after relapse, more frequent use of hematopoietic cell transplant, and better supportive care.

Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study.

BACKGROUND: Patients with relapsed or refractory large B-cell lymphoma after first-line treatment who are not intended for haematopoietic stem-cell transplantation (HSCT) have poor outcomes and limited treatment options. We assessed the antitumour activity and safety of lisocabtagene maraleucel, an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell product, as second-line treatment in adults with relapsed or refractory large B-cell lymphoma not intended for HSCT. METHODS: PILOT, an open-label, phase 2 trial done at 18 clinical sites in the USA, included adults aged 18 years or older who had relapsed or refractory large B-cell lymphoma and PET-positive disease, had received first-line therapy containing an anthracycline and a CD20-targeted agent, were not intended for HSCT by their physician, and met at least one prespecified transplantation not intended criterion. Patients received lymphodepleting chemotherapy (intravenous fludarabine 30 mg/m2 and intravenous cyclophosphamide 300 mg/m2 daily for 3 days) followed 2-7 days later by two sequential lisocabtagene maraleucel infusions (equal target doses of CD8+ and CD4+ CAR+ T cells for a total target dose of 100 × 106 CAR+ T cells). The primary endpoint was the overall response rate and was assessed in all patients who received lisocabtagene maraleucel and had confirmed PET-positive disease before lisocabtagene maraleucel administration based on an independent review committee according to the Lugano 2014 criteria. Safety was assessed in all patients who received lisocabtagene maraleucel. Patient follow-up is ongoing. This study is registered with ClinicalTrials.gov, NCT03483103. FINDINGS: Between July 26, 2018, and Sept 24, 2021 (data cutoff for the primary analysis), 74 patients underwent leukapheresis and 61 received lisocabtagene maraleucel (efficacy and safety sets); median age was 74 years (IQR 70-78), 24 (39%) patients were women versus 37 (61%) men, and 54 (89%) patients were White. 16 (26%) of 61 patients had an Eastern Cooperative Oncology Group performance status of 2, 33 (54%) had refractory disease, 13 (21%) relapsed within 1 year of first-line therapy, and 15 (25%) relapsed after 12 months of first-line therapy. Median on-study follow-up was 12·3 months (IQR 6·1-18·0). 49 (80% [95% CI 68-89]; p<0·0001) patients had an overall response. The most common grade 3 or worse treatment-emergent adverse events were neutropenia (29 [48%] patients), leukopenia (13 [21%]), and thrombocytopenia (12 [20%]). Lisocabtagene maraleucel-related serious treatment-emergent adverse events were reported in 13 (21%) patients. There were no treatment-related deaths. Cytokine release syndrome occurred in 23 (38%; grade 3 in one) patients and neurological events in 19 (31%; grade 3 in three) patients, with no grade 4 events or deaths. INTERPRETATION: These results support lisocabtagene maraleucel as a potential second-line treatment in patients with large B-cell lymphoma for whom HSCT is not intended. FUNDING: Juno Therapeutics, a Bristol-Myers Squibb company.

Resistance to natural and synthetic gene drive systems.

Scientists are rapidly developing synthetic gene drive elements intended for release into natural populations. These are intended to control or eradicate disease vectors and pests, or to spread useful traits through wild populations for disease control or conservation purposes. However, a crucial problem for gene drives is the evolution of resistance against them, preventing their spread. Understanding the mechanisms by which populations might evolve resistance is essential for engineering effective gene drive systems. This review summarizes our current knowledge of drive resistance in both natural and synthetic gene drives. We explore how insights from naturally occurring and synthetic drive systems can be integrated to improve the design of gene drives, better predict the outcome of releases and understand genomic conflict in general.

Urelumab alone or in combination with rituximab in patients with relapsed or refractory B-cell lymphoma.

Urelumab, a fully human, non-ligand binding, CD137 agonist IgG4 monoclonal antibody, enhances T-cell and natural killer-cell antitumor activity in preclinical models, and may enhance cytotoxic activity of rituximab. Here we report results in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and other B-cell lymphomas, in phase 1 studies evaluating urelumab alone (NCT01471210) or combined with rituximab (NCT01775631). Sixty patients received urelumab (0.3 mg/kg IV Q3W, 8 mg IV Q3W, or 8 mg IV Q6W); 46 received urelumab (0.1 mg/kg, 0.3 mg/kg, or 8 mg IV Q3W) plus rituximab 375 mg/m2 IV QW. The maximum tolerated dose (MTD) of urelumab was determined to be 0.1 mg/kg or 8 mg Q3W after a single event of potential drug-induced liver injury occurred with urelumab 0.3 mg/kg. Treatment-related AEs were reported in 52% (urelumab: grade 3/4, 15%) and 72% (urelumab + rituximab: grade 3/4, 28%); three led to discontinuation (grade 3 increased AST, grade 4 acute hepatitis [urelumab]; one death from sepsis syndrome [urelumab plus rituximab]). Objective response rates/disease control rates were 6%/19% (DLBCL, n = 31), 12%/35% (FL, n = 17), and 17%/42% (other B-cell lymphomas, n = 12) with urelumab and 10%/24% (DLBCL, n = 29) and 35%/71% (FL, n = 17) with urelumab plus rituximab. Durable remissions in heavily pretreated patients were achieved; however, many were observed at doses exceeding the MTD. These data show that urelumab alone or in combination with rituximab demonstrated manageable safety in B-cell lymphoma, but the combination did not enhance clinical activity relative to rituximab alone or other current standard of care.

Female Mimicry by Sneaker Males Has a Transcriptomic Signature in Both the Brain and the Gonad in a Sex-Changing Fish.

Phenotypic plasticity represents an elegant adaptive response of individuals to a change in their environment. Bluehead wrasses (Thalassoma bifasciatum) exhibit astonishing sexual plasticity, including female-to-male sex change and discrete male morphs that differ strikingly in behavior, morphology, and gonadal investment. Using RNA-seq transcriptome profiling, we examined the genes and physiological pathways underlying flexible behavioral and gonadal differences among female, dominant (bourgeois) male, and female-mimic (sneaker) male blueheads. For the first time in any organism, we find that female mimicry by sneaker males has a transcriptional signature in both the brain and the gonad. Sneaker males shared striking similarity in neural gene expression with females, supporting the idea that males with alternative reproductive phenotypes have "female-like brains." Sneaker males also overexpressed neuroplasticity genes, suggesting that their opportunistic reproductive strategy requires a heightened capacity for neuroplasticity. Bourgeois males overexpressed genes associated with socio-sexual behaviors (e.g., isotocin), but also neuroprotective genes and biomarkers of oxidative stress and aging, indicating a hitherto unexplored cost to these males of attaining the reproductively privileged position at the top of the social hierarchy. Our novel comparison of testicular transcriptomes in a fish with male sexual polymorphism associates greater gonadal investment by sneaker males with overexpression of genes involved in cell proliferation and sperm quality control. We propose that morphological female-mimicry by sneaker male teleosts entails pervasive downregulation of androgenesis genes, consistent with low androgen production in males lacking well-developed secondary sexual characters.

Controlling invasive rodents via synthetic gene drive and the role of polyandry.

House mice are a major ecosystem pest, particularly threatening island ecosystems as a non-native invasive species. Rapid advances in synthetic biology offer new avenues to control pest species for biodiversity conservation. Recently, a synthetic sperm-killing gene drive construct called t-Sry has been proposed as a means to eradicate target mouse populations owing to a lack of females. A factor that has received little attention in the discussion surrounding such drive applications is polyandry. Previous research has demonstrated that sperm-killing drivers are extremely damaging to a male's sperm competitive ability. Here, we examine the importance of this effect on the t-Sry system using a theoretical model. We find that polyandry substantially hampers the spread of t-Sry such that release efforts have to be increased three- to sixfold for successful eradication. We discuss the implications of our finding for potential pest control programmes, the risk of drive spread beyond the target population, and the emergence of drive resistance. Our work highlights that a solid understanding of the forces that determine drive dynamics in a natural setting is key for successful drive application, and that exploring the natural diversity of gene drives may inform effective gene drive design.

Rodent gene drives for conservation: opportunities and data needs.

Invasive rodents impact biodiversity, human health and food security worldwide. The biodiversity impacts are particularly significant on islands, which are the primary sites of vertebrate extinctions and where we are reaching the limits of current control technologies. Gene drives may represent an effective approach to this challenge, but knowledge gaps remain in a number of areas. This paper is focused on what is currently known about natural and developing synthetic gene drive systems in mice, some key areas where key knowledge gaps exist, findings in a variety of disciplines relevant to those gaps and a brief consideration of how engagement at the regulatory, stakeholder and community levels can accompany and contribute to this effort. Our primary species focus is the house mouse, Mus musculus, as a genetic model system that is also an important invasive pest. Our primary application focus is the development of gene drive systems intended to reduce reproduction and potentially eliminate invasive rodents from islands. Gene drive technologies in rodents have the potential to produce significant benefits for biodiversity conservation, human health and food security. A broad-based, multidisciplinary approach is necessary to assess this potential in a transparent, effective and responsible manner.

Sexual plasticity: A fishy tale.

Teleost fish exhibit remarkably diverse and plastic patterns of sexual development. One of the most fascinating modes of plasticity is functional sex change, which is widespread in marine fish including species of commercial importance; however, the regulatory mechanisms remain elusive. In this review, we explore such sexual plasticity in fish, using the bluehead wrasse (Thalassoma bifasciatum) as the primary model. Synthesizing current knowledge, we propose that cortisol and key neurochemicals modulate gonadotropin releasing hormone and luteinizing hormone signaling to promote socially controlled sex change in protogynous fish. Future large-scale genomic analyses and systematic comparisons among species, combined with manipulation studies, will likely uncover the common and unique pathways governing this astonishing transformation. Revealing the molecular and neuroendocrine mechanisms underlying sex change in fish will greatly enhance our understanding of vertebrate sex determination and differentiation as well as phenotypic plasticity in response to environmental influences. Mol. Reprod. Dev. 84: 171-194, 2017. © 2016 Wiley Periodicals, Inc.

Characterizing the neurotranscriptomic states in alternative stress coping styles.

BACKGROUND: Animals experience stress in many contexts and often successfully cope. Individuals exhibiting the proactive versus reactive stress coping styles display qualitatively different behavioral and neuroendocrine responses to stressors. The predisposition to exhibiting a particular coping style is due to genetic and environmental factors. In this study we explore the neurotranscriptomic and gene network biases that are associated with differences between zebrafish (Danio rerio) lines selected for proactive and reactive coping styles and reared in a common garden environment. RESULTS: Using RNA-sequencing we quantified the basal transcriptomes from the brains of wild-derived zebrafish lines selectively bred to exhibit the proactive or reactive stress coping style. We identified 1953 genes that differed in baseline gene expression levels. Weighted gene coexpression network analyses identified one gene module associated with line differences. Together with our previous pharmacological experiment, we identified a core set of 62 genes associated with line differences. Gene ontology analyses reveal that many of these core genes are implicated in neurometabolism (e.g. organic acid biosynthetic and fatty acid metabolic processes). CONCLUSIONS: Our results show that proactive and reactive stress coping individuals display distinct basal neurotranscriptomic states. Differences in baseline expression of select genes or regulation of specific gene modules are linked to the magnitude of the behavioral response and the display of a coping style, respectively. Our results expand the molecular mechanisms of stress coping from one focused on the neurotransmitter systems to a more complex system that involves an organism's capability to handle neurometabolic loads and allows for comparisons with other animal taxa to uncover potential conserved mechanisms.

A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia.

This trial tested the safety and efficacy of a regimen consisting of hydroxyurea followed by azacitidine, 75 mg/m(2) for 7 days, and gemtuzumab ozogamicin, 3 mg/m(2) on day 8, in older patients with newly diagnosed acute myeloid leukemia. Those achieving a complete remission received 1 consolidation treatment followed by 4 cycles of azacitidine. The patients were stratified into good-risk (age 60-69 years or performance status 0-1) and poor-risk (age ≥70 years and performance status 2 or 3) groups. Specific efficacy and safety goals were defined as being supportive of further study of the regimen. Eighty-three patients were registered in the good-risk cohort and 59 in poor-risk cohort, with median age of 71 and 75 years, respectively. In the good-risk group, 35 patients (44%) achieved a complete remission. Median relapse-free and overall survivals were 8 and 11 months, respectively. Six patients (8%) died within 30 days of registration. In the poor-risk group, 19 (35%) achieved a complete remission. Median relapse-free and overall survivals were 7 and 11 months, respectively. Seven patients (14%) died early. The results of this trial met predefined goals for efficacy and safety for the poor-risk cohort but not the good-risk group. .

Limited sex-biased neural gene expression patterns across strains in Zebrafish (Danio rerio).

BACKGROUND: Male and female vertebrates typically differ in a range of characteristics, from morphology to physiology to behavior, which are influenced by factors such as the social environment and the internal hormonal and genetic milieu. However, sex differences in gene expression profiles in the brains of vertebrates are only beginning to be understood. Fishes provide a unique complement to studies of sex differences in mammals and birds given that fish show extreme plasticity and lability of sexually dimorphic characters and behaviors during development and even adulthood. Hence, teleost models can give additional insight into sexual differentiation. The goal of this study is to identify neurotranscriptomic mechanisms for sex differences in the brain. RESULTS: In this study we examined whole-brain sex-biased gene expression through RNA-sequencing across four strains of zebrafish. We subsequently conducted systems level analyses by examining gene network dynamics between the sexes using weighted gene coexpression network analysis. Surprisingly, only 61 genes (approximately 0.4% of genes analyzed) showed a significant sex effect across all four strains, and 48 of these differences were male-biased. Several of these genes are associated with steroid hormone biosynthesis. Despite sex differences in a display of stress-related behaviors, basal transcript levels did not predict the intensity of the behavioral display. WGCNA revealed only one module that was significantly associated with sex. Intriguingly, comparing intermodule dynamics between the sexes revealed only moderate preservation. Further we identify sex-specific gene modules. CONCLUSIONS: Despite differences in morphology, physiology, and behavior, there is limited sex-biased neural gene expression in zebrafish. Further, genes found to be sex-biased are associated with hormone biosynthesis, suggesting that sex steroid hormones may be key contributors to sexual behavioral plasticity seen in teleosts. A possible mechanism is through regulating specific brain gene networks.

Righting the mismatch between law, policy and the sexual and reproductive health needs of young people in the Asia-Pacific Region.

The context of sexual relations is changing in the Asia-Pacific. While the age of sexual debut remains the same, young people are generally marrying later and sex outside of marriage is increasing. The first systematic review of how laws and policies govern young people's access to sexual and reproductive health services was conducted in 2013. The study considered >400 national documents and held focus group discussions with >60 young people across three countries in the region. This paper examines the study findings in light of epidemiological data on young people's sexual behaviour and health, exposing a critical mismatch between the onset of sexual activity and laws and policies governing consent (to sex and medical treatment), and the restriction and orientation of services to married persons. An enabling legal and policy environment is an essential foundation for efforts to improve young people's sexual and reproductive health. This paper argues that international guidance and commitments (including the widely ratified Convention on the Rights of the Child) provide a framework for recognising young people's evolving capacity for independent decision-making, including in the realm of sexual and reproductive health. A number of countries in the region are using these frameworks to expand access to services, providing valuable examples for others to build on.

Temperature regulates sex determination and growth in the paralichthid flatfish California halibut.

California halibut (Paralichthys californicus) is a candidate species for aquaculture and stock enhancement. These applications rely on sex control, either to maximize the production of faster growing females or to match sex ratios in the wild. Other paralichthids exhibit temperature-dependent sex determination (TSD), but the presence and pattern of TSD is not well defined in California halibut. Juvenile California halibut were cultured at three distinct temperatures (15°C, 19°C, and 23°C) through the developmental period presumed to be thermosensitive based on findings from congeners. Sex ratios were quantified in each treatment using phenotypic sex identification techniques applied early (molecular biomarkers; 51-100 mm total length [TL]) and late (visual examination of the gonads; ≥100 mm TL) in the juvenile phase. Both techniques indicated similar sex determination trends at each temperature, with overall sex ratios assessed as 49.9% male at 15°C, 74.5% male at 19°C, and 98.2% male at 23°C. Growth rates were highest at 23°C and lowest at 15°C, with intrinsically fast- and slow-growing individuals at all temperatures. At 15°C and 19°C, females comprised a higher proportion among the fast growers than they did among the slow growers. These data show that California halibut exhibit TSD, with temperatures of 19°C and 23°C masculinizing fish while 15°C appears to produce a 1:1 sex ratio. This study will help optimize sex ratios and growth in hatcheries through thermal manipulation. Furthermore, the developed biomolecular tools and identified temperature thresholds will be important in future work to understand the influence of global warming on wild population demographics.

Nanosorbent based on coprecipitation of ZnO in goethite for competitive sorption of Cd(II)-Pb(II) and Cd(II)-Pb(II)-Ni(II) systems.

Amongst the various water pollutants, heavy metal ions require special attention because of their toxic nature and effects on humans and the environment. Preserving natural resources will have positive impacts on living conditions by reducing diseases and water treatment by nanotechnology is effective in solving this problem owing to the properties of nanomaterials. In this study, a goethite nanoparticle was prepared by hydrothermal method, while ZnO/goethite nanocomposite by co-precipitation was developed. The nanoparticles were characterized using Scanning Electron Microscopy (SEM), X-ray Diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR), Transform Electron Microscopy (TEM), Thermogravimetric Differential Thermal Analysis (TGA-DTA), Dynamic Light Scattering (DLS), and Breunner-Emmet-Teller (BET) surface area analysis. The adsorption of Cd(II)-Pb(II) and Cd(II)-Pb(II)-Ni(II) ions systems on ZnO/goethite nanocomposite was investigated in a batch mode. The findings of the study showed that nanoparticles ZnO/goethite composite were mixed of spherical and rod-like shapes. The BET results revealed average particle sizes of 41.11 nm for nanoparticles for ZnO/goethite while TGA/DTA confirmed the stability of the adsorbents. The optimum adsorption capacities of the nanocomposite for Pb(II), Cd(II), and Ni(II) ions from the Pb-Cd-Ni ternary system were 415.5, 195.3, and 87.13 mg g-1, respectively. The adsorption isotherm data fitted well with the Langmuir isotherm model. The study concluded that the nanoparticle adsorbents are efficient for the remediation of toxic pollutants and are, therefore, recommended for wastewater treatment.

A Multicenter Phase II Clinical Trial of Low-Dose Subcutaneous Decitabine in Myelofibrosis.

Myelofibrosis (MF) in the chronic phase is a challenging disease entity to treat, and conventional treatment options are geared towards symptom palliation. In this prospective, multicenter, phase II trial, 21 patients with myelofibrosis (18 chronic-phase, 2 accelerated-phase, 1 blast-phase) were treated with a 10-day schedule of subcutaneous decitabine at 0.3 mg/kg/day. The overall response rate was 33% (95% CI, 15-57), primarily manifested as an improvement in cytopenias. The median duration of response was 7 months (range, 3-44). A high IPSS risk score, high baseline fetal hemoglobin level, and sustained decreases in circulating CD34+ cell counts were associated with response to decitabine. All patients experienced at least one grade 3 or 4 cytopenia. Non-hematologic toxicities were less frequent, with fatigue, anorexia, and hypocalcemia being the most common. Given the lack of effective therapies in myelofibrosis with severe cytopenias, this study supports further investigation into the use of hypomethylating agents as single agents or in combination therapies. NCT00095784.

Behavioral and neurogenomic transcriptome changes in wild-derived zebrafish with fluoxetine treatment.

BACKGROUND: Stress and anxiety-related behaviors are seen in many organisms. Studies have shown that in humans and other animals, treatment with selective serotonin reuptake inhibitors (e.g. fluoxetine) can reduce anxiety and anxiety-related behaviors. The efficacies and side effects, however, can vary between individuals. Fluoxetine can modulate anxiety in a stereospecific manner or with equal efficacy regardless of stereoisomer depending on the mechanism of action (e.g. serotonergic or GABAergic effects). Zebrafish are an emerging and valuable translational model for understanding human health related issues such as anxiety. In this study we present data showing the behavioral and whole brain transcriptome changes with fluoxetine treatment in wild-derived zebrafish and suggest additional molecular mechanisms of this widely-prescribed drug. RESULTS: We used automated behavioral analyses to assess the effects of racemic and stereoisomeric fluoxetine on male wild-derived zebrafish. Both racemic and the individual isomers of fluoxetine reduced anxiety-related behaviors relative to controls and we did not observe stereospecific fluoxetine effects. Using RNA-sequencing of the whole brain, we identified 411 genes showing differential expression with racemic fluoxetine treatment. Several neuropeptides (neuropeptide Y, isotocin, urocortin 3, prolactin) showed consistent expression patterns with the alleviation of stress and anxiety when anxiety-related behavior was reduced with fluoxetine treatment. With gene ontology and KEGG pathway analyses, we identified lipid and amino acid metabolic processes, and steroid biosynthesis among other terms to be over-enriched. CONCLUSION: Our results demonstrate that fluoxetine reduces anxiety-related behaviors in wild-derived zebrafish and alters their neurogenomic state. We identify two biological processes, lipid and amino acid metabolic synthesis that characterize differences in the fluoxetine treated fish. Fluoxetine may be acting on several different molecular pathways to reduce anxiety-related behaviors in wild-derived zebrafish. This study provides data that could help identify common molecular mechanisms of fluoxetine action across animal taxa.