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Relative to other Oregon counties, Klamath County experiences worse air quality due to wildfire smoke, as well as elevated rates of infant mortality and low birthweight. Klamath County Public Health (KCPH) raised concerns that wildfire smoke is a contributor to poor infant health. Thus, we built a multidisciplinary team and designed a community-engaged research (CEnR) project to capture community and individual-level exposure to wildfire smoke contaminants, alongside perinatal health outcomes. Through partnerships, we identified 24 individuals across academic, public health, and community organizations that met five times over three months to develop a study design. We initially used a modified Delphi method, but adjusted our approach to find multidisciplinary areas of agreement across a highly diverse team. Our team used structured meetings, surveys, and iterative feedback to build consensus on a study design. KCPH and our community partners reviewed and approved all proposed activities to ensure community input was integrated. The resultant study, trialed in Klamath County, included the use of environmental, residential, and personal samplers and health surveys with a cohort of pregnant individuals during the wildfire season. We discuss the advantages and challenges of building a multidisciplinary CEnR study in a rural county disproportionately impacted by wildfire smoke and infant mortality.

Dibutyl phthalate (DBP), di-2-ethylhexyl phthalate (DEHP), and benzyl butyl phthalate (BBP) are used in personal and medical care products. In the ovary, antral follicles are essential for steroidogenesis and ovulation. DBP, BBP, and DEHP are known to inhibit mouse antral follicle growth and ovulation in vitro, and associate with decreased antral follicle counts in women. Given that the in vivo effects of a three-phthalate mixture on antral follicles are unknown, we evaluated the effects of a human-relevant mixture of DBP, BBP, and DEHP on ovarian follicles through proteome profiling analysis. Adult CD-1 female mice were fed corn oil (vehicle), or two dose levels of a phthalate mixture based on estimated exposures in general (32 µg/kg/d; PHT 32) and occupationally exposed (500 µg/kg/d; PHT 500) populations for 10 d. Antral follicles (>250 µm) were isolated and subjected to proteome profiling via label-free tandem mass spectrometry. A total of 5,417 antral follicle proteins were detected, of which 194 were differentially abundant between vehicle and PHT 32, and 136 between vehicle and PHT 500. Bioinformatic analysis revealed significantly different responses between the two phthalate doses. Protein abundance differences in the PHT 32 exposure mapped to cytoplasm, mitochondria, and lipid metabolism; whereas those in the PHT 500 exposure mapped to cytoplasm, nucleus, and phosphorylation. When both doses altered proteins mapped to common processes, the associated predicted transcription factors were different. These findings provide novel mechanistic insight into phthalate-associated, ovary-driven reproductive outcomes in women., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The paper analyzes opportunities for integrating Open access resources (Abstract Sifter, US EPA and NTP Toxicity Value and Toxicity Reference [ToxVal/ToxRefDB]) and New Approach Methodologies (NAM) integration into Community Engaged Research (CEnR)., Methods: CompTox Chemicals Dashboard and Integrated Chemical Environment with in vivo ToxVal/ToxRef and NAMs (in vitro) databases are presented in three case studies to show how these resources could be used in Pilot Projects involving Community Engaged Research (CEnR) from the University of California, Davis, Environmental Health Sciences Center., Results: Case #1 developed a novel assay methodology for testing pesticide toxicity. Case #2 involved detection of water contaminants from wildfire ash and Case #3 involved contaminants on Tribal Lands. Abstract Sifter/ToxVal/ToxRefDB regulatory data and NAMs could be used to screen/prioritize risks from exposure to metals, PAHs and PFAS from wildfire ash leached into water and to investigate activities of environmental toxins (e.g., pesticides) on Tribal lands. Open access NAMs and computational tools can apply to detection of sensitive biological activities in potential or known adverse outcome pathways to predict points of departure (POD) for comparison with regulatory values for hazard identification. Open access Systematic Empirical Evaluation of Models or biomonitoring exposures are available for human subpopulations and can be used to determine bioactivity (POD) to exposure ratio to facilitate mitigation., Conclusions: These resources help prioritize chemical toxicity and facilitate regulatory decisions and health protective policies that can aid stakeholders in deciding on needed research. Insights into exposure risks can aid environmental justice and health equity advocates., (© 2024 Wiley Periodicals LLC.)

Camptothesome is a sphingomyelin-conjugated camptothecin (SM-CSS-CPT) nanovesicle that fortified the therapeutic delivery of CPT in diverse cancer types. To mitigate the Camptothesome-induced IDO1 negative feedback mechanism, we had co-encapsulated, indoximod (IND, IDO1 inhibitor) into Camptothesome using doxorubicin-derived IND (DOX-IND). To maximize the therapeutic potential of DOX-IND/Camptothesome, herein, we first dissected the synergistic drug ratio (DOX-IND/SM-CSS-CPT) via systematical in vitro screening. DOX-IND/Camptothesome with optimal drug ratio synchronized in vivo drug delivery with significantly higher tumor uptake compared to free drugs. This optimum DOX-IND/Camptothesome outperformed the combination of Camptothesome, Doxil and IND or other IDO1 inhibitors (BMS-986205 or epacadostat) in treating mice bearing late-stage MC38 tumors, and combination with immune checkpoint blockade (ICB) enabled it to eradicate 60 % of large tumors. Further, this optimized co-delivery Camptothesome beat Folfox and Folfiri, two first-line combination chemotherapies for colorectal cancer in antitumor efficacy and exhibited no side effects as compared to the severe systemic toxicities associated with Folfox and Folfiri. Finally, we demonstrated that the synergistic DOX-IND/Camptothesome was superior to the combined use of Onivyde + Doxil + IND in curbing the advanced orthotopic CT26-Luc tumors and eliminated 40 % tumors with complete metastasis remission when cooperated with ICB, eliciting stronger anti-CRC immune responses and greater reversal of immunosuppression. These results corroborated that with precise optimal synergistic drug ratio, the therapeutic potential of DOX-IND/Camptothesome can be fully unleased, which warrants further clinical investigation to benefit the cancer patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jianqin Lu has patent Immunogenic Nanovesicles for Cancer Immunotherapy pending to New International Patent Application No. PCT/US2021/060642., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cement is the most widely used construction material due to its strength and affordability, but its production is energy intensive. Thus, the need to replace cement with widely available waste material such as incinerated black filter cake (IBFC) in order to reduce energy consumption and the associated CO 2 emissions. However, because IBFC is a newly discovered cement replacement material, several parameters affecting the mechanical properties of IBFC-cement composite have not been thoroughly investigated yet. Thus, this work aims to investigate the impact of IBFC as a cement replacement and the addition of the calcifying bacterium Lysinibacillus sp. WH on the mechanical and self-healing properties of IBFC cement pastes. The properties of the IBFC-cement pastes were assessed by determining compressive strength, permeable void, water absorption, cement hydration product, and self-healing property. Increases in IBFC replacement reduced the durability of the cement pastes. The addition of the strain WH to IBFC cement pastes, resulting in biocement, increased the strength of the IBFC-cement composite. A 20% IBFC cement-replacement was determined to be the ideal ratio for producing biocement in this study, with a lower void percentage and water absorption value. Adding strain WH decreases pore sizes, densifies the matrix in ≤ 20% IBFC biocement, and enhances the formation of calcium silicate hydrate (C-S-H) and AFm ettringite phases. Biogenic CaCO 3 and C-S-H significantly increase IBFC composite strength, especially at ≤ 20% IBFC replacement. Moreover, IBFC-cement composites with strain WH exhibit self-healing properties, with bacteria precipitating CaCO 3 crystals to bridge cracks within two weeks. Overall, this work provides an approach to produce a "green/sustainable" cement using biologically enabled self-healing characteristics., (© 2024. The Author(s).)

Inflammatory bowel disease (IBD) is one of the most prevalent chronic inflammations of the gastrointestinal tract (GIT). The gut microbial population, the cytokine milieu, the aryl hydrocarbon receptor (AHR) expressed by immune and nonimmune cells and the intrinsic pathway of Th-cell differentiation are implicated in the immunopathology of IBD. AHR activation requires a delicate balance between regulatory and effector T-cells; loss of this balance can cause local gut microbial dysbiosis and intestinal inflammation. Thus, the study of the gut microbiome in association with AHR provides critical insights into IBD pathogenesis and interventions. This review will focus on the recent advancements to form conceptional frameworks on the benefits of AHR activation by commensal gut bacteria in IBD.

Cholesterol (Chol) fortifies packing and reduces fluidity and permeability of the lipid bilayer in vesicles (liposomes)-mediated drug delivery. However, under the physiological environment, Chol is rapidly extracted from the lipid bilayer by biomembranes, which jeopardizes membrane stability and results in premature leakage for delivered payloads, yielding suboptimal clinic efficacy. Herein, we report a Chol-modified sphingomyelin (SM) lipid bilayer via covalently conjugating Chol to SM (SM-Chol), which retains membrane condensing ability of Chol. Systemic structure activity relationship screening demonstrates that SM-Chol with a disulfide bond and longer linker outperforms other counterparts and conventional phospholipids/Chol mixture systems on blocking Chol transfer and payload leakage, increases maximum tolerated dose of vincristine while reducing systemic toxicities, improves pharmacokinetics and tumor delivery efficiency, and enhances antitumor efficacy in SU-DHL-4 diffuse large B-cell lymphoma xenograft model in female mice. Furthermore, SM-Chol improves therapeutic delivery of structurally diversified therapeutic agents (irinotecan, doxorubicin, dexamethasone) or siRNA targeting multi-drug resistant gene (p-glycoprotein) in late-stage metastatic orthotopic KPC-Luc pancreas cancer, 4T1-Luc2 triple negative breast cancer, lung inflammation, and CT26 colorectal cancer animal models in female mice compared to respective FDA-approved nanotherapeutics or lipid compositions. Thus, SM-Chol represents a promising platform for universal and improved drug delivery., (© 2024. The Author(s).)

Embryonic zebrafish represent a useful test system to screen substances for their ability to perturb development. The exposure scenarios, endpoints captured, and data analysis vary among the laboratories who conduct screening. A lack of harmonization impedes the comparison of the substance potency and toxicity outcomes across laboratories and may hinder the broader adoption of this model for regulatory use. The Systematic Evaluation of the Application of Zebrafish in Toxicology (SEAZIT) initiative was developed to investigate the sources of variability in toxicity testing. This initiative involved an interlaboratory study to determine whether experimental parameters altered the developmental toxicity of a set of 42 substances (3 tested in duplicate) in three diverse laboratories. An initial dose-range-finding study using in-house protocols was followed by a definitive study using four experimental conditions: chorion-on and chorion-off using both static and static renewal exposures. We observed reasonable agreement across the three laboratories as 33 of 42 test substances (78.6%) had the same activity call. However, the differences in potency seen using variable in-house protocols emphasizes the importance of harmonization of the exposure variables under evaluation in the second phase of this study. The outcome of the Def will facilitate future practical discussions on harmonization within the zebrafish research community.

Over the past several decades, liposomes have been extensively developed and used for various clinical applications such as in pharmaceutical, cosmetic, and dietetic fields, due to its versatility, biocompatibility, and biodegradability, as well as the ability to enhance the therapeutic index of free drugs. However, some challenges remain unsolved, including liposome premature leakage, manufacturing irreproducibility, and limited translation success. This article reviews various aspects of liposomes, including its advantages, major compositions, and common preparation techniques, and discusses present U.S. FDA-approved, clinical, and preclinical liposomal nanotherapeutics for treating and preventing a variety of human diseases. In addition, we summarize the significance of and challenges in liposome-enabled nanotherapeutic development and hope it provides the fundamental knowledge and concepts about liposomes and their applications and contributions in contemporary pharmaceutical advancement.

Epacadostat (EPA), the most advanced IDO1 inhibitor, in combination with PD-1 checkpoint inhibitor, has failed in a recent Phase III clinical trial for treating metastatic melanoma. Here we report an EPA nanovesicle therapeutic platform (Epacasome) based on chemically attaching EPA to sphingomyelin via an oxime-ester bond highly responsive to hydrolase cleavage. Via clathrin-mediated endocytosis, Epacasome displays higher cellular uptake and enhances IDO1 inhibition and T cell proliferation compared to free EPA. Epacasome shows improved pharmacokinetics and tumour accumulation with efficient intratumoural drug release and deep tumour penetration. Additionally, it outperforms free EPA for anticancer efficacy, potentiating PD-1 blockade with boosted cytotoxic T lymphocytes (CTLs) and reduced regulatory T cells and myeloid-derived suppressor cells responses in a B16-F10 melanoma model in female mice. By co-encapsulating immunogenic dacarbazine, Epacasome further enhances anti-tumor effects and immune responses through the upregulation of NKG2D-mediated CTLs and natural killer cells responses particularly when combined with the PD-1 inhibitor in the late-stage metastatic B16-F10-Luc2 model in female mice. Furthermore, this combination prevents tumour recurrence and prolongs mouse survival in a clinically relevant, post-surgical melanoma model in female mice. Epacasome demonstrates potential to synergize with PD-1 blockade for improved response to melanoma immunotherapy., (© 2023. The Author(s).)

Introduction: Cleaning protocols were changed in response to the COVID-19 pandemic with unknown occupational health impacts. There is evidence that COVID-19 transmission risks from contaminated surfaces are low and that exposure to cleaning products can increase risks of work-related asthma. The study objective was to investigate relationships between reported COVID-19-related changes in cleaning protocols and prevalence of asthma-related respiratory symptoms for asthmatic and non-asthmatic janitors and maids. A secondary objective was to characterize experiences of respiratory symptoms associated with cleaning and barriers to personal protective equipment (PPE) use., Methods: Employees from two Tucson-based maid service companies (approximately 30 personnel in total) and one Phoenix-based school district (>300 janitors/custodians) were invited to participate in a written survey and/or a one-on-one interview in Spanish or English. Fisher's exact tests ( α  = 0.05) were used to test for statistically significant associations between reported respiratory symptoms by self-reported physician-diagnosed asthma status and changes in cleaning protocols. Interviews were transcribed and then analyzed by at least two researchers in English or Spanish., Results: Eighty-three percent reported that cleaning protocols had changed during COVID-19, with the two most reported changes including increased cleaning frequency (92%) and change of application type (e.g., fog, spray, wipe) (53%). There was a statistically significant association between multiple respiratory symptoms and self-reported physician diagnosed asthma. Reporting a type of application change (e.g., fog, spray, wipe) and being awakened during the night by attack/episode of cough were statistically significantly associated ( p  = 0.04). Interviews elucidated respiratory issues related to fogging devices., Discussion: This study provides preliminary evidence that changes in cleaning and disinfection protocols during COVID-19 (namely, the use of fogging/mechanical spraying devices) may have had negative impacts on the health of workers in the cleaning industry with little benefit to reducing COVID-19 risks. Further research is needed to evaluate the generalizability of our findings across larger geographical areas and to develop guidance for employers and employees on how to protect and promote respiratory health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wilson, Jung, Mooneyham, Klymko, Eck, Romo, Vaidyula, Sneed, Gerald and Beamer.)

Neurodegenerative diseases are posing pressing health issues due to the high prevalence among aging populations in the 21st century. They are evidenced by the progressive loss of neuronal function, often associated with neuronal necrosis and many related devastating complications. Nevertheless, effective therapeutical strategies to treat neurodegenerative diseases remain a tremendous challenge due to the multisystemic nature and limited drug delivery to the central nervous system. As a result, there is a pressing need to develop effective alternative therapeutics to manage the progression of neurodegenerative diseases. By utilizing the functional reconstructive materials and technologies with specific targeting ability at the nanoscale level, nanotechnology-empowered medicines can transform the therapeutic paradigms of neurodegenerative diseases with minimal systemic side effects. This review outlines the current applications and progresses of the nanotechnology-enabled drug delivery systems to enhance the therapeutic efficacy in treating neurodegenerative diseases. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies., (© 2023 Wiley Periodicals LLC.)

Phthalates are compounds used in consumer and medical products worldwide. Phthalate exposure in women has been demonstrated by detection of phthalate metabolites in their urine and ovarian follicular fluid. High urinary phthalate burden has been associated with reduced ovarian reserve and oocyte retrieval in women undergoing assisted reproduction. Unfortunately, no mechanistic explanation for these associations is available. In short term in vivo and in vitro animal studies modeling human-relevant exposures to di-n-butyl phthalate (DBP), we have identified ovarian folliculogenesis as a target for phthalate exposures. In the present study, we investigated whether DBP exposure negatively influences insulin-like growth factor 1 (IGF1) signaling in the ovary and disrupts ovarian folliculogenesis. CD-1 female mice were exposed to corn oil (vehicle) or DBP (10 µg/kg/day, 100 µg/kg/day, or 1000 mg/kg/day) for 20-32 days. Ovaries were collected as animals reached the proestrus stage to achieve estrous cycle synchronization. Levels of mRNAs encoding IGF1 and 2 (Igf1 and Igf2), IGF1 receptor (Igf1r), and IGF-binding proteins 1-6 (Ifgbp1-6) were measured in whole ovary homogenates. Ovarian follicle counts and immunostaining for phosphorylated IGF1R protein (pIGF1R) were used to evaluate folliculogenesis and IGF1R activation, respectively. DBP exposure, at a realistic dose that some women may experience (100 µg/kg/day for 20-32 days), reduced ovarian Igf1 and Igf1r mRNA expression and reduced small ovarian follicle numbers and primary follicle pIGF1R positivity in DBP-treated mice. These findings reveal that DBP tampers with the ovarian IGF1 system and provide molecular insight into how phthalates could influence the ovarian reserve in females., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cyanobacterial harmful algal blooms (CyanoHABs) originate from the excessive growth or bloom of cyanobacteria often referred to as blue-green algae. They have been on the rise globally in both marine and freshwaters in recently years with increasing frequency and severity owing to the rising temperature associated with climate change and increasing anthropogenic eutrophication from agricultural runoff and urbanization. Humans are at a great risk of exposure to toxins released from CyanoHABs through drinking water, food, and recreational activities, making CyanoHAB toxins a new class of contaminants of emerging concern., Objectives: We investigated the toxic effects and mechanisms of microcystin-LR (MC-LR), the most prevalent CyanoHAB toxin, on the ovary and associated reproductive functions., Methods: Mouse models with either chronic daily oral or acute intraperitoneal exposure, an engineered three-dimensional ovarian follicle culture system, and human primary ovarian granulosa cells were tested with MC-LR of various dose levels. Single-follicle RNA sequencing, reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, immunohistochemistry (IHC), and benchmark dose modeling were used to examine the effects of MC-LR on follicle maturation, hormone secretion, ovulation, and luteinization., Results: Mice exposed long term to low-dose MC-LR did not exhibit any differences in the kinetics of folliculogenesis, but they had significantly fewer corpora lutea compared with control mice. Superovulation models further showed that mice exposed to MC-LR during the follicle maturation window had significantly fewer ovulated oocytes. IHC results revealed ovarian distribution of MC-LR, and mice exposed to MC-LR had significantly lower expression of key follicle maturation mediators. Mechanistically, in both murine and human granulosa cells exposed to MC-LR, there was reduced protein phosphatase 1 (PP1) activity, disrupted PP1-mediated PI3K/AKT/FOXO1 signaling, and less expression of follicle maturation-related genes., Discussion: Using both in vivo and in vitro murine and human model systems, we provide data suggesting that environmentally relevant exposure to the CyanoHAB toxin MC-LR interfered with gonadotropin-dependent follicle maturation and ovulation. We conclude that MC-LR may pose a nonnegligible risk to women's reproductive health by heightening the probability of irregular menstrual cycles and infertility related to ovulatory disorders. https://doi.org/10.1289/EHP12034.

Muscle wasting occurs with aging and may be a result of oxidative stress damage and potentially inadequate protection by lipophilic antioxidants, such as vitamin E. Previous studies have shown muscular abnormalities and behavioral defects in vitamin E-deficient adult zebrafish. To test the hypothesis that there is an interaction between muscle degeneration caused by aging and oxidative damage caused by vitamin E deficiency, we evaluated long-term vitamin E deficiency in the skeletal muscle of aging zebrafish using metabolomics. Zebrafish (55 days old) were fed E+ and E- diets for 12 or 18 months. Then, skeletal muscle samples were analyzed using UPLC-MS/MS. Data were analyzed to highlight metabolite and pathway changes seen with either aging or vitamin E status or both. We found that aging altered purines, various amino acids, and DHA-containing phospholipids. Vitamin E deficiency at 18 months was associated with changes in amino acid metabolism, specifically tryptophan pathways, systemic changes in the regulation of purine metabolism, and DHA-containing phospholipids. In sum, while both aging and induced vitamin E deficiency did have some overlap in altered and potentially dysregulated metabolic pathways, each factor also presented unique alterations, which require further study with more confirmatory approaches.

Autism spectrum disorder (ASD) comprises a heterogeneous group of neurodevelopmental outcomes in children with a commonality in deficits in social communication and language combined with repetitive behaviors and interests. The etiology of ASD is heterogeneous, as several hundred genes have been implicated as well as multiple in utero environmental exposures. Over the past two decades, epigenetic investigations, including DNA methylation, have emerged as a novel way to capture the complex interface of multivariate ASD etiologies. More recently, epigenome-wide association studies using human brain and surrogate accessible tissues have revealed some convergent genes that are epigenetically altered in ASD, many of which overlap with known genetic risk factors. Unlike transcriptomes, epigenomic signatures defined by DNA methylation from surrogate tissues such as placenta and cord blood can reflect past differences in fetal brain gene transcription, transcription factor binding, and chromatin. For example, the discovery of NHIP (neuronal hypoxia inducible, placenta associated) through an epigenome-wide association in placenta, identified a common genetic risk for ASD that was modified by prenatal vitamin use. While epigenomic signatures are distinct between different genetic syndromic causes of ASD, bivalent chromatin and some convergent gene pathways are consistently epigenetically altered in both syndromic and idiopathic ASD, as well as some environmental exposures. Together, these epigenomic signatures hold promising clues towards improved early prediction and prevention of ASD as well genes and gene pathways to target for pharmacological interventions. Future advancements in single cell and multi-omic technologies, machine learning, as well as non-invasive screening of epigenomic signatures during pregnancy or newborn periods are expected to continue to impact the translatability of the recent discoveries in epigenomics to precision public health., (© 2022. The Author(s).)

Introduction: Despite gene therapy is ideal for genetic abnormality-related diseases, the easy degradation, poor targeting, and inefficiency in entering targeted cells are plaguing the effective delivery of gene therapy. Viral and non-viral vectors have been used for delivering gene therapeutics in vivo by safeguarding nucleic acid agents to target cells and to reach the specific intracellular location. A variety of nanotechnology-enabled safe and efficient systems have been successfully developed to improve the targeting ability for effective therapeutic delivery of genetic drugs., Areas Covered: In this review, we outline the multiple biological barriers associated with gene delivery process, and highlight recent advances to gene therapy strategy in vivo, including gene correction, gene silencing, gene activation and genome editing. We point out current developments and challenges exist of non-viral and viral vector systems in association with chemical and physical gene delivery technologies and their potential for the future., Expert Opinion: This review focuses on the opportunities and challenges to various gene therapy strategy, with specific emphasis on overcoming the challenges through the development of biocompatibility and smart gene vectors for potential clinical application.

Tumor immunotherapy has revolutionized the field of oncology treatments in recent years. As one of the promising strategies of cancer immunotherapy, tumor immunogenic cell death (ICD) has shown significant potential for tumor therapy. Nanoparticles are widely used for drug delivery due to their versatile characteristics, such as stability, slow blood elimination, and tumor-targeting ability. To increase the specificity of ICD inducers and improve the efficiency of ICD induction, functionally specific nanoparticles, such as liposomes, nanostructured lipid carriers, micelles, nanodiscs, biomembrane-coated nanoparticles and inorganic nanoparticles have been widely reported as the vehicles to deliver ICD inducers in vivo. In this review, we summarized the strategies of different nanoparticles for ICD-induced cancer immunotherapy, and systematically discussed their advantages and disadvantages as well as provided feasible strategies for solving these problems. We believe that this review will offer some insights into the design of effective nanoparticulate systems for the therapeutic delivery of ICD inducers, thus, promoting the development of ICD-mediated cancer immunotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Excretion of toxicants accumulated from firefighter exposures through breastmilk represents a potential hazard. We investigated if firefighting exposures could increase the concentration of polybrominated diphenyl ethers (PBDEs) and aryl hydrocarbon receptor (AhR) activation in excreted breastmilk. Firefighters and non-firefighters collected breastmilk samples prior to any firefighting responses (baseline) and at 2, 8, 24, 48, and 72 hours after a structural fire (firefighters only). Five PBDE analytes (BDEs 15, 28, 47, 99, and 153) detected in at least 90% of samples were summed for analyses. The AhR in vitro DR CALUX® bioassay assessed the mixture of dioxin-like compounds and toxicity from breastmilk extracts. Baseline PBDEs and AhR response were compared between firefighters and non-firefighters. Separate linear mixed models assessed changes in sum of PBDEs and AhR response among firefighters over time and effect modification by interior or exterior response was assessed. Baseline PBDE concentrations and AhR responses did not differ between the 21 firefighters and 10 non-firefighters. There were no significant changes in sum of PBDEs or AhR response among firefighters over time post-fire, and no variation by interior or exterior response. Plots of sum of PBDEs and AhR response over time demonstrated individual variation but no consistent pattern. Currently, our novel study results do not support forgoing breastfeeding after a fire exposure. However, given study limitations and the potential hazard of accumulated toxicants from firefighter exposures excreted via breastfeeding, future studies should consider additional contaminants and measures of toxicity by which firefighting may impact maternal and child health., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology.)

During an episode of acute kidney injury (AKI), a sudden and rapid decline in renal function is often accompanied by a persistent reduction in mitochondrial function, microvasculature dysfunction/rarefaction, and tubular epithelial injury/necrosis. Additionally, patients who have experienced an AKI are at an elevated risk of developing other progressive renal, cardiovascular, and cardiorenal related diseases. While restoration of the microvasculature is imperative for oxygen and nutrient delivery/transport during proper renal repair processes, the mechanism(s) by which neovascularization and/or inhibition of microvascular dysfunction improves renal recovery remain understudied. Interestingly, pharmacological stimulation of mitochondrial biogenesis (MB) post-AKI has been shown to restore mitochondrial and renal function in mice. Thus, targeting MB pathways in microvasculature endothelial cell (MV-EC) may provide a novel strategy to improve renal vascular function and repair processes post-AKI. However, limitations to studying such mechanisms include a lack of commercially available primary renal peritubular MV-ECs, the variability in both purity and outgrowth of primary renal MV-EC in monoculture, the tendency of primary renal MV-ECs to undergo phenotypic loss in primary monoculture, and a limited quantity of published protocols to obtain primary renal peritubular MV-ECs. Thus, we focused on refining the isolation and phenotypic retention of mouse renal peritubular endothelial cells (MRPEC) for future physiological and pharmacological based studies. Here, we present a refined isolation method that augments the purity, outgrowth, and phenotypic retention of primary MRPEC monocultures by utilizing a collagenase type I enzymatic digestion, CD326+ (EPCAM) magnetic microbead epithelial cell depletion, and two CD146+ (MCAM) magnetic microbead purification cycles to achieve a monoculture MRPEC purity of ≅ 91-99% by all markers evaluated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Thompson, Janda and Schnellmann.)

In this study, we focus on investigating the therapeutic effects of camptothesome on treating metastatic triple-negative breast cancer (TNBC). We elucidate that camptothesome elicited stronger immunogenic cell death (ICD) compared to free camptothecin (CPT) and Onivyde in 4T1 TNBC cells. In addition, camptothesome is mainly internalized by the 4T1 and MDA-MB-231 cells through clathrin-mediated endocytosis based on the results of flow cytometry. Through real-time Lago optical imaging, camptothesome shows excellent tumor-targeting efficiency in orthotopic TNBC tumors. We demonstrate that camptothesome can upregulate programmed death-ligand 1 (PD-L1) in 4T1 tumors in an interferon gamma (IFN-γ)-dependent manner. Furthermore, the anti-TNBC efficacy studies reveal that camptothesome is superior to Onivyde and markedly potentiates PD-L1 immune checkpoint blockade therapy with complete lung metastasis remission in an orthotopic 4T1-Luc2 tumor model. This combination therapy eliciting robust cytotoxic T lymphocytes (CTL) response via boosting tumor-infiltrating cluster of differentiation 8 (CD8), calreticulin (CRT), high mobility group box 1 protein (HMGB-1), low-density lipoprotein receptor-related protein 1 (LRP1), IFN-γ, and granzyme B. Our work corroborates the promise of camptothesome in favorably modulating tumor immune microenvironment via inducing ICD to fortify the PD-L1 checkpoint blockade therapy for improved treatment of intractable TNBC.

Atherosclerosis is a chronic and metabolic-related disease that is a serious threat to human health. Currently available diagnostic and therapeutic measures for atherosclerosis lack adequate efficiency which requires promising alternative approaches. Nanotechnology-based nano-delivery systems allow for new perspectives for atherosclerosis therapy. Surface-modified nanoparticles could achieve highly effective therapeutic effects by binding to specific receptors that are abnormally overexpressed in atherosclerosis, with less adverse effects on non-target tissues. The main purpose of this review is to summarize the research progress and design ideas to target atherosclerosis using a variety of ligand-modified nanoparticle systems, discuss the shortcomings of current vector design, and look at future development directions. We hope that this review will provide novel research strategies for the design and development of nanotherapeutics targeting atherosclerosis.

Camptothesome is an innovative nanovesicle therapeutic comprising the sphingomyelin-derived camptothecin (CPT) lipid bilayer. In this work, we deciphered that Camptothesome was taken up by colorectal cancer (CRC) cells through primarily the clathrin-mediated endocytotic pathway and displayed the potential of eliciting robust immunogenic cancer cell death (ICD) via upregulating calreticulin, high mobility group box 1 protein (HMGB-1), and adenosine triphosphate (ATP), three hallmarks involved in the induction of ICD. In addition, use of dying MC38 tumor cells treated with Camptothesome as vaccine prevented tumor growth in 60% mice that received subsequent injection of live MC38 cells on the contralateral flank, validating Camptothesome was a legitimate ICD inducer in vivo. Camptothesome markedly reduced the acute bone marrow toxicity and gastrointestinal mucositis associated with free CPT and beat free CPT and Onivyde on anti-CRC efficacy and immune responses in a partially interferon gamma (IFN-γ)-dependent manner. Furthermore, Camptothesome enhanced the efficacy of immune checkpoint inhibitors to shrink late-stage orthotopic MC38 CRC tumors with diminished tumor metastasis and markedly prolonged mice survival., Competing Interests: Declaration of Competing Interest J.L. has applied for patents related to Camptothesome technology. The other authors have no competing interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Environmental exposures to endocrine disrupting compounds (EDCs) such as the organochlorines have been linked with various diseases including neurodevelopmental disorders. Autism spectrum disorder (ASD) is a highly complex neurodevelopmental disorder that is considered strongly genetic in origin due to its high heritability. However, the rapidly rising prevalence of ASD suggests that environmental factors may also influence risk for ASD. In the present study, whole genome bisulfite sequencing was used to identify genome-wide differentially methylated regions (DMRs) in a total of 52 sperm samples from a cohort of men from the Faroe Islands (Denmark) who were equally divided into high and low exposure groups based on their serum levels of the long-lived organochlorine 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), a primary breakdown product of the now banned insecticide dichlorodiphenyltrichloroethane (DDT). Aside from being considered a genetic isolate, inhabitants of the Faroe Islands have a native diet that potentially exposes them to a wide range of seafood neurotoxicants in the form of persistent organic pollutants (POPs). The DMRs were mapped to the human genome using Bismark, a 3-letter aligner used for methyl-seq analyses. Gene ontology, functional, and pathway analyses of the DMR-associated genes showed significant enrichment for genes involved in neurological functions and neurodevelopmental processes frequently impacted by ASD. Notably, these genes also significantly overlap with autism risk genes as well as those previously identified in sperm from fathers of children with ASD in comparison to that of fathers of neurotypical children. These results collectively suggest a possible mechanism involving altered methylation of a significant number of neurologically relevant ASD risk genes for introducing epigenetic changes associated with environmental exposures into the sperm methylome. Such changes may provide the potential for transgenerational inheritance of ASD as well as other disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Maggio, Shu, Laufer, Bi, Lai, LaSalle and Hu.)

Per- and polyfluoroalkyl substances (PFAS) are a class of widely used chemicals with limited human health effects data relative to the diversity of structures manufactured. To help fill this data gap, an extensive in vivo developmental toxicity screen was performed on 139 PFAS provided by the US EPA. Dechorionated embryonic zebrafish were exposed to 10 nominal water concentrations of PFAS (0.015-100 µM) from 6 to 120 h post-fertilization (hpf). The embryos were assayed for embryonic photomotor response (EPR), larval photomotor response (LPR), and 13 morphological endpoints. A total of 49 PFAS (35%) were bioactive in one or more assays (11 altered EPR, 25 altered LPR, and 31 altered morphology). Perfluorooctanesulfonamide (FOSA) was the only structure that was bioactive in all 3 assays, while Perfluorodecanoic acid (PFDA) was the most potent teratogen. Low PFAS volatility was associated with developmental toxicity (p < 0.01), but no association was detected between bioactivity and five other physicochemical parameters. The bioactive PFAS were enriched for 6 supergroup chemotypes. The results illustrate the power of a multi-dimensional in vivo platform to assess the developmental (neuro)toxicity of diverse PFAS and in the acceleration of PFAS safety research., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Messages and materials developed to communicate risk to the public are often misunderstood because the public misperceives risk, science information is too complex, leading to audience misunderstandings, and an overarching focus on the details of the problem without supplying solutions or actions to keep the public safe. This article describes the creation of a communication model to improve risk communication that includes safety information. The authors describe essential components of Risk and Safety Communication based on features of Environmental Health Literacy (EHL), which informed the creation of a protocol for developing risk communication messages and materials. An online training module was developed to aid communicators in creating information to enable the public to protect themselves, their family, and their community, leading to improved comprehension of how the environment impacts health. These principles were developed in a series of focus groups, identifying how the public perceives risk, how they prefer to receive communication, and how participants respond to materials developed using the principles. Important topics discussed are understanding the literacy levels of the target audience, applying that understanding to developing messages, how risk perception leads to misperceptions and how to address those misperceptions by using plain language when developing focused messages and materials.

The etiology of autism spectrum disorders (ASD) is complex, involving different combinations of genetic and environmental factors. My lab's approach has been to investigate DNA methylation as a tractable genome-wide modification at the interface of these complex interactions, reflecting past and future events in the molecular pathogenesis of ASD. Since X-linked genes were enriched in DNA methylation differences discovered from cord blood from newborns later diagnosed with ASD, this has prompted me to review and revisit the recent advancements in the field of X chromosome inactivation (XCI), particularly in humans and other primates. In this Perspective, I compare XCI mechanisms in different mammalian species, including the finding of the noncoding transcript XACT associated with X chromosome erosion in human pluripotent stem cells and recent findings from non-human primate post-implantation embryos. I focus on the experimentally challenging peri- and post-implantation stages of human development when the timing of XCI is prolonged and imprecise in humans. Collectively, this research has raised some important unanswered questions involving biased sex ratios in human births and the male bias in the incidence of ASD., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 LaSalle.)

Competing Interests: The author declares no competing interests.

Rationale: Enhanced proliferation and distal migration of human pulmonary arterial smooth muscle cells (hPASMCs) both contribute to the progressive increases in pulmonary vascular remodeling and resistance in pulmonary arterial hypertension (PAH). Our previous studies revealed that Rictor deletion, to disrupt mTOR Complex 2 (mTORC2), over longer periods result in a paradoxical rise in platelet-derived growth factor receptor (PDGFR) expression in PASMCs. Thus, the purpose of this study was to evaluate the role of combination therapy targeting both mTOR signaling with PDGFR inhibition to attenuate the development and progression of PAH. Methods and Results: Immunoblotting analyses revealed that short-term exposure to rapamycin (6h) significantly reduced phosphorylation of p70S6K (mTORC1-specific) in hPASMCs but had no effect on the phosphorylation of AKT (p-AKT S473, considered mTORC2-specific). In contrast, longer rapamycin exposure (>24 h), resulted in differential AKT (T308) and AKT (S473) phosphorylation with increases in phosphorylation of AKT at T308 and decreased phosphorylation at S473. Phosphorylation of both PDGFRα and PDGFRβ was increased in hPASMCs after treatment with rapamycin for 48 and 72 h. Based on co-immunoprecipitation studies, longer exposure to rapamycin (24-72 h) significantly inhibited the binding of mTOR to Rictor, mechanistically suggesting mTORC2 inhibition by rapamycin. Combined exposure of rapamycin with the PDGFR inhibitor, imatinib significantly reduced the proliferation and migration of hPASMCs compared to either agent alone. Pre-clinical studies validated increased therapeutic efficacy of rapamycin combined with imatinib in attenuating PAH over either drug alone. Specifically, combination therapy further attenuated the development of monocrotaline (MCT)- or Hypoxia/Sugen-induced pulmonary hypertension (PH) in rats as demonstrated by further reductions in the Fulton index, right ventricular systolic pressure (RVSP), pulmonary vascular wall thickness and vessel muscularization, and decreased proliferating cell nuclear antigen (PCNA) staining in PASMCs. Conclusion: Prolonged rapamycin treatment activates PDGFR signaling, in part, via mTORC2 inhibition. Combination therapy with rapamycin and imatinib may be a more effective strategy for the treatment of PAH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shi, Gu, Zhao, Jia, Bao, Luo, Guo, Han, Wang, Black, Desai and Tang.)

"Environmental Health Literacy" (EHL) is embraced as important for improving public health by preventing disability and disease from our environment. This study aimed to determine knowledge and skill items identified by Environmental Health (EH) professionals as being associated with EHL and to understand how these items rank by importance. Such a coordinated effort to tease out skills and knowledge needed for EHL had not previously been made. We utilized a mixed-methods approach of semi-structured interviews of 24 EH professionals and a quantitative survey with 275 EH professionals across the United States. Interviews identified 37 skill and 69 knowledge items, which were used to create the survey questions. Survey results indicate 32 knowledge items and six skill items considered essential by >50% of respondents where consensus was reached between professional groups (chi square test: p > 0.05). We further identified six knowledge items, which >70% of EH professionals agreed were essential for EHL. The identification of these knowledge and skill items sets the stage for further research that includes exploring agreement with more diverse stakeholders, developing comprehensive measures of EHL and evaluation of methods and materials designed to improve EHL.

Despite the enormous therapeutic potential of immune checkpoint blockade (ICB), it benefits only a small subset of patients. Some chemotherapeutics can switch 'immune-cold' tumours to 'immune-hot' to synergize with ICB. However, safe and universal therapeutic platforms implementing such immune effects remain scarce. We demonstrate that sphingomyelin-derived camptothecin nanovesicles (camptothesomes) elicit potent granzyme-B- and perforin-mediated cytotoxic T lymphocyte (CTL) responses, potentiating PD-L1/PD-1 co-blockade to eradicate subcutaneous MC38 adenocarcinoma with developed memory immunity. In addition, camptothesomes improve the pharmacokinetics and lactone stability of camptothecin, avoid systemic toxicities, penetrate deeply into the tumour and outperform the antitumour efficacy of Onivyde. Camptothesome co-load the indoleamine 2,3-dioxygenase inhibitor indoximod into its interior using the lipid-bilayer-crossing capability of the immunogenic cell death inducer doxorubicin, eliminating clinically relevant advanced orthotopic CT26-Luc tumours and late-stage B16-F10-Luc2 melanoma, and achieving complete metastasis remission when combined with ICB and folate targeting. The sphingomyelin-derived nanotherapeutic platform and doxorubicin-enabled transmembrane transporting technology are generalizable to various therapeutics, paving the way for transformation of the cancer immunochemotherapy paradigm., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Environmental health literacy (EHL) is developing as a framework that can inform educational interventions designed to facilitate individual and collective action to protect health, yet EHL measurement poses several challenges. While some studies have measured environmental health knowledge resulting from interventions, few have incorporated skills and self-efficacy. In this study, a process-focused EHL instrument was developed, using the Newest Vital Sign (NVS) health literacy instrument as a model and tailoring it for the context of private well contamination with toxic metals. Forty-seven (47) participants, including undergraduate students and residents of communities with contaminated well water, piloted a prototype EHL instrument alongside NVS. Results suggested a moderate degree of correlation between NVS and the EHL prototype, and significant differences in scores were observed between students and residents. Responses to a self-efficacy survey, tailored for drinking water contaminated with arsenic, revealed significant differences between students and residents on items related to cost and distance. In response to open-ended questions, participants identified a range of potential environmental contaminants in drinking water and deemed varied information sources as reliable. This study highlights differences in knowledge and self-efficacy among students and residents and raises questions about the adequacy of EHL assessments that mimic formal education approaches.

Vaping is the process of inhaling and exhaling an aerosol produced by an e-cigarette, vape pen, or personal aerosolizer. When the device contains nicotine, the Food and Drug Administration (FDA) lists the product as an electronic nicotine delivery system or ENDS device. Similar electronic devices can be used to vape cannabis extracts. Over the past decade, the vaping market has increased exponentially, raising health concerns over the number of people exposed and a nationwide outbreak of cases of severe, sometimes fatal, lung dysfunction that arose suddenly in otherwise healthy individuals. In this review, we discuss the various vaping technologies, which are remarkably diverse, and summarize the use prevalence in the U.S. over time by youths and adults. We examine the complex chemistry of vape carrier solvents, flavoring chemicals, and transformation products. We review the health effects from epidemiological and laboratory studies and, finally, discuss the proposed mechanisms underlying some of these health effects. We conclude that since much of the research in this area is recent and vaping technologies are dynamic, our understanding of the health effects is insufficient. With the rapid growth of ENDS use, consumers and regulatory bodies need a better understanding of constituent-dependent toxicity to guide product use and regulatory decisions., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Even though nanoparticle drug delivery systems (nanoDDSs) have improved antitumor efficacy by delivering more drugs to tumor sites compared to free and unencapsulated therapeutics, achieving satisfactory distribution and penetration of nanoDDSs inside solid tumors, especially in stromal fibrous tumors, remains challenging. As one of the most common stromal cells in solid tumors, tumor-associated fibroblasts (TAFs) not only promote tumor growth and metastasis but also reduce the drug delivery efficiency of nanoparticles through the tumor's inherent physical and physiological barriers. Thus, TAFs have been emerging as attractive targets, and TAF-targeting nanotherapeutics have been extensively explored to enhance the tumor delivery efficiency and efficacy of various anticancer agents. The purpose of this Review is to opportunely summarize the underlying mechanisms of TAFs on obstructing nanoparticle-mediated drug delivery into tumors and discuss the current advances of a plethora of nanotherapeutic approaches for effectively targeting TAFs.

The aryl hydrocarbon receptor (AhR) acts as a receptor that responds to ligands, including dioxin. The AhR-ligand complex translocates from the cytoplasm into the nucleus to induce gene expression. Because dioxin exposure impairs cognitive and neurobehavioral functions, AhR-expressing neurons need to be identified for elucidation of the dioxin neurotoxicity mechanism. Immunohistochemistry was performed to detect AhR-expressing neurons in the mouse brain and confirm the specificity of the anti-AhR antibody using Ahr -/- mice. Intracellular distribution of AhR and expression level of AhR-target genes, Cyp1a1, Cyp1b1, and Ahr repressor (Ahrr), were analyzed by immunohistochemistry and quantitative RT-PCR, respectively, using mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The mouse brains were shown to harbor AhR in neurons of the locus coeruleus (LC) and island of Calleja major (ICjM) during developmental period in Ahr +/+ mice but not in Ahr -/- mice. A significant increase in nuclear AhR of ICjM neurons but not LC neurons was found in 14-day-old mice compared to 5- and 7-day-old mice. AhR was significantly translocated into the nucleus in LC and ICjM neurons of TCDD-exposed adult mice. Additionally, the expression levels of Cyp1a1, Cyp1b1, and Ahrr genes in the brain, a surrogate of TCDD in the tissue, were significantly increased by dioxin exposure, suggesting that dioxin-activated AhR induces gene expression in LC and ICjM neurons. This histochemical study shows the ligand-induced nuclear translocation of AhR at the single-neuron level in vivo. Thus, the neurotoxicological significance of the dioxin-activated AhR in the LC and ICjM warrants further studies., (© 2021. The Author(s).)

African-American (AA) women are at higher risk of breast cancer mortality than women of other races. Factors influencing breast cancer risk, including exogenous environmental exposures, and debate around timing of exposure and dose-response relationship, can cause misunderstanding. Collaboration with priority populations encourages culturally relevant health messaging that imparts source reliability, influences message adoption, and improves understanding. Through six focus groups with AA individuals in rural and urban counties in the southeastern United States, this study used a community-engaged participatory approach to design an innovative visual tool for disseminating breast cancer information. Results demonstrated that participants were generally aware of environmental breast cancer risks and were willing to share new knowledge with families and community members. Recommended communication channels included pastors, healthcare providers, social media, and the Internet. Participants agreed that a collaboratively designed visual tool serves as a tangible, focused "conversation starter" to promote community prevention and education efforts.

We hereby provide the initial portrait of lincNORS, a spliced lincRNA generated by the MIR193BHG locus, entirely distinct from the previously described miR-193b-365a tandem. While inducible by low O 2 in a variety of cells and associated with hypoxia in vivo, our studies show that lincNORS is subject to multiple regulatory inputs, including estrogen signals. Biochemically, this lincRNA fine-tunes cellular sterol/steroid biosynthesis by repressing the expression of multiple pathway components. Mechanistically, the function of lincNORS requires the presence of RALY, an RNA-binding protein recently found to be implicated in cholesterol homeostasis. We also noticed the proximity between this locus and naturally occurring genetic variations highly significant for sterol/steroid-related phenotypes, in particular the age of sexual maturation. An integrative analysis of these variants provided a more formal link between these phenotypes and lincNORS, further strengthening the case for its biological relevance.

Flame retardant chemicals (FRCs) commonly added to many consumer products present a human exposure burden associated with adverse health effects. Under pressure from consumers, FRC manufacturers have adopted some purportedly safer replacements for first-generation brominated diphenyl ethers (BDEs). In contrast, second and third-generation organophosphates and other alternative chemistries have limited bioactivity data available to estimate their hazard potential. In order to evaluate the toxicity of existing and potential replacement FRCs, we need efficient screening methods. We built a 61-FRC library in which we systemically assessed developmental toxicity and potential neurotoxicity effects in the embryonic zebrafish model. Data were compared to publicly available data generated in a battery of cell-based in vitro assays from ToxCast, Tox21, and other alternative models. Of the 61 FRCs, 19 of 45 that were tested in the ToxCast assays were bioactive in our zebrafish model. The zebrafish assays detected bioactivity for 10 of the 12 previously classified developmental neurotoxic FRCs. Developmental zebrafish were sufficiently sensitive at detecting FRC structure-bioactivity impacts that we were able to build a classification model using 13 physicochemical properties and 3 embryonic zebrafish assays that achieved a balanced accuracy of 91.7%. This work illustrates the power of a multi-dimensional in vivo platform to expand our ability to predict the hazard potential of new compounds based on structural relatedness, ultimately leading to reliable toxicity predictions based on chemical structure., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Despite a call for better understanding of the role of environmental pollutant influences on mental health and the tremendous public health burden of mental health, this issue receives far less attention than many other effects of pollutants. Here we summarize the body of literature on non-occupational environmental pollutant exposures and adult depression, anxiety, and suicide-in PubMed, Embase, Web of Science, and PsychINFO through the end of year 2018., Recent Findings: One hundred twelve articles met our criteria for further review. Of these, we found 88 articles on depression, 33 on anxiety, and 22 on suicide (31 articles covered multiple outcomes). The earliest article was published in 1976, and the most frequent exposure of interest was air pollution (n = 33), followed by secondhand smoke (n = 20), metals (n = 18), noise (n = 17), and pesticides (n = 10). Other exposures studied less frequently included radiation, magnetic fields, persistent organic pollutants (POPs), volatile organic compounds, solvents, and reactive sulfur compounds. The current literature, although limited, clearly suggests many kinds of environmental exposures may be risk factors for depression, anxiety, and suicide. For several pollutants, important limitations exist with many of the studies. Gaps in the body of research include a need for more longitudinal, life-course studies, studies that can measure cumulative exposures as well as shorter-term exposures, studies that reduce the possibility of reverse causation, and mechanistic studies focused on neurotoxic exposures.

Self-assembling prodrugs represents a robust and effective nanotherapeutic approach for delivering poorly soluble anticancer drugs. With numerous intrinsic advantages, self-assembling prodrugs possess the maximum drug loading capacity, controlled drug release kinetics, prolonged blood circulation, and preferential tumor accumulation based on the enhanced permeability and retention (EPR) effect. These prodrug conjugates allow for efficient self-assembly into nanodrugs with the potential of encapsulating other therapeutic agents that have different molecular targets, enabling simultaneous temporal-spatial release of drugs for synergistic antitumor efficacy with reduced systemic side effects. The aim of this review is to summarize the recent progress of self-assembling prodrug cancer nanotherapeutics that are made through conjugating therapeutically active agents to Polyethylene glycol, Vitamin E, or drugs with different physicochemical properties via rational design, for synergistic tumor targeted drug delivery. STATEMENT OF SIGNIFICANCE: All current FDA-approved nanomedicines use inert biomaterials as drug delivery carriers. These biomaterials lack any therapeutic potential, contributing not only to the cost, but may also elicit severe unfavorable adverse effects. Despite the reduction in toxicity associated with the payload, these nanotherapeutics have been met with limited clinical success, likely due to the monotherapy regimen. The self-assembling prodrug (SAP) has been emerging as a powerful platform for enhancing efficacy through co-delivering other therapeutic modalities with distinct molecular targets. Herein, we opportunely present a comprehensive review article summarizing three unique approaches of making SAP for synergistic drug delivery: pegylation, vitamin E-derivatization, and drug-drug conjugation. These SAPs may inevitably pave the way for developing more efficacious, clinically translatable, combination cancer nanotherapies., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to declare., (Copyright © 2020. Published by Elsevier Ltd.)

Distal axonopathy is a recognized pathological feature of amyotrophic lateral sclerosis (ALS). In the peripheral nerves of ALS patients, motor axon loss elicits a Wallerian-like degeneration characterized by denervated Schwann cells (SCs) together with immune cell infiltration. However, the pathogenic significance of denervated SCs accumulating following impaired axonal growth in ALS remains unclear. Here, we analyze SC phenotypes in sciatic nerves of ALS patients and paralytic SOD1 G93A rats, and identify remarkably similar and specific reactive SC phenotypes based on the pattern of S100β, GFAP, isolectin and/or p75 NTR immunoreactivity. Different subsets of reactive SCs expressed colony-stimulating factor-1 (CSF1) and Interleukin-34 (IL-34) and closely interacted with numerous endoneurial CSF-1R-expressing monocyte/macrophages, suggesting a paracrine mechanism of myeloid cell expansion and activation. SCs bearing phagocytic phenotypes as well as endoneurial macrophages expressed stem cell factor (SCF), a trophic factor that attracts and activates mast cells through the c-Kit receptor. Notably, a subpopulation of Ki67+ SCs expressed c-Kit in the sciatic nerves of SOD1 G93A rats, suggesting a signaling pathway that fuels SC proliferation in ALS. c-Kit+ mast cells were also abundant in the sciatic nerve from ALS donors but not in controls. Pharmacological inhibition of CSF-1R and c-Kit with masitinib in SOD1 G93A rats potently reduced SC reactivity and immune cell infiltration in the sciatic nerve and ventral roots, suggesting a mechanism by which the drug ameliorates peripheral nerve pathology. These findings provide strong evidence for a previously unknown inflammatory mechanism triggered by SCs in ALS peripheral nerves that has broad application in developing novel therapies., (© 2019 Wiley Periodicals, Inc.)

Since 2007, electronic cigarette (e-cigarette) sales in the U.S. have surpassed those of tobacco cigarettes. This is due, in part, to manufacturer's claims that they are a safer alternative to tobacco cigarettes. However, formaldehyde, acrolein, and diacetyl have been detected in e-cigarettes and public knowledge of e-cigarette composition and ingredient bioactivity is conspicuously lacking. We evaluated the toxicity of nine e-cigarette flavor mixtures and their constituents in the developmental zebrafish, an excellent whole animal biosensor of chemical hazard. Seven of the nine flavors (78%) elicited adverse developmental responses at 1% by volume. The number of toxic endpoints varied greatly between flavors. Two flavors, Grape and Bubble Gum, had similar chemical compositions, but different toxicity profiles. We hypothesized that the toxicity was driven by a constituent present only in the Bubble Gum flavor, cinnamaldehyde. To replicate this toxicity, we built our own defined mixture. The addition of varying concentrations of cinnamaldehyde suggested that it drove the toxicity of these mixtures and that e-cigarette hazard can be flavor dependent., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Core-shell silver nanoparticles (NPs) consisting of an inner Ag core and successive layers of Au and Ag (Ag@Au@Ag) were used to measure the simultaneous association of Ag NPs and ionic Ag by the green alga Chlamydomonas (C.) reinhardtii . Dissolution of the inner Ag core was prevented by a gold (Au) layer, while the outer Ag layer was free to dissolve. In short-term experiments, we exposed C. reinhardtii to a range of environmentally realistic Ag concentrations added as AgNO 3 or as NPs. Results provide three lines of evidence for the greater cell-association of NPs compared to dissolved Ag over the concentration range tested, assuming that cell-association comprises both uptake and adsorption. First, the cell-association rate constants ( k uw ) for total Ag (Ag NP+D ), NPs (Ag NP ) and Au NP were similar and 2.2-fold higher than the one from Ag D exposure, suggesting predominant association of the particles over the dissolved form. Second, model calculations based on Ag fluxes suggested that only 6-33% of algal burden was from Ag D . Third, the significantly lower Ag NP /Au ratio measured with the algae after exposure (2.1 ± 0.1) compared to the Ag NP /Au ratio of the NPs in the media (2.47 ± 0.05) suggests cell-association of NPs depleted in Ag. Core-shell NPs provide an innovative tool to understand NP behavior and to directly delineate Ag accumulation from ion and NPs in aquatic systems.

Alkyl phenanthrene (A-Phen) and Dechlorane Plus (DP) are ubiquitous environmental pollutants that widely co-exist in the environment. It has been established that both A-Phen and DP elicit neurotoxicity, but the potential interactive toxicity of these contaminants is not well-known. To determine whether a mixture of A-Phen and DP would exhibit interactive effects on neurodevelopment, we co-exposed 3-methylphenanthrene (3-MP), a representative of A-Phen, with DP. Our results illustrated that exposure to 5 or 20 μg/L 3-MP alone or in combination with 60 μg/L DP caused neurobehavioral anomalies in zebrafish. In accordance with the behavioral deficits, 3-MP alone or co-exposed with DP significantly decreased axonal growth of secondary motoneurons, altered intracellular Ca 2+ homeostasis and induced cell apoptosis in the muscle of zebrafish. Additionally, 3-MP alone or co-exposed with DP significantly increased reactive oxygen species (ROS) and the mRNA levels of apoptosis-related genes. These findings indicate that 3-MP alone or co-exposed with DP induces neurobehavioral deficits through the combined effects on neuronal connectivity and muscle function. Chemical analysis revealed significant increases in 3-MP and DP bioaccumulation in zebrafish co-exposed with 3-MP and DP. Elevated bioaccumulation resulting from mixture exposure may represent a significant contribution of the synergistic effects observed in combined chemical exposure., (Copyright © 2019 Elsevier Inc. All rights reserved.)