Human serous cavity macrophages and dendritic cells possess counterparts in the mouse with a distinct distribution between species.

In mouse peritoneal and other serous cavities, the transcription factor GATA6 drives the identity of the major cavity resident population of macrophages, with a smaller subset of cavity-resident macrophages dependent on the transcription factor IRF4. Here we showed that GATA6+ macrophages in the human peritoneum were rare, regardless of age. Instead, more human peritoneal macrophages aligned with mouse CD206+ LYVE1+ cavity macrophages that represent a differentiation stage just preceding expression of GATA6. A low abundance of CD206+ macrophages was retained in C57BL/6J mice fed a high-fat diet and in wild-captured mice, suggesting that differences between serous cavity-resident macrophages in humans and mice were not environmental. IRF4-dependent mouse serous cavity macrophages aligned closely with human CD1c+CD14+CD64+ peritoneal cells, which, in turn, resembled human peritoneal CD1c+CD14-CD64- cDC2. Thus, major populations of serous cavity-resident mononuclear phagocytes in humans and mice shared common features, but the proportions of different macrophage differentiation stages greatly differ between the two species, and dendritic cell (DC2)-like cells were especially prominent in humans.

Hormone and receptor activator of NF-κB (RANK) pathway gene expression in plasma and mammographic breast density in postmenopausal women.

BACKGROUND: Hormones impact breast tissue proliferation. Studies investigating the associations of circulating hormone levels with mammographic breast density have reported conflicting results. Due to the limited number of studies, we investigated the associations of hormone gene expression as well as their downstream mediators within the plasma with mammographic breast density in postmenopausal women. METHODS: We recruited postmenopausal women at their annual screening mammogram at Washington University School of Medicine, St. Louis. We used the NanoString nCounter platform to quantify gene expression of hormones (prolactin, progesterone receptor (PGR), estrogen receptor 1 (ESR1), signal transducer and activator of transcription (STAT1 and STAT5), and receptor activator of nuclear factor-kB (RANK) pathway markers (RANK, RANKL, osteoprotegerin, TNFRSF18, and TNFRSF13B) in plasma. We used Volpara to measure volumetric percent density, dense volume, and non-dense volume. Linear regression models, adjusted for confounders, were used to evaluate associations between gene expression (linear fold change) and mammographic breast density. RESULTS: One unit increase in ESR1, RANK, and TNFRSF18 gene expression was associated with 8% (95% CI 0-15%, p value = 0.05), 10% (95% CI 0-20%, p value = 0.04) and % (95% CI 0-9%, p value = 0.04) higher volumetric percent density, respectively. There were no associations between gene expression of other markers and volumetric percent density. One unit increase in osteoprotegerin and PGR gene expression was associated with 12% (95% CI 4-19%, p value = 0.003) and 7% (95% CI 0-13%, p value = 0.04) lower non-dense volume, respectively. CONCLUSION: These findings provide new insight on the associations of plasma hormonal and RANK pathway gene expression with mammographic breast density in postmenopausal women and require confirmation in other studies.

Overall survival in patients with FIGO stage IVA cervical cancer.

OBJECTIVE: FIGO stage IVA cervical cancer is a unique diagnosis that conveys a poor prognosis. Despite the use of PET/CT for staging, concurrent chemotherapy, and image-guided brachytherapy, overall survival (OS) in these patients is low. Treatment requires aggressive use of radiotherapy and chemotherapy. We report results of a prospective observational cohort study for patients with de novo stage IVA cervical cancer treated at a single institution. METHODS: Patients with a new diagnosis of stage IVA cervical cancer treated at an academic institution between 1997 and 2020 were prospectively monitored. Staging was retroactively assigned using the 2018 FIGO staging system. All patients had a PET/CT prior to treatment and were treated with definitive intent radiotherapy with or without chemotherapy. The primary outcome of interest was OS. Secondary outcomes were local control, progression-free survival (PFS), and disease-specific survival (DSS). RESULTS: 32 patients with de novo stage IVA cervical cancer were treated with definitive intent radiotherapy. Median follow-up time was 4.27 years (1.31-10.35). 22/32 (69%) of patients received brachytherapy as a part of their definitive treatment, and 28/32 (88%) received chemotherapy concurrently with radiotherapy. 14/32 (44%) of patients had no evidence of disease at last follow-up. The 5-year local control, PFS, DFS, and OS estimates were 79%, 49%, 53%, and 48%, respectively. On multivariate analysis, complete metabolic response was associated with a statistically significant improvement in PFS (HR = 0.256, 95% CI = 0.078-0.836, p = 0.024) and OS (HR = 0.273, 95% CI 0.081-0.919). CONCLUSIONS: These data demonstrate a robust OS in patients with stage IVA cervical cancer when treated with definitive chemoradiotherapy.

Engineered Mesenchymal Stem Cell/Nanomedicine Spheroid as an Active Drug Delivery Platform for Combinational Glioblastoma Therapy.

Mesenchymal stem cell (MSC) has been increasingly applied to cancer therapy because of its tumor-tropic capability. However, short retention at target tissue and limited payload option hinder the progress of MSC-based cancer therapy. Herein, we proposed a hybrid spheroid/nanomedicine system, comprising MSC spheroid entrapping drug-loaded nanocomposite, to address these limitations. Spheroid formulation enhanced MSC's tumor tropism and facilitated loading of different types of therapeutic payloads. This system acted as an active drug delivery platform seeking and specifically targeting glioblastoma cells. It enabled effective delivery of combinational protein and chemotherapeutic drugs by engineered MSC and nanocomposite, respectively. In an in vivo migration model, the hybrid spheroid showed higher nanocomposite retention in the tumor tissue compared with the single MSC approach, leading to enhanced tumor inhibition in a heterotopic glioblastoma murine model. Taken together, this system integrates the merits of cell- and nanoparticle- mediated drug delivery with the tumor-homing characteristics of MSC to advance targeted combinational cancer therapy.

Will CRISPR Germline Engineering Close the Door to an Open Future?

The bioethical principle of autonomy is problematic regarding the future of the embryo who lacks the ability to self-advocate but will develop this defining human capacity in time. Recent experiments explore the use of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 for germline engineering in the embryo, which alters future generations. The embryo's inability to express an autonomous decision is an obvious bioethical challenge of germline engineering. The philosopher Joel Feinberg acknowledged that autonomy is developing in children. He advocated that to reserve this future autonomy, parents should be guided to make ethical decisions that provide children with open futures. Here, Feinberg's 1980 open future theory is extended to the human embryo in the context of CRISPR germline engineering. Although the embryo does not possess the autonomous decision-making capacity at the time of germline engineering, the parental decision to permanently change the unique genetic fabric of the embryo and subsequent generations disregards future autonomy. Therefore, germline engineering in many instances is objectionable considering Feinberg's open future theory.

Magnesium improves cisplatin-mediated tumor killing while protecting against cisplatin-induced nephrotoxicity.

Approximately 30% of all cancer patients treated with cisplatin, a widely used broad-spectrum chemotherapeutic agent, experience acute kidney injury (AKI). Almost all patients receiving cisplatin have magnesium (Mg) losses, which are proposed to aggravate AKI. Currently, there are no methods to successfully treat or prevent cisplatin-AKI. Whereas Mg supplementation has been shown to reduce AKI in experimental models and several small clinical trials, the effects of Mg status on tumor outcomes in immunocompetent tumor-bearing mice and humans have not been investigated. The purpose of this study was to further examine the effects of Mg deficiency (±Mg supplementation) on cisplatin-mediated AKI and tumor killing in immunocompetent mice bearing CT26 colon tumors. Using a model where cisplatin alone (20 mg/kg cumulative dose) produced minimal kidney injury, Mg deficiency significantly worsened cisplatin-mediated AKI, as determined by biochemical markers (blood urea nitrogen and plasma creatinine) and histological renal changes, as well as markers of renal oxidative stress, inflammation, and apoptosis. By contrast, Mg supplementation blocked cisplatin-induced kidney injury. Using LLC-PK1 renal epithelial cells, we observed that Mg deficiency or inhibition of Mg uptake significantly enhanced cisplatin-induced cytotoxicity, whereas Mg supplementation protected against cytotoxicity. However, neither Mg deficiency nor inhibition of Mg uptake impaired cisplatin-mediated killing of CT26 tumor cells in vitro. Mg deficiency was associated with significantly larger CT26 tumors in BALB/c mice when compared with normal-fed control mice, and Mg deficiency significantly reduced cisplatin-mediated tumor killing in vivo. Finally, Mg supplementation did not compromise cisplatin's anti-tumor efficacy in vivo.

Soil-Air Mercury Flux near a Large Industrial Emission Source before and after Closure (Flin Flon, Manitoba, Canada).

Prior to its closure, the base-metal smelter in Flin Flon, Manitoba, Canada was one of the North America's largest mercury (Hg) emission sources. Our project objective was to understand the exchange of Hg between the soil and the air before and after the smelter closure. Field and laboratory Hg flux measurements were conducted to identify the controlling variables and used for spatial and temporal scaling. Study results showed that deposition from the smelter resulted in the surrounding soil being enriched in Hg (up to 99 µg g(-1)) as well as other metals. During the period of smelter operation, air concentrations were elevated (30 ± 19 ng m(-3)), and the soil was a net Hg sink (daily flux: -3.8 ng m(-2) h(-1)). Following the smelter closure, air Hg(0) concentrations were reduced, and the soils had large emissions (daily flux: 108 ng m(-2) h(-1)). The annual scaling of soil Hg emissions following the smelter closure indicated that the landscape impacted by smelter deposition emitted or re-emitted almost 100 kg per year. Elevated soil Hg concentrations and emissions are predicted to continue for hundreds of years before background concentrations are re-established. Overall, the results indicate that legacy Hg deposition will continue to cycle in the environment long after point-source reductions.

Magnesium protects against cisplatin-induced acute kidney injury by regulating platinum accumulation.

Despite its success as a potent antineoplastic agent, ∼25% of patients receiving cisplatin experience acute kidney injury (AKI) and must discontinue therapy. Impaired magnesium homeostasis has been linked to cisplatin-mediated AKI, and because magnesium deficiency is widespread, we examined the effect of magnesium deficiency and replacement on cisplatin-induced AKI in physiologically relevant older female mice. Magnesium deficiency significantly increased cisplatin-associated weight loss and markers of renal damage (plasma blood urea nitrogen and creatinine), histological changes, inflammation, and renal cell apoptosis and modulated signaling pathways (e.g., ERK1/2, p53, and STAT3). Conversely, these damaging effects were reversed by magnesium. Magnesium deficiency alone significantly induced basal and cisplatin-mediated oxidative stress, whereas magnesium replacement attenuated these effects. Similar results were observed using cisplatin-treated LLC-PK1 renal epithelial cells exposed to various magnesium concentrations. Magnesium deficiency significantly amplified renal platinum accumulation, whereas magnesium replacement blocked the augmented platinum accumulation after magnesium deficiency. Increased renal platinum accumulation during magnesium deficiency was accompanied by reduced renal efflux transporter expression, which was reversed by magnesium replacement. These findings demonstrate the role of magnesium in regulating cisplatin-induced AKI by enhancing oxidative stress and thus promoting cisplatin-mediated damage. Additional in vitro experiments using ovarian, breast, and lung cancer cell lines showed that magnesium supplementation did not compromise cisplatin's chemotherapeutic efficacy. Finally, because no consistently successful therapy to prevent or treat cisplatin-mediated AKI is available for humans, these results support developing more conservative magnesium replacement guidelines for reducing cisplatin-induced AKI in cancer patients at risk for magnesium deficiency.

An antifouling membrane-fusogenic liposome for effective intracellular delivery in vivo.

The membrane-fusion-based internalization without lysosomal entrapment is advantageous for intracellular delivery over endocytosis. However, protein corona formed on the membrane-fusogenic liposome surface converts its membrane-fusion performance to lysosome-dependent endocytosis, causing poorer delivery efficiency in biological conditions. Herein, we develop an antifouling membrane-fusogenic liposome for effective intracellular delivery in vivo. Leveraging specific lipid composition at an optimized ratio, such antifouling membrane-fusogenic liposome facilitates fusion capacity even in protein-rich conditions, attributed to the copious zwitterionic phosphorylcholine groups for protein-adsorption resistance. Consequently, the antifouling membrane-fusogenic liposome demonstrates robust membrane-fusion-mediated delivery in the medium with up to 38% fetal bovine serum, outclassing two traditional membrane-fusogenic liposomes effective at 4% and 6% concentrations. When injected into mice, antifouling membrane-fusogenic liposomes can keep their membrane-fusion-transportation behaviors, thereby achieving efficient luciferase transfection and enhancing gene-editing-mediated viral inhibition. This study provides a promising tool for effective intracellular delivery under complex physiological environments, enlightening future nanomedicine design.

Engineered Nanomaterials to Potentiate CRISPR/Cas9 Gene Editing for Cancer Therapy.

Clustered regularly interspaced short palindromic repeats/associated protein 9 (CRISPR/Cas9) gene-editing technology shows promise for manipulating single or multiple tumor-associated genes and engineering immune cells to treat cancers. Currently, most gene-editing strategies rely on viral delivery; yet, while being efficient, many limitations, mainly from safety and packaging capacity considerations, hinder the use of viral CRISPR vectors in cancer therapy. In contrast, recent advances in non-viral CRISPR/Cas9 nanoformulations have paved the way for better cancer gene editing, as these nanoformulations can be engineered to improve safety, efficiency, and specificity through optimizing the packaging capacity, pharmacokinetics, and targetability. In this review, the advance in non-viral CRISPR delivery is highlighted, and there is a discussion on how these approaches can be potentially used to treat cancers in addressing the aforementioned limitations, followed by the perspectives in designing a proper CRISPR/Cas9-based cancer nanomedicine system with translational potential.

CRISPR/Cas detection with nanodevices: moving deeper into liquid biopsy.

The emerging field of liquid biopsy has garnered significant interest in precision diagnostics, offering a non-invasive and repetitive method for analyzing bodily fluids to procure real-time diagnostic data. The precision and accuracy offered by the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (CRISPR/Cas) technology have advanced and broadened the applications of liquid biopsy. Significantly, when combined with swiftly advancing nanotechnology, CRISPR/Cas-mediated nanodevices show vast potential in precise liquid biopsy applications. However, persistent challenges are still associated with off-target effects, and the current platforms also constrain the performance of the assays. In this review, we highlight the merits of CRISPR/Cas systems in liquid biopsy, tracing the development of CRISPR/Cas systems and their current applications in disease diagnosis particularly in liquid biopsies. We also outline ongoing efforts to design nanoscale devices with improved sensing and readout capabilities, aiming to enhance the performance of CRISPR/Cas detectors in liquid biopsy. Finally, we identify the critical obstacles hindering the widespread adoption of CRISPR/Cas liquid biopsy and explore potential solutions. This feature article presents a comprehensive overview of CRISPR/Cas-mediated liquid biopsies, emphasizing the progress in integrating nanodevices to improve specificity and sensitivity. It also sheds light on future research directions in employing nanodevices for CRISPR/Cas-based liquid biopsies in the realm of precision medicine.

Starfysh integrates spatial transcriptomic and histologic data to reveal heterogeneous tumor-immune hubs.

Spatially resolved gene expression profiling provides insight into tissue organization and cell-cell crosstalk; however, sequencing-based spatial transcriptomics (ST) lacks single-cell resolution. Current ST analysis methods require single-cell RNA sequencing data as a reference for rigorous interpretation of cell states, mostly do not use associated histology images and are not capable of inferring shared neighborhoods across multiple tissues. Here we present Starfysh, a computational toolbox using a deep generative model that incorporates archetypal analysis and any known cell type markers to characterize known or new tissue-specific cell states without a single-cell reference. Starfysh improves the characterization of spatial dynamics in complex tissues using histology images and enables the comparison of niches as spatial hubs across tissues. Integrative analysis of primary estrogen receptor (ER)-positive breast cancer, triple-negative breast cancer (TNBC) and metaplastic breast cancer (MBC) tissues led to the identification of spatial hubs with patient- and disease-specific cell type compositions and revealed metabolic reprogramming shaping immunosuppressive hubs in aggressive MBC.

Gut-associated lymphoid tissue attrition associates with response to anti-α4ß7 therapy in ulcerative colitis.

Vedolizumab (VDZ) is a first-line treatment in ulcerative colitis (UC) that targets the α4ß7- mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) axis. To determine the mechanisms of action of VDZ, we examined five distinct cohorts of patients with UC. A decrease in naïve B and T cells in the intestines and gut-homing (ß7+) plasmablasts in circulation of VDZ-treated patients suggested that VDZ targets gut-associated lymphoid tissue (GALT). Anti-α4ß7 blockade in wild-type and photoconvertible (KikGR) mice confirmed a loss of GALT size and cellularity because of impaired cellular entry. In VDZ-treated patients with UC, treatment responders demonstrated reduced intestinal lymphoid aggregate size and follicle organization and a reduction of ß7+IgG+ plasmablasts in circulation, as well as IgG+ plasma cells and FcγR-dependent signaling in the intestine. GALT targeting represents a previously unappreciated mechanism of action of α4ß7-targeted therapies, with major implications for this therapeutic paradigm in UC.

Impact of closing Canada's largest point-source of mercury emissions on local atmospheric mercury concentrations.

The Flin Flon, Manitoba copper smelter was Canada's largest point source of mercury emissions until its closure in 2010 after ~80 years of operation. The objective of this study was to understand the variables controlling the local ground-level air mercury concentrations before and after this major point source reduction. Total gaseous mercury (TGM) in air, mercury in precipitation, and other ancillary meteorological and air quality parameters were measured pre- and postsmelter closure, and mercury speciation measurements in air were collected postclosure. The results showed that TGM was significantly elevated during the time period when the smelter operated (4.1 ± 3.7 ng m(-3)), decreased only 20% during the year following its closure, and remained ~2-fold above background levels. Similar trends were observed for mercury concentrations in precipitation. Several lines of evidence indicated that while smelter stack emissions would occasionally mix down to the surface resulting in large spikes in TGM concentrations (up to 61 ng m(-3)), the largest contributor to elevated TGM concentrations before and after smelter closure was from surface-air fluxes from mercury-enriched soils and/or tailings. These findings highlight the ability of legacy mercury, deposited to local landscapes over decades from industrial activities, to significantly affect local air concentrations via emissions/re-emissions.

Structural and componential design: new strategies regulating the behavior of lipid-based nanoparticles in vivo.

Lipid-based nanoparticles have made a breakthrough in clinical disease as delivery systems due to their biocompatibility, thermal and long-term stability, high loading ability, simplicity of preparation, inexpensive production costs, and scalable manufacturing production. In particular, during the COVID-19 pandemic, this delivery system served as a vital vaccine component for virus confrontation. To obtain effective drug delivery, lipid-based nanoparticles should reach the desired sites with high efficiency, enter target cells, and release drugs. The structures and compositions of lipid-based nanoparticles can be modified to regulate these behaviors in vivo to enhance the therapeutic effects. Herein, we briefly review the development of lipid-based nanoparticles, from simple self-assembled nanovesicle-structured liposomes to multifunctional lipid nanoparticles. Subsequently, we summarize the strategies that regulate their tissue distribution, cell internalization, and drug release, highlighting the importance of the structural and componential design. We conclude with insights for further research to advance lipid-based nanotechnology.

Websites about, not for, adolescents? A systematic analysis of online fertility preservation information for adolescent and young adult cancer patients.

Purpose Fertility preservation is an increasingly important topic in adolescent and young adult cancer survivorship, yet treatments remain under-utilized, possibly due to lack of awareness and understanding. The internet is widely used by adolescents and young adults and has been proposed to fill knowledge gaps and advance high-quality, more equitable care. As a first step, this study analyzed the quality of current fertility preservation resources online and identified opportunities for improvement. Methods We conducted a systematic analysis of 500 websites to assess the quality, readability, and desirability of website features, and the inclusion of clinically relevant topics. Results The majority of the 68 eligible websites were low quality, written at college reading levels, and included few features that younger patients find desirable. Websites mentioned more common fertility preservation treatments than promising experimental treatments, and could be improved with cost information, socioemotional impacts, and other equity-related fertility topics. Conclusions Currently, the majority of fertility preservation websites are about, but not for, adolescent and young adult patients. High-quality educational websites are needed that address outcomes that matter to teens and young adults, with a priority on solutions that prioritize equity. Implications for Cancer Survivors: Adolescent and young adult survivors have limited access to high-quality fertility preservation websites that are designed for their needs. There is a need for the development of fertility preservation websites that are clinically comprehensive, written at appropriate reading levels, inclusive, and desirable. We include specific recommendations that future researchers can use to develop websites that could better address AYA populations and improve the fertility preservation decision making process.

Self-intensified synergy of a versatile biomimetic nanozyme and doxorubicin on electrospun fibers to inhibit postsurgical tumor recurrence and metastasis.

Tumor-positive resection margins after surgery can result in tumor recurrence and metastasis. Although adjuvant postoperative radiotherapy and chemotherapy have been adopted in clinical practice, they lack efficacy and result in unavoidable side effects. Herein, a self-intensified in-situ therapy approach using electrospun fibers loaded with a biomimetic nanozyme and doxorubicin (DOX) is developed. The fabricated PEG-coated zeolite imidazole framework-67 (PZIF67) is demonstrated as a versatile nanozyme triggering reactions in cancer cells based on endogenous H2O2 and •O2-. The PZIF67-generated •OH induces reactive oxygen species (ROS) overload, implementing chemodynamic therapy (CDT). The O2 produced by PZIF67 inhibits the expression of hypoxia-up-regulated proteins, thereby suppressing tumor progression. PZIF67 also catalyzes the degradation of glutathione, further disturbing the intracellular redox homeostasis and enhancing CDT. Furthermore, the introduced DOX not only kills cancer cells individually, but also replenishes the continuously consumed substrates for PZIF67-catalyzed reactions. The PZIF67-weakened drug resistance strengthens the cytotoxicity of DOX. The combined application of PZIF67 and DOX also suppresses metastasis-associated genes. Both in vitro and in vivo results demonstrate that the self-intensified synergy of PZIF67 and DOX on electrospun fibers efficiently prevents postsurgical tumor recurrence and metastasis, offering a feasible therapeutic regimen for operable malignant tumors.

Implantable 3D Printed Hydrogel Scaffolds Loading Copper-Doxorubicin Complexes for Postoperative Chemo/Chemodynamic Therapy.

Biomaterial-based implants hold great potential for postoperative cancer treatment due to the enhanced drug dosage at the disease site and decreased systemic toxicity. However, the elaborate design of implants to avoid complicated chemical modification and burst release remains challenging. Herein, we report a three-dimensional (3D) printed hydrogel scaffold to enable sustained release of drugs for postoperative synergistic cancer therapy. The hydrogel scaffold is composed of Pluronic F127 and sodium alginate (SA) as well as doxorubicin (DOX) and copper ions (F127-SA/Cu-DOX hydrogel scaffold). Benefiting from the coordination of Cu(II) with both SA and DOX, burst release of DOX can be overcome, and prolonged release time can be achieved. The therapeutic efficiency can be adjusted by altering the amount of DOX and Cu(II) in the scaffolds. Moreover, apoptosis and ferroptosis of cancer cells can be induced through the combination of chemotherapy and chemodynamic therapy. In addition, DOX supplies excess hydrogen peroxide to enhance the efficiency of Cu-based chemodynamic therapy. When implanted in the resection site, hydrogel scaffolds effectively inhibit tumor growth. Overall, this study may offer a new strategy for fabricating local implants with synergistic therapeutic performance for preventing postoperative cancer recurrence.