Spon1+ inflammatory monocytes promote collagen remodeling and lung cancer metastasis through lipoprotein receptor 8 signaling.

Lung cancer is the leading cause of cancer-related deaths in the world, and non-small cell lung cancer (NSCLC) is the most common subset. We previously found that infiltration of tumor inflammatory monocytes (TIMs) into lung squamous carcinoma (LUSC) tumors is associated with increased metastases and poor survival. To further understand how TIMs promote metastases, we compared RNA-Seq profiles of TIMs from several LUSC metastatic models with inflammatory monocytes (IMs) of non-tumor-bearing controls. We identified Spon1 as upregulated in TIMs and found that Spon1 expression in LUSC tumors corresponded with poor survival and enrichment of collagen extracellular matrix signatures. We observed SPON1+ TIMs mediate their effects directly through LRP8 on NSCLC cells, which resulted in TGF-ß1 activation and robust production of fibrillar collagens. Using several orthogonal approaches, we demonstrated that SPON1+ TIMs were sufficient to promote NSCLC metastases. Additionally, we found that Spon1 loss in the host, or Lrp8 loss in cancer cells, resulted in a significant decrease of both high-density collagen matrices and metastases. Finally, we confirmed the relevance of the SPON1/LRP8/TGF-ß1 axis with collagen production and survival in patients with NSCLC. Taken together, our study describes how SPON1+ TIMs promote collagen remodeling and NSCLC metastases through an LRP8/TGF-ß1 signaling axis.

Normalizing granuloma vasculature and matrix improves drug delivery and reduces bacterial burden in tuberculosis-infected rabbits.

Host-directed therapies (HDTs) represent an emerging approach for bacterial clearance during tuberculosis (TB) infection. While most HDTs are designed and implemented for immuno-modulation, other host targets-such as nonimmune stromal components found in pulmonary granulomas-may prove equally viable. Building on our previous work characterizing and normalizing the aberrant granuloma-associated vasculature, here we demonstrate that FDA-approved therapies (bevacizumab and losartan, respectively) can be repurposed as HDTs to normalize blood vessels and extracellular matrix (ECM), improve drug delivery, and reduce bacterial loads in TB granulomas. Granulomas feature an overabundance of ECM and compressed blood vessels, both of which are effectively reduced by losartan treatment in the rabbit model of TB. Combining both HDTs promotes secretion of proinflammatory cytokines and improves anti-TB drug delivery. Finally, alone and in combination with second-line antitubercular agents (moxifloxacin or bedaquiline), these HDTs significantly reduce bacterial burden. RNA sequencing analysis of HDT-treated lung and granuloma tissues implicates up-regulated antimicrobial peptide and proinflammatory gene expression by ciliated epithelial airway cells as a putative mechanism of the observed antitubercular benefits in the absence of chemotherapy. These findings demonstrate that bevacizumab and losartan are well-tolerated stroma-targeting HDTs, normalize the granuloma microenvironment, and improve TB outcomes, providing the rationale to clinically test this combination in TB patients.

A critical role for staphylococcal nitric oxide synthase in controlling flavohemoglobin toxicity.

Most coagulase-negative staphylococcal species, including the opportunistic pathogen Staphylococcus epidermidis, struggle to maintain redox homeostasis and grow under nitrosative stress. Under these conditions, growth can only resume once nitric oxide (NO) is detoxified by the flavohemoglobin Hmp. Paradoxically, S. epidermidis produces endogenous NO through its genetically encoded nitric oxide synthase (seNOS) and heavily relies on its activity for growth. In this study, we investigate the basis of the growth advantage attributed to seNOS activity. Our findings reveal that seNOS supports growth by countering Hmp toxicity. S. epidermidis relies on Hmp activity for its survival in the host under NO stress. However, in the absence of nitrosative stress, Hmp generates significant amounts of the harmful superoxide radical (O2•-) from its heme prosthetic group which impedes growth. To limit Hmp toxicity, nitrite (NO2-) derived from seNOS promotes CymR-CysK regulatory complex activity, which typically regulates cysteine metabolism, but we now demonstrate to also repress hmp transcription. These findings reveal a critical mechanism through which the bacterial NOS-Hmp axis drives staphylococcal fitness.

Elevated CRP and TNF-α levels are associated with blunted neural oscillations serving fluid intelligence.

INTRODUCTION: Inflammatory processes help protect the body from potential threats such as bacterial or viral invasions. However, when such inflammatory processes become chronically engaged, synaptic impairments and neuronal cell death may occur. In particular, persistently high levels of C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α) have been linked to deficits in cognition and several psychiatric disorders. Higher-order cognitive processes such as fluid intelligence (Gf) are thought to be particularly vulnerable to persistent inflammation. Herein, we investigated the relationship between elevated CRP and TNF-α and the neural oscillatory dynamics serving Gf. METHODS: Seventy adults between the ages of 20-66 years (Mean = 45.17 years, SD = 16.29, 21.4% female) completed an abstract reasoning task that probes Gf during magnetoencephalography (MEG) and provided a blood sample for inflammatory marker analysis. MEG data were imaged in the time-frequency domain, and whole-brain regressions were conducted using each individual's plasma CRP and TNF-α concentrations per oscillatory response, controlling for age, BMI, and education. RESULTS: CRP and TNF-α levels were significantly associated with region-specific neural oscillatory responses. In particular, elevated CRP concentrations were associated with altered gamma activity in the right inferior frontal gyrus and right cerebellum. In contrast, elevated TNF-α levels scaled with alpha/beta oscillations in the left anterior cingulate and left middle temporal, and gamma activity in the left intraparietal sulcus. DISCUSSION: Elevated inflammatory markers such as CRP and TNF-α were associated with aberrant neural oscillations in regions important for Gf. Linking inflammatory markers with regional neural oscillations may hold promise in identifying mechanisms of cognitive and psychiatric disorders.

Lung microenvironments harbor Mycobacterium tuberculosis phenotypes with distinct treatment responses.

Tuberculosis lung lesions are complex and harbor heterogeneous microenvironments that influence antibiotic effectiveness. Major strides have been made recently in understanding drug pharmacokinetics in pulmonary lesions, but the bacterial phenotypes that arise under these conditions and their contribution to drug tolerance are poorly understood. A pharmacodynamic marker called the RS ratio® quantifies ongoing rRNA synthesis based on the abundance of newly synthesized precursor rRNA relative to mature structural rRNA. Application of the RS ratio in the C3HeB/FeJ mouse model demonstrated that Mycobacterium tuberculosis populations residing in different tissue microenvironments are phenotypically distinct and respond differently to drug treatment with rifampin, isoniazid, or bedaquiline. This work provides a foundational basis required to address how anatomic and pathologic microenvironmental niches may contribute to long treatment duration and drug tolerance during the treatment of human tuberculosis.

Macrophage internalization creates a multidrug-tolerant fungal persister reservoir and facilitates the emergence of drug resistance.

Candida glabrata is a major fungal pathogen notable for causing recalcitrant infections, rapid emergence of drug-resistant strains, and its ability to survive and proliferate within macrophages. Resembling bacterial persisters, a subset of genetically drug-susceptible C. glabrata cells can survive lethal exposure to the fungicidal echinocandin drugs. Herein, we show that macrophage internalization induces cidal drug tolerance in C. glabrata, expanding the persister reservoir from which echinocandin-resistant mutants emerge. We show that this drug tolerance is associated with non-proliferation and is triggered by macrophage-induced oxidative stress, and that deletion of genes involved in reactive oxygen species detoxification significantly increases the emergence of echinocandin-resistant mutants. Finally, we show that the fungicidal drug amphotericin B can kill intracellular C. glabrata echinocandin persisters, reducing emergence of resistance. Our study supports the hypothesis that intra-macrophage C. glabrata is a reservoir of recalcitrant/drug-resistant infections, and that drug alternating strategies can be developed to eliminate this reservoir.

Activity of Tricyclic Pyrrolopyrimidine Gyrase B Inhibitor against Mycobacterium abscessus.

Tricyclic pyrrolopyrimidines (TPPs) are a new class of antibacterials inhibiting the ATPase of DNA gyrase. TPP8, a representative of this class, is active against Mycobacterium abscessus in vitro. Spontaneous TPP8 resistance mutations mapped to the ATPase domain of M. abscessus DNA gyrase, and the compound inhibited DNA supercoiling activity of recombinant M. abscessus enzyme. Further profiling of TPP8 in macrophage and mouse infection studies demonstrated proof-of-concept activity against M. abscessus ex vivo and in vivo.

A Novel Oral GyrB/ParE Dual Binding Inhibitor Effective against Multidrug-Resistant Neisseria gonorrhoeae and Other High-Threat Pathogens.

Drug-resistant Neisseria gonorrhoeae is a serious global health concern. New drugs are needed that can overcome existing drug resistance and limit the development of new resistances. Here, we describe the small molecule tricyclic pyrimidoindole JSF-2414 [8-(6-fluoro-8-(methylamino)-2-((2-methylpyrimidin-5-yl)oxy)-9H-pyrimido[4,5-b]indol-4-yl)-2-oxa-8-azaspiro[4.5]decan-3-yl)methanol], which was developed to target both ATP-binding regions of DNA gyrase (GyrB) and topoisomerase (ParE). JSF-2414 displays potent activity against N. gonorrhoeae, including drug-resistant strains. A phosphate pro-drug, JSF-2659, was developed to facilitate oral dosing. In two different animal models of Neisseria gonorrhoeae vaginal infection, JSF-2659 was highly efficacious in reducing microbial burdens to the limit of detection. The parent molecule also showed potent in vitro activity against high-threat Gram-positive organisms, and JSF-2659 was shown in a deep tissue model of vancomycin-resistant Staphylococcus aureus (VRSA) and a model of Clostridioides difficile-induced colitis to be highly efficacious and protective. JSF-2659 is a novel preclinical drug candidate against high-threat multidrug resistant organisms with low potential to develop new resistance.

Spatial quantitation of antibiotics in bone tissue compartments by laser-capture microdissection coupled with UHPLC-tandem mass spectrometry.

Bones are the site of multiple diseases requiring chemotherapy, including cancer, arthritis, osteoporosis and infections. Yet limited methodologies are available to investigate the spatial distribution and quantitation of small molecule drugs in bone compartments, due to the difficulty of sectioning undecalcified bones and the interference of decalcification methods with spatially resolved drug quantitation. To measure drug concentrations in distinct anatomical bone regions, we have developed a workflow that enables spatial quantitation of thin undecalcified bone sections by laser-capture microdissection coupled to HPLC/tandem mass spectrometry, and spatial mapping on adjacent sections by mass spectrometry imaging. The adhesive film and staining methods were optimized to facilitate histology staining on the same sections used for mass spectrometry image acquisition, revealing drug accumulation in the underlying bone tissue architecture, for the first time. Absolute spatial concentrations of rifampicin, bedaquiline, doxycycline, vancomycin and several of their active metabolites are shown for both small rodent bones and larger rabbit bones that more closely resemble human bone density. Overlaid MALDI mass spectrometry images of drugs and histology staining enabled the generation of semi-quantitative data from regions of interest within anatomical bone compartments. These data correlated with absolute drug concentrations determined by HPLC-MS/MS in laser-capture microdissection samples. Collectively, these techniques enable semi- and fully quantitative drug distribution investigations within bone tissue compartments for the first time. Our workflow can be translated to image and quantify not only drugs but also biomarkers of disease to investigate drug penetration as well as mechanisms underlying bone disorders.

Activation of the CREB Coactivator CRTC2 by Aberrant Mitogen Signaling promotes oncogenic functions in HPV16 positive head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and incidence rates are continuing to rise globally. Patients often present with locally advanced disease and a staggering 50% chance of relapse following treatment. Aberrant activation of adaptive response signaling pathways, such as the cAMP/PKA pathway, induce an array of genes associated with known cancer pathways that promote tumorigenesis and drug resistance. We identified the cAMP Regulated Transcription Coactivator 2 (CRTC2) to be overexpressed and constitutively activated in HNSCCs and this confers poor prognosis. CRTCs are regulated through their subcellular localization and we show that CRTC2 is exclusively nuclear in HPV(+) HNSCC, thus constitutively active, due to non-canonical Mitogen-Activated Kinase Kinase 1 (MEKK1)-mediated activation via a MEKK1-p38 signaling axis. Loss-of-function and pharmacologic inhibition experiments decreased CRTC2/CREB transcriptional activity by reducing nuclear CRTC2 via nuclear import inhibition and/or by eviction of CRTC2 from the nucleus. This shift in localization was associated with decreased proliferation, migration, and invasion. Our results suggest that small molecules that inhibit nuclear CRTC2 and p38 activity may provide therapeutic benefit to patients with HPV(+) HNSCC.

Hydrogen Peroxide Scavenging Restores N-Type Calcium Channels in Cardiac Vagal Postganglionic Neurons and Mitigates Myocardial Infarction-Evoked Ventricular Arrhythmias in Type 2 Diabetes Mellitus.

Objective: Withdrawal of cardiac vagal activity is associated with ventricular arrhythmia-related high mortality in patients with type 2 diabetes mellitus (T2DM). Our recent study found that reduced cell excitability of cardiac vagal postganglionic (CVP) neurons is involved in cardiac vagal dysfunction and further exacerbates myocardial infarction (MI)-evoked ventricular arrhythmias and mortality in T2DM. However, the mechanisms responsible for T2DM-impaired cell excitability of CVP neurons remain unclear. This study tested if and how elevation of hydrogen peroxide (H2O2) inactivates CVP neurons and contributes to cardiac vagal dysfunction and ventricular arrhythmogenesis in T2DM. Methods and Results: Rat T2DM was induced by a high-fat diet plus streptozotocin injection. Local in vivo transfection of adenoviral catalase gene (Ad.CAT) successfully induced overexpression of catalase and subsequently reduced cytosolic H2O2 levels in CVP neurons in T2DM rats. Ad.CAT restored protein expression and ion currents of N-type Ca2+ channels and increased cell excitability of CVP neurons in T2DM. Ad.CAT normalized T2DM-impaired cardiac vagal activation, vagal control of ventricular function, and heterogeneity of ventricular electrical activity. Additionally, Ad.CAT not only reduced the susceptibility to ventricular arrhythmias, but also suppressed MI-evoked lethal ventricular arrhythmias such as VT/VF in T2DM. Conclusions: We concluded that endogenous H2O2 elevation inhibited protein expression and activation of N-type Ca2+ channels and reduced cell excitability of CVP neurons, which further contributed to the withdrawal of cardiac vagal activity and ventricular arrhythmogenesis in T2DM. Our current study suggests that the H2O2-N-type Ca2+ channel signaling axis might be an effective therapeutic target to suppress ventricular arrhythmias in T2DM patients with MI.

The association of weight loss with changes in the gut microbiota diversity, composition, and intestinal permeability: a systematic review and meta-analysis.

The gut microbiome may be a mediator between obesity and health outcomes. However, it is unclear how intentional weight loss changes the gut microbiota and intestinal permeability. We aimed to systematically review and quantify this association. We searched Medline, Embase, CINAHL, Cochrane databases, and trial registries until June 2020 (PROSPERO: CRD42020205292). We included trials of weight loss interventions (energy-restricted diets, pharmacotherapy, bariatric surgery) reporting on the microbiome. Two reviewers independently completed screening, extraction, and risk assessment with the ROBINS-I tool. Pooled standardized mean differences (SMDs) were obtained from random-effects meta-analyses. Forty-seven trials with 1,916 participants (81% female) and a median follow-up of 6 months (range: 2-24) were included. Based on imprecise evidence but with fairly consistent direction of effect, weight loss was associated with a statistically significant increase in α-diversity [SMD: 0.4 (95% CI: 0.2, 0.6], p < .0001, I2 = 70%, n = 30 studies) and a statistically significant reduction in intestinal permeability [SMD: -0.7 (95% CI: -0.9, -0.4), p < .0001, I2 = 83%, n = 17 studies]. Each kg of weight loss was associated with a 0.012 (95% CI: 0.0003, 0.024, p = .045) increase in α-diversity and a -0.017 (95% CI: -0.034, -0.001, p = .038) reduction in intestinal permeability. There was clear evidence of increases in the relative abundance of Akkermansia, but no clear evidence of changes in individual phyla, species, or fecal short-chain fatty acids. Restricting the analyses to the studies with lower risk of bias did not materially alter the estimates. Increasing weight loss is positively associated with increases in gut microbiota α-diversity and reductions in intestinal permeability.

On-Slide Heat Sterilization Enables Mass Spectrometry Imaging of Tissue Infected with High-Threat Pathogens Outside of Biocontainment: A Study Directed at Mycobacterium tuberculosis.

Mass spectrometry imaging investigations of tissues infected with agents that require high-security biocontainment, such as Mycobacterium tuberculosis, have been limited due to incompatible sterilization techniques. Here we describe an on-slide heat sterilization method that enables mass spectrometry imaging investigations of pharmaceuticals, lipids, and metabolites in infected tissue samples outside of biocontainment. An evaluation of different temperatures and incubation times determined that 100 °C for 1 h was essential to sterilize 5 times the bacterial burden observed in tuberculosis (TB) cavity sections. Laser-capture microdissection combined with liquid chromatography with tandem mass spectrometry quantitation, in addition to mass spectrometry imaging, showed that no degradation was observed following the on-slide heat sterilization protocol for a variety of drug classes covering a range of physicochemical properties. Utilizing the tissue mimetic model, we demonstrated that the detection of lipid and metabolite ions was not impacted by heat sterilization and that, for several metabolites, the on-slide heat sterilization method improved the sensitivity when compared to control samples. An application of the on-slide heat sterilization to M. tuberculosis infected tissue enabled the first detection and spatial distribution of lipids indicative of a lysosomal storage disease phenotype within TB granuloma macrophages, in addition to the differential distribution of metabolites central to the fatty acid oxidation pathway. These initial investigations detected a pronounced heterogeneity within the cellular regions and necrotic cores of individual TB granulomas and across different evolving granulomas. This study provides the framework for mass spectrometry imaging investigations of high-threat pathogens outside of biocontainment.

Targeting Mycobacterium tuberculosis response to environmental cues for the development of effective antitubercular drugs.

Sensing and response to environmental cues, such as pH and chloride (Cl-), is critical in enabling Mycobacterium tuberculosis (Mtb) colonization of its host. Utilizing a fluorescent reporter Mtb strain in a chemical screen, we have identified compounds that dysregulate Mtb response to high Cl- levels, with a subset of the hits also inhibiting Mtb growth in host macrophages. Structure-activity relationship studies on the hit compound "C6," or 2-(4-((2-(ethylthio)pyrimidin-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole, demonstrated a correlation between compound perturbation of Mtb Cl- response and inhibition of bacterial growth in macrophages. C6 accumulated in both bacterial and host cells, and inhibited Mtb growth in cholesterol media, but not in rich media. Subsequent examination of the Cl- response of Mtb revealed an intriguing link with bacterial growth in cholesterol, with increased transcription of several Cl--responsive genes in the simultaneous presence of cholesterol and high external Cl- concentration, versus transcript levels observed during exposure to high external Cl- concentration alone. Strikingly, oral administration of C6 was able to inhibit Mtb growth in vivo in a C3HeB/FeJ murine infection model. Our work illustrates how Mtb response to environmental cues can intersect with its metabolism and be exploited in antitubercular drug discovery.

What proportion of people have a follow-up biopsy in randomized trials of treatments for non-alcoholic steatohepatitis?: A systematic review and meta-analysis.

BACKGROUND AND AIM: Trials of treatments for non-alcoholic steatohepatitis require endpoint assessment with liver biopsies. Previous large-scale trials have calculated their sample size expecting high retention but on average did not achieve this. We aimed to quantify the proportion of participants with a valid follow-up biopsy. METHODS: We conducted a systematic review of MEDLINE and Embase until May 2020 and included randomized clinical trials of any intervention in non-alcoholic steatohepatitis with at least 1-year follow-up. We were guided by Cochrane methods to run a meta-analysis with generalized linear mixed models with random effects. RESULTS: Forty-one trials (n = 6,695) were included. The proportion of participants with a valid follow-up biopsy was 82% (95%CI: 78%-86%, I2 = 92%). There was no evidence of a difference by location, trial length, or by allocated treatment group. Reasons for missing follow-up biopsies were, in ranked order, related to participants (95 per 1,000 participants (95%CI: 69-129, I2 = 92%), medical factors, protocol, trial conduct, and other/unclear. Biopsy-related serious adverse events occurred in 16 per 1,000 participants (95% CI: 8-33, I2 = 54%). No biopsy-related deaths were reported. CONCLUSIONS: The proportion of participants with a valid follow-up biopsy in therapeutic trials in non-alcoholic steatohepatitis is on average 82%, with around 1 in 10 participants declining a follow-up biopsy. These findings can inform adequately-powered trials.

A replication-competent adenovirus-vectored influenza vaccine induces durable systemic and mucosal immunity.

BACKGROUNDTo understand the features of a replicating vaccine that might drive potent and durable immune responses to transgene-encoded antigens, we tested a replication-competent adenovirus type 4 encoding influenza virus H5 HA (Ad4-H5-Vtn) administered as an oral capsule or via tonsillar swab or nasal spray.METHODSViral shedding from the nose, mouth, and rectum was measured by PCR and culturing. H5-specific IgG and IgA antibodies were measured by bead array binding assays. Serum antibodies were measured by a pseudovirus entry inhibition, microneutralization, and HA inhibition assays.RESULTSAd4-H5-Vtn DNA was shed from most upper respiratory tract-immunized (URT-immunized) volunteers for 2 to 4 weeks, but cultured from only 60% of participants, with a median duration of 1 day. Ad4-H5-Vtn vaccination induced increases in H5-specific CD4+ and CD8+ T cells in the peripheral blood as well as increases in IgG and IgA in nasal, cervical, and rectal secretions. URT immunizations induced high levels of serum neutralizing antibodies (NAbs) against H5 that remained stable out to week 26. The duration of viral shedding correlated with the magnitude of the NAb response at week 26. Adverse events (AEs) were mild, and peak NAb titers were associated with overall AE frequency and duration. Serum NAb titers could be boosted to very high levels 2 to 5 years after Ad4-H5-Vtn vaccination with recombinant H5 or inactivated split H5N1 vaccine.CONCLUSIONReplicating Ad4 delivered to the URT caused prolonged exposure to antigen, drove durable systemic and mucosal immunity, and proved to be a promising platform for the induction of immunity against viral surface glycoprotein targets.TRIAL REGISTRATIONClinicalTrials.gov NCT01443936 and NCT01806909.FUNDINGIntramural and Extramural Research Programs of the NIAID, NIH (U19 AI109946) and the Centers of Excellence for Influenza Research and Surveillance (CEIRS), NIAID, NIH (contract HHSN272201400008C).

Sympathoinhibition and Vasodilation Contribute to the Acute Hypotensive Response of the Superoxide Dismutase Mimic, MnTnBuOE-2-PyP5+, in Hypertensive Animals.

The pathogenesis of hypertension has been linked to excessive levels of reactive oxygen species (ROS), particularly superoxide (O2•-), in multiple tissues and organ systems. Overexpression of superoxide dismutase (SOD) to scavenge O2•- has been shown to decrease blood pressure in hypertensive animals. We have previously shown that MnTnBuOE-2-PyP5+ (BuOE), a manganese porphyrin SOD mimic currently in clinical trials as a normal tissue protector for cancer patients undergoing radiation therapy, can scavenge O2•- and acutely decrease normotensive blood pressures. Herein, we hypothesized that BuOE decreases hypertensive blood pressures. Using angiotensin II (AngII)-hypertensive mice, we demonstrate that BuOE administered both intraperitoneally and intravenously (IV) acutely decreases elevated blood pressure. Further investigation using renal sympathetic nerve recordings in spontaneously hypertensive rats (SHRs) reveals that immediately following IV injection of BuOE, blood pressure and renal sympathetic nerve activity (RSNA) decrease. BuOE also induces dose-dependent vasodilation of femoral arteries from AngII-hypertensive mice, a response that is mediated, at least in part, by nitric oxide, as demonstrated by ex vivo video myography. We confirmed this vasodilation in vivo using doppler imaging of the superior mesenteric artery in AngII-hypertensive mice. Together, these data demonstrate that BuOE acutely decreases RSNA and induces vasodilation, which likely contribute to its ability to rapidly decrease hypertensive blood pressure.

Gross and Histological Examination of a Large Spheno-Orbital Meningioma.

Meningiomas arise from arachnoid cap cells and are the most common heavily researched intracranial tumors. Most of these neoplasms are benign and are classified as World Health Organization (WHO) grade I. They are often found in parasagittal and falx regions, over cerebral convexities, and in the sphenoid ridges. Spheno-orbital meningiomas (SOMs) occupy the cranium and the orbit and are less commonly encountered. Nonetheless, in this case study, a 9.5 cm × 5 cm SOM occurring in a 93-year-old female cadaver was identified and examined. The tumor spanned from the left middle cranial fossa, through the anterior fossa and invaded the orbit. It caused proptosis of the left eye, compression of the temporal lobe, and damage to the optic nerve. Histological examination of the tumor revealed characteristics of a WHO grade I meningothelial meningioma.

Nanoformulation of the superoxide dismutase mimic, MnTnBuOE-2-PyP5+, prevents its acute hypotensive response.

Scavenging superoxide (O2•-) via overexpression of superoxide dismutase (SOD) or administration of SOD mimics improves outcomes in multiple experimental models of human disease including cardiovascular disease, neurodegeneration, and cancer. While few SOD mimics have transitioned to clinical trials, MnTnBuOE-2-PyP5+ (BuOE), a manganese porphyrin SOD mimic, is currently in clinical trials as a radioprotector for cancer patients; thus, providing hope for the use of SOD mimics in the clinical setting. However, BuOE transiently alters cardiovascular function including a significant and precipitous decrease in blood pressure. To limit BuOE's acute hypotensive action, we developed a mesoporous silica nanoparticle and lipid bilayer nanoformulation of BuOE (nanoBuOE) that allows for slow and sustained release of the drug. Herein, we tested the hypothesis that unlike native BuOE, nanoBuOE does not induce an acute hypotensive response, as the nanoformulation prevents BuOE from scavenging O2•- while the drug is still encapsulated in the formulation. We report that intact nanoBuOE does not effectively scavenge O2•-, whereas BuOE released from the nanoformulation does retain SOD-like activity. Further, in mice, native BuOE, but not nanoBuOE, rapidly, acutely, and significantly decreases blood pressure, as measured by radiotelemetry. To begin exploring the physiological mechanism by which native BuOE acutely decreases blood pressure, we recorded renal sympathetic nerve activity (RSNA) in rats. RSNA significantly decreased immediately following intravenous injection of BuOE, but not nanoBuOE. These data indicate that nanoformulation of BuOE, a SOD mimic currently in clinical trials in cancer patients, prevents BuOE's negative side effects on blood pressure homeostasis.