Systematic evidence mapping of potential correlates of exposure for per- and poly-fluoroalkyl substances (PFAS) based on measured occurrence in biomatrices and surveys of dietary consumption and product use.

Per- and poly-fluoroalkyl substances (PFAS) are widely observed in environmental media and often are found in indoor environments as well as personal-care and consumer products. Humans may be exposed through water, food, indoor dust, air, and the use of PFAS-containing products. Information about relationships between PFAS exposure sources and pathways and the amounts found in human biomatrices can inform source-contribution assessments and provide targets for exposure reduction. This work collected and collated evidence for correlates of PFAS human exposure as measured through sampling of biomatrices and surveys of dietary consumption and use of consumer products and articles. A systematic evidence mapping approach was applied to perform a literature search, conduct title-abstract and full-text screening, and to extract primary data into a comprehensive database for 16 PFAS. Parameters of interest included: sampling dates and locations, cohort descriptors, PFAS measured in a human biomatrix, information about food consumption in 11 categories, use of products/articles in 11 categories, and reported correlation values (and their statistical strength). The literature search and screening process yielded 103 studies with information for correlates of PFAS exposures. Detailed data were extracted and compiled on measures of PFAS correlations between biomatrix concentrations and dietary consumption and other product/article use. A majority of studies (61/103; 59%) were published after 2015 with few (8/103; 8%) prior to 2010. Studies were most abundant for dietary correlates (n = 94) with fewer publications reporting correlate assessments for product use (n = 56), while some examined both. PFOA and PFOS were assessed in almost all studies, followed by PFHxS, PFNA, and PFDA which were included in >50% of the studies. No relevant studies included PFNS or PFPeS. Among the 94 studies of dietary correlates, significant correlations were reported in 83% of the studies for one or more PFAS. The significant dietary correlations most commonly were for seafood, meats/eggs, and cereals/grains/pulses. Among the 56 studies of product/article correlates, significant correlations were reported in 70% of the studies. The significant product/article correlations most commonly were for smoking/tobacco, cosmetics/toiletries, non-stick cookware, and carpet/flooring/furniture and housing. Six of 11 product/article categories included five or fewer studies, including food containers and stain- and water-resistant products. Significant dietary and product/article correlations most commonly were positive. Some studies found a mix of positive and negative correlations depending on the PFAS, specific correlate, and specific response level, particularly for fats/oils, dairy consumption, food containers, and cosmetics/toiletries. Most of the significant findings for cereals/grains/pulses were negative correlations. Substantial evidence was found for correlations between dietary intake and biomatrix levels for several PFAS in multiple food groups. Studies examining product/article use relationships were relatively sparse, except for smoking/tobacco, and would benefit from additional research. The resulting database can inform further assessments of dietary and product use exposure relationships and can inform new research to better understand PFAS source-to-exposure relationships. The search strategy should be extended and implemented to support living evidence review in this rapidly advancing area.

The role of pharmacist in community palliative care-a scoping review.

OBJECTIVES: Dynamic and adaptive services that provide timely access to care are pivotal to ensuring patients with palliative needs experience high-quality care. Patients who have palliative care needs may require symptomatic relief with medicines and, therefore, may engage with community pharmacists frequently. However, there is limited evidence for pharmacists' involvement in community palliative care models. Therefore, a scoping review was conducted to identify pharmacists' role in community palliative care. METHODS: A systematic search strategy was implemented across PubMed, PsychINFO, CINAHL, and Embase databases. Articles were screened by abstract and full text against inclusion and exclusion criteria. KEY FINDINGS: Five articles (two from Australia, two from England, and one from Scotland) met the inclusion criteria and described interventions involving pharmacists in community palliative care. This review has identified that the inclusion of trained pharmacists in community palliative care teams can improve the quality of care provided for patients with palliative needs. Pharmacists are able to undertake medication reviews and provide education to patients and other healthcare professionals on the quality use of palliative care medicines. Additionally, the underutilization of community pharmacists in palliative care, the need for further training of pharmacists, and improved community pharmacy access to patient information to deliver community palliative care were identified. CONCLUSION: Pharmacists can play a vital role in community palliative care to enhance the quality of life of patients. There is a need for greater pharmacist education/training, improved interprofessional communication, improved access to patient information and sustainable funding to strengthen community-based palliative care.

Retrospective review of the toxicities and change in dosing patterns for pegaspargase in patients with acute lymphoblastic leukemia/lymphoma and T-cell lymphoma.

INTRODUCTION: Pegaspargase (PEG) is a key component of standard regimens for acute lymphoblastic leukemia/lymphoma (ALL) and extranodal natural killer/T-cell lymphoma (NKTCL). Emerging evidence suggests an opportunity to decrease incidence of PEG-associated toxicities with dose capping, but evidence is limited. This study aims to evaluate whether a significant difference in PEG-associated toxicities related to dosing strategy exists and to identify patient-specific or regimen-specific factors for PEG-related toxicity. METHODS: A retrospective analysis of PEG-associated toxicities was completed in adult patients with ALL or NKTCL who received PEG within Cancer and Leukemia Group B (CALGB) 10403 or modified dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (mSMILE) regimens at the UW Medical Center/Fred Hutchinson Cancer Center. PEG-associated toxicities that occurred through 8 weeks after PEG doses were noted. RESULTS: Twenty-eight patients received dose-capped PEG, and 29 received noncapped PEG. Fewer all-grade and grade 3/4 toxicities were observed in the dose-capped cohort. Grade 3/4 toxicities observed were hepatotoxicity, hyperglycemia, hypersensitivity, and hypertriglyceridemia. In addition, fewer grade 3/4 pancreatitis and thrombosis events occurred in the dose-capped cohort. Hypertriglyceridemia and hepatotoxicity were associated with the highest cumulative incidence proportions among all toxicities. CONCLUSION: Dose capping of PEG was associated with a similar or later median onset for most toxicities, a less heterogeneic toxicity profile, and a lower recurrence of most toxicities upon PEG rechallenge compared to the non-dose-capped cohort. Standardizing PEG dose capping in the CALGB 10403 and mSMILE regimens may translate to improved tolerance compared to a historical standard of no dose capping PEG.

Evidence for an event-integration window: A cognitive temporal window supports flexible integration of multimodal events.

Just as the perception of simple events such as clapping hands requires a linkage of sound with movements that produce the sound, the integration of more complex events such as describing how to give an injection requires a linkage between the instructor's utterances and their actions. However, the mechanism for integrating these complex multimodal events is unclear. For example, it is possible that predictive temporal relationships are important for multimodal event understanding, but it is also possible that this form of understanding arises more from meaningful causal between-event links that are temporally unspecified. This latter approach might be supported by a cognitive temporal window within which multimodal event information integrates flexibly with few default commitments about specific temporal relationships. To test this hypothesis, we assessed the consequences of disrupting temporal relationships between instructors' actions and their speech in both narrated screen-capture instructional videos (Experiment 1) and live-action instructional videos (Experiment 2) by displacing the audio channel forward or backward relative to the video by 0, 1, 3, or 7 s. We assessed learning, event segmentation, disruption awareness, segmentation uncertainty, and perceived workload. Across two experiments, 7-s temporal disruptions consistently increased uncertainty and workload and decreased learning in Experiment 2. None of these effects appeared for 3-s disruptions, which were barely detectable. One-second disruptions produced no effects and were undetectable, even though much intraevent information falls within this range. Our results suggest the presence of an event-integration window that supports the integration of events independent of constraining temporal relationships between subevents. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Assessing community pharmacy services in health professional shortage areas across Wisconsin.

BACKGROUND: Primary care health professional shortage areas (HPSAs) lack sufficient primary care providers to meet their health care needs, which contributes to worse health outcomes within underserved populations. Community pharmacies are commonly located in HPSAs and provide nondispensing services that can help address unmet health care needs. However, there is limited data on the nature, scope, and reimbursement for community pharmacy services. OBJECTIVES: Using survey data from the state of Wisconsin, this study compares the prevalence of and reimbursement for services provided by community pharmacies in primary care HPSAs and non-HPSAs and describes barriers to pharmacy service implementation. METHODS: A survey tool on pharmacy services, reimbursement, and barriers to service implementation was developed, pilot tested, and administered to every community pharmacy in Wisconsin. Data were collected via mail and online over two waves of survey administration from November 2021 to May 2022. Pearson's chi-squared and t tests were used to compare the prevalence of and reimbursement for services between HPSA and non-HPSA pharmacies. Content analysis was used to identify themes that described barriers to pharmacy service implementation. RESULTS: Responses were received from 287 of 774 eligible community pharmacies (37.1%). HPSA pharmacies were significantly more likely to be in rural areas. Regardless of pharmacy location, community pharmacies reported commonly providing a variety of services, but reimbursement for these services was considerably less frequent. The prevalence of reimbursement was <50% for two-thirds of services. Pharmacy staffing, time, and financial issues were the most commonly reported barriers to service implementation. CONCLUSIONS: Community pharmacies provide a diverse set of services to meet the health care needs of their patients, but often do so with inadequate staffing or reimbursement. Action is needed to support community pharmacies in meeting the health care needs of their communities and to ensure patient access to medications and pharmacy services.

Mechanism underlying follicular hyperproliferation and oncogenesis in hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a skin disorder that causes chronic painful inflammation and hyperproliferation, often with the comorbidity of invasive keratoacanthoma (KA). Our research, employing high-resolution immunofluorescence and data science approaches together with confirmatory molecular analysis, has identified that the 5'-cap-dependent protein translation regulatory complex eIF4F is a key factor in the development of HS and is responsible for regulating follicular hyperproliferation. Specifically, eIF4F translational targets, Cyclin D1 and c-MYC, orchestrate the development of HS-associated KA. Although eIF4F and p-eIF4E are contiguous throughout HS lesions, Cyclin D1 and c-MYC have unique spatial localization and functions. The keratin-filled crater of KA is formed by nuclear c-MYC-induced differentiation of epithelial cells, whereas the co-localization of c-MYC and Cyclin D1 provides oncogenic transformation by activating RAS, PI3K, and ERK pathways. In sum, we have revealed a novel mechanism underlying HS pathogenesis of follicular hyperproliferation and the development of HS-associated invasive KA.

When searching helps you see: Bridging the gap between incidental and intentional change detection.

Participants in incidental change detection studies often miss large changes to visually salient or conceptually relevant objects such as actor substitutions across video cuts, but there are competing explanations of why participants fail to detect these changes. According to an integrative processing account, object-based attention typically induces integrated representation and comparison processes sufficient to detect changes to that object. On this view, participants miss changes in incidental paradigms because those paradigms fail to elicit the level of attention necessary to trigger integrated representation and comparison processes. In contrast, a selective processing account posits that representation and comparison processes needed to detect changes do not occur by default, even for attended objects, but are only elicited in response to specific functional needs. In four experiments, we tested detection of actor substitutions when participants engaged in tasks that required actor identity processing but did not necessarily require the combination of processes necessary to detect changes. Change blindness for actor substitutions persisted when participants counted the number of actors in the video and sometimes persisted when participants were instructed to remember the substituted actor for later recall. Change blindness consistently diminished, however, when participants were shown the prechange actor before or during the video and instructed to search for that actor in the video. Our results refine the contrast between selective and integrative processing by specifying how task demands to create durable visual representations can remain independent of comparison processes, while search demands can induce integrative comparison processes in a naturalistic setting. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Role of hair follicles in the pathogenesis of arsenical-induced cutaneous damage.

Arsenical vesicants cause skin inflammation, blistering, and pain. The lack of appropriate animal models causes difficulty in defining their molecular pathogenesis. Here, Ptch1+/- /C57BL/6 mice were employed to investigate the pathobiology of the arsenicals lewisite and phenylarsine oxide (PAO). Following lewisite or PAO challenge (24 h), the skin of animals becomes grayish-white, thick, leathery, and wrinkled with increased bi-fold thickness, Draize score, and necrotic patches. In histopathology, infiltrating leukocytes (macrophages and neutrophils), epidermal-dermal separation, edema, apoptotic cells, and disruption of tight and adherens junction proteins can be visualized. PCR arrays and nanoString analyses showed significant increases in cytokines/chemokines and other proinflammatory mediators. As hair follicles (HFs), which provide an immune-privileged environment, may affect immune cell trafficking and consequent inflammatory responses, we compared the pathogenesis of these chemicals in this model to that in Ptch1+/- /SKH-1 hairless mice. Ptch1+/- /SKH-1 mice have rudimentary, whereas Ptch1+/- /C57BL/6 mice have well-developed HFs. Although no significant differences were observed in qualitative inflammatory responses between the two strains, levels of cytokines/chemokines differed. Importantly, the mechanism of inflammation was identical; both reactive oxygen species induction and consequent activation of unfolded protein response signaling were similar. These data reveal that the acute molecular pathogenesis of arsenicals in these two murine models is similar.

Ex Vivo Culture Models of Hidradenitis Suppurativa for Defining Molecular Pathogenesis and Treatment Efficacy of Novel Drugs.

Hidradenitis suppurativa (HS) is a complex and debilitating inflammatory skin disease for which no effective treatment is available currently. This is partly because of the lack of adequate human or animal models for defining the pathobiology of the disease. Here, we describe the development of air-liquid (A-L) interface, liquid-submersion (L-S), and bioreactor (Bio) ex vivo skin culture models. All three ex vivo platforms were effective for culturing skin samples for up to 14 days. Tissue architecture and integrity remained intact for at least 3 days for healthy skin and 14 days for HS skin. Up to day 3, no significant differences were observed in % early apoptotic cells among all three platforms. However, late apoptotic/necrotic cell death was increased in HS skin at day 3 in A-L and Bio culture. These cultures efficiently support the growth of various cells populations, including keratinocytes and immune cells. Profiling inflammatory gene signatures in HS skin from these ex vivo cultures showed dynamic changes in expression at day 3 and day 14. All three culture platforms were necessary to represent the inflammatory gene status of HS skin at day 0, suggesting that not all gene clusters were identically altered in each culture method. Similarly, cytokine/chemokine profiling of the supernatants from vehicle- and drug-treated ex vivo HS cultures again showed a better prediction of drug efficacy against HS. Overall, development of these three culture systems collectively provides a powerful tool to uncover the pathobiology of HS progression and screen various drugs against HS.

Hepatitis C Virus Reflex Testing Protocol in an Emergency Department.

INTRODUCTION: Our aim was to measure hepatitis C virus (HCV) screening and linkage-to-care rates in an urban emergency department (ED) before and after implementing an HCV viral RNA (vRNA) reflex testing protocol within a HCV screening program for at-risk patients. Our hypothesis was that using a reflex testing protocol would increase HCV testing rates of at-risk patients in the ED, which would increase the linkage-to-care rate. METHODS: In August 2018, our institution implemented an automated, electronic health record-based HCV screening protocol in the ED for at-risk patients. In January 2019, we implemented an HCV vRNA reflex testing protocol (reflex testing) for all positive HCV antibody (Ab) tests that were initiated through the screening protocol. We compared completion rates of HCV vRNA testing and the rate of linkage to care for patients with positive HCV Ab test results before and after implementation of reflex testing (five months per study period). RESULTS: Prior to reflex testing implementation, 233/425 (55%) patients with a positive HCV Ab test had an HCV vRNA test performed, whereas 270/323 (84%) patients with a positive HCV Ab test result had vRNA testing after reflex testing implementation (odds ratio [OR], 4.2; 95% confidence interval (CI): 3.0-6.0; P < 0.001). Of the eligible patients with positive HCV Ab test results who could be linked to care, 45 (10.6%) were linked to care before HCV reflex implementation and 46 (14.2%) were linked to care with reflex testing (OR, 1.4; 95% CI: 0.9-2.2; P = 0.13). CONCLUSION: Implementing a reflex testing initiative into an HCV screening program in the ED can result in an increase of the percentage of patients who receive an HCV vRNA test after having had a positive HCV Ab. Hepatitis C virus vRNA reflex testing was not associated with a statistically significant increase in linkage-to-care rates for HCV Ab-positive patients; however, further studies are required.

Occupational health outcomes among sanitation workers: A systematic review and meta-analysis.

BACKGROUND: Sanitation workers are essential to global public health and societal wellbeing. However, the health risks and outcomes associated with exposure to occupational risk factors among sanitation workers are neither well understood nor well quantified. We undertook a systematic review to (1) identify occupational risk factors among sanitation workers and (2) assess the effect of occupational exposure to human fecal sludge and wastewater on selected health outcomes among these workers. METHODS: We searched four databases (i.e., PubMED, MEDLINE, EMBASE, and LILACS) for eligible studies from inception through to January 01, 2020. The included population was workers ≥15 years engaged, formally or informally, in installing, operating, servicing, cleaning or emptying a sanitation technology at any step of the sanitation chain. The included comparator was workers in other occupations or the general population. Eligible outcomes were: mortality (any or all causes), gastroenteritis, occupational injuries, respiratory diseases, musculoskeletal disorders, and mental and social health conditions. Risk of bias was assessed separately on exposure assessment and health outcome using a modified Liverpool Quality Assessment Tool (LQAT). We pooled sufficiently homogenous studies using inverse variance meta-analysis with random effects. RESULTS: A total of 65 studies (9 cohort studies, 56 cross-sectional studies) met the inclusion criteria. One quarter of studies (n = 15) were from middle-income countries. Few studies assessed occupational risk factor exposures directly; most assigned exposure via proxy of occupation of sanitation worker. We judged nearly all studies to have "high risk of bias" in exposure and outcome assessment. Despite these limitations, the consistency of the overall evidence suggests that sanitation workers are at increased risk of gastroenteritis and respiratory conditions, and may be at increased risk of musculoskeletal disorders and mental/social health conditions. The pooled odds ratio for hepatitis A--the only outcome deemed suitable for meta-analysis--was 2.09 (95% Predicted Interval: 1.39-3.00, 12 studies). There was conflicting evidence from studies of increased risk of mortality; only one study reported on injuries. CONCLUSION: Despite a large number of studies, there is limited evidence to date of the health risks faced by sanitation workers, particularly among groups that may be at particular risk-- women, informal workers and those living in low-income countries. Nevertheless, the research to date provides suggestive evidence of elevated occupational risk among sanitation workers across a range of health condition. More research is needed to improve the current bodies of evidence for all included health outcomes to be able to quantify disease burden among this occupational group.

A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma.

Li Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in TP53. TP53 is the most common mutated gene in human cancer, occurring in 30-50% of glioblastomas (GBM). Here, we highlight a precision medicine platform to identify potential targets for a GBM patient with LFS. We used a comparative transcriptomics approach to identify genes that are uniquely overexpressed in the LFS GBM patient relative to a cancer compendium of 12,747 tumor RNA sequencing data sets, including 200 GBMs. STAT1 and STAT2 were identified as being significantly overexpressed in the LFS patient, indicating ruxolitinib, a Janus kinase 1 and 2 inhibitors, as a potential therapy. The LFS patient had the highest level of STAT1 and STAT2 expression in an institutional high-grade glioma cohort of 45 patients, further supporting the cancer compendium results. To empirically validate the comparative transcriptomics pipeline, we used a combination of adherent and organoid cell culture techniques, including ex vivo patient-derived organoids (PDOs) from four patient-derived cell lines, including the LFS patient. STAT1 and STAT2 expression levels in the four patient-derived cells correlated with levels identified in the respective parent tumors. In both adherent and organoid cultures, cells from the LFS patient were among the most sensitive to ruxolitinib compared to patient-derived cells with lower STAT1 and STAT2 expression levels. A spheroid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. Two targeted therapies were selected for the patient of interest and resulted in radiographic disease stability. This manuscript supports the use of comparative transcriptomics to identify personalized therapeutic targets in a functional precision medicine platform for malignant brain tumors.

Genomic and Transcriptomic Profiling of Brain Metastases.

Brain metastases (BM) are the most common brain tumors in adults occurring in up to 40% of all cancer patients. Multi-omics approaches allow for understanding molecular mechanisms and identification of markers with prognostic significance. In this study, we profile 130 BM using genomics and transcriptomics and correlate molecular characteristics to clinical parameters. The most common tumor origins for BM were lung (40%) followed by melanoma (21%) and breast (15%). Melanoma and lung BMs contained more deleterious mutations than other subtypes (p < 0.001). Mutational signatures suggested that the bulk of the mutations were gained before metastasis. A novel copy number event centered around the MCL1 gene was found in 75% of all samples, suggesting a broader role in promoting metastasis. Unsupervised hierarchical cluster analysis of transcriptional signatures available in 65 samples based on the hallmarks of cancer revealed four distinct clusters. Melanoma samples formed a distinctive cluster in comparison to other BM subtypes. Characteristics of molecular profiles did not correlate with survival. However, patients with self-identified black race or those who did not receive radiation correlated with poor survival. These data identify potential new drivers of brain metastatic progression. Our data also suggest further investigation of sociodemographic and clinical features is needed in BM cohorts.

Biobanked Glioblastoma Patient-Derived Organoids as a Precision Medicine Model to Study Inhibition of Invasion.

Glioblastoma (GBM) is highly resistant to treatment and invasion into the surrounding brain is a cancer hallmark that leads to recurrence despite surgical resection. With the emergence of precision medicine, patient-derived 3D systems are considered potentially robust GBM preclinical models. In this study, we screened a library of 22 anti-invasive compounds (i.e., NF-kB, GSK-3-B, COX-2, and tubulin inhibitors) using glioblastoma U-251 MG cell spheroids. We evaluated toxicity and invasion inhibition using a 3D Matrigel invasion assay. We next selected three compounds that inhibited invasion and screened them in patient-derived glioblastoma organoids (GBOs). We developed a platform using available macros for FIJI/ImageJ to quantify invasion from the outer margin of organoids. Our data demonstrated that a high-throughput invasion screening can be done using both an established cell line and patient-derived 3D model systems. Tubulin inhibitor compounds had the best efficacy with U-251 MG cells, however, in ex vivo patient organoids the results were highly variable. Our results indicate that the efficacy of compounds is highly related to patient intra and inter-tumor heterogeneity. These results indicate that such models can be used to evaluate personal oncology therapeutic strategies.

Pulsed reduced dose-rate radiotherapy for previously irradiated tumors in the brain and spine.

BACKGROUND: Patients with unresectable locoregional cancer recurrences have limited management options. Reirradiation increases the risk of toxicity, particularly when perilesional dose-volume constraints are exceeded. We present and discuss two cases of previously irradiated tumors in the central nervous system (CNS) that was reirradiated using the pulsed reduced dose-rate radiotherapy (PRDR) technique. CASE DESCRIPTION: A 58-year-old female with a history of metastatic small cell lung cancer to the brain status post multiple rounds of radiation and chemotherapy presented with increasing weakness in her right arm and leg. Magnetic resonance imaging (MRI) revealed a growly peripherally enhancing 1.2 cm mass in the left precentral gyrus that had previously received prophylactic cranial irradiation and stereotactic radiosurgery. The patient was re-irradiated with 35 Gy in 100 fractions over 3 weeks, using PRDR with improved motor function at 3-month follow-up. A 41-year-old male with recurrent glioblastoma of the thoracic spinal cord presented with worsening neurological symptoms, including inability to ambulate due to bilateral leg weakness, causing wheelchair use. MRI thoracic spine revealed a recurrent thoracic lesion 2.2 × 1 × 0.8 cm. In addition to chronic chemotherapy, the patient was retreated palliatively in the same area at 50 Gy in 250 fractions, over 6 weeks, using PRDR. The treated lesion was stable on follow-up imaging, and the patient was able to walk with the assistance of a walker. CONCLUSION: In our two cases, PRDR proved effective in the treatment of recurrent malignant CNS tumors that were previously irradiated. Prospective studies are needed to delineate the efficacy and toxicity of PRDR.

Brain Tumor Biobank Development for Precision Medicine: Role of the Neurosurgeon.

Neuro-oncology biobanks are critical for the implementation of a precision medicine program. In this perspective, we review our first year experience of a brain tumor biobank with integrated next generation sequencing. From our experience, we describe the critical role of the neurosurgeon in diagnosis, research, and precision medicine efforts. In the first year of implementation of the biobank, 117 patients (Female: 62; Male: 55) had 125 brain tumor surgeries. 75% of patients had tumors biobanked, and 16% were of minority race/ethnicity. Tumors biobanked were as follows: diffuse gliomas (45%), brain metastases (29%), meningioma (21%), and other (5%). Among biobanked patients, 100% also had next generation sequencing. Eleven patients qualified for targeted therapy based on identification of actionable gene mutations. One patient with a hereditary cancer predisposition syndrome was also identified. An iterative quality improvement process was implemented to streamline the workflow between the operating room, pathology, and the research laboratory. Dedicated tumor bank personnel in the department of neurosurgery greatly improved standard operating procedure. Intraoperative selection and processing of tumor tissue by the neurosurgeon was integral to increasing success with cell culture assays. Currently, our institutional protocol integrates standard histopathological diagnosis, next generation sequencing, and functional assays on surgical specimens to develop precision medicine protocols for our patients. This perspective reviews the critical role of neurosurgeons in brain tumor biobank implementation and success as well as future directions for enhancing precision medicine efforts.

Presence of estrogen and progesterone receptors in proliferating and involuting infantile hemangiomas.

BACKGROUND: Studies in the literature have demonstrated the presence of sex hormone receptors in infantile hemangiomas (IHs), but further investigation is needed to determine the role of these receptors in their proliferation and involution. To date, there are no studies in the literature that aimed to quantitatively examine the expression of sex hormone receptors throughout the different phases of hemangioma development. OBJECTIVE: The objective of our study was to quantitatively evaluate the expression of estrogen (ER) and progesterone (PR) receptors in the proliferative and involuting phases of IHs through the use of real-time polymerase chain reaction (RT-PCR). METHODS: Twenty IHs (10 proliferating and 10 involuting) were harvested and prepared for molecular investigation. ER receptor alpha (ERα) and beta (ERß) and the PR expression were examined by RT-PCR and western blot. RESULTS: RT-PCR analysis demonstrated that mRNA expression of ERα, ERß, and PR was significantly lower in proliferating versus involuting IH. Western blot analysis revealed increased protein expression of ERα in involuting hemangiomas as compared to proliferating ones. CONCLUSIONS: Our study demonstrates the variable expression of ER and PR receptors in proliferating and involuting hemangiomas. Further studies are needed to determine the exact role of these hormone receptors in the growth and involution of IHs.

Lactobacillus rescues postnatal neurobehavioral and microglial dysfunction in a model of maternal microbiome dysbiosis.

Increasing reports of pregnancy events leading to maternal microbiome dysbiosis (MMD) show strong correlates with atypical neurodevelopmental outcomes. However, the mechanism(s) driving microbiome-mediated behavioral dysfunction in offspring remain understudied. Here, we demonstrate the presence of a novel gut commensal bacterium strain, Lactobacillus murinus HU-1, was sufficient to rescue behavioral deficits and brain region-specific microglial activationobserved in MMD-reared murine offspring. We furtheridentified a postnatal window of susceptibility that could prevent social impairments with timed maternal administration of the symbiotic bacterium. Moreover, MMD increased expression of microglial senescence genes, Trp53 and Il1ß, and Cx3cr1 protein in the prefrontal cortex, which correlated with dysfunctional modeling of synapses and accompanied dysbiosis-induced microglial activation. MMD male offspring harboring Lactobacillus murinus HU-1 or lacking Cx3cr1 showed amelioration of these effects. The current study describes a new avenue of influence by which maternally transferred Lactobacillus drives proper development of social behavior in the offspring through microglia-specific regulation of Cx3cr1 signaling.

Abnormal elastin and collagen deposition is present in extracranial arteriovenous malformations: A comparison to intracranial disease.

BACKGROUND: Vascular malformations are characterized by anomalous vascular channels with fragile walls and a propensity to bleed. Arteriovenous malformations (AVMs) in particular have disorganized vascular spaces with intervening fibrosis. Characterization of the structural abnormalities of these vessels has not been comprehensively evaluated. We hypothesize that AVMs are likely to demonstrate altered elastic and collagen fiber organization and distribution, reflecting their fragility, vascular instability, and abnormal development. METHODS: Fifteen AVMs were histologically evaluated by H&E, elastin and trichrome staining. To identify potential differences between extracranial and intracranial AVMs, 5 AVMs were harvested from the brain (n=5) and 10 from extracranial sites involving the skin and deep soft tissue (n=10). RESULTS: The elastin staining demonstrated reduplication, fragmentation and disruption of internal elastic lamina as well as irregular thickness, and inconsistent vascular density of all AVM specimens. Trichrome staining revealed thickening of the intimal layers of AVM arteries and demonstrated an irregular thickness of venous walls within the malformation and some areas of medial degeneration. Intracranial AVMs are characterized by more intramural inflammation with predominant neutrophil and lymphocyte infiltration. In contrast, extracranial AVMs display more extravascular inflammation with mast cell and neutrophil infiltration. Microvascular proliferations intervening between larger blood vessels were also noted in both types of AVMs, but more obvious in extracranial AVMs. CONCLUSION: These observed histologic anomalies of AVMs demonstrate disorganized deposition of elastin and collagen that point to the clinically observed vascular instability and fragility of these lesions.

Retinoic acid receptor gamma impacts cellular adhesion, Alpha5Beta1 integrin expression and proliferation in K562 cells.

The interplay between cellular adhesion and proliferation is complex; however, integrins, particularly the α5ß1 subset, play a pivotal role in orchestrating critical cellular signals that culminate in cellular adhesion and growth. Retinoids modify the expression of a variety of adhesive/proliferative signaling proteins including α5ß1 integrins; however, the role of specific retinoic acid receptors involved in these processes has not been elucidated. In this study, the effect of all-trans-retinoic acid receptor (RAR) agonists on K562 cellular adhesion, proliferation, and α5ß1 integrin cell surface expression was investigated. RARγ agonist exposure increased K562 cellular adhesion to RGD containing extracellular matrix proteins fibronectin and FN-120 in a time- and concentration dependent manner, while RARα or RARß agonist treatment had no effect on cellular adhesion. Due to the novel RARγ- dependent cellular adhesion response exhibited by K562 cells, we examined α5 and ß1 integrin subunit expression when K562 cells were exposed to retinoid agonists or vehicle for 24, 48, 72 or 96 hours. Our data demonstrates no differences in K562 cell surface expression of the α5 integrin subunit when cells were exposed to RARα, RARß, or RARγ agonists for all time points tested. In contrast, RARγ agonist exposure resulted in an increase in cell surface ß1 integrin subunit expression within 48 hours that was sustained at 72 and 96 hours. Finally, we demonstrate that while exposure to RARα or RARß agonists have no effect on K562 cellular proliferation, the RARγ agonist significantly dampens K562 cellular proliferation levels in a time- and concentration- dependent manner. Our study is the first to report that treatment with a RARγ specific agonist augments cellular adhesion to α5ß1 integrin substrates, increases cell surface levels of the ß1 integrin subunit, and dampens cellular proliferation in a time and concentration dependent manner in a human erythroleukemia cell line.