Comparison of Oncogenes, Tumor Suppressors, and MicroRNAs Between Schizophrenia and Glioma: The Balance of Power.

The risk of cancer in schizophrenia has been controversial. Confounders of the issue are cigarette smoking in schizophrenia, and antiproliferative effects of antipsychotic medications. The author has previously suggested comparison of a specific cancer like glioma to schizophrenia might help determine a more accurate relationship between cancer and schizophrenia. To accomplish this goal, the author performed three comparisons of data; the first a comparison of conventional tumor suppressors and oncogenes between schizophrenia and cancer including glioma. This comparison determined schizophrenia has both tumor-suppressive and tumor-promoting characteristics. A second, larger comparison between brain-expressed microRNAs in schizophrenia with their expression in glioma was then performed. This identified a core carcinogenic group of miRNAs in schizophrenia offset by a larger group of tumor-suppressive miRNAs. This proposed "balance of power" between oncogenes and tumor suppressors could cause neuroinflammation. This was assessed by a third comparison between schizophrenia, glioma and inflammation in asbestos-related lung cancer and mesothelioma (ALRCM). This revealed that schizophrenia shares more oncogenic similarity to ALRCM than glioma.

Derivation of first-order dissolution rates to estimate particle clearance and burden in the human respiratory tract.

Inhalation is a portal-of-entry for aerosols via the respiratory tract where particulate burden accumulates depending on sites of particle deposition, normal clearance mechanisms, and particle solubility. The time available for dissolution of particles is determined by the balance between the rate of particle clearance from a region and their solubility in respiratory solvents. Dissolution is a function of particle surface area divided by particle volume or mass (i.e., dissolution is inversely proportional to the physical diameter of particles). As a conservative approach, investigators commonly assume the complete and instantaneous dissolution of metals from particles depositing in the alveolar region of the respiratory tract. We derived first-order dissolution rate constants to facilitate biokinetic modeling of particle clearance, dissolution, and absorption into the blood. We then modeled pulmonary burden and total dissolution of particles over time as a function of particle size, density, and solubility. We show that assuming poorly soluble particle forms will enter the blood as quickly as highly soluble forms causes an overestimation of concentrations of the compound of interest in blood and other extrapulmonary tissues while also underestimating its pulmonary burden. We conclude that, in addition to modeling dose rates for particle deposition into the lung, physiologically based pharmacokinetic modeling of pulmonary and extrapulmonary tissues concentrations of moderately and poorly soluble materials can be improved by including estimates of lung burden and particle dissolution over time.

A developmental approach to diversifying neuroscience through effective mentorship practices: perspectives on cross-identity mentorship and a critical call to action.

Many early-career neuroscientists with diverse identities may not have mentors who are more advanced in the neuroscience pipeline and have a congruent identity due to historic biases, laws, and policies impacting access to education. Cross-identity mentoring relationships pose challenges and power imbalances that impact the retention of diverse early career neuroscientists, but also hold the potential for a mutually enriching and collaborative relationship that fosters the mentee's success. Additionally, the barriers faced by diverse mentees and their mentorship needs may evolve with career progression and require developmental considerations. This article provides perspectives on factors that impact cross-identity mentorship from individuals participating in Diversifying the Community of Neuroscience (CNS)-a longitudinal, National Institute of Neurological Disorders and Stroke (NINDS) R25 neuroscience mentorship program developed to increase diversity in the neurosciences. Participants in Diversifying CNS were comprised of 14 graduate students, postdoctoral fellows, and early career faculty who completed an online qualitative survey on cross-identity mentorship practices that impact their experience in neuroscience fields. Qualitative survey data were analyzed using inductive thematic analysis and resulted in four themes across career levels: (1) approach to mentorship and interpersonal dynamics, (2) allyship and management of power imbalance, (3) academic sponsorship, and (4) institutional barriers impacting navigation of academia. These themes, along with identified mentorship needs by developmental stage, provide insights mentors can use to better support the success of their mentees with diverse intersectional identities. As highlighted in our discussion, a mentor's awareness of systemic barriers along with active allyship are foundational for their role.

Accuracy of preoperative clinical examination and imaging for mandibular resection in oral cancer: a systematic review of diagnostic test accuracy studies.

The aim of this systematic review is not only to analyse the accuracy of clinical examination and radiological preoperative assessment of mandibular invasion reported in isolation, but to highlight those reports that have combined them. A total of 1636 titles and abstracts published between 1995 - 2000 were screened following a literature search in PubMed. Keywords were "mandible" and "squamous cell carcinoma". A total of 90 full manuscripts were reviewed with 24 meeting defined inclusion/exclusion criteria and yielding the data reported. The most sensitive test was single photon emission tomography with eight out of the 10 studies reporting sensitivity higher than 95%. Magnetic resonance imaging (MRI) demonstrated superior sensitivity but was less specific than computed tomography (CT). A single report attempted to report the combined CT and MRI scans with a separate expert reporting but did not result in more reliable detection. Periosteal stripping was not reported, and there was insufficient data to establish the value of new technologies. This review confirms that, to our knowledge, there are no reliable data on the results of combining imaging techniques with or without clinical examination. It emphasises the lack of data for the combination of preoperative techniques to enhance safe oncological resection of the mandible. Based on the evidence gathered in this review an algorithm of assessment of possible mandibular invasion is proposed. With new technologies available and 3-dimensional models to help plan the mandibular resection and reconstruction, the potential of combining preoperative investigations should be fully realised through prospective research.

Evaluation of the integrated exposure uptake biokinetic (IEUBK) model for lead in children.

BACKGROUND: The Integrated Exposure Uptake Biokinetic Model for Lead in Children (IEUBK model) was developed by the U.S. Environmental Protection Agency to support assessments of health risks to children from exposures to lead (Pb). OBJECTIVE: This study evaluated performance of IEUBK model (v2.0) as it would be typically applied at Superfund sites to predict blood Pb levels (BLLs) in populations of children. METHODS: The model was evaluated by comparing model predictions of BLLs to 1144 observed BLLs in a population of children at the Bunker Hill Superfund Site for which there were paired estimates of environmental Pb concentrations. RESULTS: Predicted population geometric mean (GM) BLLs (GM: 3.4 µg/dL, 95% CI: 3.3, 3.5) were within 0.3 µg/dL of observed (GM: 3.6 µg/dL, 95% CI: 3.5, 3.8). The model predicted the observed age trend in GM BLLs and explained ~90% of the variance in the observed age-stratified GM BLLs. The mean predicted probability of exceeding 5 µg/dL (P5) was 27% (95% CI: 24, 29) and observed P5 was 32% (95% CI: 29, 35), a difference of 5%. Differences between geographic area stratified mean P5 (predicted minus observed) ranged from -11 to 14% (mean difference: 2.3%). SIGNIFICANCE: Although the more general applicability of these findings to other populations remains to be determined in future studies, our results support applications of the IEUBK model (v2.0) for informing risk-based decisions regarding remediation of soils and mitigation of exposures at Superfund sites where the majority of the exposure unit GM BLLs are expected to be ≤5 µg/dL and where it is desired to limit the predicted probability of exceeding 5 µg/dL to <5%.

Treatment of cancer with antipsychotic medications: Pushing the boundaries of schizophrenia and cancer.

Over a century ago, the phenothiazine dye, methylene blue, was discovered to have both antipsychotic and anti-cancer effects. In the 20th-century, the first phenothiazine antipsychotic, chlorpromazine, was found to inhibit cancer. During the years of elucidating the pharmacology of the phenothiazines, reserpine, an antipsychotic with a long historical background, was likewise discovered to have anti-cancer properties. Research on the effects of antipsychotics on cancer continued slowly until the 21st century when efforts to repurpose antipsychotics for cancer treatment accelerated. This review examines the history of these developments, and identifies which antipsychotics might treat cancer, and which cancers might be treated by antipsychotics. The review also describes the molecular mechanisms through which antipsychotics may inhibit cancer. Although the overlap of molecular pathways between schizophrenia and cancer have been known or suspected for many years, no comprehensive review of the subject has appeared in the psychiatric literature to assess the significance of these similarities. This review fills that gap and discusses what, if any, significance the similarities have regarding the etiology of schizophrenia.

Estimating the Effects of Soil Remediation on Children's Blood Lead near a Former Lead Smelter in Omaha, Nebraska, USA.

BACKGROUND: Lead exposures from legacy sources threaten children's health. Soil in Omaha, Nebraska, was contaminated by emissions from a lead smelter and refinery. The U.S. Environmental Protection Agency excavated and replaced contaminated soil at the Omaha Lead Superfund Site between 1999 and 2016. OBJECTIVES: The goal of this study was to assess the association of soil lead level (SLL) and soil remediation status with blood lead levels (BLLs) in children living near or on the site. METHODS: We linked information on SLL at residential properties with children's BLLs and assigned remediation status to children's BLL measurements based on whether their measurements occurred during residence at remediated or unremediated properties. We examined the association of SLL and remediation status with elevated BLL (EBLL). We distinguished the roles of temporal trend and the intervention with time-by-intervention-status interaction contrasts. All analyses estimated odds ratios (ORs) with a generalized estimating equations approach to ensure robustness under the complex correlations among BLL measurements. All analyses controlled for relevant covariates including children's characteristics. RESULTS: EBLL (>5µg/dL) was associated with both residential SLL [e.g., OR=2.00; 95% confidence interval (CI): 1.83, 2.19; >400-800 vs. ≤200 ppm] and neighborhood SLL [e.g., OR=1.85 (95% CI: 1.62, 2.11; >400-800 vs. ≤200 ppm)] before remediation but only with neighborhood SLL after remediation. The odds of EBLL were higher before remediation [OR 1.52 (95% CI: 1.34, 1.72)]. Similarly, EBLL was positively associated with preremediation status in our interaction analysis [interaction OR=1.18 (95%CI: 1.02, 1.37)]. DISCUSSION: Residential and neighborhood SLLs were important predictors of EBLLs in children residing near or on this Superfund site. Neighborhood SLL remained a strong predictor following remediation. Our data analyses showed the benefit of soil remediation. Results from the interaction analyses should be interpreted cautiously due to imperfect correspondence of remediation times between remediation and comparison groups. https://doi.org/10.1289/EHP8657.

The relevance of surgical margins in clinically early oral squamous cell carcinoma.

OBJECTIVES: There is controversy regarding surgical margins in the management of early oral squamous cell carcinoma (OSCC). The main objectives of this study were to assess the: relevance of the margin independent of tumour variables; threshold for a safe margin; relevance of dysplasia at the margin. MATERIALS & METHODS: UK based retrospective multicenter cohort study of patients with previously untreated and clinically early OSCC between 1998 and 2016. All patients had surgery as the primary modality and had surgical staging of the neck. Minimum follow-up was 2 years. Margins were classified as: clear ≥5.0 mm; close 1.0-4.9 mm; involved not cut-through (INC-T) 0.1-0.9 mm; cut-through (C-T) 0 mm. RESULTS: 669 patients were included. After adjusting for tumour variables Cox multivariate regression analysis demonstrated that close margins had similar survival outcomes to clear margins (Hazard Ratio(HR) 0.99 (95%CI 0.50-1.95) for Local Recurrence Free Survival (LRFS); HR 1.08 (95%CI 0.7-1.66) for Disease Free Survival (DFS); HR 0.74 (95%CI 0.44-1.25) for Disease Specific Survival (DSS); HR 0.80 (95%CI 0.58-1.11) for Overall Survival (OS)). C-T margins had significantly worse LRFS (HR 5.01 (95%CI 2.02-12.39)) and DFS (HR 2.58 (95%CI 1.28-5.20)). INC-T margins had significantly worse DFS (HR 1.98 (95% CI 1.01-3.87)). Time dependent receiver operating characteristic curve analysis did not demonstrate a clear margin threshold for LRFS within 24 months (AUC = 0.53 (95%CI 0.41-0.64)). Dysplasia at the margin did not influence LRFS or DFS. CONCLUSION: Only resection margins <1 mm independently affected survival outcomes. This should be considered when making decisions regarding adjuvant treatment.

An audit of routine practice: a prospective study on the use of mouth props in oral surgery.

Introduction Mouth props are routinely used for patients treated under general but not local anaesthesia (LA). Patient discomfort and excess operator time is an often cited argument against the routine use of mouth props.Aim and methods We surveyed patients, surgeons and assistants following the use of mouth props during minor oral surgical procedures under LA in order to assess their acceptability and utility in clinical practice.Results Forty-seven patients were included, with 24 patients treated using mouth props and 23 without. Thirty-three patients had dental extractions, three had intraoral biopsies and one underwent a tube removal following cyst marsupialisation.Discussion Patients reported less difficulty in mouth opening where a mouth prop was used. Patients reported similarly low levels of discomfort with or without a mouth prop. Ninety-five percent of patients who used a mouth prop reported they would recommend their use. The surgeon and assistant reported mouth opening as less problematic and assisting as easier where a mouth prop was used.Conclusion The results of this study demonstrate the benefits and broad acceptability of mouth prop use in the awake patient. We question current practice in that mouth props are not routinely offered to patients during oral surgical and dental procedures.

Estimates of urinary blood lead clearance and its relationship to glomerular filtration rate based on a large population survey.

Blood lead (Pb) clearance (CbPb) and serum creatinine clearance (CsCr), a metric of glomerular filtration rate (GFR), were estimated in approximately 7,600 subjects from the NHANES (2009-2016). Median CbPb in adults was 0.04 L/day (5th-95th percentile range: 0.01-0.12). Linear regression models explained approximately 68% of variance in CbPb in adults, with >98% of explained variance attributed to CsCr. These results provide an improved quantitative understanding of the possible effects of reverse causality in the interpretation of studies of associations between blood Pb and decrements in GFR.

Interpreting Mobile and Handheld Air Sensor Readings in Relation to Air Quality Standards and Health Effect Reference Values: Tackling the Challenges.

The US Environmental Protection Agency (EPA) and other federal agencies face a number of challenges in interpreting and reconciling short-duration (seconds to minutes) readings from mobile and handheld air sensors with the longer duration averages (hours to days) associated with the National Ambient Air Quality Standards (NAAQS) for the criteria pollutants-particulate matter (PM), ozone, carbon monoxide, lead, nitrogen oxides, and sulfur oxides. Similar issues are equally relevant to the hazardous air pollutants (HAPs) where chemical-specific health effect reference values are the best indicators of exposure limits; values which are often based on a lifetime of continuous exposure. A multi-agency, staff-level Air Sensors Health Group (ASHG) was convened in 2013. ASHG represents a multi-institutional collaboration of Federal agencies devoted to discovery and discussion of sensor technologies, interpretation of sensor data, defining the state of sensor-related science across each institution, and provides consultation on how sensors might effectively be used to meet a wide range of research and decision support needs. ASHG focuses on several fronts: improving the understanding of what hand-held sensor technologies may be able to deliver; communicating what hand-held sensor readings can provide to a number of audiences; the challenges of how to integrate data generated by multiple entities using new and unproven technologies; and defining best practices in communicating health-related messages to various audiences. This review summarizes the challenges, successes, and promising tools of those initial ASHG efforts and Federal agency progress on crafting similar products for use with other NAAQS pollutants and the HAPs. NOTE: The opinions expressed are those of the authors and do not necessary represent the opinions of their Federal Agencies or the US Government. Mention of product names does not constitute endorsement.

Postoperative radiotherapy for patients with oral squamous cell carcinoma with intermediate risk of recurrence: A case match study.

BACKGROUND: The purpose of this study was to determine the effect of postoperative radiotherapy (PORT) on recurrence and survival in patients with oral squamous cell carcinoma (OSCC) of intermediate recurrence risk. METHODS: Intermediate risk patients, defined as pT1, pT2, pN0, or pN1 with at least one adverse pathological feature (eg, lymphovascular/perineural invasion), were identified from the head and neck databases of the Liverpool Head and Neck Cancer Unit and the Sydney Head and Neck Cancer Institute. Patients who received surgery and PORT were case matched with patients treated by surgery alone based on pN, pT, margins, and pathological features. RESULTS: Ninety patients were matched into 45 pairs. There was significant improvement (P = .039) in locoregional control with PORT (84%) compared with surgery alone (60%), which was concentrated in the pN1 subgroup (P = .036), but not the pN0 subgroup (P = .331). CONCLUSION: PORT significantly improves locoregional control for intermediate risk OSCC.

Personality and Neural Correlates of Mentalizing Ability.

Theory of mind, or mentalizing, defined as the ability to reason about another's mental states, is a crucial psychological function that is disrupted in some forms of psychopathology, but little is known about how individual differences in this ability relate to personality or brain function. One previous study linked mentalizing ability to individual differences in the personality trait Agreeableness. Agreeableness encompasses two major subdimensions: Compassion reflects tendencies toward empathy, prosocial behavior, and interpersonal concern, whereas Politeness captures tendencies to suppress aggressive and exploitative impulses. We hypothesized that Compassion but not Politeness would be associated with better mentalizing ability. This hypothesis was confirmed in Study 1 (N = 329) using a theory of mind task that required reasoning about the beliefs of fictional characters. Post hoc analyses indicated that the honesty facet of Agreeableness was negatively associated with mentalizing. In Study 2 (N = 217), we examined whether individual differences in mentalizing and related traits were associated with patterns of resting-state functional connectivity in the brain. Performance on the theory of mind task was significantly associated with patterns of connectivity between the dorsal medial and core subsystems of the default network, consistent with evidence implicating these regions in mentalization.

Cases of remission of psychosis following resection of pheochromocytoma or paraganglioma.

The author previously proposed that schizophrenia has similar cytokine expression compared to melanoma, a neural crest cell tumor. One possible tumor model of schizophrenia includes anti-NMDA receptor encephalitis, a paraneoplastic syndrome. While examining the possible relationship of neural crest cell tumors to schizophrenia, the author found several case reports of psychosis resulting from pheochromocytomas and paragangliomas, types of neural crest cell tumors that secrete catecholamines. In most cases, surgical resection of the tumors resulted in remission of psychotic symptoms, and some remissions were associated with reduced levels of peripheral catecholamine levels. These reports suggest, first, that the differential diagnosis of psychosis with autonomic instability should include these tumors. Second, the cases raise a theoretical question as to how these tumors might cause psychosis. On one hand, the elevated peripheral catecholamines caused by these tumors generally agree with aspects of the dopamine hypothesis of schizophrenia although the mechanism of how peripheral dopamine would cause psychosis is unknown. On the other hand, these tumors could possibly secrete an unidentified antibody to a receptor similar to what is observed in anti-NMDA receptor encephalitis.

Cancer Immune Equilibrium and Schizophrenia Have Similar Interferon-γ, Tumor Necrosis Factor-α, and Interleukin Expression: A Tumor Model of Schizophrenia.

For at least a century, a debate has continued as to whether cancer risk is reduced in schizophrenia. Genetic studies have also suggested the 2 conditions may share protein transcriptional pathways. The author predicted that if the pathophysiology of schizophrenia confers protection from cancer, then the immunology of schizophrenia should reflect a state of tumor suppression, ie, the opposite of tumor escape. To examine this possibility, the author performed a literature search for measurements of cytokines in drug-naïve first episode subjects with schizophrenia for comparison with cytokine expression in tumor escape vs tumor suppression. The comparison showed that instead of either tumor suppression or escape, schizophrenia appears to be in a state of tumor equilibrium. Based on this finding, the author hypothesized that the clinical presentation of schizophrenia may involve cell transformation similar to an early stage of cancer initiation or an attenuated tumorigenesis. While this condition could reflect the presence of an actual tumor such as an ovarian teratoma causing anti-NMDA receptor encephalitis, it would only explain a small percentage of cases. To find a more likely tumor model, the author then compared the cytokine profile of schizophrenia to individual cancers and found the best match was melanoma. To demonstrate the viability of the theory, the author compared the hallmarks, emerging hallmarks, and enabling characteristics of melanoma to schizophrenia and found that many findings in schizophrenia are understood if schizophrenia is a condition of attenuated tumorigenesis.

A new classification for mandibular defects after oncological resection.

No universally accepted classification system exists for mandibular defects after oncological resection. Here, we discuss the scientific literature on classifications for mandibular defects that are sufficiently presented either pictorially or descriptively, and propose a new classification system based on these findings. Of 167 studies included in the data analysis, 49 of these reports sufficiently described the defect for analysis. These reports were analysed for classification, reconstruction, size of defect, number of osteotomies needed, and complications. On the basis of these findings, a new classification is proposed based on the four corners of the mandible (two angles and two canines): class I (lateral), class II (hemimandibulectomy), class III (anterior), and class IV (extensive). Further classes (Ic, IIc, and IVc) include condylectomy. The increasing defect class relates to the size of the defect, osteotomy rate, and functional and aesthetic outcome, and could guide the method of reconstruction.

Nitrogen dioxide exposure and airway responsiveness in individuals with asthma.

Controlled human exposure studies evaluating the effect of inhaled nitrogen dioxide (NO2) on the inherent responsiveness of the airways to challenge by broncho-constricting agents have had mixed results. In general, existing meta-analyses show statistically significant effects of NO2 on the airway responsiveness of individuals with asthma. However, no meta-analysis has provided a comprehensive assessment of the clinical relevance of changes in airway responsiveness, the potential for methodological biases in the original papers, and the distribution of responses. This paper provides analyses showing that a statistically significant fraction (i.e. 70% of individuals with asthma exposed to NO2 at rest) experience increases in airway responsiveness following 30-min exposures to NO2 in the range of 200 to 300 ppb and following 60-min exposures to 100 ppb. The distribution of changes in airway responsiveness is log-normally distributed with a median change of 0.75 (provocative dose following NO2 divided by provocative dose following filtered air exposure) and geometric standard deviation of 1.88. About a quarter of the exposed individuals experience a clinically relevant reduction in their provocative dose due to NO2 relative to air exposure. The fraction experiencing an increase in responsiveness was statistically significant and robust to exclusion of individual studies. Results showed minimal change in airway responsiveness for individuals exposed to NO2 during exercise.

Influence of surgical margins on local recurrence in T1/T2 oral squamous cell carcinoma.

BACKGROUND: The purpose of this study was to explore the significance of resection margin status on local recurrence and survival for early (T1/T2) oral cancer and to determine if the significance of the resection margin varies with the biological aggression of the tumor as determined by pN status. METHODS: The influence of resection margin size and local recurrence for 295 patients with pT1/T2 oral cavity squamous cell carcinomas (SCCs) treated by primary surgery, including neck dissection, between 1998 and 2010 was analyzed. RESULTS: Overall, there was a trend toward increased local recurrence with close or involved margins. When stratified according to nodal status, there was no relationship between margin size and local recurrence for the pN0 group. CONCLUSION: The size of the resection margin does not seem to influence local control in stage I/II oral cancer. With future advances in preoperative neck staging, this data may help plan personalized therapy in head and neck cancer.