Immunocompetent isolated cerebral mucormycosis presenting with obstructive hydrocephalus: illustrative case.

BACKGROUND: Isolated cerebral mucormycosis is rare in immunocompetent adults and is only sparsely reported to be associated with obstructive hydrocephalus. OBSERVATIONS: Here, the authors report a case of obstructive hydrocephalus secondary to central nervous system mucormycosis without other systems or rhino-orbital involvement and its technical surgical management. A 23-year-old, incarcerated, immunocompetent patient with history of intravenous (IV) drug use presented with syncope. Although clinical and radiographic findings failed to elucidate an infectious pathology, endoscopy revealed an obstructive mass lesion at the level of the third ventricle, which, on microbiological testing, was confirmed to be Rhizopus fungal ventriculitis. Perioperative cerebrospinal fluid diversion, endoscopic third ventriculostomy, endoscopic biopsy technique, patient outcomes, and the literature are reviewed here. The patient received intrathecal and IV amphotericin B followed by a course of oral antifungal treatment and currently remains in remission. LESSONS: The patient's unique presentation and diagnosis of isolated cerebral mucormycosis reveal this pathogen as a cause of ventriculitis and obstructive hydrocephalus in immunocompetent adult patients, even in the absence of infectious sequelae on neuroimaging.

Neurodevelopmental outcomes of extremely preterm infants with bronchopulmonary dysplasia (BPD) - A retrospective cohort study.

OBJECTIVE: To investigate the neurodevelopmental outcomes for preterm infants born < 29 weeks gestation with/without bronchopulmonary dysplasia (BPD). STUDY DESIGN: Preterm infants < 29 weeks' gestation born 2007-2018 in New South Wales and the Australian Capital Territory, Australia, were included. Infants who died < 36 weeks' postmenstrual age and those with major congenital anomalies were excluded. Subjects were assessed at 18-42 months corrected age using the Bayley Scales of Infant Development, 3rd edition. RESULTS: 1436 infants without BPD (non-BPD) and 1189 infants with BPD were followed. The BPD group, 69 % infants were discharged without respiratory support (BPD1), 29 % on oxygen (BPD2) and 2 % on pressure support/tracheostomy (BPD3). Moderate neurodevelopmental impairment (NDI) was evident in 5.7 % of non-BPD infants, 11 % BPD1, 15 % BPD2, 15 % BPD3 infants. Severe NDI was seen in 1.7 % non-BPD infants, 3.4 % BPD1, 7.3 % BPD2, 35 % BPD3 infants. After adjusting for confounders, infants with BPD2 (OR 2.24, 99.9 % CI 1.25 to 5.77) or BPD3 (OR 5.99, 99.9 % CI 1.27 to 46.77) were more likely to have moderate-severe NDI compared to non-BPD infants. CONCLUSION: The majority of infants with BPD were discharged home without respiratory support and had better neurocognitive outcomes in early childhood compared to those that required home-based oxygen or respiratory support.

Mitral Regurgitation Complicated by Cardiogenic Shock: Reassessing Risk Stratification and Therapeutic Strategies.

Mitral regurgitation complicated by cardiogenic shock creates a unique and devastating risk profile for patients and poses significant difficulties for physicians who lack a comprehensive range of effective management strategies. Supportive measures such as intravenous vasodilators, intra-aortic balloon pumps, and percutaneous ventricular assist devices are often necessary to stabilize patients prior to definitive treatment with surgical mitral valve replacement or trans-catheter edge-to-edge repair. This review evaluates the evidence for the available supportive and definitive management strategies in patients with mitral regurgitation complicated by cardiogenic shock and presents a framework to aid clinicians in navigating the complex clinical decision-making process. Additionally, the authors review emerging transcatheter mitral valve replacement technologies that hold promise for expanding the therapeutic armamentarium and improving patient outcomes.

A diffusible small-RNA-based Turing system dynamically coordinates organ polarity.

The formation of a flat and thin leaf presents a developmentally challenging problem, requiring intricate regulation of adaxial-abaxial (top-bottom) polarity. The patterning principles controlling the spatial arrangement of these domains during organ growth have remained unclear. Here we show that this regulation in Arabidopsis thaliana is achieved by an organ-autonomous Turing reaction-diffusion system centred on mobile small RNAs. The data illustrate how Turing dynamics transiently instructed by prepatterned information is sufficient to self-sustain properly oriented polarity in a dynamic, growing organ, presenting intriguing parallels to left-right patterning in the vertebrate embryo. Computational modelling demonstrates that this self-organizing system continuously adapts to coordinate the robust planar polarity of a flat leaf while affording flexibility to generate the tissue patterns of evolutionarily diverse organ shapes. Our findings identify a small-RNA-based Turing network as a dynamic regulator of organ polarity that accounts for leaf shape diversity at the level of the individual organ, plant or species.

A Prospective Multicenter Longitudinal Analysis of Suicidal Ideation among Long-COVID-19 Patients.

Long coronavirus disease 19 (COVID-19) is an emerging multifaceted illness with the pathological hallmarks of chronic inflammation and neuropsychiatric symptoms. These pathologies have also been implicated in developing suicidal behaviors and suicidal ideation (SI). However, research addressing suicide risk in long COVID-19 is limited. In this prospective study, we aim to characterize SI development among long-COVID-19 patients and to determine the predictive power of inflammatory markers and long-COVID-19 symptoms-including those of psychiatric origin-for SI. During this prospective, longitudinal, multicenter study, healthy subjects and long-COVID-19 patients will be recruited from the University Hospital of Geneva, Switzerland, the University of Genova, the University of Rome "La Sapienza", and the University of San Francisco. Study participants will undergo a series of clinic visits over a follow-up period of 1 year for SI assessment. Baseline and SI-onset levels of inflammatory mediators in plasma samples, along with 12 long-COVID-19 features (post-exertional malaise, fatigue, brain fog, dizziness, gastrointestinal disturbance, palpitations, changes in sexual desire/capacity, loss/change of smell/taste, thirst, chronic cough, chest pain, and abnormal movements) will be collected for SI risk analysis. The proposed enrollment period is from 15 January 2024 to 15 January 2026 with targeted recruitment of 100 participants for each study group. The anticipated findings of this study are expected to provide important insights into suicide risk among long-COVID-19 patients and determine whether inflammation and psychiatric comorbidities are involved in the development of SI in these subjects. This could pave the way to more effective evidence-based suicide prevention approaches to address this emerging public health concern.

Fracture behaviour assessment of high-performance fibre-reinforced concrete at high strain rates using interpretable modelling approaches.

High-performance fibre-reinforced concrete (HPFRC), a type of cementitious composite material known for its exceptional mechanical performance, has widespread applications in structures exposed to severe dynamic loading conditions. However, understanding nonlinear HPFRC fracture behaviour, particularly under high strain rates, remains challenging given the complexities of assessment procedures and cost-intensive nature of experiments. This study presents an interpretable framework for modelling and analysing HPFRC fracture strength at high strain rates. A wide range of machine learning methods, including ensemble techniques, were employed to capture multivariate effects of eight essential input features (e.g., mortar compressive strength, fibre physical and mechanical properties, cross-sectional area, and strain rate) on fracture strength response. To assess the derived models, a novel evaluation procedure was proposed involving a data-based analysis, employing established metrics (i.e., coefficient of determination, root mean squared error, and mean absolute error via K-fold cross-validation) and a domain experts-involved evaluation utilising global sensitivity analysis to discern first-order and higher-order interactions among input factors. The proposed approach efficiently yielded both quantitative and qualitative insights into crucial input factors governing HPFRC fracture strength with limited experimental data. The obtained findings highlight the significance of multivariate effects, such as the interaction between strain rate and fibre tensile strength, and between fibre volume and fibre diameter, on fracture behaviour. The proposed interpretable framework aims to provide a powerful tool for proactive material failure analysis by understanding fracture behaviour and identifying potential weak and strong interactions among input factors of HPFRC-based samples. Moreover, the utilisation of the proposed approach enables researchers and civil engineers to efficiently focus on the most critical input parameters during the early design stage and ensuring the structural integrity and safety of HPFRC-based constructions.

Corrigendum to "Polysaccharide and ethanol extracts of Anoectochilus formosanus Hayata: Antioxidant, wound-healing, antibacterial, and cytotoxic activities".

[This corrects the article DOI: 10.1016/j.heliyon.2023.e13559.].

The action of endo-xylanase and endo-glucanase on cereal cell wall polysaccharides and its implications for starch digestion kinetics in an in vitro poultry model.

Endo-xylanase and endo-glucanase are supplemented to poultry diets in order to improve nutrient digestion and non-starch polysaccharide (NSP) fermentation. Here, the action of these enzymes on alcohol insoluble solids (AIS) from wheat and maize grains as well as its implications for starch digestion in milled grains were evaluated in vitro, under conditions mimicking the poultry digestive tract. For wheat AIS, GH11 endo-xylanase depolymerized soluble arabinoxylan (AX) during the gizzard phase, and proceeded to release insoluble AX under small intestine conditions. At the end of the in vitro digestion (480 min), the endo-xylanase, combined with a GH7 endo-ß-1,4-glucanase, released 30.5 % of total AX and 18.1 % of total glucan in the form of arabinoxylo- and gluco-oligosaccharides, as detected by HPAEC-PAD and MALDI-TOF-MS. For maize AIS, the combined enzyme action released 2.2 % and 7.0 % of total AX and glucan, respectively. Analogous in vitro digestion experiments of whole grains demonstrated that the enzymatic release of oligomers coincided with altered grain microstructure, as examined by SEM. In the present study, cell wall hydrolysis did not affect in vitro starch digestion kinetics for cereal grains. This study contributes to understanding the action of feed enzymes on cereal NSP under conditions mimicking the poultry digestive tract.

Assessing the clinical reasoning of ChatGPT for mechanical thrombectomy in patients with stroke.

BACKGROUND: Artificial intelligence (AI) has become a promising tool in medicine. ChatGPT, a large language model AI Chatbot, shows promise in supporting clinical practice. We assess the potential of ChatGPT as a clinical reasoning tool for mechanical thrombectomy in patients with stroke. METHODS: An internal validation of the abilities of ChatGPT was first performed using artificially created patient scenarios before assessment of real patient scenarios from the medical center's stroke database. All patients with large vessel occlusions who underwent mechanical thrombectomy at Tulane Medical Center between January 1, 2022 and December 31, 2022 were included in the study. The performance of ChatGPT in evaluating which patients should undergo mechanical thrombectomy was compared with the decisions made by board-certified stroke neurologists and neurointerventionalists. The interpretation skills, clinical reasoning, and accuracy of ChatGPT were analyzed. RESULTS: 102 patients with large vessel occlusions underwent mechanical thrombectomy. ChatGPT agreed with the physician's decision whether or not to pursue thrombectomy in 54.3% of the cases. ChatGPT had mistakes in 8.8% of the cases, consisting of mathematics, logic, and misinterpretation errors. In the internal validation phase, ChatGPT was able to provide nuanced clinical reasoning and was able to perform multi-step thinking, although with an increased rate of making mistakes. CONCLUSION: ChatGPT shows promise in clinical reasoning, including the ability to factor a patient's underlying comorbidities when considering mechanical thrombectomy. However, ChatGPT is prone to errors as well and should not be relied on as a sole decision-making tool in its present form, but it has potential to assist clinicians with more efficient work flow.

Synthesis of 2-benzyl benzoxazoles and benzothiazoles via elemental sulfur promoted cyclization of styrenes with 2-nitrophenols and N,N-dialkyl-3-nitroanilines.

Herein we report a method for affording 2-benzyl benzoxazoles from substituted styrenes and 2-nitrophenols. The success of this method relies on the use of simple reagents, namely elemental sulfur and DABCO. A combination of identical reagents was utilized for the annulation of styrenes with N,N-dialkyl-3-nitroanilines to afford 2-benzyl benzothiazoles. Overall, benzoxazoles and benzothiazoles bearing useful functionalities such as halogens, amines, and heterocyclic groups were isolated in moderate to good yields. Our methods are a rare example of divergent transformations of substituted nitroarenes towards 2-benzyl benzoxazoles and benzothiazoles.

Effect of Red Mud and Rice Husk Ash-Based Geopolymer Composites on the Adsorption of Methylene Blue Dye in Aqueous Solution for Wastewater Treatment.

In this study, geopolymer originating from locally industrial byproducts as red mud (RM) was successfully prepared in the presence of different loadings of rice husk ash (RHA) used for the adsorption of methylene blue (MB) in wastewater. During geopolymerization, various mixing amounts between RM and RHA were conducted when the weight ratio of binder solution/activated alkali-metal solution (Na2SiO3/ NaOH 7 M) was 2.5 and the curing temperature was set at 60 °C for 24 h. As a result, the surface area value of the prepared geopolymer composited with RHA at 0 and 60% was increased from 19.2 to 29.5 m2/g, while the BJH pore size of the prepared geopolymer was reduced to 6.68 and 5.76 nm, respectively. In the dye removal test, higher additions of RHA in the RM-geopolymer maintained better retention of the MB ion due to the increase in the adsorption binding site. The maximum uptake amount of dyes performed at pH 8 was changed from 6.59 to 10.74 mg/g, while RHA was from 0 to 60% after 180 min of immersion in MB solution. The adsorption isotherms well obeyed the Langmuir model, as the relative coefficient R2 was 0.999. Based on these, the initial agricultural waste as RHA and industrial byproducts as RM were valued as functional materials used for dye treatment in wastewater.

Immunomodulatory Effects of Clozapine: More Than Just a Side Effect in Schizophrenia.

Recent evidence suggests a possible relationship between the immune system and schizophrenia spectrum disorders (SSDs), as neuroinflammation appears to play a role in major psychiatric conditions. Neuroinflammation is as a broad concept representing a physiological protective response to infection or injury, but in some cases, especially if chronic, it may represent an expression of maladaptive processes, potentially driving to clinical dysfunction and neurodegeneration. Several studies are concurrently highlighting the importance of microglia, the resident immune cells of the central nervous system, in a huge number of neurodegenerative diseases, including multiple sclerosis, Alzheimer's and Parkinson's diseases, as well as SSDs. A more fundamental phenomenon of maladaptive coupling of microglia may contribute to the genesis of dysfunctional brain inflammation involved in SSDs, from the onset of their neurophenomenological evolution. Clozapine and other antipsychotic drugs seem to express a provable immunomodulant effect and a more specific action on microglia, while neuroactive steroids and nonsteroidal anti-inflammatory drugs may reduce some SSDs symptoms in add-on therapy. Given these theoretical premises, this article aims to summarize and interpret the available scientific evidence about psychotropic and anti-inflammatory drugs that could express an immunomodulant activity on microglia.

Electrochemical Aptamer-Based Biosensors for Measurements in Undiluted Human Saliva.

Although blood remains a gold standard diagnostic fluid for most health exams, it involves an unpleasant and relatively invasive sampling procedure (finger pricking or venous draw). Saliva contains many relevant and useful biomarkers for diagnostic purposes, and its collection, in contrast, is noninvasive and can be obtained with minimal effort. Current saliva analyses are, however, achieved using chromatography or lateral flow assays, which, despite their high accuracy and sensitivity, can demand expensive laboratory-based instruments operated by trained personnel or offer only semiquantitative results. In response, we investigated electrochemical aptamer-based (E-AB) biosensors, a reagentless sensing platform, to allow for continuous and real-time measurements directly in undiluted, unstimulated human whole saliva. As a proof-of-concept study, we developed E-AB biosensors capable of detecting low-molecular-weight analytes (glucose and adenosine monophosphate (AMP)). To our knowledge, we report the first E-AB sensor for glucose, an approach that is inherently independent of its chemical reactivity in contrast to home glucometers. For these three sensors, we evaluated their figures of merits, stability, and reusability over short- and long-term exposure directly in saliva. In doing so, we found that E-AB sensors allow rapid and convenient molecular measurements in whole saliva with unprecedented sensitivities in the pico- to nanomolar regime and could be regenerated and reused up to 7 days when washed and stored in phosphate-buffered saline at room temperature. We envision that salivary molecular measurements using E-AB sensors are a promising alternative to invasive techniques and can be used for improved point-of-care clinical diagnosis and at-home measurements.

The diagnostic performance of AFP and PIVKA-II models for non-B non-C hepatocellular carcinoma.

OBJECTIVE: This study aims to describe the diagnostic performance of alpha-fetoprotein (AFP), alpha-fetoprotein L3 isoform (AFP-L3), protein induced by vitamin K absence II (PIVKA-II), and combined biomarkers for non-B non-C hepatocellular carcinoma (NBNC-HCC). RESULTS: A total of 681 newly-diagnosed primary liver disease subjects (385 non-HCC, 296 HCC) who tested negativity for the hepatitis B surface antigen (HBsAg) and hepatitis C antibody (anti-HCV) enrolled in this study. At the cut-off point of 3.8 ng/mL, AFP helps to discriminate HCC from non-HCC with an area under the curve (AUC) value of 0.817 (95% confidence interval [CI]: 0.785-0.849). These values of AFP-L3 (cut-off 0.9%) and PIVKA-II (cut-off 57.7 mAU/mL) were 0.758 (95%CI: 0.725-0.791) and 0.866 (95%CI: 0.836-0.896), respectively. The Bayesian Model Averaging (BMA) statistic identified the optimal model, including patients' age, aspartate aminotransferase, AFP, and PIVKA-II combination, which helps to classify HCC with better performance (AUC = 0.896, 95%CI: 0.872-0.920, P < 0.001). The sensitivity and specificity of the optimal model reached 81.1% (95%CI: 76.1-85.4) and 83.2% (95%CI: 78.9-86.9), respectively. Further analyses indicated that AFP and PIVKA-II markers and combined models have good-to-excellent performance detecting curative resected HCC, separating HCC from chronic hepatitis, dysplastic, and hyperplasia nodules.

Developing and assessing the efficiency of VOSER software in recording dental caries according to WHO's criteria 2013.

Background/purpose: World Health Organization (WHO) oral health survey manual is the main guideline for most oral health surveys worldwide. It has been updated several times since 1971; however, using papers and pens for data recording remains unchanged. This study aimed to develop the Vietnam Oral Survey Electronics Recorder (VOSER) to record dental caries data based on the WHO 2013 criteria and assess its reliability and efficiency. Materials and methods: VOSER was developed and tested for reliability and efficiency by performing clinical examinations on 365 school children in three key indicator age groups: 120 5-year-old students with primary dentition, 123 8-year-old students with mixed dentition, and 122 12-year-old students with permanent dentition. One gold standard examiner and two trained clerks examined these children using either WHO's paper survey form or VOSER's digital form for dental caries. Recording time, spreadsheet time, DMFT/S, and dmft/s were analyzed to compare the efficiency of VOSER to the paper form. Cohen's Kappa, intraclass correlation coefficient, and Wilcoxon signed-rank test were adopted in the data analyses. Results: Median time of using VOSER was significantly shorter than the standard time in all three dentitions (P < 0.001). Cohen's Kappa values between data collected by VOSER and paper form showed almost perfect agreements (0.927-0.958). DMFT/S and dmft/s values calculated from data collected by both methods had good to excellent reliabilities (0.791-0.997). Conclusion: VOSER is efficient and reliable for conducting dental caries surveys according to the WHO 2013 criteria and should be utilized in the era of digital technology.

Clinician Response to Pharmacogenetic Clinical Decision Support Alerts.

The objective of this study was to characterize clinician response following standardization of pharmacogenetic (PGx) clinical decision support alerts at University of Florida (UF) Health. A retrospective analysis of all PGx alerts that fired at a tertiary academic medical center from August 2020 through May 2022 was performed. Alert acceptance rate was calculated and compared across six gene-drug pairs, patient care setting, and clinician specialty. The disposition of the triggering medication was compared with the alert response and evaluated for congruence. There were a total of 818 alerts included for analysis of alert response, 557 alerts included in acceptance rate calculations, and 392 alerts with sufficient information to assess clinical response. The overall acceptance rate was 63%. The alert response and clinical response were congruent for 47% of alerts. Alert response was influenced by the triggering gene-drug pair, clinician specialty, patient care setting, and specialty of the provider who initially ordered the PGx test. Clinical response was mostly incongruent with alert response. Alert acceptance is influenced by the triggering gene-drug pair, clinician specialty, and care setting. Alert response is not a reliable surrogate marker for clinical action. Any future research into the impact of clinical decision support (CDS) alerts should focus on clinical response rather than alert response. Given the reliance on CDS alerts to enhance uptake of PGx, it is worthwhile to further investigate their impact on prescribing and patient outcomes.

Lessons from clinical implementation of a preemptive pharmacogenetic panel as part of a testing pilot program with an employer-sponsored medical plan.

Introduction: This manuscript reports on a pilot program focused on implementing pharmacogenetic testing within the framework of an employer-sponsored medical plan at University of Florida (UF) Health. The aim was to understand the challenges associated with program implementation and to gather insights into patient attitudes towards PGx testing. Methods: The pilot program adopted a partially preemptive approach, targeting patients on current prescriptions for medications with relevant gene-drug associations. Patients were contacted via phone or through the MyChart system and offered pharmacogenetic testing with no additional direct costs. Results: Of 244 eligible patients, 110 agreed to participate. However, only 61 returned the mailed DNA collection kits. Among these, 89% had at least one potentially actionable genotype-based phenotype. Post-test follow-up revealed that while the majority viewed the process positively, 71% preferred a consultation with a pharmacogenetic specialist for better understanding of their results. Barriers to implementation ranged from fatigue with the healthcare system to a lack of understanding of the pharmacogenetic testing and concerns about privacy and potential misuse of genetic data. Conclusion: The findings underscore the need for clearer patient education on pharmacogenetic results and suggest the importance of the role of pharmacogenetic-trained pharmacists in delivering this education. They also highlight issues with relying on incomplete or inaccurate medication lists in patients' electronic health record. The implementation revealed less obvious challenges, the understanding of which could be beneficial for the success of future preemptive pharmacogenetic implementation programs. The insights from the pilot program served to bridge the information gap between patients, providers, and pharmacogenetic -specialists, with the ultimate goal of improving patient care.

Alpinia nelumboides Nob.Tanaka, T.T.K.Van & V.Hoang: phytochemical analysis and antioxidant activities of pseudo-stem and rhizome essential oils.

Alpinia nelumboides Nob.Tanaka, T.T.K.Van & V.Hoang is the new Alpninia species discovered in Vietnam in 2023. Herein, we first hydrodistillated its pseudo-stems and rhizomes to obtain its essential oils, PS-EO and RH-EO. Their volatile compounds and total polyphenols were analysed by gas chromatography-mass spectrometry and the Folin-Ciocalteu method, respectively. Antioxidant activities were determined using four different approaches. The results showed that PS-EO and RH-EO contained 40 and 31 compounds, accounting for 99.78% and 99.45% of their compositions, respectively. The contents of polyphenols and monoterpenes in PS-EO were higher than in RH-EO. RH-EO displayed weaker scavenging activities (17.40-19.53%) than PS-EO (30.81-44.08%). PS-EO also showed higher ferric and cupric reducing powers, with EC50 values of 3.50-5.30 mg/mL smaller than RH-EO's EC50 values of 19.0-23.0 mg/mL. These results first revealed the phytochemical profile and antioxidant activities of EOs from A. nelumboides.

Bacterial Cellulose Aerogels Derived from Pineapple Peel Waste for the Adsorption of Dyes.

Valorization of pineapple peel waste is an attractive research topic because of the huge quantities of this byproduct generated from pineapple processing industries. In this study, the extract from pineapple waste was collected to produce a hydrogel-like form containing bacterial cellulose fibers with a three-dimensional structure and nanoscale diameter by the Acetobacter xylinum fermentation process. The bacterial cellulose suspension was subsequently activated by freeze-drying, affording lightweight aerogels as potential adsorbents in wastewater treatment, in particular the adsorptive removal of organic dyes. Intensive tests were carried out with the adsorption of methylene blue, a typical cationic dye, to investigate the influence of adsorption conditions (temperature, pH, initial dye concentration, time, and experiment scale) and aerogel-preparation parameters (grinding time and bacterial cellulose concentration). The bacterial cellulose-based aerogels exhibited high adsorption capacity not only for methylene blue but also for other cationic dyes, including malachite green, rhodamine B, and crystal violet (28-49 mg/g). However, its activity was limited for most of the anionic dyes, such as methyl orange, sunset yellow, and quinoline yellow, due to the repulsion of these anionic dyes with the aerogel surface, except for the case of congo red. It is also an anionic dye but has two amine groups providing a strong interaction with the hydroxyl group of the aerogel via hydrogen bonding. Indeed, the aerogel has a substantially large congo red-trapping capacity of 101 mg/g. Notably, the adsorption process exhibited similar performances, upscaling the solution volume to 50 times. The utilization of abundant agricultural waste in the simple aerogel preparation to produce a highly efficient and biodegradable adsorbent is the highlight of this work.

Polymorphonuclear myeloid-derived suppressor cells and phosphatidylinositol-3 kinase gamma are critical to tobacco-mimicking oral carcinogenesis in mice.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a devastating disease most often associated with tobacco consumption that induces a field of mutations from which a tumor arises. Identification of ways to prevent the emergence of cancer in high-risk patients is an ultimate goal for combatting all types of cancer, including OSCC. METHODS: Our study employs a mouse model of tongue carcinogenesis induced by tobacco carcinogen mimetic, 4-nitroquinoline 1-oxide (4NQO), to establish tongue dysplasia and OSCC. We use conventional histology, immunohistochemistry, multispectral imaging, mass cytometry, novel cell lines, pharmaceutical inhibition of PI3Kγ, T-cell suppression assays and mouse transplant models in our functional experimentation. RESULTS: In our study, we identify Ly6G+ granulocytes as the most abundant immune cell type in a model of tongue carcinogenesis induced by tobacco carcinogen mimetic 4NQO. Targeting Ly6G+ granulocytes with a pharmacologic inhibitor of PI3Kγ, an isoform of PI3K exclusively expressed by myeloid cells, resulted in reduced tongue dysplasia severity, and reduced rates of OSCC. Importantly, we performed functional assays with the Ly6G+ granulocytes induced in cell line models of 4NQO carcinogenesis to demonstrate that these granulocytes have increased polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) activity against T-cell proliferation and these PMN-MDSCs play a functional role in promoting tumor formation by inhibiting tumor regression in a PI3Kγ-dependent manner. CONCLUSIONS: Overall, our data suggest that recruitment of PMN-MDSCs to sites of dysplasia is critical to immune suppression of CD8 T cells, thereby permitting malignancy, and PI3Kγ inhibitors are one mechanism to reduce PMN-MDSC recruitment, immunosuppression and tumorigenesis in OSCC.