Testing novel strategies for patients hospitalised with HIV-associated disseminated tuberculosis (NewStrat-TB): protocol for a randomised controlled trial.

BACKGROUND: HIV-associated tuberculosis (TB) contributes disproportionately to global tuberculosis mortality. Patients hospitalised at the time of the diagnosis of HIV-associated disseminated TB are typically severely ill and have a high mortality risk despite initiation of tuberculosis treatment. The objective of the study is to assess the safety and efficacy of both intensified TB treatment (high dose rifampicin plus levofloxacin) and immunomodulation with corticosteroids as interventions to reduce early mortality in hospitalised patients with HIV-associated disseminated TB. METHODS: This is a phase III randomised controlled superiority trial, evaluating two interventions in a 2 × 2 factorial design: (1) high dose rifampicin (35 mg/kg/day) plus levofloxacin added to standard TB treatment for the first 14 days versus standard tuberculosis treatment and (2) adjunctive corticosteroids (prednisone 1.5 mg/kg/day) versus identical placebo for the first 14 days of TB treatment. The study population is HIV-positive patients diagnosed with disseminated TB (defined as being positive by at least one of the following assays: urine Alere LAM, urine Xpert MTB/RIF Ultra or blood Xpert MTB/RIF Ultra) during a hospital admission. The primary endpoint is all-cause mortality at 12 weeks comparing, first, patients receiving intensified TB treatment to standard of care and, second, patients receiving corticosteroids to those receiving placebo. Analysis of the primary endpoint will be by intention to treat. Secondary endpoints include all-cause mortality at 2 and 24 weeks. Safety and tolerability endpoints include hepatoxicity evaluations and corticosteroid-related adverse events. DISCUSSION: Disseminated TB is characterised by a high mycobacterial load and patients are often critically ill at presentation, with features of sepsis, which carries a high mortality risk. Interventions that reduce this high mycobacterial load or modulate associated immune activation could potentially reduce mortality. If found to be safe and effective, the interventions being evaluated in this trial could be easily implemented in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT04951986. Registered on 7 July 2021 https://clinicaltrials.gov/study/NCT04951986.

An Analysis of Orientation and Preceptorship Influence on Nurse Job Satisfaction Across Two States.

A large public nursing data set was used to determine whether orientation and/or preceptor programs impact job satisfaction among registered nurses in Maine and Massachusetts. There was no association between orientation and preceptor programs and satisfaction, nor evidence that new nurse status modified the relationship. There is a need for evaluation of orientation and preceptor programs' structure and effectiveness, and innovation is needed in promoting job satisfaction, thereby increasing nurse retention.

Posterior-only 2-level vertebrectomy and fusion in a medically complex patient with lumbar metastasis: illustrative case.

BACKGROUND: Spinal metastases are commonly seen in patients with cancer and often indicate a poor prognosis. Treatment can include curative or palliative surgery, chemotherapy, and radiation therapy. The surgical approach varies widely on the basis of the affected region of the spine, the location of the tumor (anterior versus posterior), the goal of surgery, the health of the patient, and surgeon preference. OBSERVATIONS: The authors present a case of a 68-year-old male with intractable lower-back pain and substantially diminished ambulation. Diagnostic imaging revealed a lumbar metastasis from a cholangiocarcinoma primary at L2-3 (4.5 cm anteroposterior × 5.7 cm transverse × 7.0 cm craniocaudal). The patient underwent a 2-level vertebrectomy with expandable cage placement and T10 to S2 fusion via a posterior-only approach. The patient regained much of his mobility and quality of life after the surgery. LESSONS: Although this was a high-risk surgery, the authors show that a posterior-only approach can be used for lumbar vertebrectomies and fusion when necessary. Palliative surgeries carrying a high risk, especially in the setting of a limited prognosis, should include multidisciplinary deliberations and a thorough discussion of the risks and outcome expectations with the patient.

Evaluation of Patient-Centric Sample Collection Technologies for Pharmacokinetic Assessment of Large and Small Molecules.

Low-volume sampling devices offer the promise of lower discomfort and greater convenience for patients, potentially reducing patient burden and enabling decentralized clinical trials. In this study, we determined whether low-volume sampling devices produce pharmacokinetic (PK) data comparable to conventional venipuncture for a diverse set of monoclonal antibodies (mAbs) and small molecules. We adopted an open-label, non-randomized, parallel-group, single-site study design, with four cohorts of 10 healthy subjects per arm. The study drugs, doses, and routes of administration included: crenezumab (15 mg/kg, intravenous infusion), etrolizumab (210 mg, subcutaneous), GDC-X (oral), and hydroxychloroquine (HCQ, 200 mg, oral). Samples were collected after administration of a single dose of each drug using conventional venipuncture and three low-volume capillary devices: TassoOne Plus for liquid blood, Tasso-M20 for dry blood, both applied to the arm, and Neoteryx Mitra® for dry blood obtained from fingertips. Serum/plasma concentrations from venipuncture and TassoOne Plus samples overlapped and PK parameters were comparable for all drugs, except HCQ. After applying a baseline hematocrit value, the dry blood concentrations and PK parameters for the two monoclonal antibodies were comparable to those obtained from venipuncture. For the two small molecules, two bridging strategies were evaluated for converting dry blood concentrations to equivalent plasma concentrations. A baseline hematocrit correction and/or linear regression-based correction was effective for GDC-X, but not for HCQ. Additionally, the study evaluated the bioanalytical data quality and comparability from the various collection methods, as well as patient preference for the devices.

Automated Cell Lineage Reconstruction using Label-Free 4D Microscopy.

Here we describe embGAN, a deep learning pipeline that addresses the challenge of automated cell detection and tracking in label-free 3D time lapse imaging. embGAN requires no manual data annotation for training, learns robust detections that exhibits a high degree of scale invariance and generalizes well to images acquired in multiple labs on multiple instruments.

Characteristics of Maine and Massachusetts nurses interested in advanced nursing degrees.

BACKGROUND: Maine (ME) and Massachusetts (MA) nursing programs aim to develop collaborative training programs, but need to identify which nurses have interest in such programs. PURPOSE: We sought to determine sociodemographics of nurses seeking advanced nursing degrees nationally, and in ME and MA using the 2018 publicly available, National Sample Survey of Registered Nurses (NSSRN). METHODS: Weighted multivariable logistic regression for advanced degree-seeking, adjusted for sociodemographics. RESULTS: Of the n = 47,274 nurses (weighted n [Wn] = 3,608,633), 90.7 % were female, 74.1 % were white, and 15.8 % sought an advanced nursing degree on average 12.7 (SD 0.2) years after their first. Females vs. males had lower odds (OR 0.63, 95%CI [0.44-0.90]) and Black vs. White race had higher odds (OR 1.30, 95%CI [1.05-1.60]) of seeking doctorates. In Maine (Wn = 20,389), age 24-29 had higher odds (OR 2.98 (95%CI [1.06-3.74]), but in Massachusetts (Wn = 101,984), age 30+ had lower odds (OR 0.32, 95%CI [0.13-0.78]) of degree-seeking vs. <24 years. Initial nursing degrees earned between 1980 and 1989 had higher odds (OR 1.99, 95%CI [1.06-3.74]) in Maine, but between 2010 and 2014 had lower odds (OR 0.32, 95%CI [0.14-0.72]) in Massachusetts of degree-seeking, vs. before 1980. CONCLUSIONS: Targets for advanced nursing training programs may vary by state and sociodemographic profile.

Unlocking Pb2+ Sensing Potential in a DNA G-Quadruplex via Loop Modification with Fluorescent Chalcone Surrogates.

The ability of guanine (G)-rich DNA to bind toxic lead (Pb2+) ions within a G-quadruplex (GQ) motif is a leading DNA biosensor strategy. A major analytical hurdle for GQ detection of Pb2+ is competitive GQ templating by potassium (K+) ions. We employ the on-strand DNA synthesis of internal fluorescent chalcone surrogates within the 15-mer thrombin binding aptamer (TBA15) to address this challenge. Replacement of thymidine at the 3-position (T3) within TBA15 with an indole-4-hydroxy-indanone (Ind4HI) chalcone strongly decreases K+-GQ stability while enhancing Pb2+-GQ stability to increase Pb2+ binding specificity. The new T3-Ind4HI probe exhibits a 15-fold increase in fluorescence intensity upon binding of Pb2+ by the modified TBA15 and can detect 6.4 nM Pb2+ in the presence of 10 mM K+. Thus, replacement of the T3 residue of TBA15 with the new Ind4HI probe modulates metal ion affinity by native TBA15 to solve the analytical challenge posed by K+ in real water samples for detecting Pb2+ to meet regulatory guidelines by using a GQ biosensor.

Staphylococcus aureus α-toxin impairs early neutrophil localization via electrogenic disruption of store-operated calcium entry.

The pore-forming S. aureus α-toxin (Hla) contributes to virulence and disease pathogenesis. While high concentrations of toxin induce cell death, neutrophils exhibit relative resistance to lysis, suggesting that the action of Hla may not be solely conferred by lytic susceptibility. Using intravital microscopy, we observed that Hla disrupts neutrophil localization and clustering early in infection. Hla forms a narrow, ion-selective pore, suggesting that Hla may dysregulate calcium or other ions to impair neutrophil function. We found that sub-lytic Hla did not permit calcium influx but caused rapid membrane depolarization. Depolarization decreases the electrogenic driving force for calcium, and concordantly, Hla suppressed calcium signaling in vitro and in vivo and calcium-dependent leukotriene B4 (LTB4) production, a key mediator of neutrophil clustering. Thus, Hla disrupts the early patterning of the neutrophil response to infection, in part through direct impairment of neutrophil calcium signaling. This early mis-localization of neutrophils may contribute to establishment of infection.

Association Between Hypercholesterolemia and Lumbar Degenerative Back Pain: A Medicare Expenditure Panel Survey (MEPS) Study.

Introduction Hypercholesterolemia is known to be a major contributor to the morbidity associated with cardiovascular disease and has been hypothesized to result in degenerative changes to the spine through atherosclerosis of segmental lumbar vessels. The purpose of this study is to determine the relationship between hypercholesterolemia and degenerative lumbar spine conditions in a U.S. cohort. Methods A total of 30,461 participated in the 2018 Medicare Expenditure Panel Survey (MEPS). Of those, 1,063 subjects responded to whether a diagnosis of lumbar disorders with low back pain was present. Odds ratios (OR) were calculated, and logistic regression analyses were adjusted for demographic, education, occupation, cardiovascular and mental health conditions. Results Of the 1,063 respondents, 455 (43%) reported back pain. Mean age of the respondents was 62.7±16.1. Men and women reported back pain at similar rates (43% vs 45%, p=0.664). Age, race, education level and occupation were similar between those with and without back pain (p>0.05). Those with a diagnosis of depression had higher odds of having back pain (p<0.05). Prevalence of back pain in subjects who responded to the back pain diagnosis item on the survey was 42.6%. On univariate analysis, diagnosis of total cholesterol levels was significantly higher in those with a diagnosis of back pain (OR 1.36, 95% CI [1.20-1.54], p<.0001). Multivariable analysis showed that hypercholesterolemia was independently associated with back pain (adjusted OR 1.32, 95% CI [1.04-1.68], p=0.021) after controlling for covariates. Conclusions In this study, subjects with hypercholesterolemia were 34% more likely to have back pain after controlling for confounders which presents as a recent discovery amongst U.S. populations. Further studies should be performed to investigate the management of hypercholesterolemia in the development and progression of degenerative lumbar back pain.

Visual Outcomes of a Second-Generation, Enhanced UV Protected Light Adjustable Lens in Cataract Patients with Previous LASIK and/or PRK.

Purpose: To report on the visual outcomes of the second-generation (ActivShieldTM) Light Adjustable Lens (LAL) used in cataract surgery for patients with a history of laser refractive surgery (LASIK and/or photorefractive keratectomy [PRK]) using a co-managed, open-access methodology. Patients and Methods: This retrospective case series of consecutive patients with history of laser refractive surgery implanted with the second-generation LAL with an emmetropic target were included in the study. Following surgery, all patients received their ultraviolet (UV) light treatments at a separate open-access facility through a co-managed arrangement. Uncorrected distance visual acuity (UDVA), spherical equivalent (SE), and residual cylinder for eyes with an emmetropic refractive target were the primary outcome measures as documented at the patient's final, stable, refractive postoperative exam. Results: Thirty-three patients (34 eyes) with a history of laser refractive surgery were included in the study and implanted with the second-generation LAL with a postoperative emmetropic refractive target. Twenty-eight (82.4%) saw 20/20 or better and 9 (26.5%) saw 20/15 or better. The mean SE was 0.01 ± 0.31 D and 33 (97.1%) were within ±0.50 D SE of plano. The mean residual cylinder was -0.28 ± 0.32 D and 30 (88.2%) were within ±0.50 D. Conclusion: Use of the second-generation LAL was efficacious in cataract surgical patients with a history of LASIK and/or PRK using a co-managed, open-access methodology.

Harnessing a 4-Formyl-Aniline Handle to Tune the Stability of a DNA Aptamer-Protein Complex via Fluorescent Surrogates.

Interactions between DNA aptamers and protein targets hold promise for the development of pharmaceuticals and diagnostics. As such, the utilization of fluorescent nucleobase surrogates in studying aptamer-protein interactions is a powerful tool due to their ability to provide site-specific information through turn-on fluorescence. Unfortunately, previously described turn-on probes serving as nucleobase replacements have only been strongly disruptive to the affinity of aptamer-protein interactions. Herein, we present a modified TBA15 aptamer for thrombin containing a fluorescent surrogate that provides site-specific turn-on emission with low nanomolar affinity. The modification, referred to as AnBtz, was substituted at position T3 and provided strong turn-on emission (Irel ≈ 4) and brightness (ε·Φ > 20 000 cm-1 M-1) with an apparent dissociation constant (Kd) of 15 nM to afford a limit of detection (LOD) of 10 nM for thrombin in 20% human serum. The probe was selected through a modular "on-strand" synthesis process that utilized a 4-formyl-aniline (4FA) handle. Using this platform, we were able to enhance the affinity of the final aptamer conjugate by ∼30-fold in comparison with the initial conjugate design. Molecular dynamics simulations provide insight into the structural basis for this phenomenon and highlight the importance of targeting hydrophobic protein binding sites with fluorescent nucleobase surrogates to create new contacts with protein targets.

Minimally Invasive Bilateral Decompressive Lumbar Laminectomy with Unilateral Approach Among Obese versus Nonobese Patients.

OBJECTIVE: Decompressive lumbar laminectomy (DLL) is a common procedure for lumbar stenosis. A unilateral approach, unlike the traditional open approach, spares the posterior elements to mitigate the risk of iatrogenic instability associated with a DLL. Various minimally invasive techniques have been described but little attention has been aimed toward this specific microsurgical approach, particularly regarding obese patients. We aimed to compare operative details, perioperative outcomes, and complication profiles between obese and nonobese patients. METHODS: One hundred and ninety-four patients who underwent bilateral laminectomy with a unilateral approach by the study surgeon from July 2013 to June 2018 were included. Of these patients, 105 were classified as obese, with body mass index (BMI) ≥30.0 kg/m2, and 89 were nonobese, with BMI <30.0 kg/m2. The obese and nonobese groups were compared; operative time, blood loss, and complications were assessed. RESULTS: Operative time was nonsignificantly increased in the obese group (177 vs. 166 minutes; P = 0.21) and estimated blood loss was nonsignificantly lower (91 mL vs. 97 mL; P = 1.00) in the obese group. Durotomy rates (3 [2.9%] obese vs. 2 [2.2%] nonobese; P = 0.789) and postoperative wound drainage rates (4 [3.8%] obese vs. 2 [3.8%] nonobese; P = 0.92) did not significantly differ between the 2 groups. Length of stay was significantly longer in the obese group (1.5 vs. 1.0 days; P = 0.0005). CONCLUSIONS: Compared with the nonobese group, the obese group had significantly longer length of hospitalization, as well as nonsignificantly increased length of operation and decreased blood loss. The 2 groups had similar perioperative complication rates.

Cationic Cobalt(II) Bisphosphine Hydroformylation Catalysis: In Situ Spectroscopic and Reaction Studies.

[HCo(CO)x(bisphosphine)](BF4), x = 1-3, is a highly active hydroformylation catalyst system, especially for internal branched alkenes. In situ infrared spectroscopy (IR), electron paramagnetic resonance (EPR), and nuclear magnetic resonance studies support the proposed catalyst formulation. IR studies reveal the formation of a dicationic Co(I) paramagnetic CO-bridged dimer, [Co2(µ-CO)2(CO)(bisphosphine)2]2+, at lower temperatures formed from the reaction of two catalyst complexes via the elimination of H2. DFT studies indicate a dimer structure with square-pyramidal and tetrahedral cobalt centers. This monomer-dimer equilibrium is analogous to that seen for HCo(CO)4, reacting to eliminate H2 and form Co2(CO)8. EPR studies on the catalyst show a high-spin (S = 3/2) Co(II) complex. Reaction studies are presented that support the cationic Co(II) bisphosphine catalyst as the catalyst species present in this system and minimize the possible role of neutral Co(I) species, HCo(CO)4 or HCo(CO)3(phosphine), as catalysts.

A 10-Year Report on the Trends of Osteopathic Medical Students (OMS) in Osteopathic Orthopaedic Residency over the Past Decade.

OBJECTIVES: Osteopathic match rates in competitive specialties, such as orthopaedics, have been under intense scrutiny. This study aimed to quantify trends in the characteristics of Osteopathic Orthopaedic Surgical Residency training and education from graduating classes of 2010-2020. METHODS: This was a retrospective evaluation of a large, longitudinally maintained database of the American Osteopathic Association (AOA) from orthopaedic residency graduating classes of 2010-2020. Trends in characteristics were analyzed, including the resident's age at graduation from medical school and residency, gender, advanced degree status, College or School of Osteopathic Medicine (COM/SOM), residency, and residency class year. RESULTS: Overall, the number of osteopathic orthopaedic residents had a 32.9% increase from 85 to 113 per year, graduating over the past decade. Statistical forecasting predicts a 27.8% increase in osteopathic orthopaedic residents over the next decade. The percent composition of osteopathic students entering orthopaedic residency class by gender remained relatively stable. The average percent male composition of the orthopaedic residency class was 90.5%, ranging from a maximum of 96.1% and a minimum of 83.7%. While the average percent female composition of orthopaedic residency class was 9.5% for the past decade, statistical forecasting predicts that over the next decade, the average percent composition of females in orthopaedic residency will be 5.8%. The average age of residents at graduation was 33.4 years, while across the decade, resident age at graduation decreased by 9.8%. On average, female orthopaedic residents at graduation were younger than male orthopaedic residents. Osteopathic Postdoctoral Training Institute (OPTI)-West/Community Memorial Health System Orthopaedic Surgery Residency had the highest average age at residency graduation (35.7 years), and Lake Erie COM/York Hospital Orthopaedic Surgery Residency had the youngest average age at residency graduation (32 years). Edward Via COM-Carolinas Campus had the highest average age at graduation from medical school (30.5 years), and Touro COM had the lowest average age at graduation from medical school (26.7 years). Only 3.3% of osteopathic orthopaedic residents had additional advanced degrees. Philadelphia COM produced the most significant number of orthopaedic residents (89) and trained the most female orthopaedic surgeons of any program over the ten years. CONCLUSIONS: The number of osteopathic medical students entering orthopaedics has increased over the past decade. However, there remains a lack of a similar increasing trend of female osteopathic medical students entering osteopathic orthopaedic residency programs. Interestingly, the age of osteopathic orthopaedic residents at graduation decreased across the decade, while advanced degrees did not play a statistically significant factor in matching into orthopaedic surgery. The osteopathic medical school was the most significant predicting factor in matching into orthopaedic surgery. With such knowledge, greater efforts should aim to enhance osteopathic medical student exposure to orthopaedic programs to maintain quality candidate interest in this competitive field, including female prospects, while also increasing the holistic diversity of characteristics within the field of orthopaedic surgery.

Genetic variations that influence paclitaxel pharmacokinetics and intracellular effects that may contribute to chemotherapy-induced neuropathy: A narrative review.

Taxanes, particularly paclitaxel and docetaxel, are chemotherapeutic agents commonly used to treat breast cancers. A frequent side effect is chemotherapy-induced peripheral neuropathy (CIPN) that occurs in up to 70% of all treated patients and impacts the quality of life during and after treatment. CIPN presents as glove and stocking sensory deficits and diminished motor and autonomic function. Nerves with longer axons are at higher risk of developing CIPN. The causes of CIPN are multifactorial and poorly understood, limiting treatment options. Pathophysiologic mechanisms can include: (i) disruptions of mitochondrial and intracellular microtubule functions, (ii) disruption of axon morphology, and (iii) activation of microglial and other immune cell responses, among others. Recent work has explored the contribution of genetic variation and selected epigenetic changes in response to taxanes for any insights into their relation to pathophysiologic mechanisms of CIPN20, with the hope of identifying predictive and targetable biomarkers. Although promising, many genetic studies of CIPN are inconsistent making it difficult to develop reliable biomarkers of CIPN. The aims of this narrative review are to benchmark available evidence and identify gaps in the understanding of the role genetic variation has in influencing paclitaxel's pharmacokinetics and cellular membrane transport potentially related to the development of CIPN.

A modular aldol approach for internal fluorescent molecular rotor chalcone surrogates for DNA biosensing applications.

Fluorescent molecular rotors (FMRs) are critical tools for probing nucleic acid structure and function. Many valuable FMRs have been incorporated into oligonucleotides, although the methods of doing so can be cumbersome. Development of synthetically simple, high yielding modular methods to fine-tune dye performance is crucial to expand the biotechnological applications of oligonucleotides. Herein, we report the utility of 6-hydroxy-indanone (6HI) with a glycol backbone to serve as a handle for on-strand aldehyde capture as a modular aldol approach for site-specific insertion of internal FMR chalcones. Aldol reactions with aromatic aldehydes containing N-donors proceed in high yield to create modified DNA oligonucleotides, which in the duplex match the stability of the fully paired canonical B-form with strong stacking interactions between the planar probe and the flanking base pairs, as evidenced by molecular dynamics (MD) simulations. The FMR chalcones possess remarkable quantum yields (Φfl up to 76%) in duplex DNA, coupled with large Stokes shifts (Δν up to 155 nm), light-up emissions (Irel up to 60-fold) that span the visible region (λem 518-680 nm) with brightness up to 17 480 cm-1 M-1. The library also contains a FRET pair and dual emission probes, suitable for ratiometric sensing. The ease of aldol insertion coupled with the excellent performance of the FMR chalcones permits their future wide-spread use.

The wheat stem rust resistance gene Sr43 encodes an unusual protein kinase.

To safeguard bread wheat against pests and diseases, breeders have introduced over 200 resistance genes into its genome, thus nearly doubling the number of designated resistance genes in the wheat gene pool1. Isolating these genes facilitates their fast-tracking in breeding programs and incorporation into polygene stacks for more durable resistance. We cloned the stem rust resistance gene Sr43, which was crossed into bread wheat from the wild grass Thinopyrum elongatum2,3. Sr43 encodes an active protein kinase fused to two domains of unknown function. The gene, which is unique to the Triticeae, appears to have arisen through a gene fusion event 6.7 to 11.6 million years ago. Transgenic expression of Sr43 in wheat conferred high levels of resistance to a wide range of isolates of the pathogen causing stem rust, highlighting the potential value of Sr43 in resistance breeding and engineering.

Pilot Study of the Effects of Paced Breathing on Measures of Convergent and Divergent Thinking.

BACKGROUND: The ability of the autonomic nervous system's stress response to impair aspects of cognitive flexibility is known. However, the ability to modulate the sympathetic response and improve these cognitive impairments via nonpharmacological intervention, such as paced breathing (PB), requires further investigation. OBJECTIVE: To better elucidate the effects of PB on cognition. METHOD: We employed a PB protocol in a total of 52 healthy men and women and measured performance on convergent and divergent cognitive tasks, perceived stress, and physiological measures (eg, blood pressure, heart rate). Participants attended two experimental sessions consisting of either PB or normal breathing followed by cognitive assessments including convergent (compound remote associate, anagram) and divergent (alternate use, fluency) tasks. Experiment 2 consisted of more difficult versions of cognitive tasks compared with Experiment 1. RESULTS: In Experiment 1, PB significantly reduced the female participants' systolic and diastolic blood pressure immediately after the breathing protocol without affecting their cognition. In Experiment 2, PB significantly reduced perceived stress immediately after the breathing protocol, regardless of sex. There was no effect on cognition in Experiment 2, but a correlation was observed between perceived stress change and anagram number solved change. CONCLUSION: While PB modulates sympathetic activity in females, there was a lack of improvement in cognitive flexibility performance. At least for a single trial of PB, cognitive flexibility did not improve.

Acquisition of Immune Privilege in GBM Tumors: Role of Prostaglandins and Bile Salts.

Based on the postulate that glioblastoma (GBM) tumors generate anti-inflammatory prostaglandins and bile salts to gain immune privilege, we analyzed 712 tumors in-silico from three GBM transcriptome databases for prostaglandin and bile synthesis/signaling enzyme-transcript markers. A pan-database correlation analysis was performed to identify cell-specific signal generation and downstream effects. The tumors were stratified by their ability to generate prostaglandins, their competency in bile salt synthesis, and the presence of bile acid receptors nuclear receptor subfamily 1, group H, member 4 (NR1H4) and G protein-coupled bile acid receptor 1 (GPBAR1). The survival analysis indicates that tumors capable of prostaglandin and/or bile salt synthesis are linked to poor outcomes. Tumor prostaglandin D2 and F2 syntheses are derived from infiltrating microglia, whereas prostaglandin E2 synthesis is derived from neutrophils. GBMs drive the microglial synthesis of PGD2/F2 by releasing/activating complement system component C3a. GBM expression of sperm-associated heat-shock proteins appears to stimulate neutrophilic PGE2 synthesis. The tumors that generate bile and express high levels of bile receptor NR1H4 have a fetal liver phenotype and a RORC-Treg infiltration signature. The bile-generating tumors that express high levels of GPBAR1 are infiltrated with immunosuppressive microglia/macrophage/myeloid-derived suppressor cells. These findings provide insight into how GBMs generate immune privilege and may explain the failure of checkpoint inhibitor therapy and provide novel targets for treatment.