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Severe Traumatic Brain Injury (TBI) is a significant health issue, with neurofeedback and Hyperbaric Oxygen Therapy (HBOT) as potentially effective treatments. Neurofeedback uses operant conditioning for real-time psychological and physiological awareness, and HBOT increases blood oxygen levels, potentially enhancing cognitive abilities and the body's innate healing processes and reducing symptoms. On July 30, 2018, a 33-year-old female runner was hit by a car going 40 mph and thrown 30 feet, resulting in a severe TBI and a seven-week coma. After seven months of intensive rehabilitation, she started HBOT and neurofeedback treatments in November 2021, as recommended by her neuropsychiatrist. These treatments led to noticeable improvements in her cognition, sleep, conversation skills, emotional control, and relationships by January 2022. By December 2023, after 195 neurofeedback and over 300 HBOT sessions, she reported further improvements in various cognitive and emotional aspects and daily activities like feeding, toileting, grooming, and communication. Post-treatment quantitative electroencephalogram (qEEG) results in June 2024 showed moderate to large effects on her brain's average frequency band parameters (g = .612) and small to moderate average effects on 19 scalp electrode placement sites outcomes (uV2 g=.339 and Hz g=.333). This indicates significant progress in her recovery journey over a 31-month treatment period. This patient's case demonstrated noteworthy improvements in cognitive variables, namely, feeding (p=0.046), toileting (p=0.046), grooming (p=0.046), and communication abilities (p=0.046) per the objective measures, Disability Rating Scale (DRS) and the Glasgow Outcome Scale Extended (GOSE). Based on the qEEG effect sizes, DRS, and GOSE results from the pretest (2021) and posttest (2024), the patient has made noteworthy gains in brain recovery and overall quality of life., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Peterson et al.)

Purpose: Plexiform neurofibromas (PNF) are benign peripheral nerve sheath tumors (PNST) associated with neurofibromatosis type 1 (NF1). Despite similar histologic appearance, these neoplasms exhibit diverse evolutionary trajectories, with a subset progressing to malignant peripheral nerve sheath tumor (MPNST), the leading cause of premature death in individuals with NF1. Malignant transformation of PNF often occurs through the development of atypical neurofibroma (ANF) precursor lesions characterized by distinct histopathologic features and CDKN2A copy-number loss. Although genomic studies have uncovered key driver events promoting tumor progression, the transcriptional changes preceding malignant transformation remain poorly defined., Experimental Design: Here we resolve gene-expression profiles in PNST across the neurofibroma-to-MPNST continuum in NF1 patients and mouse models, revealing early molecular features associated with neurofibroma evolution and transformation., Results: Our findings demonstrate that ANF exhibit enhanced signatures of antigen presentation and immune response, which are suppressed as malignant transformation ensues. MPNST further displayed deregulated survival and mitotic fidelity pathways, and targeting key mediators of these pathways, CENPF and BIRC5, disrupted the growth and viability of human MPNST cell lines and primary murine Nf1-Cdkn2a-mutant Schwann cell precursors. Finally, neurofibromas contiguous with MPNST manifested distinct alterations in core oncogenic and immune surveillance programs, suggesting that early molecular events driving disease progression may precede histopathologic evidence of malignancy., Conclusions: If validated prospectively in future studies, these signatures may serve as molecular diagnostic tools to augment conventional histopathologic diagnosis by identifying neurofibromas at high risk of undergoing malignant transformation, facilitating risk-adapted care., (©2023 American Association for Cancer Research.)

Purpose: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity., Experimental Design: Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice., Results: Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced antitumor activity in Nf1flox/flox;PostnCre mice in vivo., Conclusions: These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1., (©2023 American Association for Cancer Research.)

Neurofibromatosis Type II (NF2) is an autosomal dominant cancer predisposition syndrome in which germline haploinsufficiency at the NF2 gene confers a greatly increased propensity for tumor development arising from tissues of neural crest derived origin. NF2 encodes the tumor suppressor, Merlin, and its biochemical function is incompletely understood. One well-established function of Merlin is as a negative regulator of group A serine/threonine p21-activated kinases (PAKs). In these studies we explore the role of PAK1 and its closely related paralog, PAK2, both pharmacologically and genetically, in Merlin-deficient Schwann cells and in a genetically engineered mouse model (GEMM) that develops spontaneous vestibular and spinal schwannomas. We demonstrate that PAK1 and PAK2 are both hyper activated in Merlin-deficient murine schwannomas. In preclinical trials, a pan Group A PAK inhibitor, FRAX-1036, transiently reduced PAK1 and PAK2 phosphorylation in vitro, but had insignificant efficacy in vivo. NVS-PAK1-1, a PAK1 selective inhibitor, had a greater but still minimal effect on our GEMM phenotype. However, genetic ablation of Pak1 but not Pak2 reduced tumor formation in our NF2 GEMM. Moreover, germline genetic deletion of Pak1 was well tolerated, while conditional deletion of Pak2 in Schwann cells resulted in significant morbidity and mortality. These data support the further development of PAK1-specific small molecule inhibitors and the therapeutic targeting of PAK1 in vestibular schwannomas and argue against PAK1 and PAK2 existing as functionally redundant protein isoforms in Schwann cells., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by plexiform neurofibromas (pNF), which are thought to be congenital tumors that arise in utero and enlarge throughout life. Genetic studies in murine models delineated an indispensable role for the stem cell factor (SCF)/c-kit pathway in pNF initiation and progression. A subsequent phase 2 clinical trial using imatinib mesylate to inhibit SCF/c-kit demonstrated tumor shrinkage in a subset of preexisting pNF; however, imatinib's role on preventing pNF development has yet to be explored., Procedure: We evaluated the effect of imatinib dosed at 10-100 mg/kg/day for 12 weeks to one-month-old Nf1 flox/flox ;PostnCre(+) mice, prior to onset of pNF formation. To determine durability of response, we then monitored for pNF growth at later time points, comparing imatinib- with vehicle-treated mice. We assessed gross and histopathological analysis of tumor burden., Results: Imatinib administered preventatively led to a significant decrease in pNF number, even at doses as low as 10 mg/kg/day. Tumor development continued to be significantly inhibited after cessation of imatinib dosed at 50 and 100 mg/kg/day. In the cohort of treated mice that underwent prolonged follow-up, the size of residual tumors was significantly reduced as compared with age-matched littermates that received vehicle control., Conclusions: Early administration of imatinib inhibits pNF genesis in vivo, and effects are sustained after discontinuation of therapy. These findings may guide clinical use of imatinib in young NF1 patients prior to the substantial development of pNF., (© 2020 Wiley Periodicals LLC.)

Plexiform neurofibroma (PN) tumors are a hallmark manifestation of neurofibromatosis type 1 (NF1) that arise in the Schwann cell (SC) lineage. NF1 is a common heritable cancer predisposition syndrome caused by germline mutations in the NF1 tumor suppressor, which encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras proteins. Whereas most PN are clinically indolent, a subset progress to atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) and/or to malignant peripheral nerve sheath tumors (MPNSTs). In small clinical series, loss of 9p21.3, which includes the CDKN2A locus, has been associated with the genesis of ANNUBP. Here we show that the Cdkn2a alternate reading frame (Arf) serves as a gatekeeper tumor suppressor in mice that prevents PN progression by inducing senescence-mediated growth arrest in aberrantly proliferating Nf1-/- SC. Conditional ablation of Nf1 and Arf in the neural crest-derived SC lineage allows escape from senescence, resulting in tumors that accurately phenocopy human ANNUBP and progress to MPNST with high penetrance. This animal model will serve as a platform to study the clonal development of ANNUBP and MPNST and to identify new therapies to treat existing tumors and to prevent disease progression., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential.

Background: Viral respiratory infections may promote bacterial super-infection decreasing the host immune response efficiency. However, using a mice model we recently demonstrated that preventive treatment with the bacterial extract OM-85 reduces the susceptibility to a secondary Streptococcus (S.) pneumoniae infection after influenza virus (I.V.) challenge., Methods: To better characterize the efficacy of OM-85 against S. pneumoniae super-infection, a post-hoc analysis was conducted, comparing efficacy (survival) and morbidity signs (clinical score, body temperature and weight loss) in the OM-85 and the control (BLANC) groups of mice after: a) I.V. infection; b) primary S. pneumoniae infection and c) post-I.V. S. pneumoniae super-infection., Results: After a sublethal I.V. dose, all mice stayed alive at day 5 and no differences in morbidity signs were detected between the OM-85 and the BLANC groups. However, OM-85 pretreatment led to a significantly reduction of the viral load in the lung on day 5 post viral infection and, on day 10, reduced neutrophilic inflammation while increasing influenza-specific CD8 + T-cell proportion in the airways. Conversely to viral infection, exposure to S. pneumoniae induced a dramatic reduction of survival, with no mice surviving on day 3 post infection in the BLANC group, whereas a partial protective effect was observed in OM-85 pre-treated mice (20% of mice surviving at day 3, and 10% at day 4 and 5). The morbidity data substantiated the survival results. Interestingly, in the "super-infection" study, when mice were exposed to a sublethal I.V. dose followed by a secondary S. pneumoniae infection, all mice died by day 4 in the BLANC group. In contrast, in the OM-85 treated group, the survival rate was 70% at day 4 and still 50% at day 5, with positive effects on the clinical scores and on the body temperature already detectable at days 1 and 2., Conclusions: The efficacy of OM-85 pre-treatment against S. pneumoniae super-infection reflects a strong and immediate immune reaction from the host, an event that can be explained in part by a "non-specific" activation of the immune system, a positive "immune effect" of the general OM-85- induced immune response against I.V.

The aim of all medical treatment is "primum nihil nocere" ("First, do no harm").Restoring the integrity of intestinal microbiota and optimising the immune response in recurrent infections, especially in the urinary tract, are treatment alternatives which are closer to this target than the usual focus on antibiotic prevention of recurrence.In the future, antibiotics will continue to be recommended for the prevention of urinary tract infections on a case-by-case basis. However, the problems of an excessive use of antibiotics, e. g. resistance and long-term interference with intestinal microbiota, are forcing us to search for alternatives. The use of probiotics alone or in combination with immunotherapeutics, or the sole use of immunotherapeutics, are important treatment options, which are already routinely available in clinical practice. These therapies are focused on the pathomechanism of an infection and tackle the root cause of the problem. Phytotherapeutics or small molecules like mannose, which restricts the adherence of bacteria to the urothelium, are complementary approaches.The EAU guidelines recommend the following treatments for the long-term prevention of urinary tract infections:Oral and parenteral immunostimulants (StroVac(®)), local estrogen replacement and administration of Lactobacillus rhamnosus and Lactobacillus reuteri., (© Georg Thieme Verlag KG Stuttgart · New York.)