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Introduction: Pancreaticobiliary carcinomas rarely harbor targetable genetic alterations, including microsatellite instability (MSI) or neurotrophic tyrosine receptor kinase (NTRK) gene fusions. As these malignancies are typically present at an advanced stage and have suboptimal response to chemotherapy, the discovery of an actionable genomic alteration provides an additional avenue of treatment for chemotherapy-refractory cases., Materials and Methods: In this study, we evaluate 319 cases of pancreaticobiliary carcinoma diagnosed on fine-needle aspiration biopsy or biliary brushing for DNA mismatch repair (MMR) protein deficiency and pan-TRK overexpression by immunohistochemistry (IHC) and compare these results to MSI and NTRK gene fusion molecular testing., Results and Conclusion: Although we find a high concordance between MMR protein IHC and MSI molecular testing in the evaluation of MMR deficiency and between pan-TRK IHC and NTRK fusion testing by next-generation sequencing, the low prevalence of either of these genetic alterations in our cohort casts doubt on the value of screening cases of pancreaticobiliary carcinoma for MMR protein deficiency and NTRK fusions., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Irritable bowel syndrome (IBS), a disorder of gut-brain interaction, is often comorbid with somatic pain and psychological disorders. Dysregulated signaling of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), has been implicated in somatic-psychological symptoms in individuals with IBS. We investigated the association of 10 single-nucleotide polymorphisms (SNPs) in the regulatory 3' untranslated region of neurotrophic receptor tyrosine kinase-2 (NTRK2) kinase domain-deficient truncated isoform (TrkB.T1) and BDNF Val66Met SNP with somatic and psychological symptoms and quality-of-life (QoL) in a cohort from the United States (IBS, n = 464; healthy controls, n = 156). We found that the homozygous recessive genotype (G/G) of rs2013566 in individuals with IBS is associated with worsened somatic symptoms, including headache, back pain, joint pain, muscle pain, and somatization as well as diminished sleep quality, energy level, and overall QoL. Validation using United Kingdom BioBank data confirmed the association of rs2013566 with an increased likelihood of headache. Several SNPs (rs1627784, rs1624327, and rs1147198) showed significant associations with muscle pain in our U.S. cohort. These 4 SNPs are predominantly located in H3K4Me1-enriched regions, suggesting their enhancer and/or transcription regulation potential. Our findings suggest that genetic variation within the 3' untranslated region region of the TrkB.T1 isoform may contribute to comorbid conditions in individuals with IBS, resulting in a spectrum of somatic and psychological symptoms impacting their QoL. These findings advance our understanding of the genetic interaction between BDNF/TrkB pathways and somatic-psychological symptoms in IBS, highlighting the importance of further exploring this interaction for potential clinical applications. PERSPECTIVE: This study aims to understand the genetic effects on IBS-related symptoms across somatic, psychological, and quality-of-life (QoL) domains, validated by United Kingdom BioBank data. The rs2013566 homozygous recessive genotype correlates with worsened somatic symptoms and reduced QoL, emphasizing its clinical significance., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Neurotrophin receptors of the Trk family are involved in the regulation of brain development and neuroplasticity, and therefore can serve as targets for anti-cancer and stroke-recovery drugs, antidepressants, and many others. The structures of Trk protein domains in various states upon activation need to be elucidated to allow rational drug design. However, little is known about the conformations of the transmembrane and juxtamembrane domains of Trk receptors. In the present study, we employ NMR spectroscopy to solve the structure of the TrkB dimeric transmembrane domain in the lipid environment. We verify the structure using mutagenesis and confirm that the conformation corresponds to the active state of the receptor. Subsequent study of TrkB interaction with the antidepressant drug fluoxetine, and the antipsychotic drug chlorpromazine, provides a clear self-consistent model, describing the mechanism by which fluoxetine activates the receptor by binding to its transmembrane domain., (© 2024. The Author(s).)

Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we develop a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. All tested NTRK fusions are oncogenic in vivo. The NTRK variant, N-terminal fusion partners, and resistance-associated point mutations all influence tumor histology and aggressiveness. Additional tumor suppressor losses greatly enhance tumor aggressiveness. Treatment with TRK kinase inhibitors significantly extends the survival of NTRK fusion-driven glioma mice, but fails to fully eradicate tumors, leading to recurrence upon treatment discontinuation. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors., Competing Interests: Declaration of interests The authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neurotrophic receptor tyrosine kinases (TrkA, TrkB, TrkC), despite their homology, contribute to the clinical heterogeneity of the childhood cancer neuroblastoma. TrkA expression is associated with low-stage disease and is often seen with spontaneous tumour regression. Conversely, TrkB is present in unfavourable neuroblastomas that often harbour amplification of the MYCN oncogene. The role of TrkC is less clearly defined, although some studies suggest its association with a favourable outcome. Understanding the differences in activity of Trk receptors that drive divergent clinical phenotypes as well as the influence of MYCN amplification on downstream Trk receptor signalling remains poorly understood. Here, we present a comprehensive label-free mass spectrometry-based total proteomics and phosphoproteomics dataset (432 raw files with FragPipe search outputs; available on PRIDE with accession number PXD054441) where we identified and quantified 4,907 proteins, 16,744 phosphosites and 5,084 phosphoproteins, derived from NGF/BDNF/NT-3 treated TrkA/B/C-overexpressing neuroblastoma cells with differential MYCN status. Analysing our dataset offers valuable insights into TrkA/B/C receptor signalling in neuroblastoma and its modulation by MYCN status; and holds potential for advancing therapeutic strategies in this challenging childhood cancer., (© 2024. The Author(s).)

In recent years, there has been a surge in interest in investigating the mechanisms underlying memory consolidation. However, our understanding of the behavioural tagging (BT) model and its establishment in diverse brain regions remains limited. This study elucidates the contributions of the anterior cingulate cortex (ACC) and hippocampus in the formation of long-term memory (LTM) employing behaviour tagging as a model for studying the underlying mechanism of LTM formation in rats. Existing knowledge highlights a protein synthesis-dependent phase as imperative for LTM. Brain-derived neurotrophic factor (BDNF) stands as a pivotal plasticity-related protein (PRP) in mediating molecular alterations crucial for long-term synaptic plasticity and memory consolidation. Our study offers evidence suggesting that tropomyosin receptor kinase B (TrkB), the receptor of BDNF, may act as a combined "behavioural tag/PRP". Interfering with the expression of these molecules resulted in impaired LTM after 24 h. Furthermore, augmenting BDNF expression led to an elevation in Arc protein levels in both the ACC and hippocampus regions. Introducing novelty around weak inhibitory avoidance (IA) training resulted in heightened step-down latencies and expression of these molecules, respectively. We also demonstrate that the increase in Arc expression relies on BDNF synthesis, which is vital for the memory consolidation process. Additionally, inhibiting BDNF using an anti-BDNF function-blocking antibody impacted Arc expression in both the ACC and hippocampus regions, disrupting the transformations from labile to robust memory. These findings mark the initial identification of a "behavioural tag/PRP" combination and underscore the involvement of the TrkB-BDNF-Arc cascade in the behavioural tagging model of learning and memory., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Premature ovarian failure (POF) is characterized by a significant decline in the ovarian follicle pool and oocyte reserve, alongside an increase in the number of low-quality oocytes and apoptosis of granulosa cells (GCs). Exosome-derived miRNA plays a regulatory role in crucial cellular activities and contributes to the onset and progression of POF. In this study, we successfully established a rabbit model of POF and conducted in vitro and in vivo experiments that confirmed DiI-labeled Pla-Exos (exosomes derived from plasma) could enter the follicle through blood circulation, with GCs capable of uptaking these exosomes. Our RNA-seq analysis revealed elevated expression of miR-10a-5p in Pla-Exos from POF rabbits. Moreover, our findings demonstrate that exosomal miR-10a-5p suppresses GCs proliferation and induces apoptosis via the mitochondrial pathway. Additionally, exosomal miR-10a-5p inhibits the TrkB/Akt/mTOR signaling pathway by downregulating BDNF expression, thereby modulating the expression levels of proteins and genes associated with the cell cycle, follicle development, and GCs senescence. In conclusion, our study highlights the role of Pla-Exos miR-10a-5p in promoting rabbit POF through the TrkB/Akt/mTOR signaling pathway by targeting BDNF. These findings provide new insights into potential therapeutic targets for POF, offering valuable references for addressing concerns related to female reproductive function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Postmenopausal osteoporosis (PMO) is characterized by bone loss and microstructural damage, and it is most common in older adult women. Currently, there is no cure for PMO. The flavonoid chemical 7,8-dihydroxyflavone (7,8-DHF) specifically activates tropomyosin receptor kinase B (TRKB). Furthermore, 7,8-DHF has various biological characteristics, including anti-inflammatory and antioxidant effects. However, the specific implications and fundamental mechanisms of 7,8-DHF in PMO remain unclear. We used protein imprinting, flow cytometry, tissue staining, and other methods to estimate the preventive mechanisms of 7,8-DHF against hydrogen peroxide (H 2 O 2 )-induced apoptosis in primary mouse bone marrow mesenchymal stem cells (BMSCs), osteogenic differentiation ability, and bone mass in ovariectomized (OVX) mice. We found that 7,8-DHF effectively prevented H 2 O 2 -induced reductions in the viability and osteogenic differentiation capacity of primary BMSCs. Mechanistically, 7,8-DHF induced the TRKB to activate the PI3K/AKT/NRF2 pathway. In vivo experiments with the OVX mouse model confirmed that 7,8-DHF can inhibit oxidative stress and promote bone formation, indicating that 7,8-DHF improves the viability and osteogenic differentiation ability of BMSCs stimulated via H 2 O 2 by activating the TRKB/PI3K/AKT and NRF2 pathways, thereby improving PMO., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Glaucoma is a common retinal disorder characterized by progressive optic nerve damage, resulting in visual impairment and potential blindness. Elevated intraocular pressure (IOP) is a major risk factor, but some patients still experience disease progression despite IOP-lowering treatments. Genome-wide association studies have linked variations in the Caveolin1/2 (CAV-1/2) gene loci to glaucoma risk. Cav-1, a key protein in caveolae membrane invaginations, is involved in signaling pathways and its absence impairs retinal function. Recent research suggests that Cav-1 is implicated in modulating the BDNF/TrkB signaling pathway in retinal ganglion cells, which plays a critical role in retinal ganglion cell (RGC) health and protection against apoptosis. Understanding the interplay between these proteins could shed light on glaucoma pathogenesis and provide potential therapeutic targets.

Objective: Previous research has shown that the role of neurotrophic receptor tyrosine kinase 2 (NTRK2) in breast cancer (BRCA) remains ambiguous. To help elucidate this, we conducted a retrospective study to investigate the relationship between NTRK2 protein expression and BRCA., Methods: The prognostic significance of NTRK2 protein expression patterns was assessed by performing immunohistochemistry assays on 131 BRCA tissues and 56 adjacent normal tissues in a retrospective study. Furthermore, the sensitivity to chemotherapeutic drugs was quantified by "pRRophetic" and the sensitivity to immunotherapy was estimated using The Cancer Immunome Atlas website., Results: NTRK2 protein was expressed at significantly higher levels in BRCA samples compared with normal tissues. The data indicated that NTRK2 expression is an independent risk factor for BRCA patient prognosis. Additionally, the high NTRK2 group exhibited increased sensitivity to certain chemotherapy drugs and achieved higher scores for immune checkpoint blockade therapy compared with the low NTRK2 group., Conclusions: Our study demonstrated that higher NTRK2 protein expression is related to a less favorable prognosis in BRCA patients, as well as to enhanced sensitivity to specific chemotherapy and immunotherapy drugs., Competing Interests: Declaration of conflicting interestThe authors declare that there is no conflict of interest.

Tissue-agnostic, molecularly targeted therapies are becoming increasingly common in cancer treatment. The molecular drivers of some classes and subclasses of tumors are rapidly being uncovered in an era of deep tumor sequencing occurring at the time of diagnosis. When and how targeted therapies should fit within up-front cytotoxic chemotherapy and radiation paradigms is yet to be determined, because many of them have been studied in single-arm studies in patients with relapsed or refractory cancer. Infant high-grade gliomas (HGGs) are biologically and clinically distinct from older child and adult HGGs, and are divided into 3 molecular subgroups. Group 1 infant HGGs are driven by receptor tyrosine kinase fusions, most commonly harboring an ALK, ROS1, NTRK, or MET fusion. Both larotrectinib and entrectinib are tropomyosin receptor kinase inhibitors with tissue-agnostic approvals for the treatment of patients with solid tumors harboring an NTRK fusion. This report discusses an 11-month-old female who presented with infantile spasms, found to have an unresectable, NTRK fusion-positive infant HGG. Larotrectinib was prescribed when the NTRK fusion was identified at diagnosis, and without additional intervention to date, the patient has continued with stable disease for >3 years. The only adverse event experienced was grade 1 aspartate transaminase and alanine transaminase elevations. The patient has a normal neurologic examination, is developing age-appropriately in all domains (gross motor, fine motor, cognitive, language, and social-emotional). She is no longer on antiseizure medications. To our knowledge, this is the first report of a patient with an infantile HGG receiving targeted therapy as first-line treatment with prolonged stable disease. A prospective study of larotrectinib in patients with newly diagnosed infant HGG is ongoing, and will hopefully help answer questions about durability of response, the need for additional therapies, and long-term toxicities seen with TRK inhibitors.

Trk (NTRK) receptor and NTRK gene fusions are oncogenic drivers of a wide variety of tumors. Although Trk receptors are typically activated at the cell surface, signaling of constitutive active Trk and diverse intracellular NTRK fusion oncogenes is barely investigated. Here, we show that a high intracellular abundance is sufficient for neurotrophin-independent, constitutive activation of TrkB kinase domains. In HEK293 cells, constitutive active TrkB kinase and an intracellular NTRK2-fusion oncogene (SQSTM1-NTRK2) reduced actin filopodia dynamics, phosphorylated FAK, and altered the cell morphology. Atypical cellular responses could be mimicked with the intracellular kinase domain, which did not activate the Trk-associated MAPK/ERK pathway. In glioblastoma-like U87MG cells, expression of TrkB or SQSTM1-NTRK2 reduced cell motility and caused drastic changes in the transcriptome. Clinically approved Trk inhibitors or mutating Y 705 in the kinase domain, blocked the cellular effects and transcriptome changes. Atypical signaling was also seen for TrkA and TrkC. Moreover, hallmarks of atypical pTrk kinase were found in biopsies of Nestin-positive glioblastoma. Therefore, we suggest Western blot-like immunoassay screening of NTRK-related (brain) tumor biopsies to identify patients with atypical panTrk or phosphoTrk signals. Such patients could be candidates for treatment with NTRK inhibitors such as Larotrectinhib or Entrectinhib., (© 2024. The Author(s).)

Aging is a major risk factor for cognitive deficits, impaired locomotion, and gait disorders. Although oxidative stress and circadian disruption are involved in both normal aging and the pathogenesis of age-associated diseases, just a very few studies explore the consequences of aging on circadian rhythms in the cerebellum. Here, we investigated age-dependent changes in the circadian organization of the molecular clock, antioxidant defenses and synaptic plasticity-related factors, in the rat cerebellum, and discussed the impact of that altered temporal organization on the cognitive function of this brain area. Particularly, we examined the circadian patterns of Brain and muscle ARNT-like 1 (BMAL1) protein levels, Glutathione peroxidase 4 (GPx4) gene expression, GPx and Catalase (CAT) enzymes activity, reduced glutathione (GSH) levels, and the Brain-derived neurotrophic factor (Bdnf) and its Tyrosine kinase receptor B (TrkB) circadian expression. Endogenously-driven circadian rhythms of BMAL1, GPx4, CAT, GSH, and Bdnf/TrkB factors, were observed in the young rat cerebellum. The rhythms' acrophases show a circadian organization that might be crucial for the daily cerebellar-dependent cognitive functions. Notably, aging disrupted circadian rhythms and the temporal organization of BMAL1, antioxidant defenses, and cognitive Bdnf/TrkB gene expression. Increased oxidative stress and disruption of clock-controlled rhythms during aging, might precede and cause the loss of circadian organization in the aged cerebellum. We expect our results highlight circadian rhythms of the studied factors as new targets for the treatment of age-dependent cerebellar disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Previous studies have shown that genes in brain development pathways may have important roles in affecting risk of suicidal behaviors, with our previous meta-analysis supporting a role of the brain-derived neurotrophic factor (BDNF) gene. NTRK2 is a gene that encodes the neurotrophic receptor tyrosine kinase 2, which is a receptor for BDNF. In the current study, we aim to examine the potential association between NTRK2 single nucleotide polymorphism (SNPs) and suicidal ideation/behaviors., Methods: We first conducted a literature search using keywords like 'NTRK2', 'TRKB', and 'suicid*' to identify papers on NTRK2 SNPs and suicidal ideation/behaviors. In addition, we have individual-level genotype data for all the identified SNPs in literature search. We used the R meta package to perform meta-analyses on both the genotype count and the allele count data. Moreover, we performed meta-analyses on specific haplotypes within each haplotype block., Main Results: Following our literature search and meta-analyses on 20 NTRK2 SNPs across up to 8467 samples, we found three SNPs, rs10868235 [N = 5,318, odds ratio (OR) = 1.34, P = 0.02], rs1867283 (N = 5,134, OR = 0.73, P = 0.04), and rs1147198 (N = 5,132, OR = 1.36, P = 0.03) to be nominally associated with suicidal attempts. Those three findings, however, did not survive multiple-testing corrections. Also, none of the haplotype blocks showed significant involvement in suicidality., Conclusion: Our results suggest that the NTRK2 gene may not have a major role in suicidality. Future efforts, however, should explore gene-gene interaction and pathway analyses., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Chimeric antigen receptor (CAR) T-cell therapy is highly effective for treating blood cancers such as B-cell malignancies, however, its effectiveness as an approach to treat solid tumors remains to be further explored. Here, we focused on the development of CAR-T cell therapies targeting tropomyosin-related kinase receptor B (TRKB), a highly expressed protein that is significantly associated with tumor progression, malignancy, and drug resistance in multiple forms of aggressive solid tumors. To achieve this, we screened brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NTF4) ligand-based CAR-T cells for their efficiency in targeting the TRKB receptor in the context of solid tumors, particularly hepatocellular carcinoma and pancreatic cancer. We demonstrated that TRKB is overexpressed not only in hepatocellular carcinoma and pancreatic carcinoma cell lines but also in cancer stem-like cells (CSCs). Notably, BDNF-CAR T and NTF4-CAR T cells could not only effectively target and kill TRKB-expressing pan-cancer cell lines in a dose-dependent manner but also effectively kill CSCs. We also performed in vivo studies to show that NTF4-CAR T cells have a better potential to inhibit the tumor growth of hepatocellular carcinoma xenografts in mice, compared with BDNF-CAR T cells. Taken together, our findings suggest that CAR-T targeting TRKB may be a promising approach for developing novel therapies to treat solid cancers., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Infection during pregnancy is a substantial risk factor for the unborn child to develop autism or schizophrenia later in life, and is thought to be driven by maternal immune activation (MIA). MIA can be modelled by exposing pregnant mice to Polyinosinic: polycytidylic acid (Poly-I:C), a viral mimetic that induces an immune response and recapitulates in the offspring many neurochemical features of ASD and schizophrenia, including altered BDNF-TrkB signalling and disruptions to excitatory/inhibitory balance. Therefore, we hypothesised that a BDNF mimetic, 7,8-Dihydroxyflavone (7,8-DHF), administered prophylactically to the dam may prevent the neurobehavioural sequelae of disruptions induced by MIA. Dams were treated with 7,8-DHF in the drinking water (0.08 mg/ML) from gestational day (GD) 9-20 and were exposed to Poly-I:C at GD17 (20 mg/kg, i.p.). Foetal brains were collected 6 h post Poly-I:C exposure for RT-qPCR analysis of BDNF, cytokine, GABAergic and glutamatergic gene targets. A second adult cohort were tested in a battery of behavioural tests relevant to schizophrenia and the prefrontal cortex and ventral hippocampus dissected for RT-qPCR analysis. Foetal brains exposed to Poly-I:C showed increased IL-6, but reduced expression of Ntrk2 and multiple GABAergic and glutamatergic markers. Anxiety-like behaviour was observed in adult offspring prenatally exposed to poly-I:C, which was accompanied by altered expression of Gria2 in the prefrontal cortex and Gria4 in the ventral hippocampus. While 7-8 DHF normalised the expression of some glutamatergic (Grm5) and GABAergic (Gabra1) genes in Poly-I:C exposed offspring, it also led to substantial alterations in offspring not exposed to Poly-I:C. Furthermore, mice exposed to 7,8-DHF prenatally showed increased pre-pulse inhibition and reduced working memory in adulthood. These data advance understanding of how 7,8-DHF and MIA prenatal exposure impacts genes critical to excitatory/inhibitory pathways and related behaviour., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Background: Neurodevelopmental disorders (NDDs) like intellectual disability (ID) are highly heritable, but the environment plays an important role. For example, endocrine disrupting chemicals (EDCs), including bisphenol A (BPA) and its analogues, have been termed neuroendocrine disruptors. This study aimed to evaluate the influence of different genetic polymorphisms (SNPs) on cognitive function in Spanish schoolchildren according to dietary bisphenol exposure., Methods: A total of 102 children aged 6-12 years old were included. Ten SNPs in genes involved in brain development, synaptic plasticity, and neurotransmission ( BDNF , NTRK2 , HTR2A , MTHFR , OXTR , SLC6A2 , and SNAP25 ) were genotyped. Then, dietary exposure to bisphenols (BPA plus BPS) was estimated and cognitive functions were assessed using the WISC-V Spanish form., Results: BDNF rs11030101-T and SNAP25 rs363039-A allele carriers scored better on the fluid reasoning domain, except for those inheriting the BDNF rs6265-A allele, who had lower scores. Secondly, relevant SNP-bisphenol interactions existed in verbal comprehension ( NTRK2 rs10868235 ( p -int = 0.043)), working memory ( HTR2A rs7997012 ( p -int = 0.002), MTHFR rs1801133 ( p -int = 0.026), and OXTR rs53576 ( p -int = 0.030)) and fluid reasoning ( SLC6A2 rs998424 ( p -int = 0.004))., Conclusions: Our findings provide the first proof that exploring the synergistic or additive effects between genetic variability and bisphenol exposure on cognitive function could lead to a better understanding of the multifactorial and polygenic aetiology of NDDs.

Background: While NTRK fusion-positive cancers can be exquisitely sensitive to first-generation TRK inhibitors, resistance inevitably occurs, mediated in many cases by acquired NTRK mutations. Next-generation inhibitors (e.g., selitrectinib, repotrectinib) maintain activity against these TRK mutant tumors; however, there are no next-generation TRK inhibitors approved by the FDA and select trials have stopped treating patients. Thus, the identification of novel, potent and specific next-generation TRK inhibitors is a high priority., Methods: In silico modeling and in vitro kinase assays were performed on TRK wild type (WT) and TRK mutant kinases. Cell viability and clonogenic assays as well as western blots were performed on human primary and murine engineered NTRK fusion-positive TRK WT and mutant cell models. Finally, zurletrectinib was tested in vivo in human xenografts and murine orthotopic glioma models harboring TRK-resistant mutations., Results: In vitro kinase and in cell-based assays showed that zurletrectinib, while displaying similar potency against TRKA, TRKB, and TRKC WT kinases, was more active than other FDA approved or clinically tested 1 st - (larotrectinib) and next-generation (selitrectinib and repotrectinib) TRK inhibitors against most TRK inhibitor resistance mutations (13 out of 18). Similarly, zurletrectinib inhibited tumor growth in vivo in sub-cute xenograft models derived from NTRK fusion-positive cells at a dose 30 times lower when compared to selitrectinib. Computational modeling suggests this stronger activity to be the consequence of augmented binding affinity of zurletrectinib for TRK kinases. When compared to selitrectinib and repotrectinib, zurletrectinib showed increased brain penetration in rats 0.5 and 2 h following a single oral administration. Consistently, zurletrectinib significantly improved the survival of mice harboring orthotopic NTRK fusion-positive, TRK-mutant gliomas (median survival = 41.5, 66.5, and 104 days for selitrectinib, repotrectinib, and zurletrectinib respectively; P < 0.05)., Conclusion: Our data identifies zurletrectinib as a novel, highly potent next-generation TRK inhibitor with stronger in vivo brain penetration and intracranial activity than other next-generation agents., (© 2024. The Author(s).)

Major depressive disorder (MDD) is a complex and devastating illness that affects people of all ages. Despite the large use of antidepressants in current medical practice, neither their mechanisms of action nor the aetiology of MDD are completely understood. Experimental evidence supports the involvement of Parvalbumin-positive GABAergic neurons (PV-neurons) in the pathogenesis of MDD. DLX5 and DLX6 ( DLX5/6 ) encode two homeodomain transcription factors involved in cortical GABAergic differentiation and function. In the mouse, the level of expression of these genes is correlated with the cortical density of PV-neurons and with anxiety-like behaviours. The same genomic region generates the lncRNA DLX6-AS1, which, in humans, participates in the GABAergic regulatory module downregulated in schizophrenia and ASD. Here, we show that the expression levels of Dlx5/6 in the adult mouse brain are correlated with the immobility time in the forced swim test, which is used to measure depressive-like behaviours. We show that the administration of the antidepressant fluoxetine (Flx) to normal mice induces, within 24 h, a rapid and stable reduction in Dlx5 , Dlx6 and Dlx6-AS1 expression in the cerebral cortex through the activation of the TrkB-CREB pathway. Experimental Dlx5 overexpression counteracts the antidepressant effects induced by Flx treatment. Our findings show that one of the short-term effects of Flx administration is the reduction in Dlx5/6 expression in GABAergic neurons, which, in turn, has direct consequences on PV expression and on behavioural profiles. Variants in the DLX5/6 regulatory network could be implicated in the predisposition to depression and in the variability of patients' response to antidepressant treatment.

Background Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are found in 1% of gliomas across children and adults. TRK inhibitors are promising therapeutic agents for NTRK-fused gliomas because they are tissue agnostic and cross the blood-brain barrier (BBB). Methods We investigated twelve NGS-verified NTRK-fused gliomas from a single institute, Seoul National University Hospital. Results The patient cohort included six children (aged 1-15 years) and six adults (aged 27-72 years). NTRK2 fusions were found in ten cerebral diffuse low-grade and high-grade gliomas (DLGGs and DHGGs, respectively), and NTRK1 fusions were found in one cerebral desmoplastic infantile ganglioglioma and one spinal DHGG. In this series, the fusion partners of NTRK2 were HOOK3, KIF5A, GKAP1, LHFPL3, SLMAP, ZBTB43, SPECC1L, FKBP15, KANK1, and BCR, while the NTRK1 fusion partners were TPR and TPM3. DLGGs tended to harbour only an NTRK fusion, while DHGGs exhibited further genetic alterations, such as TERT promoter/TP53/PTEN mutation, CDKN2A/2B homozygous deletion, PDGFRA/KIT/MDM4/AKT3 amplification, or multiple chromosomal copy number aberrations. Four patients received adjuvant TRK inhibitor therapy (larotrectinib, repotrectinib, or entrectinib), among which three also received chemotherapy (n = 2) or proton therapy (n = 1). The treatment outcomes for patients receiving TRK inhibitors varied: one child who received larotrectinib for residual DLGG maintained stable disease. In contrast, another child with DHGG in the spinal cord experienced multiple instances of tumour recurrence. Despite treatment with larotrectinib, ultimately, the child died as a result of tumour progression. An adult patient with glioblastoma (GBM) treated with entrectinib also experienced tumour progression and eventually died. However, there was a successful outcome for a paediatric patient with DHGG who, after a second gross total tumour removal followed by repotrectinib treatment, showed no evidence of disease. This patient had previously experienced relapse after the initial surgery and underwent autologous peripheral blood stem cell therapy with carboplatin/thiotepa and proton therapy. Conclusions Our study clarifies the distinct differences in the pathology and TRK inhibitor response between LGG and HGG with NTRK fusions., (© 2024. The Author(s).)

Neuropsychological studies report anxiety and depression like symptoms in patients suffering from lifestyle disorder but its impact on locomotor function lacks clarity. Our study investigates locomotor deficits resulting due to perturbations in cerebellum of high fat diet (HFD), chronodisruption (CD) or a combination (HCD) model of lifestyle disorder. Significant downregulation in levels of cerebellar clock genes (Bmal-1, Clock, Per 1 and Per 2) and Bdnf-Trkb pathway genes (Bdnf, TrkB and Syn1 levels) were recorded. Further, locomotor deficits were observed in all the three experimental groups as evidenced by actimeter test, pole test and wire hanging test. Nuclear pyknosis of Purkinje cells, their derangement and inflammation were the hallmark of cerebellar tissue of all the three experimental groups. Taken together, this study generates important links between cerebellar clock oscillations, locomotor function and Bdnf-TrkB signaling., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Neural stem cell (NSC) proliferation and differentiation in the mammalian brain decreases to minimal levels postnatally. Nevertheless, neurogenic niches persist in the adult cortex and hippocampus in rodents, primates and humans, with adult NSC differentiation sharing key regulatory mechanisms with development. Adult neurogenesis impairments have been linked to Alzheimer's disease (AD) pathology. Addressing these impairments by using neurotrophic factors is a promising new avenue for therapeutic intervention based on neurogenesis. However, this possibility has been hindered by technical difficulties of using in-vivo models to conduct screens, including working with scarce NSCs in the adult brain and differences between human and mouse models or ethical limitations., Methods: Here, we use a combination of mouse and human stem cell models for comprehensive in-vitro characterization of a novel neurogenic compound, focusing on the brain-derived neurotrophic factor (BDNF) pathway. The ability of ENT-A011, a steroidal dehydroepiandrosterone derivative, to activate the tyrosine receptor kinase B (TrkB) receptor was tested through western blotting in NIH-3T3 cells and its neurogenic and neuroprotective action were assessed through proliferation, cell death and Amyloid-β (Aβ) toxicity assays in mouse primary adult hippocampal NSCs, mouse embryonic cortical NSCs and neural progenitor cells (NPCs) differentiated from three human induced pluripotent stem cell lines from healthy and AD donors. RNA-seq profiling was used to assess if the compound acts through the same gene network as BDNF in human NPCs., Results: ENT-A011 was able to increase proliferation of mouse primary adult hippocampal NSCs and embryonic cortical NSCs, in the absence of EGF/FGF, while reducing Aβ-induced cell death, acting selectively through TrkB activation. The compound was able to increase astrocytic gene markers involved in NSC maintenance, protect hippocampal neurons from Αβ toxicity and prevent synapse loss after Aβ treatment. ENT-A011 successfully induces proliferation and prevents cell death after Aβ toxicity in human NPCs, acting through a core gene network shared with BDNF as shown through RNA-seq., Conclusions: Our work characterizes a novel BDNF mimetic with preferable pharmacological properties and neurogenic and neuroprotective actions in Alzheimer's disease via stem cell-based screening, demonstrating the promise of stem cell systems for short-listing competitive candidates for further testing., (© 2024. The Author(s).)

Background: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers. Using the Auria Biobank in Finland, we aimed to identify and characterize patients with these gene fusions, and describe their clinical and tumor characteristics, treatments received, and outcomes., Material and Methods: We evaluated pediatrics with any solid tumor type and adults with colorectal cancer (CRC), non-small cell lung cancer (NSCLC), sarcoma, or salivary gland cancer. We determined tropomyosin receptor kinase (TRK) protein expression by pan-TRK immunohistochemistry (IHC) staining of tumor samples from the Auria Biobank, scored by a certified pathologist. NTRK gene fusion was confirmed by next generation sequencing (NGS). All 2,059 patients were followed-up starting 1 year before their cancer diagnosis., Results: Frequency of NTRK gene fusion tumors was 3.1% (4/127) in pediatrics, 0.7% (8/1,151) for CRC, 0.3% (1/288) for NSCLC, 0.9% (1/114) for salivary gland cancer, and 0% (0/379) for sarcoma. Among pediatrics there was one case each of fibrosarcoma (TPM3::NTRK1), Ewing's sarcoma (LPPR1::NTRK2), primitive neuroectodermal tumor (DAB2IP::NTRK2), and papillary thyroid carcinoma (RAD51B::NTRK3). Among CRC patients, six harbored tumors with NTRK1 fusions (three fused with TPM3), one harbored a NTRK3::GABRG1 fusion, and the other a NTRK2::FXN/LPPR1 fusion. Microsatellite instability was higher in CRC patients with NTRK gene fusion tumors versus wild-type tumors (50.0% vs. 4.4%). Other detected fusions were SGCZ::NTRK3 (NSCLC) and ETV6::NTRK3 (salivary gland cancer). Four patients (three CRC, one NSCLC) received chemotherapy; one patient (with CRC) received radiotherapy., Conclusion: NTRK gene fusions are rare in adult CRC, NSCLC, salivary tumors, sarcoma, and pediatric solid tumors.

Sepsis-associated encephalopathy (SAE) is a frequent complication of severe systemic infection resulting in delirium, premature death, and long-term cognitive impairment. We closely mimicked SAE in a murine peritoneal contamination and infection (PCI) model. We found long-lasting synaptic pathology in the hippocampus including defective long-term synaptic plasticity, reduction of mature neuronal dendritic spines, and severely affected excitatory neurotransmission. Genes related to synaptic signaling, including the gene for activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and members of the transcription-regulatory EGR gene family, were downregulated. At the protein level, ARC expression and mitogen-activated protein kinase signaling in the brain were affected. For targeted rescue we used adeno-associated virus-mediated overexpression of ARC in the hippocampus in vivo. This recovered defective synaptic plasticity and improved memory dysfunction. Using the enriched environment paradigm as a non-invasive rescue intervention, we found improvement of defective long-term potentiation, memory, and anxiety. The beneficial effects of an enriched environment were accompanied by an increase in brain-derived neurotrophic factor (BDNF) and ARC expression in the hippocampus, suggesting that activation of the BDNF-TrkB pathway leads to restoration of the PCI-induced reduction of ARC. Collectively, our findings identify synaptic pathomechanisms underlying SAE and provide a conceptual approach to target SAE-induced synaptic dysfunction with potential therapeutic applications to patients with SAE., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Neurotrophic tyrosine receptor kinase ( NTRK ) gene fusions are rare oncogenic drivers prevalent in 0.3% of solid tumors. They are most common in salivary gland cancer (2.6%), thyroid cancer (1.6%), and soft-tissue sarcoma (1.5%). Currently, there are 2 US Food and Drug Administration-approved targeted therapies for NTRK gene fusions: larotrectinib, approved in 2018, and entrectinib, approved in 2019. To date, the real-world uptake of tyrosine receptor kinase inhibitor (TRKi) use for NTRK -positive solid tumors in academic cancer centers remains largely unknown., Objective: To describe the demographics, clinical and genomic characteristics, and testing and treatment patterns of patients with NTRK -positive solid tumors treated at US academic cancer centers., Methods: This was a retrospective chart review study conducted in academic cancer centers in the United States. All patients diagnosed with an NTRK fusion-positive ( NTRK 1, NTRK 2, NTRK 3) solid tumor (any stage) and who received cancer treatment at participating sites between January 1, 2012, and July 1, 2023, were included in this study. Patient demographics, clinical characteristics, genomic characteristics, NTRK testing data, and treatment patterns were collected from electronic medical records and analyzed using descriptive statistics as appropriate., Results: In total, 6 centers contributed data for 55 patients with NTRK -positive tumors. The mean age was 49.3 (SD = 20.5) years, 51% patients were female, and the majority were White (78%). The median duration of time from cancer diagnosis to NTRK testing was 85 days (IQR = 44-978). At the time of NTRK testing, 64% of patients had stage IV disease, compared with 33% at cancer diagnosis. Prevalent cancer types in the overall cohort included head and neck (15%), thyroid (15%), brain (13%), lung (13%), and colorectal (11%). NTRK 1 fusions were most common (45%), followed by NTRK 3 (40%) and NTRK 2 (15%). Across all lines of therapy, 51% of patients (n = 28) received a TRKi. Among TRKi-treated patients, 71% had stage IV disease at TRKi initiation. The median time from positive NTRK test to initiation of TRKi was 48 days (IQR = 9-207). TRKis were commonly given as first-line (30%) or second-line (48%) therapies. Median duration of therapy was 610 (IQR = 182-764) days for TRKi use and 207.5 (IQR = 42-539) days for all other first-line therapies., Conclusions: This study reports on contemporary real-world NTRK testing patterns and use of TRKis in solid tumors, including time between NTRK testing and initiation of TRKi therapy and duration of TRKi therapy.

Epidermal growth factor receptor (EGFR) is reportedly overexpressed in most esophageal squamous cell carcinoma (ESCC) patients, but anti-EGFR treatments offer limited survival benefits. Our preclinical data showed the promising antitumor activity of afatinib in EGFR-overexpressing ESCC. This proof-of-concept, phase II trial assessed the efficacy and safety of afatinib in pretreated metastatic ESCC patients (n = 41) with EGFR overexpression (NCT03940976). The study met its primary endpoint, with a confirmed objective response rate (ORR) of 39% in 38 efficacy-evaluable patients and a median overall survival of 7.8 months, with a manageable toxicity profile. Transcriptome analysis of pretreatment tumors revealed that neurotrophic receptor tyrosine kinase 2 (NTRK2) was negatively associated with afatinib sensitivity and might serve as a predictive biomarker, irrespective of EGFR expression. Notably, knocking down or inhibiting NTRK2 sensitized ESCC cells to afatinib treatment. Our study provides novel findings on the molecular factors underlying afatinib resistance and indicates that afatinib has the potential to become an important treatment for metastatic ESCC patients., (© 2024. The Author(s).)

Neurotrophic receptor tyrosine kinases (NTRKs) belong to the receptor tyrosine kinase (RTK) family. NTRKs are responsible for the activation of multiple downstream signaling pathways that regulate cell growth, proliferation, differentiation, and apoptosis. NTRK-associated mutations often result in oncogenesis and lead to aberrant activation of downstream signaling pathways including MAPK, JAK/STAT, and PLCγ1. This study characterizes the NACC2-NTRK2 oncogenic fusion protein that leads to pilocytic astrocytoma and pediatric glioblastoma. This fusion joins the BTB domain (Broad-complex, Tramtrack, and Bric-a-brac) domain of NACC2 (Nucleus Accumbens-associated protein 2) with the transmembrane helix and tyrosine kinase domain of NTRK2. We focus on identifying critical domains for the biological activity of the fusion protein. Mutations were introduced in the charged pocket of the BTB domain or in the monomer core, based on a structural comparison of the NACC2 BTB domain with that of PLZF, another BTB-containing protein. Mutations were also introduced into the NTRK2-derived portion to allow comparison of two different breakpoints that have been clinically reported. We show that activation of the NTRK2 kinase domain relies on multimerization of the BTB domain in NACC2-NTRK2. Mutations which disrupt BTB-mediated multimerization significantly reduce kinase activity and downstream signaling. The ability of these mutations to abrogate biological activity suggests that BTB domain inhibition could be a potential treatment for NACC2-NTRK2-induced cancers. Removal of the transmembrane helix leads to enhanced stability of the fusion protein and increased activity of the NACC2-NTRK2 fusion, suggesting a mechanism for the oncogenicity of a distinct NACC2-NTRK2 isoform observed in pediatric glioblastoma., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Progressive lung fibrosis is associated with poorly understood aging-related endothelial cell dysfunction. To gain insight into endothelial cell alterations in lung fibrosis we performed single cell RNA-sequencing of bleomycin-injured lungs from young and aged mice. Analysis reveals activated cell states enriched for hypoxia, glycolysis and YAP/TAZ activity in ACKR1+ venous and TrkB+ capillary endothelial cells. Endothelial cell activation is prevalent in lungs of aged mice and can also be detected in human fibrotic lungs. Longitudinal single cell RNA-sequencing combined with lineage tracing demonstrate that endothelial activation resolves in young mouse lungs but persists in aged ones, indicating a failure of the aged vasculature to return to quiescence. Genes associated with activated lung endothelial cells states in vivo can be induced in vitro by activating YAP/TAZ. YAP/TAZ also cooperate with BDNF, a TrkB ligand that is reduced in fibrotic lungs, to promote capillary morphogenesis. These findings offer insights into aging-related lung endothelial cell dysfunction that may contribute to defective lung injury repair and persistent fibrosis., (© 2024. The Author(s).)

Background : NTRK1, NTRK2, and NTRK3 are members of the neurotrophic receptor tyrosine kinases (NTRK) family, which encode TrkA, TrkB, and TrkC receptors, respectively. Hematologic cancers are also linked to point mutations in the NTRK gene's kinase domain. Trk fusions are the most common genetic change associated with oncogenic activity in Trk-driven liquid tumors. Thus, point mutations in NTRK genes may also play a role in tumorigenesis. The structural and functional effect of mutations in Trk-B & Trk-C proteins remains unclear. Methods : In this research, Homology (threading-based approach) modeling and the all-atom molecular dynamics simulations approaches are applied to examine the structural and functional behavior of native and mutant Trk-B and Trk-C proteins at the molecular level. Results: The result of this study reveals how the mutations in Trk-B (A203T & R458G) and Trk-C (E176D & L449F) proteins lost their stability and native conformations. The Trk-B mutant A203T became more flexible than the native protein, whereas the R458G mutation became more rigid than the native conformation of the Trk-B protein. Also, the Trk-C mutations (E176D & L449F) become more rigid compared to the native structure. Conclusions: This structural transition may interrupt the function of Trk-B and Trk-C proteins. Observing the impact of NTRK-2/3 gene alterations at the atomic level could aid in discovering a viable treatment for Trk-related leukemias., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 M Al-Subaie A et al.)

Objective: To investigate the clinicopathological, immunophenotypic and molecular genetic characteristics, and differential diagnosis of NTRK-rearranged spindle cell neoplasms (NTRK-RSCNs) in the gastrointestinal tract. Methods: Two NTRK-RSCNs diagnosed at the Department of Pathology of the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China and one case diagnosed at Zhengzhou Central Hospital, Zhengzhou, China from 2019 to 2022 were collected. The clinical data, histopathology, immunophenotypes and prognosis were analyzed. Fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) were used to detect NTRK gene rearrangements, while relevant literature was also reviewed and discussed. Results: Two patients were male and one was female, with the age of 17, 47 and 62 years, respectively. The tumors were located in the duodenum, ascending colon and descending colon, respectively. The tumors were protuberant masses with gray and rubbery sections. Their maximum diameter was 2.5, 5.0 and 10.0 cm, respectively. Histologically, the tumors invaded mucosa, intrinsic muscle and serosal adipose tissue. Tumor cells consisted of spindle or oval shaped cells with monotonous morphology and arranged in bundles or stripes pattern. Spindle cells were mildly to moderately atypical, with slightly eosinophilic cytoplasm and inconspicuous nucleoli. Necrosis and mitotic figures were observed in one high-grade tumor. All tumors expressed CD34, S-100 and pan-TRK in varying degrees. FISH analysis showed that NTRK1 gene was break-apart in 1 case and NTRK2 gene break-apart in 2 cases. NGS technologies showed LMNA::NTRK1 fusion in one case, STRN::NTRK2 fusion in another case. All patients recovered well after the surgery without recurrence at the end of the follow-up. Conclusions: NTRK-RSCN is rarely diagnosed in the gastrointestinal tract and has significant variations in morphology. It overlaps with various other mesenchymal tumors which should be considered as differential diagnoses. Be familiar with the features of histological morphology in combination with immunophenotype and molecular genetic characteristics can not only help diagnose NTRK-RSCNs, but provide therapeutic targets for clinical treatment.

Methyl-CpG-binding protein 2 ( Mecp2 ) is an epigenetic modulator and numerous studies have explored its impact on the central nervous system manifestations. However, little attention has been given to its potential contributions to the peripheral nervous system (PNS). To investigate the regulation of Mecp2 in the PNS on specific central regions, we generated Mecp2 fl/fl Advillin cre mice with the sensory-neuron-specific deletion of the Mecp2 gene and found the mutant mice had a heightened sensitivity to temperature, which, however, did not affect the sense of motion, social behaviors, and anxiety-like behavior. Notably, in comparison to Mecp2 fl/fl mice, Mecp2 fl/fl Advillin cre mice exhibited improved learning and memory abilities. The levels of hippocampal synaptophysin and PSD95 proteins were higher in Mecp2 fl/fl Advillin cre mice than in Mecp2 fl/fl mice. Golgi staining revealed a significant increase in total spine density, and dendritic arborization in the hippocampal pyramidal neurons of Mecp2 fl/fl Advillin cre mice compared to Mecp2 fl/fl mice. In addition, the activation of the BDNF-TrkB-CREB1 pathway was observed in the hippocampus and spinal cord of Mecp2 fl/fl Advillin cre mice. Intriguingly, the hippocampal BDNF/CREB1 signaling pathway in mutant mice was initiated within 5 days after birth. Our findings suggest a potential therapeutic strategy targeting the BDNF-TrkB-CREB1 signaling pathway and peripheral somasensory neurons to treat learning and cognitive deficits associated with Mecp2 disorders.

Background: Members of the neurotrophic tropomyosin receptor kinase (NTRK) gene family, NTRK1, NTRK2, and NTRK3 encode TRK receptor tyrosine kinases. Intra- or inter-chromosomal gene rearrangements produce NTRK gene fusions encoding fusion proteins which are oncogenic drivers in various solid tumors., Methods: This study investigated the prevalence of NTRK fusion genes and identified fusion partners in Japanese patients with solid tumors recorded in the Center for Cancer Genomics and Advanced Therapeutics database of comprehensive genomic profiling test., Results: In the analysis population (n = 46,621), NTRK fusion genes were detected in 91 patients (0.20%). The rate was higher in pediatric cases (<18 years; 1.69%) than in adults (0.16%). NTRK gene fusions were identified in 21 different solid tumor types involving 38 different partner genes including 22 (57.9%) previously unreported NTRK gene fusions. The highest frequency of NTRK gene fusions was head and neck cancer (1.31%) and thyroid cancer (1.31%), followed by soft tissue sarcoma (STS; 0.91%). A total of 97 NTRK fusion gene partners were analyzed involving mainly NTRK1 (49.5%) or NTRK3 (44.2%) gene fusions. The only fusion gene detected in head and neck cancer was ETV6::NTRK3 (n = 22); in STS, ETV6::NTRK3 (n = 7) and LMNA::NTRK1 (n = 5) were common. Statistically significant mutual exclusivity of NTRK fusions with alterations was confirmed in TP53, KRAS, and APC. NTRK gene fusion was detected from 11 STS cases: seven unclassified sarcoma, three sarcoma NOS, and one Ewing sarcoma., Conclusions: NTRK gene fusion identification in solid tumors enables accurate diagnosis and potential TRK inhibitor therapy., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

The fusion of neurotrophic tyrosine receptor kinase (NTRK) is a novel target for cancer therapy and offers hope for patients with gastric cancer (GC). However, there are few studies on the prevalence and detection methods of NTRK fusions in GC. In this study, we used immunohistochemistry (IHC) as a screening method to select cases for molecular testing and evaluated the effectiveness of IHC, fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS). We retrospectively collected 1970 patients with GC. Pan-TRK IHC was conducted in all cases, and three cases were positive: one with strong and diffuse cytoplasmic staining, while two with weak cytoplasmic staining. All three cases were validated using NTRK1/2/3 FISH. FISH results revealed a single 3' signal of NTRK1 in 95% of the tumor cells in the first case, while the remaining two cases were negative. NGS confirmed LMNA-NTRK1 fusion in the first case, with no gene fusion detected in the other two cases. Out of 46 negative controls, one had a non-functional fusion of IGR-NTRK1, and four had point mutations. The case with LMNA-NTRK1 fusion were negative for pMMR, EBV, HER2, and AFP. The pan-TRK IHC showed a 33.33% (1/3) concordance rate with RNA-based NGS. If the criterion for positivity was 3+ cytoplasmic staining, the agreement between IHC and RNA-based NGS was 100% (1/1). In conclusion, the incidence of NTRK fusion in GC is extremely low (0.05%). If the criteria are strict, pan-TRK IHC is highly effective for screening NTRK fusions. FISH could complement NGS detection, particularly when NTRK fusion is detected by DNA sequencing. NTRK fusion in GC may not be limited to specific subtypes., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Charcot-Marie-Tooth disease (CMT) is a genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which transfer amino acids to partner tRNAs for protein synthesis, represent the largest protein family genetically linked to CMT aetiology, suggesting pathomechanistic commonalities. Dominant intermediate CMT type C (DI-CMTC) is caused by YARS1 mutations driving a toxic gain-of-function in the encoded tyrosyl-tRNA synthetase (TyrRS), which is mediated by exposure of consensus neomorphic surfaces through conformational changes of the mutant protein. In this study, we first showed that human DI-CMTC-causing TyrRS E196K mis-interacts with the extracellular domain of the BDNF receptor TrkB, an aberrant association we have previously characterised for several mutant glycyl-tRNA synthetases linked to CMT type 2D (CMT2D). We then performed temporal neuromuscular assessments of Yars E196K mice modelling DI-CMT. We determined that Yars E196K homozygotes display a selective, age-dependent impairment in in vivo axonal transport of neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. This impairment is replicated by injection of recombinant TyrRS E196K , but not TyrRS WT , into muscles of wild-type mice. Augmenting BDNF in DI-CMTC muscles, through injection of recombinant protein or muscle-specific gene therapy, resulted in complete axonal transport correction. Therefore, this work identifies a non-cell autonomous pathomechanism common to ARS-related neuropathies, and highlights the potential of boosting BDNF levels in muscles as a therapeutic strategy., Competing Interests: Declaration of competing interest The technology described in this work has been protected in the patent GB2303495.2 (patent applicant, UCL Business Ltd., status pending), in which GS and JNS are named as inventors. The other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are recurrent oncogenic drivers found in a variety of solid tumours, including lung cancer. Several tropomyosin receptor kinase (TRK) inhibitors have been developed to treat tumours with NTRK gene fusions. Larotrectinib and entrectinib are first-generation TRK inhibitors that have demonstrated efficacy in patients with TRK fusion lung cancers. Genomic testing is recommended for all patients with metastatic non-small cell lung cancer for optimal drug therapy selection. Multiple testing methods can be employed to identify NTRK gene fusions in the clinic and each has its own advantages and limitations. Among these assays, RNA-based next-generation sequencing (NGS) can be considered a gold standard for detecting NTRK gene fusions; however, several alternatives with minimally acceptable sensitivity and specificity are also available in areas where widespread access to NGS is unfeasible. This review highlights the importance of testing for NTRK gene fusions in lung cancer, ideally using the gold-standard method of RNA-based NGS, the various assays that are available, and treatment algorithms for patients., Competing Interests: Declaration of competing interest Support for attending meetings and/or travel: Sanofi. Marina Chiara Garassino: Personal financial interests: AstraZeneca, Abion, MSD International GmbH, Bayer, BMS, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Incyte, Novartis, Pfizer, Roche, Takeda, Seattle Genetics, Mirati, Daiichi Sankyo, Regeneron, Merck, Blueprint, Jansenn, Sanofi, AbbVie, BeiGenius, Oncohost, Medscape, Gilead, Io Biotech; Institutional financial interests: Eli Lilly, MSD, Pfizer (MISP); AstraZeneca, MSD International GmbH, BMS, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Ignyta, Incyte, MedImmune, Novartis, Pfizer, Roche, Takeda, Tiziana, Foundation Medicine, GSK, Spectrum Pharmaceuticals; Others: AIRC, AIFA, Italian Moh, TRANSCAN; Research funding, Horizon 2020. Herbert H. Loong: Advisory: Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Illumina, Novartis, Merck Sereno, Takeda, George Clinical; Speakers’ bureau: AbbVie, Bayer, Daiichi Sankyo, Eisai, Eli Lilly, Guardant Health, Novartis; Travel support: Bayer, Boehringer Ingelheim, MSD, Novartis, Pfizer; Research funding: MSD, Mundipharma, Novartis; Others: Member of Pharmacy and Poisons (Registration of Pharmaceutical Products and Substances: Certification of Clinical Trial/Medicinal Test) Committee, Pharmacy & Poisons Board of Hong Kong. Fernando Lopez-Rios: Honoraria/advisory boards: Abbvie, Astellas, AstraZeneca, Bayer, BMS, Daiichi Sankyo, Janssen, Lilly, MSD, Merck, Pfizer, Roche, Sanofi, Takeda, Thermo Fisher Scientific; Associated research paid to institution: AstraZeneca, Lilly, Pfizer, Roche, Thermo Fisher Scientific. Tony Mok: Grant/research support from (paid to institution): AstraZeneca, BMS, G1 Therapeutics, MSD, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, XCovery; Speaker’s fees received from: ACEA Pharma, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., Ltd., AstraZeneca (before 1/1/19), BeiGene, Boehringer Ingelheim, BMS, Daiichi Sankyo, Daz Group, Fishawack Facilitate Ltd., InMed Medical Communication, Janssen Pharmaceutica NV, Jiahui Holdings Co. Limited, LiangYiHui Healthcare, Lilly, Lucence Health Inc., MD Health Brazil, Medscape LLC, Merck Pharmaceuticals HK Ltd., Merck Sharp & Dohme, MiRXES, Novartis, OrigiMed Co. Ltd., P. Permanyer SL, PeerVoice, Physicians’ Education Resource (PER), Pfizer, PrIME Oncology, Research to Practice, Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting Co., Ltd., Shanghai Promedican Pharmaceuticals Co., Ltd., Taiho Pharmaceutical Co. Ltd, Takeda Oncology, Touch Independent Medical Education Ltd; Honoraria/honorarium received (for consultation services/as independent consultant) from: Abbvie Inc., ACEA Pharma, Adagene, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., Ltd., AnHeart Therapeutics, AstraZeneca (before 1/1/19), AVEO Pharmaceuticals, Inc., Bayer Healthcare Pharmaceuticals Ltd., BeiGene, BerGenBio ASA, Berry Oncology, Boehringer Ingelheim, Blueprint Medicines Corporation, BMS, Bowtie Life Insurance Company Limited, Bridge Biotherapeutics Inc., Covidien LP, C4 Therapeutics Inc., Cirina Ltd., CStone Pharmaceuticals, Curio Science, D3 Bio Ltd., Da Volterra, Daiichi Sankyo, Eisai, Elevation Oncology, F. Hoffmann-La Roche Ltd., Genentech, GLG’s Healthcare, Fishawack Facilitate Ltd., G1 Therapeutics Inc., geneDecode Co., Ltd, Gilead Sciences, Inc. Gritstone Oncology, Inc., Guardant Health, Hengrui Therapeutics Inc., HutchMed, Ignyta, Inc., Illumina, Inc., Incyte Corporation, Inivata, IQVIA, Janssen, Lakeshore Biotech Ltd, Lilly, Lunit USA, Inc., Loxo Oncology, Lucence Health Inc., Medscape LLC/ WebMD, Medtronic, Merck Serono, MSD, Mirati Therapeutics Inc., MiRXES, MoreHealth, Novartis, Novocure GmbH, Omega Therapeutics Inc., OrigiMed, OSE Immunotherapeutics, PeerVoice, Pfizer, PrIME Oncology, Prenetics, Puma Biotechnology Inc., Qiming Development (HK) Ltd., Regeneron Pharmaceuticals Inc., Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, SFJ Pharmaceutical Ltd., Simcere of America Inc., Summit Therapeutics Sub, Inc., Synergy Research, Takeda Pharmaceuticals HK Ltd., Tigermed, Vertex Pharmaceuticals, Virtus Medical Group, XENCOR, Inc., Yuhan Corporation; Stock shareholder in: Alentis Therapeutics AG, AstraZeneca, Aurora Tele-Oncology Ltd., Biolidics Ltd., HutchMed, Prenetics, D3 Bio, Lunit Inc.; Stock options: Bowtie Life Insurance Co. Ltd., D3 Bio, Lakeshore Biotech Ltd, Loxo Oncology, Lunit USA, Inc., Virtus Medical Group, Phanes Therapeutics, Inc., Insighta; Advisory board for: AbbVie Inc., ACEA Pharma, Amgen, AstraZeneca, BerGenBio ASA, Berry Oncology, Blueprint Medicines Corporation, Boehringer Ingelheim, Bowtie Life Insurance Co Ltd, BMS, C4 Therapeutics Inc, Covidien LP, CStone Pharmaceuticals, Curio Science, D3 Bio Ltd., Daiichi Sankyo Inc., Eisai, Fishawack Facilitate Ltd., G1 Therapeutics Inc., Gilead Sciences Inc., Gritstone Oncology, Inc., Guardant Health, geneDecode Co. Ltd. (uncompensated), Hengrui Therapeutics Inc., HutchMed, Ignyta Inc., Incyte Corporation, Imagene AI Ltd., Inivata, IQVIA, Janssen, Lakeshore Biotech, Lily, Loxo Oncology Inc., Lunit, Inc., Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc., MiRXES Group, Novartis, OrigiMed, Pfizer, Prenetics, Puma Biotechnology Inc., Roche/Genentech, Regeneron Pharmaceuticals Inc., Sanofi-Aventis R&D, SFJ Pharmaceutical, Simcere of America Inc., Simcere Zaiming, Inc., Takeda, Vertex Pharmaceuticals, Virtus Medical Group, Yuhan Corporation; Board of directors/leadership roles (remunerated): AstraZeneca PLC (from January 2019–Present), HutchMed, Aurora, Insighta (from July 2023–Present); Board of directors/leadership roles (non-remunerated): American Society of Clinical Oncology (2018–2022), Asian Thoracic Oncology Research Group (2016–Present), Chinese Lung Cancer Research Foundation Limited (2005–2012), Chinese Society of Clinical Oncology (2009–2020), Hong Kong Cancer Fund (2011–Present), Hong Kong Cancer Therapy Society (2004–Present), International Association for the Study of Lung Cancer (2007–2019), St. Stephen’s College & Prep. School (2017–Present), Hong Kong Academy of Sciences (2022–Present). Solange Peters: I have Received education grants, provided consultation, attended advisory boards and/or provided lectures for the following organizations, from whom honoraria received (all fees to institution): Consultation/Advisory role: AbbVie, Amgen, Arcus, AstraZeneca, Bayer, Beigene, BerGenBio, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Hutchmed, Illumina, Incyte, Ipsen, iTeos, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Nykode Therapeutics, Novartis, Novocure, Pharma Mar, Promontory Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda; Board of director position: Galenica; Talk in a company’s organized public event: AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Foundation Medicine, GSK, Illumina, Ipsen, Merck Sharp and Dohme, Mirati, Novartis, Pfizer, Roche/Genentech, Sanofi, Takeda; Receipt of grants/research supports: Principal investigator in trials (institutional financial support for clinical trials) sponsored by: Amgen, Arcus, AstraZeneca, Beigene, BMS, GSK, iTeos, Merck Sharp and Dohme, Mirati, Pharma Mar, Promontory Therapeutics, Roche/Genentech, Seattle Genetics. David Planchard: Consulting, advisory role or lectures: AstraZeneca, Abbvie, BMS, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Janssen, Pfizer, Roche, Pierre-fabre, Takeda, ArriVent, Mirati, Seagen; Clinical trials research as principal or co-investigator (institutional financial interests): AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, Abbvie, Janssen, Pierre-Fabre, Takeda, ArriVent, Mirati, Seagen; Travel, accommodations and/or expenses: AstraZeneca, Roche, Novartis, Pfizer. Sanjay Popat: Consulting fees (personal fees): Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, GSK, Guardant Health, Incyte, Janssen, Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, EQRx; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (personal fees): AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche, Takeda; Payment for expert testimony (personal fees): Roche, Merck Serono; Support for attending meetings and/or travel (travel expenses reimbursement): Janssen, Roche; Leadership in fiduciary role in other board, society, committee or advocacy group (unpaid): British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation; ETOP-IBCSG Partners Foundation Board. Erin R. Rudzinski: Clinical trials research: ON-TRK study (Bayer). Alexander Drilon: Honoraria/advisory boards: 14ner/Elevation Oncology, Amgen, Abbvie, ArcherDX, AstraZeneca, Beigene, BergenBio, Blueprint Medicines, Chugai Pharmaceutical, EcoR1, EMD Serono, Entos, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Janssen, Loxo/Bayer/Lilly, Merus, Monopteros, MonteRosa, Novartis, Nuvalent, Pfizer, Prelude, Repare RX, Takeda/Ariad/Millenium, Treeline Bio, TP Therapeutics, Tyra Biosciences, Verastem; Associated research paid to institution: Pfizer, Exelixis, GSK, Teva, Taiho, PharmaMar; Royalties: Wolters Kluwer; Other (food/beverage): Merck, Puma, Merus, Boehringer Ingelheim; CME honoraria: Answers in CME, Applied Pharmaceutical Science, Inc., AXIS, Clinical Care Options, EPG Health, Harborside Nexus, I3 Health, Imedex, Liberum, Medendi, Medscape, Med Learning, MJH Life Sciences, MORE Health, Ology, OncLive, Paradigm, Peerview Institute, PeerVoice, Physicians Education Resources, Remedica Ltd., Research to Practice, RV More, Targeted Oncology, TouchIME, WebMD. Caicun Zhou: Consulting fees: Innovent Biologics, Hengrui, Qilu, TopAlliance Biosciences; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Lily China, Sanofi, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Alice, C-Stone, LUYE Pharma, TopAlliance Biosciences, Amoy Diagnostics, AnHeart., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cathepsin S (CTSS) is a cysteine protease that played diverse roles in immunity, tumor metastasis, aging and other pathological alterations. At the cellular level, increased CTSS levels have been associated with the secretion of pro-inflammatory cytokines and disrupted the homeostasis of Ca 2+ flux. Once CTSS was suppressed, elevated levels of anti-inflammatory cytokines and changes of Ca 2+ influx were observed. These findings have inspired us to explore the potential role of CTSS on cognitive functions., Methods: We conducted classic Y-maze and Barnes Maze tests to assess the spatial and working memory of Ctss -/- mice, Ctss +/+ mice and Ctss +/+ mice injected with the CTSS inhibitor (RJW-58). Ex vivo analyses including long-term potentiation (LTP), Golgi staining, immunofluorescence staining of sectioned whole brain tissues obtained from experimental animals were conducted. Furthermore, molecular studies were carried out using cultured HT-22 cell line and primary cortical neurons that treated with RJW-58 to comprehensively assess the gene and protein expressions., Results: Our findings reported that targeting cathepsin S (CTSS) yields improvements in cognitive function, enhancing both working and spatial memory in behavior models. Ex vivo studies showed elevated levels of long-term potentiation levels and increased synaptic complexity. Microarray analysis demonstrated that brain-derived neurotrophic factor (BDNF) was upregulated when CTSS was knocked down by using siRNA. Moreover, the pharmacological blockade of the CTSS enzymatic activity promoted BDNF expression in a dose- and time-dependent manner. Notably, the inhibition of CTSS was associated with increased neurogenesis in the murine dentate gyrus. These results suggested a promising role of CTSS modulation in cognitive enhancement and neurogenesis., Conclusion: Our findings suggest a critical role of CTSS in the regulation of cognitive function by modulating the Ca 2+ influx, leading to enhanced activation of the BDNF/TrkB axis. Our study may provide a novel strategy for improving cognitive function by targeting CTSS., (© 2024. The Author(s).)

Objectives: We evaluated the prognostic value of the neurotrophic tyrosine receptor kinase (NTRK) gene fusions by comparing the survival of patients with NTRK+ tumours with patients without NTRK+ tumours., Methods: We used genomic and clinical registry data from the Center for Personalized Cancer Treatment (CPCT-02) study containing a cohort of cancer patients who were treated in Dutch clinical practice between 2012 and 2020. We performed a propensity score matching analysis, where NTRK+ patients were matched to NTRK- patients in a 1:4 ratio. We subsequently analysed the survival of the matched sample of NTRK+ and NTRK- patients using the Kaplan-Meier method and Cox regression, and performed an analysis of credibility to evaluate the plausibility of our result., Results: Among 3556 patients from the CPCT-02 study with known tumour location, 24 NTRK+ patients were identified. NTRK+ patients were distributed across nine different tumour types: bone/soft tissue, breast, colorectal, head and neck, lung, pancreas, prostate, skin and urinary tract. NTRK fusions involving the NTRK3 gene (46%) and NTRK1 gene (33%) were most common. The survival analysis rendered a hazard ratio (HR) of 1.44 (95% CI 0.81-2.55) for NTRK+ patients. Using the point estimates of three prior studies on the prognostic value of NTRK fusions, our finding that the HR is > 1 was deemed plausible., Conclusions: NTRK+ patients may have an increased risk of death compared with NTRK- patients. When using historic control data to assess the comparative effectiveness of TRK inhibitors, the prognostic value of the NTRK fusion biomarker should therefore be accounted for., (© 2024. The Author(s).)

Purpose: Our study aimed to explore real-world treatment scenarios for children and adolescents with neurotrophic tropomyosin receptor kinase (NTRK)-fused tumors, emphasizing access, responses, side effects, and outcomes., Patients and Methods: Pooled clinical data from 17 pediatric cases (11 soft-tissue sarcomas, five brain tumors, and one neuroblastoma) treated with larotrectinib and radiologic images for 14 patients were centrally reviewed. Testing for gene fusions was prompted by poor response to treatment, tumor progression, or aggressiveness., Results: Six different NTRK fusion subtypes were detected, and various payment sources for testing and medication were reported. Radiologic review revealed objective tumor responses (OR) in 11 of 14 patients: Complete responses: two; partial responses: nine; and stable disease: three cases. Grades 1 or 2 Common Terminology Criteria for Adverse Events adverse effects were reported in five patients. Regarding the entire cohort's clinical information, 15 of 17 patients remain alive (median observation time: 25 months): four with no evidence of disease and 11 alive with disease (10 without progression). One patient developed resistance to the NTRK inhibitor and died from disease progression while another patient died due to an unrelated cause., Conclusion: This real-world study confirms favorable agnostic tumor OR rates to larotrectinib in children with NTRK-fused tumors. Better coordination to facilitate access to medication remains a challenge, particularly in middle-income countries like Brazil.

Pulmonary atypical carcinoid (AC) is an extremely rare neuroendocrine tumor. The neurotrophic tropomyosin receptor kinase (NTRK) fusions are reported in only 0.5% of nonsmall cell lung cancer, and are more rare in AC with only one previously reported case. Currently, there is little established evidence on the optimal therapeutic strategies and prognosis for advanced cases. We present a female patient with metastatic AC after complete resection. Due to low expression of somatostatin receptor in this case, somatostatin analogs and peptide receptor radionuclide therapy were not available. After pursuing other alternative treatments, including chemotherapy (ie, carboplatin, etoposide, capecitabine, temozolomide, and paclitaxel), everolimus, and atezolizumab, she returned with significant progression, including innumerable subcutaneous nodules, left pleura metastasis, multiple bone metastases, and brain metastases. New biopsy analysis revealed an ETV6-NTRK2 fusion. She was immediately administered the first-generation tropomyosin receptor kinase inhibitor entrectinib at a dose of 600 mg q.d. A subsequent month of treatment resulted in a complete response in all of the metastatic lung lesions. To date, she has maintained sustained benefit for at least 1 year from initiation of entrectinib. Here, we present the first case of a female patient with metastatic AC harboring the ETV6-NTRK2 fusion, and successfully treated with entrectinib, providing evidence for the application of entrectinib in patients with NTRK-positive AC, and underscoring the critical role of molecular profiling for such cases., Competing Interests: Disclosure The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Signaling mediated by brain-derived neurotrophic factor (BDNF), which is supported by the postsynaptic scaffolding protein PSD-95, has antidepressant effects. Conversely, clinical depression is associated with reduced BDNF signaling. We found that peptidomimetic compounds that bind to PSD-95 promoted signaling by the BDNF receptor TrkB in the hippocampus and reduced depression-like behaviors in mice. The compounds CN2097 and Syn3 both bind to the PDZ3 domain of PSD-95, and Syn3 also binds to an α-helical region of the protein. Syn3 reduced depression-like behaviors in two mouse models of stress-induced depression; CN2097 had similar but less potent effects. In hippocampal neurons, application of Syn3 enhanced the formation of TrkB-Gα i1/3 -PSD-95 complexes and potentiated downstream PI3K-Akt-mTOR signaling. In mice subjected to chronic mild stress (CMS), systemic administration of Syn3 reversed the CMS-induced, depression-associated changes in PI3K-Akt-mTOR signaling, dendrite complexity, spine density, and autophagy in the hippocampus and reduced depression-like behaviors. Knocking out Gα i1/3 in hippocampal neurons prevented the therapeutic effects of Syn3, indicating dependence of these effects on the TrkB pathway. The findings suggest that compounds that induce the formation of PSD-95-TrkB complexes have therapeutic potential to alleviate depression.

Objectives: To observe the effect of electroacupuncture (EA) at "Baihui" (GV20) and "Shenting" (GV24) on the rats' behavior and the transforming precursor of brain-derived neurotrophic factor (proBDNF) into mature brain-derived neurotrophic factor (mBDNF) in the hippocampus of rats with learning and memory impairment induced by cerebral ischemia-reperfusion (IR), so as to explore its mechanisms underlying improvement of learning and memory ability., Methods: SD rats were randomly divided into blank, sham operation, model, and EA groups, with 6 rats in each group. The model of IR was established by occlusion of the middle cerebral artery. EA (1 Hz/20 Hz) was applied to GV24 and GV20 for 30 min, once daily for 14 days. The neurological function was evaluated according to the Zea Longa's score criteria 24 h after modeling and after intervention. Morris water maze test was used to detect the learning and memory function of the rats. TTC staining was used to evaluate the cerebral infarction volume on the affected side. The protein expression levels of proBDNF, mBDNF, tissue plasminogen activator (tPA), tyrosine kinase receptor B (TrkB) and p75 neurotrophin receptor (p75NTR) in hippocampal tissue were detected by Western blot., Results: Compared with the sham operation group, the neurological function score, the percentage of cerebral infarction volume and the expression levels of proBDNF and p75NTR protein in hippocampus were increased ( P <0.01), while the times of crossing the original platform and the total distance in the target quadrant, the expression levels of mBDNF, TrkB and tPA protein and the ratio of mBDNF/proBDNF were decreased ( P <0.01, P <0.05) in the model group. Compared with the model group, the neurological function score, the percentage of cerebral infarction volume, and the expression levels of proBDNF and p75NTR protein in hippocampus were decreased ( P <0.01, P <0.05), while the times of crossing the original platform, the total distance in the target quadrant, and the expression levels of mBDNF, TrkB and tPA protein and the ratio of mBDNF/proBDNF were increased ( P <0.05, P <0.01) in the EA group., Conclusions: EA can alleviate learning and memory impairment in IR rats, which may be related to its function in up-regulating the expression of tPA protein and promoting the transformation of proBDNF to mBDNF, thus improving the synaptic plasticity.

Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptic physiology, as well as mechanisms underlying various neuropsychiatric diseases and their treatment. Despite its clear physiological role and disease relevance, BDNF's function at the presynaptic terminal, a fundamental unit of neurotransmission, remains poorly understood. In this study, we evaluated single synapse dynamics using optical imaging techniques in hippocampal cell cultures. We find that exogenous BDNF selectively increases evoked excitatory neurotransmission without affecting spontaneous neurotransmission. However, acutely blocking endogenous BDNF has no effect on evoked or spontaneous release, demonstrating that different approaches to studying BDNF may yield different results. When we suppressed BDNF-Tropomyosin receptor kinase B (TrkB) activity chronically over a period of days to weeks using a mouse line enabling conditional knockout of TrkB, we found that evoked glutamate release was significantly decreased while spontaneous release remained unchanged. Moreover, chronic blockade of BDNF-TrkB activity selectively downscales evoked calcium transients without affecting spontaneous calcium events. Via pharmacological blockade by voltage-gated calcium channel (VGCC) selective blockers, we found that the changes in evoked calcium transients are mediated by the P/Q subtype of VGCCs. These results suggest that BDNF-TrkB activity increases presynaptic VGCC activity to selectively increase evoked glutamate release., Competing Interests: Competing interests statement:The authors declare no competing interest.

Brain-derived neurotrophic factor (BDNF) is a growth factor that promotes the survival and growth of developing neurons. It also enhances circuit formation to synaptic transmission for mature neurons in the brain. However, reduced BDNF expression and single nucleotide polymorphisms (SNP) are reported to be associated with functional deficit and disease development in the brain, suggesting that BDNF is a crucial molecule for brain health. Interestingly, BDNF is also expressed in the hypothalamus in appetite and energy metabolism. Previous reports demonstrated that BDNF knockout mice exhibited overeating and obesity phenotypes remarkably. Therefore, we could raise a hypothesis that the loss of function of BDNF may be associated with metabolic syndrome and peripheral diseases. In this review, we describe our recent finding that BDNF knockout mice develop metabolic dysfunction-associated steatohepatitis and recent reports demonstrating the role of one of the BDNF receptors, TrkB-T1, in some peripheral organ functions and diseases, and would provide an insight into the role of BDNF beyond the brain.

Brain-derived neurotrophic factor (BDNF), one of the neurotrophins, and its specific receptor TrkB, are abundantly distributed in the central nervous system (CNS) and have a variety of biological effects, such as neural survival, neurite elongation, neural differentiation, and enhancing synaptic functions. Currently, there are two TrkB subtypes: full-length TrkB (TrkB-FL), which has a tyrosine kinase in the intracellular domain, and TrkB-T1, which is a tyrosine kinase-deficient form. While TrkB-FL is a typical tyrosine kinase receptor, TrkB-T1 is a main form expressed in the CNS of adult mammals, but its function is unknown. In this study, we performed fluorescent staining of the cerebral cortex of adult mice, by using TrkB-T1 antiserum and various antibodies of marker molecules for neurons and glial cells. We found that TrkB-T1 was expressed not only in neurons but also in astrocytes. In contrast, little expression of TrkB-T1 was found in oligodendrocytes and microglia. TrkB-T1 was expressed in almost all of the cells expressing TrkB-FL, indicating the direct interaction between TrkB subtypes. These findings suggest that a part of various functions of BDNF-TrkB signaling might be due to the interaction and cellular localization of TrkB subtypes in the cerebral cortex., Competing Interests: Declaration of competing interest Author declares no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The relationship between schizophrenia (SCZ) and cancer development remains controversial. Based on the disease-gene association platform, it has been revealed that tumor necrosis factor receptor (TNFR) could be an important mediatory factor in both cancer and SCZ development. TNF-α also increases the expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) in the development of SCZ and tumor, but the role of TNFR in mediating the association between the two diseases remains unclear. We studied the vital roles of TNFR2 in the progression of tumor and SCZ-like behavior using A549 lung cancer cell xenografted TNFR2 knockout mice. TNFR2 knockout mice showed significantly decreased tumor size and weight as well as schizophrenia-like behaviors compared to wild-type mice. Consistent with the reduced tumor growth and SCZ-like behaviors, the levels of TrkB and BDNF expression were significantly decreased in the lung tumor tissues and pre-frontal cortex of TNFR2 knockout mice. However, intravenous injection of BDNF (160 μg/kg) to TNFR2 knockout mice for 4 weeks increased tumor growth and SCZ-like behaviors as well as TrkB expression. In in vitro study, significantly decreased cell growth and expression of TrkB and BDNF by siTNFR2 transfection were found in A549 lung cancer cells. However, the addition of BDNF (100 ng/ml) into TNFR2 siRNA transfected A549 lung cancer cells recovered cell growth and the expression of TrkB. These results suggest that TNFR2 could be an important factor in mediating the comorbidity between lung tumor growth and SCZ development through increased TrkB-dependent BDNF levels., (© 2024. The Author(s).)

Various mechanisms through which maternal diet influences offspring brain development in gestational diabetes mellitus (GDM) remains unclear. We speculate that prenatal omega 3 fatty acids will improve the levels of brain neurotrophins and vascular endothelial growth factor (VEGF), an angiogenic factor leading to improved cognitive performance in the offspring. GDM was induced in Wistar rats using streptozotocin. They were assigned to either control, GDM or GDM+O (GDM + omega-3 fatty acid supplementation). The offspring were followed till 3 mo of age and cognitive assessment was undertaken. Data analysis was carried out using one-way ANOVA followed by LSD test. GDM induction increased (p < 0.01) dam glucose levels and lowered brain derived neurotrophic factor (BDNF) levels (p = 0.056) in the offspring at birth. At 3 months, GDM group showed significantly lower levels of neurotrophic tyrosine kinase receptor-2 (NTRK-2) and VEGF, lower mRNA levels of NTRK-2 and cAMP response element-binding protein (CREB) (P < 0.05 for all) as compared to control. The GDM offspring had a higher escape latency (p < 0.01), made lesser % correct choices and more errors (p < 0.05 for both). Prenatal supplementation with omega 3 polyunsaturated fatty acids was beneficial since it ameliorated some of the adverse effects of GDM., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Tropomyosin receptor kinases (TRK) are attractive targets for cancer therapy. As TRK-inhibitors are approved for all solid cancers with detectable fusions involving the Neurotrophic tyrosine receptor kinase (NTRK)-genes, there has been an increased interest in optimizing testing regimes. In this project, we wanted to find the prevalence of NTRK fusions in a cohort of various histopathological types of early-stage lung cancer in Norway and to investigate the association between TRK protein expression and specific histopathological types, including their molecular and epidemiological characteristics. We used immunohistochemistry (IHC) as a screening tool for TRK expression, and next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) as confirmatory tests for underlying NTRK-fusion. Among 940 cases, 43 (4.6%) had positive TRK IHC, but in none of these could a NTRK fusion be confirmed by NGS or FISH. IHC-positive cases showed various staining intensities and patterns including cytoplasmatic or nuclear staining. IHC-positivity was more common in squamous cell carcinoma (LUSC) (10.3%) and adenoid cystic carcinoma (40.0%), where the majority showed heterogeneous staining intensity. In comparison, only 1.1% of the adenocarcinomas were positive. IHC-positivity was also more common in men, but this association could be explained by the dominance of LUSC in TRK IHC-positive cases. Protein expression was not associated with differences in time to relapse or overall survival. Our study indicates that NTRK fusion is rare in early-stage lung cancer. Due to the high level of false positive cases with IHC, Pan-TRK IHC is less suited as a screening tool for NTRK-fusions in LUSC and adenoid cystic carcinoma., (© 2024. The Author(s).)

The brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase receptor B (TrkB) are widely expressed in the central nervous system. It is well documented that neurons express BDNF and full-length TrkB (TrkB.FL) as well as a lower level of truncated TrkB (TrkB.T). However, there are conflicting reports regarding the expression of BDNF and TrkB in glial cells, particularly microglia. In this study, we employed a sensitive and reliable genetic method to characterize the expression of BDNF and TrkB in glial cells in the mouse brain. We utilized three Cre mouse strains in which Cre recombinase is expressed in the same cells as BDNF, TrkB.FL, or all TrkB isoforms, and crossed them to Cre-dependent reporter mice to label BDNF- or TrkB-expressing cells with soma-localized EGFP. We performed immunohistochemistry with glial cell markers to examine the expression of BDNF and TrkB in microglia, astrocytes, and oligodendrocytes. Surprisingly, we found no BDNF- or TrkB-expressing microglia in examined CNS regions, including the somatomotor cortex, hippocampal CA1, and spinal cord. Consistent with previous studies, most astrocytes only express TrkB.T in the hippocampus of adult brains. Moreover, there are a small number of astrocytes and oligodendrocytes that express BDNF in the hippocampus, the function of which is to be determined. We also found that oligodendrocyte precursor cells, but not mature oligodendrocytes, express both TrkB.FL and TrkB.T in the hippocampus of adult mice. These results not only clarify the expression of BDNF and TrkB in glial cells but also open opportunities to investigate previously unidentified roles of BDNF and TrkB in astrocytes and oligodendrocytes.

Dysregulation of brain-derived neurotrophic factor (BDNF) has been implicated in Alzheimer's disease (AD). In this study, we investigated the temporal dynamics of BDNF expression in the hippocampus of 5xFAD mice, an AD model, focusing on sex and age differences and Bdnf mRNA splice variants. At 3 months of age, female wild-type (WT) mice exhibited significantly higher Bdnf mRNA levels compared to males. However, this difference was abolished in female 5xFAD mice. At 6 months of age, no sex differences in Bdnf mRNA levels were observed in WT mice, and the levels tended to be lower in female 5xFAD mice. Additionally, a significant decrease in the mRNA levels of full-length tropomyosin-related kinase B (TrkB), a BDNF receptor, was found in female 5xFAD mice at 6 months, while mRNA levels of the truncated TrkB were increased in both male and female 5xFAD mice. Specifically, among the Bdnf mRNA splice variants, the levels of Bdnf exon IIA-IX, exon IIB-IX, exon IIC-IX, and exon IXA mRNA were significantly higher in female WT mice compared to male WT mice at 3 months, but this difference was lost in female 5xFAD mice. These findings suggest that the expression of specific Bdnf splice variants would be maintained at higher levels in the hippocampus of young female mice than in males but may be disrupted in AD model mice. Our study may provide insights into the relationship between sex differences in AD onset and BDNF expression.

Heart failure (HF) is often accompanied by cognitive impairment (CI). Brain-derived neurotrophic factor (BDNF) deficiency is closely associated with CI. However, the role and mechanism of BDNF in HF with CI is still not fully understood. Here, the case-control study was designed including 25 HF without CI patients (HF-NCI) and 50 HF with CI patients (HF-CI) to investigate the predictive value of BDNF in HF-CI while animal and cell experiments were used for mechanism research. Results found that BDNF levels in serum neuronal-derived exosomes were downregulated in HF-CI patients. There was no significant difference in serum BDNF levels among the two groups. HF rats showed obvious impairment in learning and memory; also, they had reduced thickness and length of postsynaptic density (PSD) and increased synaptic cleft width. Expression of BDNF, TrkB, PSD95, and VGLUT1 was significantly decreased in HF rats brain. In addition, compared with sham rats, amino acids were significantly reduced with no changes in the acetylcholine and monoamine neurotransmitters. Further examination showed that the number of synaptic bifurcations and the expression of BDNF, TrkB, PSD95, and VGLUT1 were all decreased in the neurons that interfered with BDNF-siRNA compared with those in the negative control neurons. Together, our results demonstrated that neuronal-derived exosomal BDNF act as effective biomarkers for prediction of HF-CI. The decrease of BDNF in the brain triggers synaptic structural damage and a decline in amino acid neurotransmitters via the BDNF-TrkB-PSD95/VGLUT1 pathway. This discovery unveils a novel pathological mechanism underlying cognitive impairment following heart failure., (© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)