Neurotrophic receptor tyrosine kinase family members in secretory and non-secretory breast carcinomas

BACKGROUND Breast cancer is the most common female cancer and a major cause of morbidity and mortality.Progress in breast cancer therapeutics has been attained with the introduction of targeted therapies for specific sub-sets.However,other subsets lack targeted interventions and thus there is persisting need for identification and characterization of molecular targets in order to advance breast cancer therapeutics.AIM To analyze the role of lesions in neurotrophic receptor tyrosine kinase(NTRK)genes in breast cancers.METHODS Analysis of publicly available genomic breast cancer datasets was performed for identification and characterization of cases with fusions and other molecular abnormalities involving NTRK1,NTRK2 and NTRK3 genes.RESULTS NTRK fusions are present in a small number of breast cancers at the extensive GENIE project data set which contains more than 10000 breast cancers.These cases are not identified as secretory in the database,suggesting that the histologic characterization is not always evident.In the breast cancer The Cancer Genome Atlas(TCGA)cohort the more common molecular lesion in NTRK genes is amplification of NTRK1 observed in 7.9% of breast cancers.CONCLUSION Neurotrophin receptors molecular lesions other than fusions are observed more often than fusions.However,currently available NTRK inhibitors are effective mainly for fusion lesions.Amplifications of NTRK1,being more frequent in breast cancers,could be a viable therapeutic target if inhibitors efficacious for them become available.

Interferon beta(IFN-β) treatment exerts potential neuroprotective effects through neurotrophic factors and novel neurotensin/neurotensin high affinity receptor 1 pathway

Multiple sclerosis（MS）is a chronic autoimmune disease of the central nervous system（CNS）characterized by coexisting processes of inflammation,demyelination,axonal neurodegeneration,and gliosis.It is the most common disabling neurological disease in young adulthood.

Ectopic expression of neurotrophic peptide derived from saposin C increases proliferation and upregulates androgen receptor expression and transcriptional activity in human prostate cancer cells

Aim： To determine the effects of the functional domain of saposin C （neurotrophic peptide [NP]） on androgen receptor （AR） expression and transcriptional activity. Methods： We constructed DNA vectors expressing NP or a chimeric peptide of the viral TAT transduction domain and NP （TAT-NP） using gene cloning technology. The effects of ectopic expression of NP or TAT-NP on cell growth were examined by 3-（4, 5-dimethylthiazol-2-yl）-2, 5-diphenyl-2H-tetrazolium bromide （MTT） assay. Reverse transcription-polymerase chain reaction （RT-PCR）, Western blot, transient transfection and reporter gene assays were used to determine the effects of NP on AR expression and activation. Results： NP stimulated proliferation of androgen responsive LNCaP cells in the absence of androgens. RT-PCR and Western blot analyses showed that ectopic expression of NP resulted in induction of AR gene expression, and that the NP-stimulated expression of AR could be synergistically enhanced in the presence of androgens. Furthermore, reporter gene assay results showed that NP could enhance AR transactivation by increasing androgen-inducible gene reporter activity. Conclusion： We provided evidence that ectopic expression of saposin C-originated NP could upregulate AR gene expression and activate the AR transcriptional function in an androgen-independent manner in prostate cancer cells.

Role of cytokine receptor-like factor 1 in hepatic stellate cells and fibrosis

AIM: To elucidate the role of cytokine receptor-like factor 1 (CRLF1) in hepatic stellate cells and liver fibrosis.

Therapeutic potential of brain-derived neurotrophic factor(BDNF)and a small molecular mimics of BDNF for traumatic brain injury

Traumatic brain injury（TBI） is a major health problem worldwide.Following primary mechanical insults,a cascade of secondary injuries often leads to further neural tissue loss.Thus far there is no cure to rescue the damaged neural tissue.Current therapeutic strategies primarily target the secondary injuries focusing on neuroprotection and neuroregeneration.The neurotrophin brain-derived neurotrophic factor（BDNF） has significant effect in both aspects,promoting neuronal survival,synaptic plasticity and neurogenesis.Recently,the flavonoid 7,8-dihydroxyflavone（7,8-DHF）,a small Trk B agonist that mimics BDNF function,has shown similar effects as BDNF in promoting neuronal survival and regeneration following TBI.Compared to BDNF,7,8-DHF has a longer half-life and much smaller molecular size,capable of penetrating the blood-brain barrier,which makes it possible for non-invasive clinical application.In this review,we summarize functions of the BDNF/Trk B signaling pathway and studies examining the potential of BDNF and 7,8-DHF as a therapy for TBI.

Paradigm shift of chemotherapy and systemic treatment for biliary tract cancer

Biliary tract cancers(BTC)are frequently identified at late stages and have a poor prognosis due to limited systemic treatment regimens.For more than a decade,the combination of gemcitabine and cis-platin has served as the first-line standard treatment.There are few choices for second-line chemo-therapy.Targeted treatment with fibroblast growth factor receptor 2 inhibitors,neurotrophic tyrosine receptor kinase inhibitors,and isocitrate dehydrogenase 1 inhibitors has had important results.Immune checkpoint inhibitors(ICI)such as pembrolizumab are only used in first-line treatment for microsatellite instability high patients.The TOPAZ-1 trial's outcome is encouraging,and there are several trials underway that might soon put targeted treatment and ICI combos into first-line options.Newer targets and agents for existing goals are being studied,which may represent a paradigm shift in BTC management.Due to a scarcity of targetable mutations and the higher toxicity profile of the current medications,the new category of drugs may occupy a significant role in BTC therapies.

Expression and significance of GFRal Gene in the regeneration of spermatogenesis in mice

Objective: To analyze the expression and significance of glial cell-derived neurotrophic factor receptor a1 gene (GFRα1) in the regeneration of spermatogenesis in mice. Methods: Adult Kunming mice were given intraperitoneally 2 doses of busulfan (10 mg/kg) 24 days apart to establish the spermatogenesis regeneration model. Testes were harvested at weeks 1, 2, 3, 4, 6, 8 and 10 after the second injection. The spermatogenesis regeneration was observed by light and electron microscopy and the GFRα1 mRNA measured by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and in situ hybridization. Results: The expression of GFRal mRNA increased significantly at week 1 and reached its peak at week 2 after the second injection (P<0.01, vs the control); the expression reduced significantly at week 3 and reached its nadir at week 4 (P<0.01, vs the control); then it increased gradually and returned to the normal level at week 10. GFRal mRNA was mainly expressed by the undifferentiated spermatogonia. Conclusion: In the course of spermatogenesis regeneration, the expression of GFRal plays an important role in regulating the direction of spermatogonial development and their reactivity to the glial cell-derived neurotrophic factor; a high level of expression promotes the self-renewal of spermatogonia and a low level, their differentiation.

Development of small-molecule tropomyosin receptor kinase(TRK) inhibitors for NTRK fusion cancers

Tropomyosin receptor kinase A,B and C(TRKA,TRKB and TRKC),which are well-known members of the cell surface receptor tyrosine kinase(RTK)family,are encoded by the neurotrophic receptor tyrosine kinase 1,2 and 3(NTRK1,NTRK2 and NTRK3)genes,respectively.TRKs can regulate cell proliferation,differentiation and even apoptosis through the RAS/MAPKs,PI3 K/AKT and PLCγtyrosine kinase fusions;Small-molecule inhibitor;NTRK fusion cancer pathways.Gene fusions involving NTRK act as oncogenic drivers of a broad diversity of adult and pediatric tumors,and TRKs have become promising antitumor targets.Therefore,achieving a comprehensive understanding of TRKs and relevant TRK inhibitors should be urgently pursued for the further development of novel TRK inhibitors for potential clinical applications.This review focuses on summarizing the biological functions of TRKs and NTRK fusion proteins,the development of small-molecule TRK inhibitors with different chemotypes and their activity and selectivity,and the potential therapeutic applications of these inhibitors for future cancer drug discovery efforts.