Specific activation of mGlu2 induced IGF-1R transactivation in vitro through FAK phosphorylation.

Metabotropic glutamate receptor 2 (mGlu2) belongs to the group-II metabotropic glutamate (mGlu) receptors and is a neurotransmitter G protein-coupled receptor. The group-II mGlu receptors are promising antipsychotic targets, but the specific role of mGlu2 signaling remains unclear. Receptor tyrosine kinases (RTKs) are also believed to participate in brain pathogenesis. To investigate whether there is any communication between mGlu2 and RTKs, we generated a CHO-mGlu2 cell line that stably expresses mGlu2 and showed that activation of mGlu2 by LY379268, a group II mGlu agonist, was able to transactivate insulin-like growth factor 1 receptor (IGF-1R). We further determined that the Gi/o protein, Gßγ subunits, phospholipase C, and focal adhesion kinase (FAK) were involved in the IGF-1R transactivation signaling axis, which further induced the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) and cAMP response element-binding protein. In primary mouse cortical neurons, similar signaling pathways were observed when mGlu2 were stimulated by LY487379, an mGlu2 positive allosteric modulator. Transactivation of IGF-1R through FAK in response to mGlu2 should provide a better understanding of the association of mGlu2 with brain disease.

Circulating tumor DNA in NK/T and peripheral T cell lymphoma.

Natural killer (NK)/T-cell lymphomas (NK/TCL) and peripheral T-cell lymphomas (PTCL) are aggressive hematological malignancies. With the development of next-generation sequencing, circulating tumor DNA (ctDNA) can be detected by several techniques with clinical implications. So far, the effect of ctDNA in pretreatment prognosis prediction, longitudinal monitoring of treatment response and surveillance of long-term remission or relapse in NK/TCL and PTCL has been reported in several researches.

All roads lead to targeted diffuse large B-cell lymphoma approaches.

Two recent reports in the New England Journal of Medicine highlight the successful application of novel targeted therapies to improve the clinical outcomes of diffuse large B-cell lymphoma (DLBCL). These findings encourage us to pursue further mechanism-based therapeutic uses to make DLBCL curable in the era of precision medicine.

Dynamic change of soluble interleukin-2 receptor distinguished molecular heterogeneity and microenvironment alterations in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with variable clinical outcomes and prediction of prognosis remains important for long-term remission. We performed serial serum soluble interleukin-2 receptor (sIL-2R) measurement pretreatment and before each cycle of the treatment in 599 patients with de novo DLBCL. Genomic and transcriptomic features were analyzed by 223 DNA- and 227 RNA-sequencing, respectively. Applying the cut-off value to sIL-2R pretreatment and cycle 2 (C2) level, patients were classified into FINE subtype (pretreatment low level) with good prognosis, RES subtype (pretreatment high level and C2 low level) with intermediate prognosis, and RET subtype (pretreatment high level and C2 high level) with poor prognosis, independent of International Prognostic Index. In "others" genetic subtype, dynamic change of sIL-2R showed prognostic significance and genetic features. Compared with FINE subtype, RES subtype had increased ARID1A and MYD88 mutations, and RET subtype had increased KMT2D, LYN and SOCS1 mutations. RES and RET subtypes showed significant enrichment in oncogenic pathways, such as ERK, NF-κB, JAK-STAT, and immune-associated pathways. As for tumor microenvironment, RES subtype exhibited increased recruiting activity of CD8 + T, T helper 1, and natural killer cells, and RET subtype with increased recruiting activity of CD4 + T and regulatory T cells in silico. There was a positive correlation between transcripts of IL-2R and immune checkpoint expressions including PD-1 and CTLA-4. Our findings identified that dynamic change of sIL-2R, with this simple and easy detection method in peripheral blood, had long-term prognostic effect and specific relation to microenvironment alterations in DLBCL.

Advances in targeted therapy for malignant lymphoma.

The incidence of lymphoma has gradually increased over previous decades, and it ranks among the ten most prevalent cancers worldwide. With the development of targeted therapeutic strategies, though a subset of lymphoma patients has become curable, the treatment of refractory and relapsed diseases remains challenging. Many efforts have been made to explore new targets and to develop corresponding therapies. In addition to novel antibodies targeting surface antigens and small molecular inhibitors targeting oncogenic signaling pathways and tumor suppressors, immune checkpoint inhibitors and chimeric antigen receptor T-cells have been rapidly developed to target the tumor microenvironment. Although these targeted agents have shown great success in treating lymphoma patients, adverse events should be noted. The selection of the most suitable candidates, optimal dosage, and effective combinations warrant further investigation. In this review, we systematically outlined the advances in targeted therapy for malignant lymphoma, providing a clinical rationale for mechanism-based lymphoma treatment in the era of precision medicine.

MreBCD-associated Cytoskeleton is Required for Proper Segregation of the Chromosomal Terminus during the Division Cycle of Escherichia Coli.

BACKGROUND: In prokaryotic organisms, the mechanism responsible for the accurate partition of newly replicated chromosomes into daughter cells is incompletely understood. Segregation of the replication terminus of the circular prokaryotic chromosome poses special problems that have not previously been addressed. The aim of this study was to investigate the roles of several protein components (MreB, MreC, and MreD) of the prokaryotic cytoskeleton for the faithful transmission of the chromosomal terminus into daughter cells. METHODS: Strain LQ1 (mreB::cat), LQ2 (mreC::cat), and LQ3 (mreD::cat) were constructed using the Red recombination system. LQ11/pLAU53, LQ12/pLAU53, LQ13/pLAU53, LQ14/pLAU53, and LQ15/pLAU53 strains were generated by P1transduction of (tetO) 240 -Gm and (lacO) 240 -Km cassettes from strains IL2 and IL29. Fluorescence microscopy was performed to observe localization pattern of fluorescently-labeled origin and terminus foci in wild-type and mutant cells. SOS induction was monitored as gfp fluorescence from PsulA-gfp in log phase cells grown in Luria-Bertani medium at 37°C by measurement of emission at 525 nm with excitation at 470 nm in a microplate fluorescence reader. RESULTS: Mutational deletion of the mreB, mreC, or mreD genes was associated with selective loss of the terminus region in approximately 40% of the cells within growing cultures. This was accompanied by significant induction of the SOS DNA damage response, suggesting that deletion of terminus sequences may have occurred by chromosomal cleavage, presumably caused by ingrowth of the division septum prior to segregation of the replicated terminal. CONCLUSIONS: These results imply a role for the MreBCD cytoskeleton in the resolution of the final products of terminus replication and/or in the specific movement of newly replicated termini away from midcell prior to completion of septal ingrowth. This would identify a previously unrecognized stage in the overall process of chromosome segregation.