Conversion therapy for advanced cholangiocarcinoma in the era of molecular targeted therapy and immune therapy

Cholangiocarcinoma(CCA)encompasses a range of neoplasms,namely intrahepatic CCA,perihilar CCA,and distal CCA,which are distinguished by their anatomical origin.In cases where radical resection of CCA is feasible and the patient’s physical condition permits surgical intervention,it is advisable to proceed with surgical treatment(1).However,the insidious onset of the disease restricts surgical candidacy to only 20-30%of patients(2,3).For those with unresectable CCAs,the recommended initial treatment is gemcitabine plus cisplatin(GemCis)chemotherapy(4).

Essential role of Msx1 in regulating anterior-posterior patterning of the secondary palate in mice

Development of the secondary palate displays molecular heterogeneity along the anterior-posterior axis;however, the underlying molecular mechanism remains largely unknown. MSX1 is an anteriorly expressed transcription repressor required for palate development. Here, we investigate the role of Msx1 in regional patterning of the secondary palate. The Wnt1-Cre-mediated expression of Msx1(Rosa Msx1^(Wnt1-Cre))throughout the palatal mesenchyme leads to cleft palate in mice, associated with aberrant cell proliferation and cell death. Osteogenic patterning of the hard palate in Rosa Msx1^(Wnt1-Cre)mice is severely impaired, as revealed by a marked reduction in palatine bone formation and decreased expression of the osteogenic regulator Sp7. Overexpression and knockout of Msx1 in mice show that the transcription repressor promotes the expression of the anterior palate-specific Alx1 but represses the expression of the medialposterior palate genes Barx1, Meox2, and Tbx22. Furthermore, Tbx22 constitutes a direct Msx1 target gene in the secondary palate, suggesting that Msx1 can directly repress the expression of medial-posterior specific genes. Finally, we determine that Sp7 is downstream of Tbx22 in palatal mesenchymal cells,suggesting that a Msx1/Tbx22/Sp7 axis participates in the regulation of palate development. Our findings unveil a novel role for Msx1 in regulating the anterior-posterior growth and patterning of the secondary palate.

TAPP1 inhibits the differentiation of oligodendrocyte precursor cells via suppressing the Mek/Erk pathway

Oligodendrocytes(OLs) are glial cells that form myelin sheaths around axons in the central nervous system(CNS).Loss of the myelin sheath in demyelinating and neurodegenerative diseases can lead to severe impairment of movement.Understanding the extracellular signals and intracellular factors that regulate OL differentiation and myelination during development can help to develop novel strategies for enhancing myelin repair in neurological disorders.Here,we report that TAPP1 was selectively expressed in differentiating OL precursor cells(OPCs).TAPP1 knockdown promoted OL differentiation and myelin gene expression in culture.Conversely,over-expression of TAPP1 in immature OPCs suppressed their differentiation.Moreover,TAPP1 inhibition in OPCs altered the expression of Erk1/2 but not AKT.Taken together,our results identify TAPP1 as an important negative regulator of OPC differentiation through the Mek/Erk signaling pathway.

Dose-dependent regulation of oligodendrocyte specification by β-catenin signaling

Dear Editor,Although various components of the Wnt/β-catenin pathway have been investigated,there are conflicting reports on the roles of Wnt/β-catenin signaling in oligodendrogenesis and differentiation.For instance,theΔExon3 mutation ofβ-catenin[1-4],which stabilizesβ-catenin by deletion of the phosphorylation site for the destruction complex,signifi cantly inhibits the differentiation of oligodendrocytes,