[Methylthioadenosine phosphorylase and p16 as surrogate diagnostic markers for CDKN2A homozygous deletion in brain tumors].

Objective: To examine whether immunohistochemistry of methylthioadenosine phosphorylase (MTAP) and p16 could be used to predict the CDKN2A status in various brain tumors. Methods: A total of 118 cases of IDH-mutant astrocytomas, 16 IDH-wildtype glioblastoma, 17 polymorphic xanthoastrocytoma (PXA) and 20 meningiomas diagnosed at Xuanwu Hospital, Capital Medical University, Beijing, China from November 2017 to October 2023 were collected and analyzed. The CDKN2A status was detected by using fluorescence in situ hybridization or next-generation sequencing. Expression of MTAP and p16 proteins was detected with immunohistochemistry. The association of loss of MTAP/p16 expression with CDKN2A homozygous/heterozygous deletion was examined. Results: Among the 118 cases of IDH-mutant astrocytoma, 13 cases showed homozygous deletion of CDKN2A. All of them had no expression of MTAP while 9 cases had no expression of p16. Among the 16 cases of IDH wild-type glioblastoma, 6 cases showed homozygous deletion of CDKN2A. All 6 cases had no expression of MTAP, while 3 of these cases had no expression of p16 expression. Among the 17 PXA cases, 4 cases showed homozygous deletion of CDKN2A, and the expression of MTAP and p16 was also absent in these 4 cases. Among the 20 cases of meningiomas, 4 cases showed homozygous deletion of CDKN2A. Their expression of MTAP and p16 was also absent. Among the four types of brain tumors, MTAP was significantly correlated with CDKN2A homozygous deletion (P<0.05), with a sensitivity of 100%. However, it was only significantly correlated with the loss of heterozygosity (LOH) of CDKN2A in astrocytomas (P<0.001). P16 was associated with CDKN2A homozygous deletion in IDH-mutant astrocytoma and PXA (P<0.001), but not with the LOH of CDKN2A. Its sensitivity and specificity were lower than that of MTAP. Conclusions: MTAP could serve as a predictive surrogate for CDKN2A homozygous deletion in adult IDH-mutant astrocytoma, PXA, adult IDH-wildtype glioblastoma and meningioma. However, p16 could only be used in the first two tumor types, and its specificity and sensitivity are lower than that of MTAP.

ERKs and mitochondria-related pathways are essential for glycyrrhizic acid-mediated neuroprotection against glutamate-induced toxicity in differentiated PC12 cells

The present study focuses on the neuroprotective effect of glycyrrhizic acid (GA, a major compound separated from Glycyrrhiza Radix, which is a crude Chinese traditional drug) against glutamate-induced cytotoxicity in differentiated PC12 (DPC12) cells. The results showed that GA treatment improved cell viability and ameliorated abnormal glutamate-induced alterations in mitochondria in DPC12 cells. GA reversed glutamate-suppressed B-cell lymphoma 2 levels, inhibited glutamate-enhanced expressions of Bax and cleaved caspase 3, and reduced cytochrome C (Cyto C) release. Exposure to glutamate strongly inhibited phosphorylation of AKT (protein kinase B) and extracellular signal-regulated kinases (ERKs); however, GA pretreatment enhanced activation of ERKs but not AKT. The presence of PD98059 (a mitogen-activated protein/extracellular signal-regulated kinase kinase [MEK] inhibitor) but not LY294002 (a phosphoinositide 3-kinase [PI3K] inhibitor) diminished the potency of GA for improving viability of glutamate-exposed DPC12 cells. These results indicated that ERKs and mitochondria-related pathways are essential for the neuroprotective effect of GA against glutamate-induced toxicity in DPC12 cells. The present study provides experimental evidence supporting GA as a potential therapeutic agent for use in the treatment of neurodegenerative diseases.

FP3: a novel VEGF blocker with antiangiogenic effects in vitro and antitumour effects in vivo

BACKGROUND Vascular endothelial growth factor (VEGF) is a critical promoter of blood vessel growth during embryonic development and neovascularisation in tumours. VEGF serves as a logical target for antiangiogenic cancer therapy because of its fundamental role in tumour angiogenesis. This study is to investigate the inhibitory effects of FP3, a novel VEGF blocker, on angiogenesis in vitro and tumour growth in vivo. METHODS The inhibitory effects of FP3 on angiogenesis in vitro were evaluated by using human umbilical vein endothelial cells (HUVECs) and rat aortic ring. The inhibitory effects of FP3 on tumour growth and angiogenesis in vivo were evaluated in a human non-small-cell lung cancer (NSCLC) cell line A549 tumour xenograft model with the methods of tumour growth regression assay and immunohistochemical staining, respectively. RESULTS In experiments with HUVECs, FP3 inhibited cell proliferation and migration. In rat aortic ring assay, FP3 suppressed VEGF-induced vessel sprouting. In tumour growth regression assay, FP3 significantly blocked the growth of A549 tumour in the subcutaneous tumour xenograft model and dramatically decreased the vessel density of tumour. CONCLUSIONS FP3 has excellent inhibitory effects on tumour angiogenesis both in vitro and in vivo, therefore it could be used as an effective antiangiogenic agent (AU)

Gallbladder carcinoma incidentally encountered during laparoscopic cholecystectomy: how to deal with it

Gallbladder cancer (GBC), characterised by rapid progression and a poor prognosis with a high mortality rate, is a complex disease to treat. Incidental gallbladder carcinoma (IGBC) is defined as carcinoma of the gallbladder suspected for the first time during cholecystectomy or accidentally found on histological examination of the gallbladder. With the increasingly widespread acceptance of laparoscopic cholecystectomy (LC) and difficulties in diagnosing GBC preoperatively, the number of cases of IGBC during and after LC has increased. However, management of IGBC is a difficult issue in the absence of established guidelines. Problems associated with IGBC related to LC are the decisions of whether, when and how to perform additional surgery. Controversy remains regarding the effectiveness of additional resection in different stages of GBC. This review gives an overview of IGBC related to LC, and further discusses the preoperative, intraoperative and postoperative diagnosis and management of IGBC during LC (AU)

Aflibercept (VEGF Trap): one more double-edged sword of anti-VEGF therapy for cancer?

The use of vascular endothelial growth factor (VEGF)-targeted agents for treating cancer has increased dramatically over recent decades. These drugs provide considerable benefits in terms of progression-free (PFS) or overall (OS) survival for cancer patients. Of particular importance to clinicians treating cancer patients by using VEGF-targeted agents is VEGF-inhibition-induced hypertension, proteinuria, thrombosis and hemorrhage. Aflibercept is a new, successful example of targeting VEGF for therapy of solid tumors. Though results from phase I and II clinical trials demonstrated aflibercept is well tolerated, it inevitably has severe adverse effects unique to this class of agents. In this review, we discuss the adverse effects associated with aflibercept (VEGF Trap), focusing on vascularassociated hypertension, proteinuria, hemorrhage, and thrombosis, and further discuss the mechanisms, significance, and potential management of these adverse effects (AU)

Patient-derived human tumour tissue xenografts in immunodeficient mice: a systematic review

Mouse cancer models have consistently been used to qualify new anticancer drugs in the development of human clinical trials. Rodent tumour models currently being used and which include transgenic tumour models, and those generated by planting human tumour cell lines subcutaneously in immunodeficient mice, do not sufficiently represent clinical cancer characteristics, especially with regard to metastasis and drug sensitivity. The increasingly used patient-derived human tumour tissue (PDTT) xenografts models implanted subcutaneously or in subrenal capsule in immunodeficient mice, such as athymic nude mice or severe combined immunedeficient (SCID) mice, may provide a more accurate reflection of human tumour biological characteristics than tumour cell lines. The ability to passage patients' fresh tumour tissues into large numbers of immunodeficient mice provides possibilities for better preclinical testing of new therapies for the treatment and better outcome for cancer. In this review, we outline the methods of establishing xenograft models, discuss the biological stability of PDTT xenograft models and demonstrate their roles in developing new anticancer drugs and testing therapeutic regimens in cancer patients (AU)