The novel TERF2::PDGFRB fusion gene enhances tumorigenesis via PDGFRB/STAT5 signalling pathways and sensitivity to TKI in ph-like ALL.

Patients with Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like ALL) often face a grim prognosis, with PDGFRB gene fusions being commonly detected in this subgroup. Our study has unveiled a newfound fusion gene, TERF2::PDGFRB, and we have found that patients carrying this fusion gene exhibit sensitivity to dasatinib. Ba/F3 cells harbouring the TERF2::PDGFRB fusion display IL-3-independent cell proliferation through activation of the p-PDGFRB and p-STAT5 signalling pathways. These cells exhibit reduced apoptosis and demonstrate sensitivity to imatinib in vitro. When transfused into mice, Ba/F3 cells with the TERF2::PDGFRB fusion gene induce tumorigenesis and a shortened lifespan in cell-derived graft models, but this outcome can be improved with imatinib treatment. In summary, we have identified the novel TERF2::PDGFRB fusion gene, which exhibits oncogenic potential both in vitro and in vivo, making it a potential therapeutic target for tyrosine kinase inhibitors (TKIs).

Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria.

Only a small proportion of patients with triple-negative breast cancer benefit from immune checkpoint inhibitor (ICI) targeting PD-1/PD-L1 signaling in combination with chemotherapy. Here, we discovered that therapeutic response to ICI plus paclitaxel was associated with subcellular redistribution of PD-L1. In our immunotherapy cohort of ICI in combination with nab-paclitaxel, tumor samples from responders showed significant distribution of PD-L1 at mitochondria, while non-responders showed increased accumulation of PD-L1 on tumor cell membrane instead of mitochondria. Our results also revealed that the distribution pattern of PD-L1 was regulated by an ATAD3A-PINK1 axis. Mechanistically, PINK1 recruited PD-L1 to mitochondria for degradation via a mitophagy pathway. Importantly, paclitaxel increased ATAD3A expression to disrupt proteostasis of PD-L1 by restraining PINK1-dependent mitophagy. Clinically, patients with tumors exhibiting high expression of ATAD3A detected before the treatment with ICI in combination with paclitaxel had markedly shorter progression-free survival compared with those with ATAD3A-low tumors. Preclinical results further demonstrated that targeting ATAD3A reset a favorable antitumor immune microenvironment and increased the efficacy of combination therapy of ICI plus paclitaxel. In summary, our results indicate that ATAD3A serves not only as a resistant factor for the combination therapy of ICI plus paclitaxel through preventing PD-L1 mitochondrial distribution, but also as a promising target for increasing the therapeutic responses to chemoimmunotherapy.

Calcyphosine promotes the proliferation of glioma cells and serves as a potential therapeutic target.

Calcyphosine (CAPS) was initially identified from the canine thyroid. It also exists in many types of tumor, but its expression and function in glioma remain unknown. Here we explored the clinical significance and the functional mechanisms of CAPS in glioma. We found that CAPS was highly expressed in glioma and high expression of CAPS was correlated with poor survival, in glioma patients and public databases. Cox regression analysis showed that CAPS was an independent prognostic factor for glioma patients. Knockdown of CAPS suppressed the proliferation, whereas overexpression of CAPS promoted the proliferation of glioma both in vitro and in vivo. CAPS regulated the G2/M phase transition of the cell cycle, but had no obvious effect on apoptosis. CAPS affected PLK1 phosphorylation through interaction with MYPT1. CAPS knockdown decreased p-MYPT1 at S507 and p-PLK1 at S210. Expression of MYPT1 S507 phosphomimic rescued PLK1 phosphorylation and the phenotype caused by CAPS knockdown. The PLK1 inhibitor volasertib enhanced the therapeutic effect of temozolomide in glioma. Our data suggest that CAPS promotes the proliferation of glioma by regulating the cell cycle and the PLK1 inhibitor volasertib might be a chemosensitizer of glioma. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Tamoxifen enhances stemness and promotes metastasis of ERα36+ breast cancer by upregulating ALDH1A1 in cancer cells.

The 66 kDa estrogen receptor alpha (ERα66) is the main molecular target for endocrine therapy such as tamoxifen treatment. However, many patients develop resistance with unclear mechanisms. In a large cohort study of breast cancer patients who underwent surgery followed by tamoxifen treatment, we demonstrate that ERα36, a variant of ERα66, correlates with poor prognosis. Mechanistically, tamoxifen directly binds and activates ERα36 to enhance the stemness and metastasis of breast cancer cells via transcriptional stimulation of aldehyde dehydrogenase 1A1 (ALDH1A1). Consistently, the tamoxifen-induced stemness and metastasis can be attenuated by either ALDH1 inhibitors or a specific ERα36 antibody. Thus, tamoxifen acts as an agonist on ERα36 in breast cancer cells, which accounts for hormone therapy resistance and metastasis of breast cancer. Our study not only reveals ERα36 as a stratifying marker for endocrine therapy but also provides a promising therapeutic avenue for tamoxifen-resistant breast cancer.

[Expression of CD146 in Adult and Children's Acute B Cell Lymphoblastic Leukemia and Its Significance].

OBJECTIVE: To explore the differences of CD146 expression in adult and children's acute B cell lymphoblastic leukemia(B-ALL), and its relation with clinical features, molecular biological and cytogenctic claracteristics. METHODS: The expression of CD146 in bone marrow samples from adult and children's B-ALL patients were detected by flow cytometry (FCM) and the relation of CD146 abnormal high expression with the patients' clinical features, molecular biological and cytogenetical characteristics, as well as other antigens were analyzed. RESULTS: The abnormal high expression rates of CD146 in adult and children's B-ALL patients were 29.17% and 9.09% respectively, showing that the expression rate of CD146 in adult patients was higher than that in children's patients(P<0.05). In adult B-ALL, CD146 was positively related with CD64 and CD117, while in children's B-ALL CD146 was positively related with CD71 and CD58 (P<0.05). After 1 course of standardized chemotherapy, the complete remission rates in adult and children's B-ALL patients with abnormal high expression of CD146 both were low as compared with adult and children's B-ALL without abnormal high expression of CD146 (P<0.05). CONCLUSION: The expression rate of CD146 in adult B-ALL is higher than that in children's B-ALL. The CD146 positively relates with poor prognostic antigens, the CD146 may be one poor prognosis marker.

[Numerical simulation and operation optimization of biological filter].

BioWin software and two sensitivity analysis methods were used to simulate the Denitrification Biological Filter (DNBF) + Biological Aerated Filter (BAF) process in Yuandang Wastewater Treatment Plant. Based on the BioWin model of DNBF + BAF process, the operation data of September 2013 were used for sensitivity analysis and model calibration, and the operation data of October 2013 were used for model validation. The results indicated that the calibrated model could accurately simulate practical DNBF + BAF processes, and the most sensitive parameters were the parameters related to biofilm, OHOs and aeration. After the validation and calibration of model, it was used for process optimization with simulating operation results under different conditions. The results showed that, the best operation condition for discharge standard B was: reflux ratio = 50%, ceasing methanol addition, influent C/N = 4.43; while the best operation condition for discharge standard A was: reflux ratio = 50%, influent COD = 155 mg x L(-1) after methanol addition, influent C/N = 5.10.

[Effects of epidural clonidine pretreatment in epidural patient-controlled analgesia using sufentanil combined with levobupivacaine].

OBJECTIVE: To investigate the clinical effects of epidural clonidine pretreatment in epidural patient-controlled analgesia (PCA) using sufentanil combined with levobupivacaine. METHODS: Sixty patients undergoing abdominal hysterectomy of ASA status I-II were randomly divided into 3 equal groups: C2 group was pretreated with epidural clonidine 2 microg/kg at the L2-3 interspace, 15 min later, epidural anesthesia was performed with 0.5% levobupivacaine, and then 0. 4 microg/ml combined with levobupivacaine 2 mg/ml was given for postoperative epidural patient-controlled analgesia. C4 group was pretreated with epidural clonidine 4 microg/kg, and C0 group was pretreated with normal saline. The analgesic effect, PCA drug dosage, adverse reaction, and visual analog scale (VAS) score were recorded. RESULTS: Anesthesia was clinically satisfactory in all patients. The rate of atropine use of the C4 group was 30%, significantly higher than those of the C2 group (15% ) and C0 group (5%, both P < 0.05). The rate of VAS < or = 3 at rest 24 h postoperatively of the C2 and C4 groups were 88% and 93% respectively, both significantly higher than that of the C0 group (75%, P < 0.01 and P < 0.01). The rate of VAS < or = 3 while coughing 24 h postoperatively of the C2 and C4 groups were 61% and 79% respectively, both significantly higher than that of the C0 group (48%). The dosages of PCA drug of the C2 and C4 groups were significantly lower than that of the C0 group by 11.8% and 22.8% respectively (both P < 0.05). The dosage of PCA drug 0-4 h after operation of the C2 was significantly higher than that of the C4 group. The sedative degree of the C4 group was higher than that of the C0 group. The rate of postoperative vomiting of the C0 group was 40%, significantly higher than that of the C4 group (10%, P < 0.05). CONCLUSION: Epidural clonidine 2-4 microg/kg pretreatment improves the clinical effects of epidural PCA using sufentanil combined with levobupivacaine.