Gene expression profiling of peripheral blood in patients with steroid-induced osteonecrosis of the femoral head.

Aim: Steroid-induced osteonecrosis of the femoral head (SONFH) is a severe complication following glucocorticoid therapy. This study aimed to identify the differential mRNA expression and investigate the molecular mechanisms of SONFH. Materials & methods: RNA sequencing was performed in eight SONFH patients, five non-SONFH patients and five healthy individuals. Results: A total of 1555, 3997 and 5276 differentially expressed mRNAs existed between the following combinations: SONFH versus non-SONFH, SONFH versus healthy subjects and non-SONFH versus healthy subjects. Increased ISM1 expression might contribute to a high risk of SONFH through antiangiogenesis. Decreased FOLR3 expression might affect the metabolism of homocysteine, leading to avascular necrosis of the femoral head. KCNJ2, which plays a pivotal role in regulating bone development, was also deregulated. Conclusion: ISM1, FOLR3 and KCNJ2 might be related to the occurrence of SONFH.

Effects of immuno-related gene polymorphisms on a bispecific antibody targeting colorectal cancer cell.

BACKGROUND: Colorectal cancer (CRC) represents the third most common type of cancer and the third leading cause of death from cancer around the world. M701 is a CD3/EpCAM bispecific antibody that shows promising cytotoxicity toward CRC cells. AIM: To investigate the influence of immuno-related gene polymorphisms on M701 mediated cytotoxicity to CRC cell HCT116. METHOD: We analyzed the influence of the effect of M701 on the activation and cytotoxicity of peripheral mononuclear blood cells from 129 healthy volunteers with different genotypes. RESULT: When incubated with M701, peripheral mononuclear blood cells from CD247 rs2949655 AA homozygotes showed significantly lower cytotoxicity than those from AG/GG heterozygotes. CONCLUSION: CD247 rs2949655 was significantly associated with the cytotoxicity of M701 to HCT116, which might contribute to personalized medicine of M701.

Polymorphisms in cytochrome P450 oxidoreductase and its effect on drug metabolism and efficacy.

Cytochrome P450 oxidoreductase (POR) has played a potential role in the metabolism of drugs and steroids by supplying electrons to microsomal cytochrome P450 (CYP) enzymes. More than 200 different POR mutations and polymorphisms causing more than 130 amino acid changes in the POR protein have been reported since 2004. A503V is a common amino acid sequence variant encoded by POR*28, whereas A287P and R457H are the most common disease-causing mutations in Europeans and Asians, respectively. Polymorphisms in the POR gene can affect POR activity, CYP-mediated drug metabolism activities, and the efficacy of several clinically used drugs. The effects of POR variants on CYP activities are substrate dependent. In this review, recent research on the effects of POR genetic polymorphisms on drug metabolism and therapy has been summarized and discussed, which can contribute to the rational use of drugs in clinic and the development of personalized medicine.

New Immunotherapy Strategies in Breast Cancer.

Breast cancer is the most commonly diagnosed cancer among women. Therapeutic treatments for breast cancer generally include surgery, chemotherapy, radiotherapy, endocrinotherapy and molecular targeted therapy. With the development of molecular biology, immunology and pharmacogenomics, immunotherapy becomes a promising new field in breast cancer therapies. In this review, we discussed recent progress in breast cancer immunotherapy, including cancer vaccines, bispecific antibodies, and immune checkpoint inhibitors. Several additional immunotherapy modalities in early stages of development are also highlighted. It is believed that these new immunotherapeutic strategies will ultimately change the current status of breast cancer therapies.

Role of Deficient Mismatch Repair in the Personalized Management of Colorectal Cancer.

Colorectal cancer (CRC) represents the third most common type of cancer in developed countries and one of the leading causes of cancer deaths worldwide. Personalized management of CRC has gained increasing attention since there are large inter-individual variations in the prognosis and response to drugs used to treat CRC owing to molecular heterogeneity. Approximately 15% of CRCs are caused by deficient mismatch repair (dMMR) characterized by microsatellite instability (MSI) phenotype. The present review is aimed at highlighting the role of MMR status in informing prognosis and personalized treatment of CRC including adjuvant chemotherapy, targeted therapy, and immune checkpoint inhibitor therapy to guide the individualized therapy of CRC.

Effect of NADPH-cytochrome P450 reductase on all-trans-retinoic acid efficacy and cytochrome P450 26A1 expression in human myeloid leukaemia HL-60 cells.

OBJECTIVES: All-trans-retinoic acid (ATRA), a naturally occurring metabolite of vitamin A, has been shown to have great potential as an antitumorigenic drug to treat acute leukaemia by promoting cancer cell differentiation. Cytochrome P450 oxidoreductase (POR) is the only obligate electron donor for all of the microsomal cytochrome P450 enzymes including CYP26A1 which is highly specific for ATRA metabolism and efficacy in human myeloid leukaemia cells. In this study, we aimed to investigate the effect of POR on ATRA efficacy and CYP26A1 expression in human myeloid leukaemia HL-60 cells. METHODS: Stably expressed POR and POR-RNAi HL-60 cell lines were established by transfecting POR overexpression or RNAi (RNA interference) vectors mediated by lentivirus. The protein expression of POR and CYP26A1 was examined by Western blot. The potential roles of POR on ATRA efficacy in HL-60 cells were explored by cell viability assay, cell cycle distribution, cellular differentiation and apoptosis analysis. KEY FINDINGS: All-trans-retinoic acid treatment caused the expression of POR upregulation and CYP26A1 downregulation in dose- and time-dependent manners. POR overexpression decreased CYP26A1 expression in HL-60 cells. When POR gene was interfered, the downregulation of CYP26A1 expression by ATRA was abolished. In addition, POR overexpression in HL-60 cells significantly compromised ATRA-induced cell proliferation inhibition, cell cycle arrest, differentiation and apoptosis, whereas downregulation of POR significantly potentiated ATRA effects. CONCLUSIONS: Our study therefore suggested that POR played an important role in regulating ATRA efficacy and CYP26A1 expression in HL-60 cells.

Epigenetic alternations and cancer chemotherapy response.

Epigenetics, referring to alterations in gene expression without a change in nucleotide sequence in eukaryotes, mainly includes DNA methylation, miRNA and histone modification. In recent years, accumulating evidences have shown that epigenetic aberrations not only play important roles in the initiation and development of human cancers but also affect cancer chemotherapy response by altering the expression of key genes involved in the absorption, distribution, metabolism and excretion of drugs or those correlated with progression or severity of cancers. These epigenetic alterations, along with advanced detecting techniques, have great potential to be used as predictive and prognostic biomarkers for personalized therapy, especially in the field of cancer treatment. Here we provide an overview of recent findings on epigenetic alterations involved in cancer chemotherapy response, with the aim of promoting rational use of chemotherapy drugs in the clinic.

Prognostic value of HMGB3 expression in patients with non-small cell lung cancer.

HMGB3 overexpression has been reported in a variety of human cancers. However, the role of HMGB3 in human non-small cell lung cancer (NSCLC) remains unclear. In this study, the HMGB3 expression was examined at mRNA and protein levels by quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemistry in NSCLC tissues and adjacent non-cancerous tissues. Statistical analyses were applied to test the associations between HMGB3 expression, clinicopathologic factors, and prognosis. Western blotting and qRT-PCR showed that the expression levels of HMGB3 mRNA and protein were both significantly higher in NSCLC tissues than those in non-cancerous tissues. Immunohistochemistry analysis showed that HMGB3 expression was significantly correlated with tumor grade, tumor size, clinical stage, and lymph node metastases. The results of Kaplan-Meier analysis indicated that a high expression level of HMGB3 resulted in a significantly poor prognosis of NSCLC patients. Importantly, multivariate analysis showed that high HMGB3 expression was an independent prognostic factor for NSCLC patients. In sum, our data suggest that HMGB3 plays an important role in NSCLC progression, and that overexpression of HMGB3 in tumor tissues could be used as a potential prognostic marker for patients with NSCLC.

[Detection of thromboxane B2, 6-keto-prostaglandin F1alpha and anticardiolipin antibody in patients with obstructive sleep apnea-hypopnea syndrome].

OBJECTIVE: To observe the changes of thromboxane B(2) (TXB(2)), 6-keto-prostaglandin F1alpha (6-K-PGF1alpha) and anticardiolipin antibody (ACA) in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) before and after institution of nasal continuous positive airway pressure (nCPAP). METHODS: Sixty cases of OSAHS confirmed by polysomnography (PSG) were selected as the trial group, and 20 normal donors without OSAHS were recruited as the control group. Nineteen patients with severe OSAHS were treated by nCPAP. Plasma levels of TXB(2), 6-K-PGF1alpha were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Plasma (serum) level of TXB(2) (ACA) was significantly higher in patients with moderate to severe OSAHS than that in control group (P < 0.01), and nCPAP therapy decreased its level significantly (P < 0.01). Plasma level of 6-K-PGF1alpha was significantly lower than that in the control group (P < 0.01), and nCPAP therapy increased its level significantly (P < 0.01). TXB(2) and ACA were correlated positively with AHI, and negatively with minimal oxygen saturation (P < 0.01). 6-K-PGF1alpha was correlated negatively with AHI, and positively with minimal oxygen saturation (P < 0.01). CONCLUSIONS: The results indicate that patients with OSAHS are susceptible to thromboembolism disease. TXB(2), 6-K-PGF1alpha, ACA may be associated with the high prevalence of thromboembolism in patients with OSAHS. nCPAP therapy is effective in correcting TXB(2), 6-K-PGF1alpha, ACA.

[Changes of the platelet function and serum anticardiolipin antibody in patients with pulmonary thromboembolism].

OBJECTIVE: To explore the changes of the platelet function and serum anticardiolipin antibody (ACA) in patients with pulmonary thromboembolism (PTE). METHODS: Forty-eight patients with PTE diagnosed by spiral computed tomographic pulmonary angiography (CTPA) were included as the trial group, while 20 person in which PTE was excluded served as the control group. P-selectin, and GPIIb/IIIa expressed on platelets were measured by flow cytometry, and plasma TXB(2), 6-Keto-PGF1alpha, vWF, D-dimer and serum ACA were measured by ELISA and the changes of these parameters were compared 1 week later. RESULTS: In the trial group, the levels of P-selectin, GPIIb/IIIa, TXB(2), vWF, D-dimer and T/K were significantly higher than those in the control group (P < 0.01). But the plasma level of 6-Keto-PGF1alpha in the patients with PTE was significantly lower than that in the control group (P < 0.01). The levels of ACA-IgG and ACA-IgA were significantly higher than those in the control group (P < 0.01). After therapy the level of 6-Keto-PGF1alpha was significantly higher than that before therapy (P < 0.01), and other parameters were significantly lower than those before therapy (P < 0.01). P-selectin, GPIIb/IIIa and vWF were positively correlated with D-dimer (P < 0.01). CONCLUSION: Endothelium damage, platelet activation and hypercoagulation combined with fibrinolytic activation occur in patients with PTE.