Advances in drug resistance of osteosarcoma caused by pregnane X receptor.

Osteosarcoma (OS) is a prevalent malignancy among adolescents, commonly manifesting during childhood and adolescence. It exhibits a high degree of malignancy, propensity for metastasis, rapid progression, and poses challenges in clinical management. Chemotherapy represents an efficacious therapeutic modality for OS treatment. However, chemotherapy resistance of OS is a major problem in clinical treatment. In order to treat OS effectively, it is particularly important to explore the mechanism of chemotherapy resistance in OS.The Pregnane X receptor (PXR) is a nuclear receptor primarily involved in the metabolism, transport, and elimination of xenobiotics, including chemotherapeutic agents. PXR involves three stages of drug metabolism: stage I: drug metabolism enzymes; stage II: drug binding enzyme; stage III: drug transporter.PXR has been confirmed to be involved in the process of chemotherapy resistance in malignant tumors. The expression of PXR is increased in OS, which may be related to drug resistance of OS. Therefore, wereviewed in detail the role of PXR in chemotherapy drug resistance in OS.

Advances in drug resistance of triple negative breast cancer caused by pregnane X receptor.

Breast cancer is the most common malignancy in women worldwide. Triple-negative breast cancer (TNBC), refers breast cancer negative for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, characterized by high drug resistance, high metastasis and high recurrence, treatment of which is a difficult problem in the clinical treatment of breast cancer. In order to better treat TNBC clinically, it is a very urgent task to explore the mechanism of TNBC resistance in basic breast cancer research. Pregnane X receptor (PXR) is a nuclear receptor whose main biological function is to participate in the metabolism, transport and clearance of allobiological agents in PXR. PXR plays an important role in drug metabolism and clearance, and PXR is highly expressed in tumor tissues of TNBC patients, which is related to the prognosis of breast cancer patients. This reviews synthesized the important role of PXR in the process of high drug resistance to TNBC chemotherapeutic drugs and related research progress.

Effectiveness of platelet-rich plasma in the treatment of Achilles tendon disease.

BACKGROUND: The effectiveness of Platelet-Rich Plasma (PRP) in the treatment of patients with Achilles tendon rupture (ATR) and Achilles tendinopathy (AT) has been controversial. AIM: To assess PRP injections' effectiveness in treating ATR and AT. METHODS: A comprehensive review of relevant literature was conducted utilizing multiple databases such as Cochrane Library, PubMed, Web of Science, Chinese Science and Technology Journal, EMBASE, and China Biomedical CD-ROM. The present investigation integrated randomized controlled trials that assessed the effectiveness of platelet-rich plasma injections in managing individuals with Achilles tendon rupture and tendinopathy. The eligibility criteria for the trials encompassed publications that were published within the timeframe of January 1, 1966 to December 2022. The statistical analysis was performed utilizing the Review Manager 5.4.1, the visual analogue scale (VAS), Victorian Institute Ankle Function Scale (VISA-A), and Achilles Tendon Thickness were used to assess outcomes. RESULTS: This meta-analysis included 13 randomized controlled trials, 8 of which were randomized controlled trials of PRP for AT and 5 of which were randomized controlled trials of PRP for ATR. PRP for AT at 6 wk [weighted mean difference (WMD) = 1.92, 95%CI: -0.54 to 4.38, I2 = 34%], at 3 mo [WMD = 0.20, 95%CI: -2.65 to 3.05, I2 = 60%], and 6 mo [WMD = 2.75, 95%CI: -2.76 to 8.26, I2 = 87%) after which there was no significant difference in VISA-A scores between the PRP and control groups. There was no significant difference in VAS scores between the PRP group and the control group after 6 wk [WMD = 6.75, 95%CI: -6.12 to 19.62, I2 = 69%] and 6 mo [WMD = 10.46, 95%CI: -2.44 to 23.37, I2 = 69%] of treatment, and at mid-treatment at 3 mo [WMD = 11.30, 95%CI: 7.33 to 15.27, I2 = 0%] after mid-treatment, the PRP group demonstrated better outcomes than the control group. Post-treatment patient satisfaction [WMD = 1.07, 95%CI: 0.84 to 1.35, I2 = 0%], Achilles tendon thickness [WMD = 0.34, 95%CI: -0.04 to 0.71, I2 = 61%] and return to sport [WMD = 1.11, 95%CI: 0.87 to 1.42, I2 = 0%] were not significantly different between the PRP and control groups. The study did not find any statistically significant distinction between the groups that received PRP treatment and those that did not, regarding the Victorian Institute of Sport Assessment - Achilles scores at 3 mo [WMD = -1.49, 95%CI: -5.24 to 2.25, I2 = 0%], 6 mo [WMD = -0.24, 95%CI: -3.80 to 3.32, I2 = 0%], and 12 mo [WMD = -2.02, 95%CI: -5.34 to 1.29, I2 = 87%] for ATR patients. Additionally, no significant difference was observed between the PRP and the control groups in improving Heel lift height respectively at 6 mo [WMD = -3.96, 95%CI: -8.61 to 0.69, I2 = 0%] and 12 mo [WMD = -1.66, 95%CI: -11.15 to 7.83, I2 = 0%] for ATR patients. There was no significant difference in calf circumference between the PRP group and the control group after 6 mo [WMD = 1.01, 95%CI: -0.78 to 2.80, I2 = 54%] and 12 mo [WMD = -0.55, 95%CI: -2.2 to 1.09, I2 = 0%] of treatment. There was no significant difference in ankle mobility between the PRP and control groups at 6 mo of treatment [WMD = -0.38, 95%CI: -2.34 to 1.58, I2 = 82%] and after 12 mo of treatment [WMD = -0.98, 95%CI: -1.41 to -0.56, I2 = 10%] there was a significant improvement in ankle mobility between the PRP and control groups. There was no significant difference in the rate of return to exercise after treatment [WMD = 1.20, 95%CI: 0.77 to 1.87, I2 = 0%] and the rate of adverse events [WMD = 0.85, 95%CI: 0.50 to 1.45, I2 = 0%] between the PRP group and the control group. CONCLUSION: The use of PRP for AT improved the patient's immediate VAS scores but not VISA-A scores, changes in Achilles tendon thickness, patient satisfaction, or return to sport. Treatment of ATR with PRP injections alone improved long-term ankle mobility but had no significant effect on VISA-A scores, single heel lift height, calf circumference or return to sport. Additional research employing more extensive sampling sizes, more strict experimental methods, and standard methodologies may be necessary to yield more dependable and precise findings.

Post-traumatic heterotopic ossification in front of the ankle joint for 23 years: A case report and review of literature.

BACKGROUND: Heterotopic ossification (HO) refers to the formation of new bone in non-skeletal tissues such as muscles, tendons or other soft tissues. Severe muscle and soft tissue injury often lead to the formation of HO. However, anterior HO of the ankle is rarely reported. CASE SUMMARY: We report a patient with massive HO in front of the ankle joint for 23 years. In 1998, the patient was injured by a falling object on the right lower extremity, which gradually formed a massive heterotopic bone change in the right calf and dorsum of the foot. The patient did not develop gradual ankle function limitations until nearly 36 mo ago, and underwent resection of HO. Even after 23 years and resection of HO, the ankle joint was still able to move. CONCLUSION: It is recommended that the orthopedist should be aware of HO and distinguish it from bone tumor.

Percutaneous calcium sulfate injection versus localized scrape bone grafting: clinical effect comparison in titanium elastic nail treatment of pathological fracture of proximal humerus caused by unicameral bone cysts in children.

Objective: A retrospective study was conducted to compare the mid-term clinical efficacy between percutaneous calcium sulfate injection (PCSI) and localized scrape bone grafting (LSBG) in using titanium elastic nails treat humerus pathologic fractures caused by unicameral bone cysts in children. Methods: Humerus pathologic fracture patients with unicameral bone cysts in our pediatric orthopedic department from January 2015 to January 2020 were retrospectively analyzed. Patients were divided into two groups, namely the PCSI group and the LSBG group, based on the type of bone grafting material they received. Preoperative assessments were made in both groups using the Cyst Index and Cyst activity. During the perioperative phase, assessments were made regarding operative time, bleeding, postoperative VAS scores, and the frequency of reoperation within 2 years. Clinical outcomes were evaluated using the Capanna scale at the last follow-up, and the occurrence of re-fractures during the follow-up period. Results: A total of 22 patients were included, with a mean follow-up duration of 33.5 ± 5.8 months. No significant differences were found between the two groups in terms of Cyst Index and Cyst activity before the operation. The operative time, bleeding, and postoperative VAS scores in the PCSI group were found to be lower than those in the LSBG group (P < 0.05). The PCSI group also showed a higher frequency of reoperation within 2 years compared to the LSBG group (P < 0.05). However, no significant differences were observed between the two groups in terms of Capanna scale scores at the last follow-up and the incidence of re-fractures during follow-up. Conclusions: Both titanium elastic nails (TEN) combined with PCSI or LSBG were found to be safe and effective treatments for humerus pathologic fractures caused by unicameral bone cysts in children. PCSI is considered as a less invasive option with shorter operative times, less bleeding, and reduced postoperative pain, although it comes with the risk of multiple injections. On the other hand, LSBG is considered as a more invasive option for the treatment of active bone cysts but is associated with a lower recurrence rate.

Co-Expression and Combined Prognostic Value of CSPG4 and PDL1 in TP53-Aberrant Triple-Negative Breast Cancer.

Background: In triple-negative breast cancer (TNBC), PDL1/PD1-directed immunotherapy is effective in less than 20% of patients. In our preliminary study, we have found CSPG4 to be highly expressed together with PDL1 in TNBCs, particularly those harboring TP53 aberrations. However, the clinical implications of co-expressed CSPG4 and PDL1 in TNBCs remain elusive. Methods: A total of 85 advanced TNBC patients treated in the Hunan Cancer Hospital between January 2017 and August 2019 were recruited. The expressions of CSPG4 and PDL1 in TNBC tissues were investigated using immunohistochemistry (IHC). The RNA-seq dataset from the TCGA-BRCA project was further used to analyze the mRNA expression of CSPG4 and PDL1 in TP53-aberrant TNBCs. Cox proportional hazards model and Kaplan-Meier curves with Logrank test was used to analyze the effects of CSPG4 and PDL1 on survival. TNBC cell lines were further used to investigate the molecular mechanism that were involved. Results: TP53 aberrations occurred in more than 50% of metastatic TNBCs and were related to higher tumor mutation burden (TMB). In TCGA-BRCA RNA-seq dataset analysis, both CSPG4 and PDL1 levels were high in TNBCs, especially in TP53-aberrant TNBCs. IHC assay showed nearly 60% of advanced TNBCs to be CSPG4-positive and about 25% to be both CSPG4-positive and PDL1-positive. The levels of CSPG4 and PDL1 were high in TNBC cell lines as revealed by flow cytometry and immunoblotting compared with non-TNBC cells. Univariate Cox regression analysis indicated that CSPG4 positivity was a significant risk factor for progression-free survival in metastatic TNBCs, with a hazard ratio (HR) of 2.26 (P = 0.05). KM curves with Logrank test also identified high level of CSPG4 as a significant risk factor for overall survival in advanced breast cancers in TCGA-BRCA samples (P = 0.02). The immunoblotting assays showed that EMT-related pathways were involved in CSPG4-mediated invasion. Conclusions: CSPG4 expression level is associated with PDL1 positivity in TP53-aberrant TNBC cells. Patients with CSPG4 expression have poor treatment response and poor overall survival. Co-expressed CSPG4 and PDL1 may have an important prognostic value and provide new therapeutic targets in TNBC patients. CSPG4 might mediate tumor invasion and PDL1 overexpression through EMT-related pathway.

miR-148a-mediated estrogen-induced cholestasis in intrahepatic cholestasis of pregnancy: Role of PXR/MRP3.

Intrahepatic cholestasis of pregnancy (ICP) is an idiopathic liver disease while the biochemical characteristic is the elevated level of total bile acid (TBA). The present study investigated whether miR-148a mediates the induced effect of estrogen on the development of ICP and the proper mechanism: PXR/MRP3 signal pathway. mRNA expression was detected by qPCR, protein expression was detected by western blotting, the concentration of estrogen and TBA were detected by reagent kit respectively. In the cinical research, it was found that miR-148a expression was positive related with the concentration of TBA in the serum of ICP patients. In in vitro research, estradiol (500 nmol/L, 12 h) significantly upregulated miR-148a expression and LV-148a-siRNA inhibited the function of estradiol (500 nmol/L, 48 h) on TBA secretion. In addition, gene silence of miR-148a upregulated PXR expression which was inhibited by estradiol in LO2 cells. Pretreatment of rifampin (10 µmol/L), the agonist of PXR alleviated the TBA secretion induced by estradiol (500 nmol/L, 48 h). miR-148a-siRNA and PXR had a synergistic action on TBA secretion of LO2. Both of miR-148a-siRNA and rifampin (10 µmol/L) inhibited the upregulated effect of estradiol on MRP3 expression. This research has demonstrated that miR-148a may be involved in the induction of estrogen on ICP via PXR signal pathway, and MRP3 may be involved.

Identification of heptapeptides interacting with IFN-α-sensitive CML cells.

BACKGROUND: Interferon-alpha (IFN-α) is the traditional therapeutic agent for chronic myeloid leukemia (CML). The molecular mechanism of IFN-α efficacy in the treatment of CML is not fully clear. OBJECTIVES: To identify the peptides and/or proteins that bind to the proteins specifically expressed on the surface of IFN-α-sensitive CML cells by using a phage display library. DESIGN/METHODS: IFN-α-sensitive KT-1/A3 cells were used as the target, and IFN-α-resistant subline KT-1/A3R was used as absorber for phage display biopanning. The positive phage clones were identified by enzyme-linked immunosorbent assay and flow cytometry. The peptides were deduced from their DNA sequences. RESULTS: Multiple clones showed high binding efficiency to KT-1/A3 cells compared with that of the other leukemia cells. One of the peptides, KLWVIPQ, has a partial amino acid sequence homology with the C-terminal domain of E3 ubiquitin-protein ligase. CONCLUSIONS: This study presents the identification of specific heptapeptides that bind to IFN-α-sensitive KT-1/A3 cells. The cancer-selective ligands provide novel strategies for early and differential diagnoses, as well as potential targeted drug delivery.

Genetic mutations of p53 and k-ras in gastric carcinoma patients from Hunan, China.

This case-control study investigated the mutations in p53 and k-ras genes of 123 gastric carcinoma patients and 129 normal individuals from Hunan, China. By isolating genomic DNA from peripheral blood and employing polymerase chain reaction-single strand conformation polymorphism and DNA sequencing, the mutations of p53 exons-5, 6, 7, and 8 and k-ras were detected. The overall mutation frequency of p53 was 29.3%, and mutation was found in all four exons studied. The point mutations were predominant and among them, G:C→A:T was the highest (41.7%), followed by A:T→G:C (25%), G:C→C:G (11.1%), G:C→T:A (8.3%), and A:T→T:A (2.8%). The frameshift mutation was 11.1%. Mutations were detected in codons-131, 132, 133, 135, 149, 151, 162, 167, 173, 174, and 175 of exon 5, codons-193, 197, 213, and 215 of exon 6, codons-245, 246, 248, 249, and 270 of exon 7, and codons-271, 272, 273, and 282 of exon 8 of p53. The overall frequency of mutation in k-ras was 9.8%, mostly in codon-12 (91.7%) and in codon-13 (8.3%). There was no significant relationship between p53 and k-ras gene mutation in gastric carcinoma patients. Also, the relationships between p53 mutation and age, sex, smoking or drinking, and tumor metastasis were not significant. However, the patients with high/high-middle differentiated gastric carcinoma had a higher association with of p53 mutations. This study identified some novel p53 mutations in gastric cancer and showed mutation pattern and frequency of p53 and k-ras in the population of the central southern region of China.

Genetic polymorphisms of metabolic enzymes CYP1A1, CYP2D6, GSTM1 and GSTT1 and leukemia susceptibility.

The genetic polymorphisms of biotransformation phase I enzymes, cytochrome P450 (CYP1A1 and CYP2D6), and phase II enzymes, glutathione S-transferase (GSTM1 and GSTT1), were analyzed in 204 healthy persons and 348 leukemia patients, who suffered from also acute lymphoblastic leukemia (ALL), acute nonlymphoblastic leukemia (ANLL) chronic myelogenous leukemia (CML), from the Han ethnic group in Changsha City of Hunan Province of China. Our results showed that the frequencies of polymorphisms of CYP1A1, CYP2D6 and GSTT1 among the groups including acute lymphoblastic leukemia, ANLL, chronic myelogenous leukemia and healthy control have no significant differences. The variation of GSTM1-null genotype alone correlated with the development of ANLL. The combined genotypes of GSTM1-null with GSTT1-null, or GSTM1-null with CYP1A1 heterozygous mutant, or GSTM1-null with CYP1A1 heterozygous mutant and CYP2D6 heterozygous mutant, or GSTM1-null with CYP1A1 heterozygous mutant, CYP2D6 heterozygous mutant and GSTT1-null were found in individuals with high risk of ANLL. All these findings suggest that GSTM1-null genotype alone or in coordination with the relevant genotypes of other metabolic enzymes might be susceptibility factors in the etiology of ANLL.