Oral administration of IPI549 protects mice from neuropathology and an overwhelming inflammatory response during experimental cerebral malaria.

Infection with Plasmodium falciparum is often deadly when it results in cerebral malaria, which is associated with neuropathology described as an overwhelming inflammatory response and mechanical obstruction of cerebral microvascular. PI3Kγ is a critical component of intracellular signal transduction and plays a central role in regulating cell chemotaxis, migration, and activation. The purpose of this study was to examine the relationship between inhibiting the PI3Kγ pathway and the outcome of experimental cerebral malaria (ECM) in C57BL/6J mice infected with the mouse malaria parasite, Plasmodium berghei ANKA. We observed that oral administration of the PI3Kγ inhibitor IPI549 after infection completely protected mice from ECM. IPI549 treatment significantly dampened the magnitude of inflammatory responses, with reduced production of pro-inflammatory factors, decreased T cell activation, and altered differentiation of antigen-presenting cells. IPI549 treatment protected the infected mice from neuropathology, as assessed by an observed reduction of pathogenic T cells in the brain. Treating the infected mice with IPI549 three days after parasite inoculation improved the murine blood brain barrier (BBB) integrity and helped the mice pass the onset of ECM. Together, these data indicate that oral administration of the PI3Kγ inhibitor IPI549 has a suppressive role in host inflammation and alleviates cerebral pathology, which supports IPI549 as a new malaria treatment option with potential therapeutic implications for cerebral malaria.

Circ_0049271 targets the miR-1197/PTRF axis to attenuate the malignancy of osteosarcoma.

BACKGROUND: Circular RNAs (circRNAs) perform key regulatory functions in osteosarcoma (OS) tumorigenesis. In this study, we aimed to explore the detailed action mechanisms of circ_0049271 in OS progression. METHODS: Cell colony formation, cell counting kit-8, and transwell assays were performed to assess the proliferation and invasion of OS cells. Quantitative reverse transcription-polymerase chain reaction and western blotting were used to determine the expression levels of polymerase 1 and transcript release factor (PTRF), microRNA (miR)-1197, and circ_0049271 in OS cells. Furthermore, RNA immunoprecipitation and dual luciferase assays were conducted to explore the targeted relationships among PTRF, miR-1197, and circ_0049271. Finally, a tumor formation assay was conducted to determine the effects of circ_0049271 on in vivo tumor growth in mice. RESULTS: High expression levels of miR-1197 and low levels of circ_0049271 and PTRF were observed in OS cells. circ _0049271 targeted miR-1197 to mediate PTRF expression. Moreover, the proliferation and invasion of OS cells were repressed by circ_0049271 or PTRF overexpression and increased by miR-1197 upregulation. Enforced circ_0049271 also impeded tumor growth in vivo. Upregulation of miR-1197 reversed the antitumor effects of circ_0049271 on OS progression in vitro; however, PTRF overexpression attenuated the cancer-promoting effects of miR-1197 on OS in vitro. CONCLUSIONS: Our findings revealed that circ_0049271 targeted the miR-1197/PTRF axis to attenuate the malignancy of OS, suggesting a potential target for its clinical treatment.

Recent Advances of Oxalate Decarboxylase: Biochemical Characteristics, Catalysis Mechanisms, and Gene Expression and Regulation.

Oxalate decarboxylase (OXDC) is a typical Mn2+/Mn3+ dependent metal enzyme and splits oxalate to formate and CO2 without any organic cofactors. Fungi and bacteria are the main organisms expressing the OXDC gene, but with a significantly different mechanism of gene expression and regulation. Many articles reported its potential applications in the clinical treatment of hyperoxaluria, low-oxalate food processing, degradation of oxalate salt deposits, oxalate acid diagnostics, biocontrol, biodemulsifier, and electrochemical oxidation. However, some questions still remain to be clarified about the role of substrate binding and/or protein environment in modulating the redox properties of enzyme-bound Mn(II)/Mn(III), the nature of dioxygen involved in the catalytic mechanism, and how OXDC acquires Mn(II) /Mn(III). This review mainly summarizes its biochemical and structure characteristics, gene expression and regulation, and catalysis mechanism. We also deep-mined oxalate decarboxylase gene data from National Center for Biotechnology Information to give some insights to explore new OXDC with diverse biochemical properties.

Outcome analysis of infrapatellar fat pad partial resection or preservation in patients with anterior cruciate ligament reconstruction.

The infrapatellar fat pad (IPFP) is one of the structures surrounding the knee joint that obscures exposure in minimally arthroscopy anterior cruciate ligament reconstruction (ACLR). Most surgeons excise the partial fat pad for better exposure of the knee. However, whether removal of IPFP in ACLR remained inconclusive. The purpose of this study was to investigate clinical outcomes of IPFP preservation or resection in patients with primary hamstring-graft ACLR. A total of 104 patients were assigned to receive either IPFP-R (n = 55) or IPFP-P (n = 49). There were no significant preoperative differences between the two groups. The anterior knee pain (AKP) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) in the two groups both recovered compared with those at baseline, but the IPFP-P group recovered more significantly at 3-, 6-, 12-month, and 3-, 6-month of follow-up, respectively. When assessing the KOOS subclasses using minimum perceptible clinical improvement (MPCI), patients with IPFP-R failed to make significant improvement at 3 months in the symptoms, pain and sports subsets of the KOOS. Knee-related complications were not significantly different between the two groups, while the resection group had a higher incidence. These results suggested that ACLR with primary hamstring grafts can achieve good effects whether performed with IPFP resection or preservation; however, the improvements in anterior knee pain and knee joint functions are better for the patients with IPFP preservation. Therefore, surgeons should avoid the resection of IPFP as much as possible while fully exposing the wild view to ensure the ACLR.

Influence of marital status on the treatment and survival of middle-aged and elderly patients with primary bone cancer.

Objective: The role of spousal support has been recognized to benefit patients with many chronic diseases and cancers. However, the impact of marital status on the survival of middle-aged and elderly patients with primary bone tumors remains elusive. Materials and methods: The data of patients aged ≥ 45 years with primary bone tumors diagnosed between 2000 and 2018 were extracted from the Surveillance, Epidemiology, and End Results Database. Kaplan-Meier analysis was used to assess the overall survival and tumor-specific survival of patients. The Cox proportional hazards and Fine-and-Gray models were used to calculate the hazard ratios (HRs) and sub-distribution HRs (sHR) and the corresponding 95% confidence interval (CI) of all-cause mortality and tumor-specific mortality, respectively. Results: A total of 5,640 primary bone tumors were included in the study. In 45-59 years cohort, married, unmarried, divorced and widowed accounted for 66.0, 21.0, 11.2, and 1.8%, respectively; while 64.3, 10.1, 8.8, and 16.8% in 60+ years cohort, respectively. The widowed patients had a lower proportion of early-stage tumors at diagnosis than that married, unmarried, and divorced patients (31.0% vs. 36% vs. 37.1% vs. 39.4%; P = 0.008), and had a higher proportion of patients who did not undergo surgery than that of married, unmarried, and divorced patients (38.6% vs. 21.3% vs. 24.6% vs. 24.4%; P < 0.001). The widowed population had an increased risk of all-cause mortality (HR, 1.68; 95% CI, 1.50-1.88; P < 0.001) and disease-related mortality (HR, 1.33; 95% CI, 1.09-1.61; P = 0.005) compared with the married population. Conclusion: The marital status of middle-aged and elderly people can affect the tumor stage at diagnosis, treatment, and survival prognosis of patients with primary bone cancer. Widowed patients are more inclined to choose non-surgical treatment and have the worst prognosis.

[Cationic liposome ceftazidime combined with nano-hydroxyapatite/beta-tricalcium phosphate for treatment of chronic osteomyelitis of rabbits].

OBJECTIVE: To observe the effect of cationic liposomal ceftazidime (CLC) combined with nano-hydroxyapatite/beta-tricalcium phosphate (n-HA/beta-TCP) in the treatment of chronic osteomyelitis of rabbits. METHODS: Thirty healthy New Zealand white rabbits (4-6 months old; weighing, 2-3 kg) were selected to prepare the chronic osteomyelitis models. After 4 weeks, the gross observation, X-ray examination, and bacteriological and histopathological examinations were done; the models were made successfully in 27 rabbits. Of 27 rabbits, 24 were randomly divided into 4 groups (n = 6): only debridement was performed in group A; ceftazidime was given (90 mg/kg), twice a day for 8 weeks after debridement in group B; ceftazidime and n-HA/beta-TC were implanted after debridement in group C; and CLC and n-HA/beta-TCP were implanted after debridement in group D. Before and after treatments, X-ray examination was done, and Norden score was recorded. At 8 weeks after treatment, the specimens were harvested for gross observation and for gross bone pathological score (GBPS) using Rissing standard; half of the specimens was used for histological observation and Smeltzer scoring, the other half for bacteriological examination and calculation of the positive rate of bacteria culture. RESULTS: At 8 weeks after treatment, Norden score of group D was significantly lower than that of groups A, B, and C (P < 0.05), but no significant difference was found among groups A, B, and C (P > 0.05). At 8 weeks after treatment, sinus healed in groups C and D, but sinus was observed in groups A and B; the GBPS scores of groups C and D were significantly lower than those of groups A and B (P < 0.05). The Smeltzer scores of groups C and D were significantly lower than those of groups A and B (P < 0.05). The positive rates of bacteria culture of groups C (0) and D (0) were significantly lower than those of group A (25.0%) and group B (16.7%) (P < 0.05). CONCLUSION: CLC combined with n-HA/beta-TCP has good effect in treating chronic osteomyelitis of rabbits, and it has better effect in treating chronic osteomyelitis of rabbits than ceftazidime with n-HA/beta-TCP.

E2F8 contributes to human hepatocellular carcinoma via regulating cell proliferation.

The E2F family member of transcription factors includes the atypical member E2F8, which has been little studied in cancer. We report that E2F8 is strongly upregulated in human hepatocellular carcinoma (HCC), where it was evidenced to contribute to oncogenesis and progression. Ectopic overexpression of E2F8 promoted cell proliferation, colony formation, and tumorigenicity, whereas E2F8 knockdown inhibited these phenotypes, as documented in Huh-7, Focus, Hep3B, and YY-8103 HCC cell lines. Mechanistic analyses indicated that E2F8 could bind to regulatory elements of cyclin D1, regulating its transcription and promoting accumulation of S-phase cells. Together, our findings suggest that E2F8 contributes to the oncogenic potential of HCC and may constitute a potential therapeutic target in this disease.