Exploratory study of autophagy inducer sirolimus for childhood cerebral adrenoleukodystrophy.

Objectives: X-linked adrenoleukodystrophy (ALD) is a peroxisomal disease caused by mutations in the ABCD1 gene. Childhood cerebral ALD (CCALD) is characterized by inflammatory demyelination, rapidly progressing, often fatal. Hematopoietic stem cell transplant only delays disease progression in patients with early-stage cerebral ALD. Based on emergency humanitarianism, this study aims to investigate the safety and efficacy of sirolimus in the treatment of patients with CCALD. Methods: This was a prospective, single-center, one-arm clinical trial. We enrolled patients with CCALD, and all enrolled patients received sirolimus treatment for three months. Adverse events were monitored and recorded to evaluate the safety. The efficacy was evaluated using the neurologic function scale (NFS), Loes score, and white matter hyperintensities. Results: A total of 12 patients were included and all presented with CCALD. Four patients dropped out and a total of eight patients in the advanced stage completed a 3-month follow-up. There were no serious adverse events, and the common adverse events were hypertonia and oral ulcers. After sirolimus treatment, three of the four patients with an initial NFS > 10 showed improvements in their clinical symptoms. Loes scores decreased by 0.5-1 point in two of eight patients and remained unchanged in one patient. Analysis of white matter hyperintensities revealed a significant decrease in signal intensity (n = 7, p = 0.0156). Conclusions: Our study suggested that autophagy inducer sirolimus is safe for CCALD. Sirolimus did not improve clinical symptoms of patients with advanced CCALD significantly. Further study with larger sample size and longer follow-up is needed to confirm the drug efficacy.Clinical Trial registration: https://www.chictr.org.cn/historyversionpuben.aspx, identifier ChiCTR1900021288.

Long-term administration of sirolimus does not affect the physical development of children with tuberous sclerosis complex.

PURPOSE: There was no evidence whether the mammalian/mechanistic target of rapamycin pathway hyperactivation and long-term use of mTOR inhibitors have any effects on the physical development of children. The aim was to evaluate these effects by comparing the physical development of children with TSC and normal children. METHODS: A total of 120 eligible children were enrolled. They were administered sirolimus and followed for at least 12 months. Height, weight, BMI and lipid metabolism index were collected during treatment. Pearson's chi-square and Fisher's exact test were used for comparison of proportions of patients exhibiting normal and abnormal physical growth before and after 1 year of treatment. Logistic regression was used to evaluate the influence of age, sex and abnormal lipid metabolism on the increased BMIs of TSC patients after treatment. RESULTS: Most of the enrolled TSC children were in the normal height, weight and BMI ranges at baseline (91.7%, 95.8% and 78.3%, respectively). Most remained in the normal height, weight and BMI ranges after 1 year of sirolimus treatment (94.2%, 95% and 76.7%, respectively). There was no significant difference in the proportion of physical development before and after treatment (p > 0.05). Thirty-eight (38/106, 35.8%) patients had increased BMIs after 1 year of treatment, but there was no significant correlation between age, sex and lipid metabolism and increased BMI. CONCLUSIONS: Overactivation of the mTOR pathway and long-term administration of sirolimus does not affect the physical development of children with TSC.

The emerging role of the MiR-1272-ADAM9-CDCP1 signaling pathway in the progression of glioma.

Glioma is a primary, malignant, and aggressive brain tumor in adults. To develop new therapeutic strategies for glioma, we must determine its underlying mechanisms. In the present study, we aimed to investigate the potential role of miR-1272-ADAM9-CDCP1 signaling in the progression of glioma. We found that ectopic expression of miR-1272 produced significant inhibitory effects on cell proliferation and migration and was associated with cell cycle G0/G1 arrest in A172 and SHG44 glioma cells. Using the luciferase reporter assay, we identified ADAM9 as a target of miR-1272. The expression of ADAM9 was markedly decreased or increased after overexpression or inhibition, respectively, of miR-1272 in glioma cells. Moreover, overexpression of ADAM9 reversed the inhibitory effects of miR-1272 on glioma cell progression. Furthermore, CDCP1 served as a potential downstream molecule of miR-1272/ADAM9 signaling in glioma and promoted the proliferation and migration of glioma. Results derived from clinical samples and online databases confirmed correlations between the expression of ADAM9 and CDCP1 and both the severity and prognosis of glioma. In conclusion, these results suggest that miR-1272 and CDCP1 may act as novel regulators in glioma. The miR-1272/ADAM9/CDCP1 pathway may serve as a potential candidate pathway for the prevention of glioma.

Sirolimus improves seizure control in pediatric patients with tuberous sclerosis: A prospective cohort study.

PURPOSE: This study aimed to analyze the therapeutic effect of sirolimus on seizures in pediatric patients with tuberous sclerosis. METHODS: We first compared the efficacy of controlling seizures in all patients after they had taken sirolimus for one year, and then we performed a subgroup analysis based on whether the administered antiepileptic drugs were changed to determine whether the efficacy was associated with changes of antiepileptic drugs. RESULTS: A total of 91 eligible children were enrolled. The response rate was 78.0 % (71/91), and 47.2 % (43/91) of all patients were became seizure-free. The improvement in seizure control before and after treatment with sirolimus was significant (p < 0.001). In the AEDs unaltered group, 34 were responders (34/45, 75.6 %, 95 % CI 17.4-88.3), of which 24 were seizure-free (24/34, 70.6 %). In the AEDs-altered group, 37 were responders (37/46, 80.4 %, 95 % CI 56.7-88.1), of which 19 were seizure-free (19/37, 51.4 %). There was no significant difference between the two groups for reductions in rate of seizure frequency (p = 0.308). In the patients with refractory epilepsy, treatment with sirolimus was also effective (p = 0.01). Logistic regression analysis showed that age was an important factor affecting outcome of epilepsy (p = 0.003, 95 % CI 2.05-38.31). No Grade 3 or 4 adverse events were noted during the follow-up. CONCLUSIONS: Sirolimus has a significant effect on seizures associated with tuberous sclerosis complex (TSC), with no or only moderate adverse events after long-term administration. Sirolimus could be used as the first-line medication for pediatric patients with TSC-associated epilepsy.

Advances in cryoablation for pancreatic cancer.

Pancreatic carcinoma is a common cancer of the digestive system with a poor prognosis. It is characterized by insidious onset, rapid progression, a high degree of malignancy and early metastasis. At present, radical surgery is considered the only curative option for treatment, however, the majority of patients with pancreatic cancer are diagnosed too late to undergo surgery. The sensitivity of pancreatic cancer to chemotherapy or radiotherapy is also poor. As a result, there is no standard treatment for patients with advanced pancreatic cancer. Cryoablation is generally considered to be an effective palliative treatment for pancreatic cancer. It has the advantages of minimal invasion and improved targeting, and is potentially safe with less pain to the patients. It is especially suitable in patients with unresectable pancreatic cancer. However, our initial findings suggest that cryotherapy combined with 125-iodine seed implantation, immunotherapy or various other treatments for advanced pancreatic cancer can improve survival in patients with unresectable or metastatic pancreatic cancer. Although these findings require further in-depth study, the initial results are encouraging. This paper reviews the safety and efficacy of cryoablation, including combined approaches, in the treatment of pancreatic cancer.

[Transcriptional activities of tumor-specific survivin promoter and PSMA promoter and enhancer in human prostate cancer: evaluation and comparison].

OBJECTIVE: To detect and compare the transcriptional activities of prostate-specific membrane antigen (PSMA) promoter and enhancer and survivin promoter in different human prostate cancer cell lines, and to search for some evidence for the targeting gene therapy of human prostate cancer. METHODS: The fragments of the PSMA promoter and enhancer and survivin promoter were amplified by PCR and inserted into pGL3-Basic. The recombinant plasmids were transiently transfected into human prostate cancer cell lines and normal Chang liver cells, and, their transcriptional activities in various cells were determined by measuring the expression of luciferase. RESULTS: The survivin promoter exhibited a higher transcriptional activity than PSMA promoter and enhancer in tumor cell lines, and the S2pro promoter showed the highest activity, reaching one third of that of the CMV promoter. CONCLUSION: The survivin promoter is highly activated in prostate cancer cell lines and may serve as a new tool for the transcriptional targeting gene therapy of prostate cancer.

[Association of the neprilysin and apolipoprotein E gene polymorphisms with Alzheimer's disease in Xinjiang Uygur population].

OBJECTIVE: To assess the association between the neprilysin (NEP) gene and apolipoprotein E (ApoE) gene polymorphisms and sporadic Alzheimer's disease (SAD) in Xinjiang Uygur population. METHODS: The polymorphisms of the NEP and ApoE gene were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 111 SAD patients and 117 healthy controls. RESULTS: (1) The frequency of the T allele in the NEP gene was significantly higher in the SAD patients than that in the controls (Chi-square= 5.005, P< 0.05); and there was higher risk to develop SAD in the T allele carriers. (2) The frequency of the ApoE 4 epsilon 4 allele was higher in the SAD patients than in the controls (Chi-square= 4.218, P< 0.05); and the ApoE 4 epsilon 4 carriers had significantly increased risk of developing SAD. (3) No significant interaction was found between the NEP and ApoE polymorphisms in SAD patients. CONCLUSION: The NEP and ApoE gene polymorphisms may be associated with SAD. NEP gene may be an independent genetic risk factor for SAD in Xinjiang Uygur population.

[Effect of HANS electroacupuncture on the expression of NPY in PAG of heroin addicted rats].

OBJECTIVE: To examine the effects of Han's acupoint and nerve stimulator (HANS) electroacupuncture on the expression of NPY in periaqueductal grey (PAG) of heroin addicted rats. METHODS: Heroin was injected subcutaneously according to the principle of daily increasing dose in rats of experimented group. The ability of special learning and memory were tested by Morris water maze; The expression of NPY in PAG of rat were detected by immunohistochemistry. RESULTS: (1) Escape latency and searching distance in heroin-addiction group were significantly increased compared with those of normal group during the place navigation test (P < 0.05). However, in acupuncture group, escape latency and searching distance was obviously shortened compared with those of heroin-addiction group (P < 0.05). The exploring time and distance of original platform area in proportion to the total distance in heroin-addiction group significantly decreased compared with those of normal group during spatial probe test (P < 0.05). The exploring time and distance of original platform area in proportion to the total distance in acupuncture group was increased compared with those in heroin-addiction group (P < 0.01). (2) The expression of NPY of heroin-addiction group was lower than that in normal group in PAG, while those of acupuncture group was higher than that in the heroin-addiction group (P < 0.05). CONCLUSION: The learning and memory induced by heroin-addiction could be reversed and the expression of NPY in PAG was increased by HANS in rats.

[Detection of transcriptional activities of tumor-specific survivin promoter in human prostatic carcinoma].

OBJECTIVE: To clone DNA sequence of the survivin promoter and study is transcriptional activities in human prostate cancer cells and normal Chang liver cells. METHODS: The fragment of the survivin promoter was acquired by PCR amplification and inserted into pPRIME vectors to reconstruct a recombinant plasmid named pPRIME-S1pro and pPRIME-S2pro. Then the reconstructed plasmid was transiently transfected into human prostate cancer cells lines LNCaP and normal Chang liver cells. The transcriptional activities of the survivin promoter in various cells was determined by measuring the expression of green fluorescent protein (GFP). RESULTS: The survivin promoter had transcriptional activities in LNCaP cells and the transcriptional activity of the S2pro was much higher that of the S1pro, reaching a level of 39% of the transcriptional activity of the CMV promoter. CONCLUSION: The survivin promoter cloned in the therapy for prostate cancer.