Statin use improves the prognosis of ovarian cancer: An updated and comprehensive meta-analysis.

Statins are lipid-lowering agents that have also been found to have anticancer effects. The relationship between statin use and clinical outcomes in ovarian cancer (OC) remains controversial, as previous assessments of the relationship between statin use and OC prognosis have yielded inconsistent results. Therefore, a comprehensive meta-analysis was performed in the present study to investigate this association. Studies were systematically retrieved by searching the PubMed, Embase and Cochrane Library databases, and consulting reference lists of the related studies. The search timeframe was from database creation to September 1, 2022. Pooled hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were calculated to assess the association. In the present meta-analysis, 16 studies with 37,660 patients with OC were included, of which 11,296 patients had been prescribed statins. The results showed that statin use markedly improved the overall survival time (OS; HR, 0.79; 95% CI, 0.73-0.85; P<0.00001) and OC-specific survival time (HR, 0.84; 95% CI, 0.80-0.89; P<0.00001), especially the OS time in patients with serous OC (HR, 0.81; 95% CI, 0.74-0.89; P<0.0001) and endometrioid OC (HR, 0.80; 95% CI, 0.66-0.98; P=0.03). In addition, survival rate was higher in patients who used statins after OC diagnosis (HR, 0.79; 95% CI, 0.73-0.85; P<0.00001). However, there was no statistically significant association between statin use and the prognosis of mucinous and clear cell OC. The results suggested that statin use markedly improved the OS in patients with OC, including in those with serous and endometrioid OC. Statins were also found to improve the prognosis of patients of both Asian and non-Asian ethnicities. In addition, both lipophilic and hydrophilic statins improved the survival in patients with OC, especially in patients using statins after OC diagnosis. However, the effect may vary depending on the statin type, duration of use and cancer type, and more well-designed studies are needed to further evaluate this.

Successful treatment of radiotherapy and apatinib in patient with mediastinal mixed non-seminomatous germ cell tumor: A case report.

RATIONALE: Mediastinal non-seminomatous germ cell tumors (MNSGCTs) are rare malignancies. Chemotherapy followed by surgical resection has been regarded as the standard management, but treatment options for chemotherapy-refractory patients or those with unresectable tumors are limited, resulting in a very poor prognosis. PATIENT CONCERNS: An 18-year-old female presented with symptoms of cough, chest tightness, and shortness of breath for 2 months, and the symptoms gradually worsened. DIAGNOSIS: Computed tomography (CT) revealed a large mediastinal mass invading the pericardium and great blood vessels. Serum human chorionic gonadotropin (HCG) and α-fetoprotein (AFP) levels were normal. Histopathological examination of biopsy specimens revealed mixed MNSGCT with embryonal carcinoma and immature teratoma components. INTERVENTIONS: The patient achieved complete remission (CR) and long-term survival after multimodal therapy comprising chemotherapy, positron emission tomography/CT (PET/CT)-guided volumetric-modulated arc therapy (VMAT), and anti-angiogenic targeted therapy. OUTCOMES: The patient was followed up for more than 4 years without recurrence, metastasis, or treatment-related adverse effects. LESSONS: The case presented here highlights the importance of multidisciplinary diagnosis and treatment, providing evidence that radiotherapy and anti-angiogenic therapy may play an important role in unresectable or residual tumors after failure of conventional treatments of MNSGCT. Percutaneous biopsy is necessary for diagnosis if the tumor is unresectable, and serum AFP and HCG levels are normal. Additionally, PET/CT is an effective method for evaluation of efficacy and radiotherapy guidance for patients with MNSGCTs.

Efficacy and Safety of Aidi Injection as an Adjuvant Therapy on Advanced Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Aidi injection (ADI) is being used widely for breast cancer in China. However, the efficacy and safety of it need to be summarized. We conducted a systematic review and meta-analysis to compare ADI and non-ADI treatment for advanced breast cancer. METHODS: We searched PubMed, EMBASE, CNKI, SinoMed, and CENTRAL from inception to Jan 2020 for randomized controlled trials (RCTs) with diagnosis of advanced breast cancer that compared the efficacy of ADI with non-ADI treatment. Two researchers screened the literature, extracted data, and evaluated risk of bias separately. The primary outcomes were overall response rate (ORR) and disease control rate (DCR). The secondary outcomes included the QOL, immune cells, and adverse events. Review Manager software was used for estimating risks of bias of included studies, data analysis, and plotting. The sensitivity analysis and the publication bias test were performed using the R language. I 2 and chi-square tests were used to estimate heterogeneity. If P > 0.1 or I 2 < 40%, the fixed-effect model meta-analysis was performed. A random or fixed-effect analysis was used depending on the heterogeneity testing. Weighted mean difference (WMD) or standard mean difference (SMD) was used for analysis of continuous data, and the rate ratio (RR) was calculated for the dichotomous variable, respectively. RESULTS: We included 14 studies with 1006 patients diagnosed as advanced breast cancer in total. The pooled effect showed that ADI increased ORR in advanced BC patients as an add-on therapy with little heterogeneity (RR = 1.14, 95% CI 1.03-1.27). DCR in BC patients could not be improved by ADI. ADI improved the KPS score in BC patients compared with chemotherapy alone (MD = 3.26, 95% CI 1.74-4.78). There were no improvements on immune markers except CD4/CD8 and NK%. Serum tumor markers CEA and CA153 were decreased while treated with ADI, but only one trial was involved. ADI decreased the numbers of myelosuppression in advanced BC patients, and AST, ALT, γ-GT, and CK-MB were all decreased. The sensitivity evaluation indicated that the result of the pooled effect size had good stability. CONCLUSION: This meta-analysis suggested that based on the existing evidence, treatment with ADI significantly changed the ORR of patients with advanced BC and improved their quality of life with few side effects. However, more randomized trials involving larger samples should be considered, and detailed mechanisms are needed to be uncovered.

Preimplantation genetic diagnosis using combined strategies on a breast cancer patient with a novel genomic deletion in BRCA2.

PURPOSE: To perform Preimplantation Genetic Diagnosis (PGD) on a paternal Brca2 unknown mutation carrier with early-onset breast cancer, whose paternal grandmother and mother had breast cancer at 60s. METHOD: Elucidating the linkage via single sperm haplotyping on patient's carrier brother, and identifying the genomic deletion via BLAST followed by PCR screening. PGD was subsequently conducted. RESULT: The mutant allele was found by using 4 microsatellite and 2 intragenic SNP markers. Recombination was detected in 8% of sperms. BLAST was utilized to locate putative hairpin structure(s), followed by PCR screening with seven sets of primers. A novel 2,596 bp deletion containing exon 15 ~ 16 was identified. Due to the severity of phenotype and the integrity of exon 11 encoding RAD51 binding domain, and the fact that the patient's mother also had breast cancer at her 60s, we speculate a possible coexistence of maternal breast cancer risk allele(s). Embryo biopsy was performed on day 3. Unaffected morula and blastocyst were replaced on day 5, resulting in a singleton livebirth. A breast lump appeared in the patient after delivery without the presence of malignant cells. CONCLUSION: Concerning the assisted reproductive option for breast cancer patients, the possibility of coexistence of multiple familial risk alleles and the significance of each mutation to the phenotype should be evaluated. To eliminate misdiagnosis resulting from recombination and/or allelic drop-out, both direct mutation detection and linkage analysis approaches may be necessary. BLAST is a very useful and cost-effective tool for identifying large genomic deletion.

Restoration of the balanced alpha/beta-globin gene expression in beta654-thalassemia mice using combined RNAi and antisense RNA approach.

The beta-thalassemia is associated with abnormality in beta-globin gene, leading to imbalanced synthesis of alpha-/beta-globin chains. Consequently, the excessive free alpha-globin chains precipitate to the erythrocyte membrane, resulting in hemolytic anemia. We have explored post-transcriptional strategies aiming at alpha-globin reduction and beta-globin enrichment on beta(654) (Hbb(th-4)/Hbb(+)) mouse, carrying a human splicing-deficient beta-globin allele (Hbb(th-4)). Lentiviral vectors of short hairpin RNA (shRNA) targeting alpha-globin and/or antisense RNA facilitating beta-globin correct splicing were microinjected into beta(654) single-cell embryos. Three transgenic strains were generated, as alpha(i)-Hbb(th-4)/Hbb(+)(shRNA), beta(a)-Hbb(th-4)/Hbb(+)(antisense) and alpha(i)beta(a)-Hbb(th-4)/Hbb(+)(both shRNA and antisense). Without notable abnormalities, all the founders and their offsprings showed sustained amelioration of hematologic parameters, ineffective erythropoiesis and extramedullary hematopoiesis. Augmented effects appeared in alpha(i)beta(a)-Hbb(th-4)/Hbb(+), which correlated with a better-balanced alpha-/beta-globin mRNA level. Among the transgenic mice integrated with shRNA and antisense RNA, one homozygous mouse (Hbb(th-4)/Hbb(th-4)) had been viable, and the 3-week survival rate for heterozygotes (Hbb(th-4)/Hbb(+)) was 97%, compared with 45.4% for untreated. Our data have demonstrated the feasibility of techniques for beta-thalassemia therapy by balancing the synthesis of alpha-/beta-globin chains.

Effect of oocyte mitochondrial DNA haplotype on bovine somatic cell nuclear transfer efficiency.

The development capability of reconstructed bovine embryos via ovum pick-up (OPU)-somatic cell nuclear transfer (SCNT) technique has been influenced by the maternal lineage of oocyte cytoplasm, but the underlying mechanism remains unclear. Since mitochondria are the richest maternal-inherited organelle, in this study, we intended to clarify the effect of mtDNA haplotypes on cloning efficiency. By PCR-RFLP method, we identified mtDNA haplotypes A and B, differing in six restriction sites. Reconstructed embryos with haplotype A cytoplast achieved better fusion and blastocyst formation rate (64.6% and 39.4%), as compared with haplotype B (53.6% and 26.3%; P < 0.05). To further evaluate the role of mitochondria, the quantity of mtDNA, ATP content, and mRNA level of mtDNA-encoded COXI, COXIII in both oocytes were measured. Our data indicated that mtDNA copy number in haplotype A oocyte was significantly higher than that in haplotype B oocyte, both at the GV (10(5.03 +/- 0.69) vs. 10(4.81 +/- 0.86) copies/oocyte) and MII stages (10(5.31 +/- 0.71) vs. 10(5.13 +/- 0.63) copies/oocyte; logarithmically transformed values; P < 0.05). ATP content in type A oocyte was also greater at the GV (1.67 +/- 0.09 vs. 1.27 +/- 0.1 pmol) and MII stages (5.18 +/- 0.07 vs. 2.68 +/- 0.03 pmol; P < 0.05). Similarly, the mRNA expression level of mtDNA-encoded COXI and COXIII in haplotype A oocyte was significantly higher comparing to haplotype B oocyte (3.3 +/- 2.0 x 10(3) vs. 0.68 +/- 0.45 x 10(3); 24.9 +/- 10.5 x 10(3) vs. 9.4 +/- 3.3 x 10(3), respectively; P < 0.05). The data suggest that mitochondrial structure, quantity, and function may significantly affect the developmental competence of reconstructed embryos.

Individual human hair mitochondrial DNA control region heteroplasmy proportions in mothers and children.

Due to maternal inheritance, lack of recombination and a high polymorphic density, the mtDNA control region hypervariable (HV) regions are well suited for forensic identification using a maternal relative as the known sample. This analysis can be performed in hair, however, heteroplasmy in this tissue is not rare and can result in an apparent sequence mismatch that complicates this application. There is little data comparing mother and child mtDNA-CR heteroplasmic proportions in hair. In this study, we assayed four hairs per individual in 26 mother-child pairs by TTGE for heteroplasmy across HV1. Single nucleotide heteroplasmy was detected in seven families, and in four families at least two hairs were heteroplasmic. In each of the latter families, sequencing and PCR-RFLP confirmed single nucleotide heteroplasmy in proportions of the variant ranging from < or =10 to > or =90% in the mothers, with far less variability in their children. Sequencing alone would have revealed apparent homoplasmic differences at one nucleotide in these families, possibly resulting in an 'inconclusive' verdict for relatedness of child and mother. However, mother-child heteroplasmic variability did not exceed intra-individual variability in the mothers alone.

Mitochondrial DNA control region sequence variation in migraine headache and cyclic vomiting syndrome.

Migraine headache is a very common condition affecting about 10% of the population that results in substantial morbidity and economic loss. The two most common variants are migraine with (MA) and without (MO) aura. Often considered to be a migraine-like variant, cyclic vomiting syndrome (CVS) is a predominately childhood condition characterized by severe, discrete episodes of nausea, vomiting, and lethargy. Disease-associated mitochondrial DNA (mtDNA) sequence variants are suggested in common migraine and CVS based upon a strong bias towards the maternal inheritance of disease, and several other factors. Temporal temperature gradient gel electrophoresis (TTGE) followed by cyclosequencing and RFLP was used to screen almost 90% of the mtDNA, including the control region (CR), for heteroplasmy in 62 children with CVS and neuromuscular disease (CVS+) and in 95 control subjects. One or two rare mtDNA-CR heteroplasmic sequence variants were found in six CVS+ and in zero control subjects (P = 0.003). These variants comprised 6 point and 2 length variants in hypervariable regions 1 and 2 (HV1 and HV2, both part of the mtDNA-CR), one half of which were clustered in the nt 16040-16188 segment of HV1 that includes the termination associated sequence (TAS), a functional location important in the regulation of mtDNA replication. Based upon our findings, sequencing and statistical analysis looking for homoplasmic nucleotide changes was performed in HV1 among 30 CVS+, 30 randomly-ascertained CVS (rCVS), 18 MA, 32 MO, and 35 control haplogroup H cases. Within the nt 16040-16188 segment, homoplasmic sequence variants were three-fold more common relative to control subjects in both CVS groups (P = 0.01 combined data) and in MO (P = 0.02), but not in MA (P = 0.5 vs. control subjects and 0.02 vs. MO). No group differences were noted in the remainder of HV1. We conclude that sequence variation in this small "peri-TAS" segment is associated with CVS and MO, but not MA. These variants likely constitute risk factors for disease development. Our findings are consistent with previous data demonstrating progression of CVS into MO in many cases, and the co-segregation in a maternal inheritance pattern of CVS and MO within families. A mitochondrial component in the pathogenesis of migraine and CVS has therapeutic implications, especially concerning the avoidance of fasting.

A methylated oligonucleotide inhibits IGF2 expression and enhances survival in a model of hepatocellular carcinoma.

IGF-II is a mitogenic peptide that has been implicated in hepatocellular oncogenesis. Since the silencing of gene expression is frequently associated with cytosine methylation at cytosine-guanine (CpG) dinucleotides, we designed a methylated oligonucleotide (MON1) complementary to a region encompassing IGF2 promoter P4 in an attempt to induce DNA methylation at that locus and diminish IGF2 mRNA levels. MON1 specifically inhibited IGF2 mRNA accumulation in vitro, whereas an oligonucleotide (ON1) with the same sequence but with nonmethylated cytosines had no effect on IGF2 mRNA abundance. MON1 treatment led to the specific induction of de novo DNA methylation in the region of IGF2 promoter hP4. Cells from a human hepatocellular carcinoma (HCC) cell line, Hep 3B, were implanted into the livers of nude mice, resulting in the growth of large tumors. Animals treated with MON1 had markedly prolonged survival as compared with those animals treated with saline or a truncated methylated oligonucleotide that did not alter IGF2 mRNA levels in vitro. This study demonstrates that a methylated sense oligonucleotide can be used to induce epigenetic changes in the IGF2 gene and that inhibition of IGF2 mRNA accumulation may lead to enhanced survival in a model of HCC.