Immune landscape in the glomerular transcriptome of nephrotic syndrome and anca-associated vasculitis.

BACKGROUND: ANCA-associated vasculitis (AAV), and nephrotic syndrome encompassing diseases including minimal change disease (MCD), focal and segmental glomerulosclerosis (FSG), membranous nephropathy (MN), remain a challenge due to their varied immunological characteristics. Recent therapeutic advancements have highlighted the importance of understanding these diseases' immunological landscapes. METHODS: This study analyzed transcriptomics data from renal glomerular tissues of patients with AAV, FSG, MCD, MN, and normal controls. Utilizing an immune-related gene set of 883 genes, methods including Gene Set Variation Analysis (GSVA), LASSO regression, and Weighted Correlation Network Analysis (WGCNA) were used. Predictions of immune cell compositions were made through CIBERSORT, TIMER, MCPcounter, and quanTIseq algorithms. RESULTS: The study revealed distinct immunogenetic pathways enriched in each disease: hematopoietic cell lineage in ANCA, linoleic acid metabolism in FSG, PPAR signaling in MCD, and drug metabolism in MN. Classifiers based on immune gene expression showed high accuracy (AUC: ANCA 0.812, FSG 0.99, MCD 1, MN 0.888). Co-expression modules and PPI networks highlighted unique pathways for each disease. Predictions of immune cell composition showed elevated macrophages in FSG and MN, with Treg levels elevated across all four diseases compared to normal controls and highest in FSG. Correlation analyses demonstrated significant associations between classifier scores and immune cell types. CONCLUSION: This study offers accurate classifiers for AAV, FSG, MCD, and MN, and reveals distinct immunological pathways. These findings advance personalized treatments and highlight potential therapeutic targets in AAV and nephrotic syndrome. Further research should validate these results for clinical applications.

Molecular characteristics and oncogenic role of CHD family genes: a pan-cancer analysis based on bioinformatic and biological analysis.

Chromodomain helicase DNA-binding protein (CHD) gene family, an ATP (adenosine triphosphate) -dependent chromatin remodeler family, is involved in multiple developmental process and tumor development. However, there have been none pan-cancer analyses of this family. The expression levels, survival profiles, mutation profiles and immune infiltration of the CHD family genes from TCGA and TARGET database were analyzed using online tools or R packages. Interestingly, all types of CHD gene expressions were associated with the prognosis of Neuroblastoma, Acute lymphoblastic leukemia-Phase 3 and Acute Myeloid Leukemia (All P < 0.05). Knock down of CHD7 and CHD9 in K562 (human erythromyeloblastoid leukemia) and HEC-1-B (human endometrial adenocarcinoma) cells significantly inhibit cell proliferation and migration (P < 0.05). Proliferation, colony formation and migration assays were performed in CHD7 and CHD9 knockdown K562 and HBC-1-B cell lines. Mechanisms were also analyzed by PPI and GO ontology for our experiments. Histone modification, especially the methylation of H3K4, might be involved in CHD7 and CHD9 related oncogenesis. Through bioinformatic analysis, we showed CHD genes significantly affected the prognosis of different tumor types, including childhood tumor. Our findings provide new insights into the function and mechanism of CHD gene family, especially in CHD7 and CHD9.

The efficacy of immune checkpoint inhibitors on low PD-L1 cervical cancer: A meta-analysis.

Background and Aims: The effectiveness of immune checkpoint inhibitors (ICIs) in low programmed death ligand 1 (PD-L1) expression in cervical cancer (CC) patients remains unknown. We aimed to evaluate the efficacy of ICIs in low PD-L1 expression CC patients. Methods: The study is an individual patient data (IPD)-based meta-analysis. IPD were compiled through KMSubtraction and IPDfromKM methodologies from high-quality randomized clinical trials and single-arm studies which reported overall survival (OS) or progression-free survival (PFS) stratified by PD-L1 expression. Kaplan-Meier curves and Cox regression analysis were employed to evaluate the survival benefits of ICIs. Results: A total of eight studies and 1110 cases were included in the analysis. Within the low PD-L1 expression subgroup, ICI combination therapy, but not ICI monotherapy, demonstrated significant OS benefits over non-ICI treatment (hazard ratio [HR] = 0.61, 95% confidence interval [CI]: 0.36-1.04, p = 0.06). Concerning PFS, ICI monotherapy was associated with a negative effect compared to non-ICI treatment (HR = 4.59, 95% CI: 2.32-9.07, p < 0.001). Notably, both OS and PFS outcomes were unfavorable for ICI monotherapy compared to both non-ICI and ICI combination therapy in the combined positive score <1 subgroup (OS: HR = 2.60, 95% CI: 1.31-5.16, p = 0.008; PFS: HR = 7.59, 95% CI: 3.53-16.31, p < 0.001). Conclusion: In patients with CC and low PD-L1 expression, ICI monotherapy may not be considered as the optimal treatment strategy when compared to non-ICI treatment or ICI combination therapy. Registration: CRD42023395103.

The role of USP7-YY1 interaction in promoting colorectal cancer growth and metastasis.

Colorectal cancer (CRC) remains a significant global health issue with high incidence and mortality. Yin Yang 1 (YY1) is a powerful transcription factor that acts dual roles in gene activation and repression. High expression level of YY1 has been reported in CRC, indicating the existence of stable factors of YY1 in CRC cells. We aimed to identify the key molecules and underlying mechanisms responsible for stabilizing YY1 expression in CRC. Mass spectrometry analysis was utilized to identify USP7 as a potential molecule that interacted with YY1. Mechanically, USP7 stabilizes YY1 expression at the protein level by interfering its K63 linkage ubiquitination. YY1 exerts its oncogenic function through transcriptionally activating TRIAP1 but suppressing LC3B. In addition, at the pathological level, there is a positive correlation between the expression of YY1 and the budding of CRC. This study has revealed the intricate interplay between YY1 and USP7 in CRC, suggesting that they could serve as novel therapeutic targets or predictive biomarkers for CRC patients.

KLF4 transcription factor in tumorigenesis.

Krüppel-like transcriptional factor is important in maintaining cellular functions. Deletion of Krüppel-like transcriptional factor usually causes abnormal embryonic development and even embryonic death. KLF4 is a prominent member of this family, and embryonic deletion of KLF4 leads to alterations in skin permeability and postnatal death. In addition to its important role in embryo development, it also plays a critical role in inflammation and malignancy. It has been investigated that KLF4 has a regulatory role in a variety of cancers, including lung, breast, prostate, colorectal, pancreatic, hepatocellular, ovarian, esophageal, bladder and brain cancer. However, the role of KLF4 in tumorigenesis is complex, which may link to its unique structure with both transcriptional activation and transcriptional repression domains, and to the regulation of its upstream and downstream signaling molecules. In this review, we will summarize the structural and functional aspects of KLF4, with a focus on KLF4 as a clinical biomarker and therapeutic target in different types of tumors.

Evolution trend of soil fertility in tobacco-planting area of Chenzhou, Hunan Province, China.

In this study, the data of fertility indicators of soil samples (0-20 cm) in 1980s, 2000 and 2015 in Chenzhou city were used, and the soil integrated fertility index (IFI) was calculated. The results showed that the soil pH was decreased, total nitrogen (TN), organic matter (OM), available phosphorus (AP) and potassium (AK), exchangeable calcium (Ca2+), magnesium (Mg2+) and available copper (Cu) contents were increased, total phosphorus (TP), available sulfur (S) and water-soluble chlorine (Cl-) contents were decreased, total potassium (TK), available boron (B), iron (Fe), manganese (Mn) and zinc (Zn) were decreased first and then increased. In 2015, most of the fields were higher in pH, OM, TN, AN, AK, Ca2+, Mg2+, S, Fe, Mn, Cu and Zn, suitable in B, but lower in TP, AP, TK, available molybdenum (Mo) and Cl-. Most of the fields were in the middle grade of IFI in 2000 and 2015, and the mean IFI increased from 0.492 to 0.556 from 2000 to 2015. Thus, for soil improvement, more attention should be paid to adjust soil pH, reduce the application of organic, nitrogen and calcium fertilizers, while increase the fertilizer application of other nutrients.

Metformin inhibits cervical cancer cell proliferation by modulating PI3K/Akt-induced major histocompatibility complex class I-related chain A gene expression.

BACKGROUND: Recent studies have shown that the classic hypoglycemic drug metformin inhibits tumor growth; however, the underlying mechanism remains unclear. We previously showed that metformin disrupts the sponge effect of long non-coding RNA MALAT1/miR-142-3p to inhibit cervical cancer cell proliferation. In this study, we interrogated the ability of metformin to modulate the anti-tumor immune response in cervical cancer. METHODS: The cell counting kit-8 assay was used to detect the viability of cervical cancer cells. Flow cytometry assays were performed to measure cell apoptosis and cell cycle. Lactate dehydrogenase (LDH) cytotoxicity assay was used to detect NK Cell Cytotoxicity. Relative protein levels were determined by immunoblotting and relative gene levels were determined by quantitative real-time PCR. Tumor Xenograft Modeling was used to evaluate the effect of metformin in vivo. RESULTS: Metformin inhibited cervical cancer cell proliferation, cervical cancer xenograft growth, expression of PCNA, p-PI3K and p-Akt. Moreover metformin induced cervical cancer cell apoptosis and caused cancer cell cycle arrest. In addition, metformin upregulated the expression of DDR-1 and p53 in human cervical cancer cells. Furthermore, metformin also regulated the mRNA and protein expression of MICA and HSP70 on the surface of human cervical cancer cells via the PI3K/Akt pathway, enhancing NK cell cytotoxicity. CONCLUSIONS: In conclusion, our results suggest that metformin may be used as immunopotentiator to inhibit cervical cancer progression and may be considered a viable candidate for combination therapy with immunotherapy.

Quantitative proteomics analysis of differentially expressed proteins induced by astragaloside IV in cervical cancer cell invasion.

BACKGROUND: Cervical cancer remains the second leading cause of mortality in women in developing countries. While surgery, chemotherapy, radiotherapy, and vaccine therapy are being applied for its treatment, individually or in combination, the survival rate in advanced cervical cancer patients is still very low. Traditional Chinese medicine has been found to be effective in the treatment of cervical cancer. Astragaloside IV (AS-IV), a compound belonging to Astragalus polysaccharides, shows anticancer activity through several cell signaling pathways. However, the detailed molecular mechanism governing the anticancer activity of AS-IV remains unknown. MATERIAL AND METHODS: In our study, we performed tumor xenograft analysis, transwell cell migration and invasion assay, Western blot analysis, and iTRAQ combination by parallel reaction monitoring (PRM) analysis to study the molecular mechanism of AS-IV in the suppression of cervical cancer cell invasion. RESULTS: Our results showed that AS-IV suppressed cervical cancer cell invasion and induced autophagy in them, with the tumor growth curve increasing slowly. We also identified 32 proteins that were differentially expressed in the SiHa cells when treated with AS-IV, with 16 of them involved in the upregulation and 16 in the downregulation of these cells. These differentially expressed proteins, which were predominantly actin-myosin complexes, controlled cell proliferation and cell development by steroid binding and altering the composition of the cell cytoskeleton. DCP1A and TMSB4X, the two proteins regulating autophagy, increased in cervical cancer cells when treated with AS-IV. CONCLUSIONS: We conclude that AS-IV could inhibit cervical cancer invasion by inducing autophagy in cervical cancer cells. Since iTRAQ combination by PRM has been observed to be useful in identifying macromolecular target compounds, it may be considered as a novel strategy in the screening of anticancer compounds used in the treatment of cervical cancer.

Vorinostat upregulates MICA via the PI3K/Akt pathway to enhance the ability of natural killer cells to kill tumor cells.

Vorinostat has good therapeutic efficacy against primary cutaneous T-cell lymphoma in the refractory stage. However, the molecular mechanism by which it inhibits solid tumors has not been clarified. To investigate the tumor inhibitory mechanism of vorinostat in cervical cancer, this study used Cell Counting Kit-8, flow cytometry, cell invasion and migration assays and the wound healing assay to evaluate the effects of vorinostat on cervical cancer cell proliferation, apoptosis, cell cycle, migration, and invasion. Real-time quantitative PCR and immunoblotting were used to detect gene and protein expression, respectively, of major histocompatibility class I-related chain A, phosphoinositide 3-kinase, phosphorylated PI3K p55 (Tyr199), and p-Akt (Ser473). The lactate dehydrogenase cytotoxicity assay was used to evaluate the ability of natural killer-92 cells to lyse cervical cancer cells. A xenograft nude mouse model was established to analyze the anti-tumor effect of vorinostat in vivo. Our results showed that vorinostat inhibited the proliferation, migration, and invasion of cervical cancer cells. Vorinostat also induced apoptosis and cell-cycle arrest in the S phase, inhibited PI3K (p110α), p-PI3K p55 (Tyr199), and p-Akt (Ser473) protein expression and upregulated MICA expression in vitro and in vivo, and promoted NK-92 cell-mediated cervical cancer cell lysis. The ability of vorinostat to upregulate MICA expression in cervical cancer cells was related to PI3K/Akt signaling. In brief, vorinostat upregulated MICA through the PI3K/Akt pathway and enhanced the sensitivity of cervical cancer cells to the NK cell-mediated cytolytic reaction. The results of this study demonstrate that vorinostat has anti-solid tumor effects on cervical cancer.

iTRAQ-based quantitative proteomic analysis of the inhibition of cervical cancer cell invasion and migration by metformin.

In recent years the anti-diabetic drug metformin has been shown to inhibit tumor growth, but the underlying mechanism is unclear. Our previous results showed that metformin can destroy the sponge effect of long-chain non-coding RNA MALAT1/miR-142-3p and inhibit the proliferation of cervical cancer cells. Metformin can inhibit the PI3K/Akt signaling pathway and synergizes with Nelfinavir to inhibit the proliferation and invasion of cervical cancer cells. In this study, we used iTRAQ-based proteomics, mass spectrometry-based targeted proteomics, immunoblotting, and bioinformatics to analyze the molecular mechanism by which metformin inhibits the proliferation and invasion of cervical cancer cells. We found that 53 proteins were differentially expressed in cervical cancer cells after metformin treatment, of which 20 were up-regulated and 33 were down-regulated. Bioinformatics analysis showed that the 53 differentially expressed proteins are negative regulators of receptor signaling that inhibit cell growth and are mainly enriched in cell growth and apoptosis signaling pathways. We performed PRM verification on 11 of the differentially expressed proteins and found that they were all associated with apoptosis. We also found that metformin up-regulated the expression of the tumor suppressor IGFBP7 to inhibit the proliferation and invasion of cervical cancer cells. Our results indicate that metformin mainly regulates the insulin signaling pathway and interferes with cell proliferation and apoptosis to inhibit proliferation and invasion of cervical cancer cells. These differentially expressed proteins may become new targets for the treatment of cervical cancer.

Evaluation and prognostic value of Cv-aCO2/Da-vO2 in patients with septic shock receiving fluid resuscitation Cv-aCO2/Ca-vO2.

The present study aimed to evaluate the prognostic value of venous-arterial CO2 to arterial-venous O2 (Cv-aCO2/Da-vO2) for patients with septic shock treated by fluid resuscitation. A total of 108 cases who received fluid resuscitation for septic shock at the Intensive Care Unit were retrospectively screened according to the 2012 surviving sepsis campaign guidelines. Patients were divided into 2 groups according to the Cv-aCO2/Da-vO2 ratio at 6 h after fluid resuscitation: Group A, Cv-aCO2/Da-vO2 >1; group B, Cv-aCO2/Da-vO2 ≤1. The resuscitation target rate and transfused resuscitation volume at 6 h exhibited no significant difference between the 2 groups. The cardiac output at 6 and 24 h, as well as the ratio of patients who reached the target of resuscitation within 24 h, the 24-h lactic acid clearance rate and the number of cases with central venous oxygen saturation >70% were significantly decreased in group A compared with those in group B (all P<0.05). The Sequential Organ Failure Assessment score at day 3 in group A was higher compared with that in group B (7.94±1.6 vs. 6.82±1.9; P=0.0013). The mortality rate at day 7 and 35 was higher in group A compared with that in group B (29/52 vs. 6/56, P<0.001; 48/52 vs. 36/56; P<0.001). In conclusion, the Cv-aCO2/Da-vO2 was able to effectively evaluate the success rate of resuscitation and, regarding prognosis, it was able to identify patients at high risk of adverse outcomes.

Efficacy and safety of leflunomide in IgA nephropathy: a systematic review and meta-analysis.

BACKGROUND: The optimal therapy for immunoglobulin A nephropathy (IgAN) remains uncertain. Leflunomide (LEF) is an immunosuppressive drug which may reduce deposition of glomerular autoantibodies and immune complexes. Several clinical trials were designed to evaluate the efficacy of LEF, but their results were controversial. METHODS: Ovid Medline, Embase, the Cochrane Library, PubMed, and CNKI were systematically searched. Search terms included ("glomerulonephritis" OR "nephritis") AND ("immunoglobulin A" OR "IgA") AND "leflunomide". Studies in which patients were diagnosed with IgAN based on renal biopsy were included. Studies needed to report clinical outcomes via either short- or long-term clinical examination, remission rate, or complication rate. RESULTS: Forty-four studies encompassing 1802 patients were included, of which 35 were randomized controlled trials. Results of 24 h post-treatment urine protein tests and serum creatinine tests were significantly lower in patients treat with LEF and corticosteroids (CS) or valsartan (ACEI) (CS + LEF or CS + ACEI) compared with patients treated with CS or ACEI alone (P < 0.05). More patients treated with CS + LEF (31.2%) achieved complete remission (CR) than patients treated with CS alone (22.2%) (RR = 0.71, 95% CI 0.59-0.85, P < 0.05). Although there was no significant difference in CR between patients treated with cyclophosphamide and CS (CS + CTX) and those treated with CS + LEF, the complication rate in the former group was higher (28.4%) than in the latter one (11.4%) (RR = 2.46, 95% CI 1.47-4.13, P < 0.005). CONCLUSION: LEF appears to improve renal function while decreasing loss of urine protein. Combination regimens including LEF were better and safer compared with CS or ACEI alone or combinations including CTX.

Long noncoding RNA GIHCG functions as an oncogene and serves as a serum diagnostic biomarker for cervical cancer.

Cervical cancer is the most common and lethal gynaecological tumor. Long noncoding RNAs (lncRNAs) have critical roles in various cancers, including cervical cancer. However, few studies investigated the diagnostic value of lncRNAs for cervical cancer. In this study, we investigated the expression pattern of a recently identified lncRNA GIHCG in cervical cancer tissues, cell lines, and serums by qRT-PCR. Furthermore, we explored the roles of GIHCG in cervical cancer using gain-of-function and loss-of-function assays. Our results revealed that GIHCG is up-regulated in cervical cancer tissues and cell lines compared with adjacent normal tissues and normal cervical epithelial cell line, respectively. Furthermore, serum GIHCG is significantly up-regulated in cervical cancer patients compared with healthy controls. ROC curve analysis revealed that serum GIHCG could accurately discriminate cervical cancer patients from healthy controls. Functionally, we found that overexpression of GIHCG promotes cell proliferation, inhibits cell apoptosis, and promotes cell migration of cervical cancer cells. Conversely, depletion of GIHCG inhibits cell proliferation, induces cell apoptosis, and inhibits cell migration of cervical cancer cells. Mechanistically, we found that GIHCG represses the expression of miR-200b. The expression of miR-200b is inversely correlated with the expression of GIHCG in cervical cancer tissues. Moreover, overexpression of miR-200b attenuates the roles of GIHCG in promoting cervical cancer tumor growth in vivo. In summary, this study demonstrated that GIHCG functions as an oncogene in cervical cancer via repressing miR-200b. This study also suggested that GIHCG may be a non-invasive diagnostic biomarker and a potential therapeutic target for cervical cancer.

Metformin combined with nelfinavir induces SIRT3/mROS-dependent autophagy in human cervical cancer cells and xenograft in nude mice.

The molecular mechanisms underlying the antineoplastic properties of metformin combined with nelfinavir remain elusive. To explore this question, transmission electron microscopy (TEM) was used to observe the combinatorial effect of inducing autophagosome formation in human cervical cancer cells. Western blotting respectively assayed protein expression of LC3I, LC3II, Beclin-1, Autophagy-related protein 7 (Atg7), Autophagy-related protein 3 (Atg3), NAD-dependent deacetylase sirtuin-3 (SIRT3) and major histocompatibility complex class I chain-related gene A (MICA). Lactate dehydrogenase (LDH) cytotoxicity assay evaluated natural killer (NK) cell cytotoxicity in the presence of metformin and nelfinavir in combination or each drug alone. Using tumor xenografts in a nude mouse model, antitumor efficacy of the drug combination was assessed. We found that the drug combination could induce autophagosome formation in human cervical cancer cells. The biomarker proteins of autophagy, including Beclin-1, Atg7 and Atg3, decreased, but the ratios of LC3I/II increased. We also found that this drug combination sensitizes human cervical cancer cells to NK cell-mediated lysis by increasing the protein of SIRT3 and MICA. Moreover, this drug combination markedly induced autophagy of SiHa xenografts in nude mice. Therefore, it can be concluded that metformin, in combination with nelfinavir, can induce SIRT3/mROS-dependent autophagy and sensitize NK cell-mediated lysis in human cervical cancer cells and cervical cancer cell xenografts in nude mice. Thus, our findings have revealed the detailed molecular mechanisms underlying the antitumor effects of metformin in combination with nelfinavir in cervical cancer.

Laparoscopic Nerve-Sparing Radical Hysterectomy vs Laparoscopic Radical Hysterectomy in Cervical Cancer: A Systematic Review and Meta-Analysis of Clinical Efficacy and Bladder Dysfunction.

It is widely accepted that nerve-sparing radical hysterectomy is associated with less postoperative morbidity compared with radical hysterectomy, whereas clinical safety is similar in the 2 procedures. However, there is insufficient evidence to compare these procedures performed via a laparoscopic approach. We performed a systematic review and meta-analysis of studies to compare the clinical efficacy and the rate of bladder dysfunction, including urodynamic assessment, in laparoscopic nerve-sparing radical hysterectomy (LNSRH) and laparoscopic radical hysterectomy (LRH). Thirty articles including a total of 2743 participants were analyzed. Operating times were shorter (MD, 29.88 minutes; 95% confidence interval [CI], 11.92-47.83 minutes) and hospital stays were longer (MD, -1.56 days; 95% CI, -2.27 to -0.84 days) in the LRH group compared with the LNSRH group. In addition, blood loss and the number of resected lymph nodes were not significantly different between the 2 groups. However, resected parametrium length (MD, -0.02 cm; 95% CI, -0.05 to -0.00 cm) and vaginal cuff width (MD, -0.06 cm; 95% CI, -0.09 to -0.04) were smaller in the LNSRH group. Furthermore, LNSRH tended to result in more satisfactory micturition (odds ratio, 2.90; 95% CI, 2.01-4.19), shorter catheterization time (MD, -7.20 days; 95% CI, -8.10 to -6.29 days), and shorter recovery to normal postvoid residual urine time (MD, -7.71 days; 95% CI, -8.92 to -6.50 days). Other bladder dysfunction symptoms, including urinary retention, nocturia, dysuria, urinary incontinence, and frequency/urgency were more frequent in the LRH group. Furthermore, LNSRH achieved better results in urodynamic assessments (all p < .05). In conclusion, LNSRH was associated with lower rates of impaired bladder function and a shorter extent of resection compared with LRH. Clinical applications involving LNSRH should be explored with caution.

Metformin, a first-line drug for type 2 diabetes mellitus, disrupts the MALAT1/miR-142-3p sponge to decrease invasion and migration in cervical cancer cells.

The molecular mechanisms underlying the anti-neoplastic properties of metformin, a first-line drug for type 2 diabetes, remain elusive. To explore the novel anti-neoplastic mechanisms of metformin, the transwell chamber and wound-healing assays were used to evaluate its effects on the migration and invasion of human cervical cancer cells. Real-time PCR and Western blotting were used to measure the gene and protein expression, respectively, of microRNA (miRNA) miR-142-3p, long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript-1 (MALAT1), and high-mobility group AT-hook 2 (HMGA2). The dual-luciferase reporter assay system was used to examine the direct interaction between miR-142-3p and lncRNA MALAT1 and HMGA2. Immunofluorescence was used to detect the protein expression of HMGA2. In addition, tumor xenografts in a nude mouse model were developed to evaluate the anti-tumor efficacy of metformin. We found that metformin could suppress cervical cancer migration and invasion. During the process of tumor metastasis, miR-142-3p was significantly upregulated, whereas lncRNA MATAL1 and HMGA2 were suppressed by metformin. The binding site that allow the direct interaction between miR-142-3p and MALAT1 were located in the 3' untranslated region (3' UTR) of lncRNA MATAL1 and HMGA2 at base pairs (bp) 4452-5255, while that between miR-142-3p and HMGA2 was located at bp 1562-2521 of HMGA2. Metformin markedly inhibited the growth and angiogenesis of SiHa xenografts in nude mice. In conclusion, this study provides evidence that metformin can prevent the MALAT1/miR-142-3p sponge from developing anti-neoplastic properties in human cervical cancer cells and cervical cancer cell xenografts in nude mice. Thus, our findings demonstrate the novel anti-tumor effects of metformin in cervical cancer.

Biphasic vesicles for topical delivery of interferon alpha in human volunteers and treatment of patients with human papillomavirus infections.

PURPOSE. Topical biphasic vesicle delivery system encapsulating interferon alpha (IFN α) was developed as an alternative to injections used to treat human papillomavirus (HPV) infections. METHODS. Biphasic lipid vesicles encapsulating increasing doses of IFN α (biphasic IFN α) were characterized for encapsulation efficiency, size, zeta potential and vesicle structure by centrifugation, dynamic light scattering, confocal microscopy and small-angle x-ray scattering. Biphasic IFN-α delivery into human skin in vivo and topical efficacy in patients with genital warts were evaluated. RESULTS. Average encapsulation efficiency of IFN α was 81-91%. The average particle size was 1000-1100 nm and zeta potential +70 to +78 mV. After application of 5, 15 and 40MU/g biphasic IFN α formulation in a topical patch on the upper inner arm in healthy volunteers, skin IFN α levels increased to 120±30, 380±60 and 400±80 IU/mg protein in skin homogenates (n=5, 5, and 7), respectively. Topical application of biphasic IFN α (1 MU/dose) twice daily for two weeks in a pilot study with 12 patients with external condylomata acuminata resulted in a decrease in lesion size, in 2',5'-oligoadenylate synthetase activity and in tissue viral load. CONCLUSIONS. Biphasic vesicles delivered clinically significant levels of IFN α across intact human skin and elicited marked therapeutic effect in patients.