Synthetic RNA Therapeutics in Cancer.

Recent advances in the RNA delivery system have facilitated the development of a separate field of RNA therapeutics, with modalities including mRNA, microRNA (miRNA), antisense oligonucleotide (ASO), small interfering RNA, and circular (circRNA) that have been incorporated into oncology research. The main advantages of the RNA-based modalities are high flexibility in designing RNA and rapid production for clinical screening. It is challenging to eliminate tumors by tackling a single target in cancer. In the era of precision medicine, RNA-based therapeutic approaches potentially constitute suitable platforms for targeting heterogeneous tumors that possess multiple sub-clonal cancer cell populations. In this review, we discussed how synthetic coding and non-coding RNAs, such as mRNA, miRNA, ASO, and circRNA, can be applied in the development of therapeutics. SIGNIFICANCE STATEMENT: With development of vaccines against coronavirus, RNA-based therapeutics have received attention. Here, the authors discuss different types of RNA-based therapeutics potentially effective against tumor that are highly heterogeneous giving rise to resistance and relapses to the conventional therapeutics. Moreover, this study summarized recent findings suggesting combination approaches of RNA therapeutics and cancer immunotherapy.

DEP-induced ZEB2 promotes nasal polyp formation via epithelial-to-mesenchymal transition.

BACKGROUND: Diesel exhaust particles (DEPs) are associated with the prevalence and exacerbation of allergic respiratory diseases, including allergic rhinitis and allergic asthma. However, DEP-induced mechanistic pathways promoting upper airway disease and their clinical implications remain unclear. OBJECTIVE: We sought to investigate the mechanisms by which DEP exposure contributes to nasal polyposis using human-derived epithelial cells and a murine nasal polyp (NP) model. METHODS: Gene set enrichment and weighted gene coexpression network analyses were performed. Cytotoxicity, epithelial-to-mesenchymal transition (EMT) markers, and nasal polyposis were assessed. Effects of DEP exposure on EMT were determined using epithelial cells from normal people or patients with chronic rhinosinusitis with or without NPs. BALB/c mice were exposed to DEP through either a nose-only exposure system or nasal instillation, with or without house dust mite, followed by zinc finger E-box-binding homeobox (ZEB)2 small hairpin RNA delivery. RESULTS: Bioinformatics analyses revealed that DEP exposure triggered EMT features in airway epithelial cells. Similarly, DEP-exposed human nasal epithelial cells exhibited EMT characteristics, which were dependent on ZEB2 expression. Human nasal epithelial cells derived from patients with chronic rhinosinusitis presented more prominent EMT features after DEP treatment, when compared with those from control subjects and patients with NPs. Coexposure to DEP and house dust mite synergistically increased the number of NPs, epithelial disruptions, and ZEB2 expression. Most importantly, ZEB2 inhibition prevented DEP-induced EMT, thereby alleviating NP formation in mice. CONCLUSIONS: Our data show that DEP facilitated NP formation, possibly via the promotion of ZEB2-induced EMT. ZEB2 may be a therapeutic target for DEP-induced epithelial damage and related airway diseases, including NPs.

Noninvasive Neurally Adjusted Ventilation in Postextubation Stabilization of Preterm Infants: A Randomized Controlled Study.

OBJECTIVE: To compare the effects of noninvasive neurally adjusted ventilatory assist (NIV-NAVA) to nasal continuous positive airway pressure (NCPAP) in achieving successful extubation in preterm infants. STUDY DESIGN: This prospective, single-center, randomized controlled trial enrolled preterm infants born at <30 weeks of gestation who received invasive ventilation. Participants were assigned at random to either NIV-NAVA or NCPAP after their first extubation from invasive ventilation. The primary outcome of the study was extubation failure within 72 hours of extubation. Electrical activity of the diaphragm (Edi) values were collected before extubation and at 1, 4, 12, and 24 hours after extubation. RESULTS: A total of 78 infants were enrolled, including 35 infants in the NIV-NAVA group and 35 infants in the NCPAP group. Extubation failure within 72 hours of extubation was higher in the NCPAP group than in the NIV-NAVA group (28.6% vs 8.6%; P = .031). The duration of respiratory support and incidence of severe bronchopulmonary dysplasia were similar in the 2 groups. Peak and swing Edi values were comparable before and at 1 hour after extubation, but values at 4, 12, and 24 hours after extubation were lower in the NIV-NAVA group compared with the NCPAP group. CONCLUSIONS: In the present trial, NIV-NAVA was more effective than NCPAP in preventing extubation failure in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02590757.

Extrauterine growth restriction in extremely preterm infants based on the Intergrowth-21st Project Preterm Postnatal Follow-up Study growth charts and the Fenton growth charts.

Growth charts are essential for monitoring the postnatal growth of preterm infants. The preterm postnatal follow-up study (PPFS) of the Intergrowth-21st Project provides new growth standards based on a longitudinal study. This study was conducted to investigate the prevalence of extrautrine growth restriction (EUGR) and the associated factors of EUGR in preterm infants, using the PPFS charts and the Fenton charts. Data of 1,356 infants with gestational age (GA) less than 28 weeks from the Korean Neonatal Network were analysed. The prevalence of small for gestational age (SGA) of weight and length was higher with the Intergrowth charts than with the Fenton charts. EUGR in weight and length was more prevalent when using the Fenton charts. Multivariate analysis showed that low GA, high birthweight z score, male, treated patent ductus arteriosus (PDA), necrotizing enterocolitis, intraventricular haemorrhage and duration of parenteral nutrition (PN) were associated with EUGR in weight by the Intergrowth charts. High birthweight z score, treated PDA and PN duration were associated with EUGR defined by the Fenton charts.Conclusion: Compared to the Fenton charts, SGA was more defined and EUGR was less prevalent in extremely low gestational infants, while EUGR defined by the Intergrowth charts categorized infants with adverse clinical courses more elaborately. What is Known: • Preterm infants are at risk of postnatal growth restriction (PGR), although optimal postnatal growth is important for the long-term outcomes. • Growth charts are essential tools to monitor the postnatal growth of preterm infants. What is New: • PGR of weight and length were less defined with the Intergrowth charts than the Fenton charts. • PGR defined by the Intergrowth preterm postnatal follow-up study (PPFS) chart categorized preterm infants with morbidities more elaborately than the Fenton charts.

High-performance and -stability graphene quantum dots-mixed conducting polymer/porous Si hybrid solar cells with titanium oxide passivation layer.

Recently, conducting polymer/Si hybrid solar cells (HSCs) based on simple fabrication processes have become highly attractive due to their low cost, but low conductivity of the polymer, high reflection index of Si, and large recombination loss on the Si back contact are major drawbacks that should be solved for the practical applications. Here, we first report HSCs composed of graphene quantum dots (GQDs)-mixed poly (3,4-ethylenedioxythiophene) (PEDOT:GQDs)/ porous Si (PSi)/n-Si/titanium oxide (TiO x , back passivation layer). Maximum power conversion efficiency (PCE) of 10.49% is obtained from the HSCs at an active area of 5 mm2, resulting from the enhanced conductivity of the PEDOT:GQDs, the reduced reflectivity of Si (the increased absorption) by the formation of PSi, and the prevented recombination loss at the Si backside due to the passivation. In addition, the HSCs of 16 mm2 active area maintain ∼78% (absolutely from 8.03% to 6.28%) of the initial PCE even while kept under ambient conditions for 15 d.

Differential roles of Sirt1 in HIF-1α and HIF-2α mediated hypoxic responses.

Hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) determine cancer cell fate under hypoxia. Despite the similarities of their structures, HIF-1α and HIF-2α have distinct roles in cancer growth under hypoxia, that is, HIF-1α induces growth arrest whereas HIF-2α promotes cell growth. Recently, sirtuin 1 (Sirt1) was reported to fine-tune cellular responses to hypoxia by deacetylating HIF-1α and HIF-2α. Yet, the roles of Sirt1 in HIF-1α and HIF-2α functions have been controversial. We here investigated the precise roles of Sirt1 in HIF-1α and HIF-2α regulations. Immunological analyses revealed that HIF-1α K674 and HIF-2α K741 are acetylated by PCAF and CBP, respectively, but are deacetylated commonly by Sirt1. In the Gal4 reporter systems, Sirt1 was found to repress HIF-1α activity constantly in ten cancer cell-lines but to regulate HIF-2α activity cell type-dependently. Moreover, Sirt1 determined cell growth under hypoxia depending on HIF-1α and HIF-2α. Under hypoxia, Sirt1 promoted cell proliferation of HepG2, in which Sirt1 differentially regulates HIF-1α and HIF-2α. In contrast, such an effect of Sirt1 was not shown in HCT116, in which Sirt1 inactivates both HIF-1α and HIF-2α because conflicting actions of HIF-1α and HIF-2α on cell growth may be offset. Our results provide a better understanding of the roles of Sirt1 in HIF-mediated hypoxic responses and also a basic concept for developing anticancer strategy targeting Sirt1.

The development of anin vitrohuman hair follicle organoid with a complexity similar to thatin vivo.

In vitrohair follicle (HF) models are currently limited toex vivoHF organ cultures (HFOCs) or 2D models that are of low availability and do not reproduce the architecture or behavior of the hair, leading to poor screening systems. To resolve this issue, we developed a technology for the construction of a humanin vitrohair construct based on the assemblage of different types of cells present in the hair organ. First, we demonstrated that epithelial cells, when isolatedin vitro, have similar genetic signatures regardless of their dissection site, and their trichogenic potential is dependent on the culture conditions. Then, using cell aggregation techniques, 3D spheres of dermal papilla (DP) were constructed, and subsequently, epithelial cells were added, enabling the production and organization of keratins in hair, similar to what is seenin vivo. These reconstructed tissues resulted in the following hair compartments: K71 (inner root-sheath), K85 (matrix region), K75 (companion layer), and vimentin (DP). Furthermore, the new hair model was able to elongate similarly toex vivoHFOC, resulting in a shaft-like shape several hundred micrometers in length. As expected, when the model was exposed to hair growth enhancers, such as ginseng extract, or inhibitors, such as TGF-B-1, significant effects similar to thosein vivowere observed. Moreover, when transplanted into skin biopsies, the new constructs showed signs of integration and hair bud generation. Owing to its simplicity and scalability, this model fully enables high throughput screening of molecules, which allows understanding of the mechanism by which new actives treat hair loss, finding optimal concentrations, and determining the synergy and antagonism among different raw materials. Therefore, this model could be a starting point for applying regenerative medicine approaches to treat hair loss.

Ginsenoside Re prevents 3-methyladenine-induced catagen phase acceleration by regulating Wnt/ß-catenin signaling in human dermal papilla cells.

Background: The human hair follicle undergoes cyclic phases-anagen, catagen, and telogen-throughout its lifetime. This cyclic transition has been studied as a target for treating hair loss. Recently, correlation between the inhibition of autophagy and acceleration of the catagen phase in human hair follicles was investigated. However, the role of autophagy in human dermal papilla cells (hDPCs), which is involved in the development and growth of hair follicles, is not known. We hypothesized that acceleration of hair catagen phase upon inhibition of autophagy is due to the downregulation of Wnt/ß-catenin signaling in hDPCs, and that components of Panax ginseng extract can increase the autophagic flux in hDPCs. Methods: We generated an autophagy-inhibited condition using 3-methyladenine (3-MA), a specific autophagy inhibitor, and investigated the regulation of Wnt/ß-catenin signaling using the luciferase reporter assay, qRT-PCR, and western blot analysis. In addition, cells were cotreated with ginsenoside Re and 3-MA and their roles in inhibiting autophagosome formation were investigated. Results: We found that the unstimulated anagen phase dermal papilla region expressed the autophagy marker, LC3. Transcription of Wnt-related genes and nuclear translocation of ß-catenin were reduced after treatment of hDPCs with 3-MA. In addition, treatment with the combination of ginsenoside Re and 3-MA changed the Wnt activity and hair cycle by restoring autophagy. Conclusions: Our results suggest that autophagy inhibition in hDPCs accelerates the catagen phase by downregulating Wnt/ß-catenin signaling. Furthermore, ginsenoside Re, which increased autophagy in hDPCs, could be useful for reducing hair loss caused by abnormal inhibition of autophagy.

Protein stabilization of ITF2 by NF-κB prevents colitis-associated cancer development.

Chronic colonic inflammation is a feature of cancer and is strongly associated with tumorigenesis, but its underlying molecular mechanisms remain poorly understood. Inflammatory conditions increased ITF2 and p65 expression both ex vivo and in vivo, and ITF2 and p65 showed positive correlations. p65 overexpression stabilized ITF2 protein levels by interfering with the binding of Parkin to ITF2. More specifically, the C-terminus of p65 binds to the N-terminus of ITF2 and inhibits ubiquitination, thereby promoting ITF2 stabilization. Parkin acts as a E3 ubiquitin ligase for ITF2 ubiquitination. Intestinal epithelial-specific deletion of ITF2 facilitated nuclear translocation of p65 and thus increased colitis-associated cancer tumorigenesis, which was mediated by Azoxymethane/Dextran sulfate sodium or dextran sulfate sodium. Upregulated ITF2 expression was lost in carcinoma tissues of colitis-associated cancer patients, whereas p65 expression much more increased in both dysplastic and carcinoma regions. Therefore, these findings indicate a critical role for ITF2 in the repression of colitis-associated cancer progression and ITF2 would be an attractive target against inflammatory diseases including colitis-associated cancer.

Extracellular histones inhibit hair shaft elongation in cultured human hair follicles and promote regression of hair follicles in mice.

Release of histone H4 in rat vibrissa dermal papilla (DP) cells exposed to sub-toxic dose of colchicines has been recently reported. In addition, exposure to histone H4 has been reported to result in inhibited proliferation and reduced alkaline phosphatase (ALP) activity of cultured vibrissa DP cells. These findings prompted us to investigate the role of extracellular histones in hair growth using cultured human hair follicles and hair cycling using back skin of mice. We report here that exposure of cultured hair follicles to histone H4 and H2A resulted in significant inhibition of elongation of hair shafts, decreased expression of IGF-1 and decreased expression and activity of ALP. Injection of histones into hypodermis of mice during anagen resulted in premature onset of catagen. Findings of the current study provide strong evidence suggesting the inhibitory role of extracellular histones in hair growth.

Conditioned media obtained from human outer root sheath follicular keratinocyte culture activates signalling pathways that contribute to maintenance of hair-inducing capacity and increases trichogenicity of cultured dermal cells.

Findings from recent studies have demonstrated that hair-inducing capacity (trichogenicity) of cultured dermal cells can be maintained by addition of conditioned media obtained from culture of epidermal keratinocytes. In this study, we investigated the question of whether treatment with human follicular keratinocyte-conditioned media (FKCM) can result in activation of signalling pathways that contribute to trichogenicity and increase the trichogenicity of cultured dermal cells. Through conduct of hair reconstitution assays, we observed that treatment of cells with FKCM resulted in induction of a greater number of hair follicles, compared with control cells. Treatment of dermal cells with FKCM resulted in the activation of BMP and ß-catenin signalling pathways. In addition, higher levels of IGFBP-7, IL-8, OPG and uPA were observed in FKCM. Altogether, our data suggest that a patient's own FKCM would be ideal for expansion of the patient's own follicular dermal cells for cell therapy for treatment of hair loss.

Factors associated with the follow-up of high risk infants discharged from a neonatal intensive care unit.

BACKGROUND: The study aimed to identify factors associated with compliance to follow-up (FU) appointments among infants following their discharge from the neonatal intensive care unit (NICU). METHODS: This retrospective cohort study reviewed 657 infants (birth weight <1500 g or gestational age [GA] <32 weeks), born between 2011 and 2015. A total of 525 eligible infants were classified into two groups: the compliant group (n = 360), who attended clinics from 18 to 24 months, and the non-compliant group (n = 165), who were lost to FU before 18 months. RESULTS: The non-compliant group was more likely to have higher usage rate of assisted reproductive technology (p = 0.023), GA (p < 0.001), weight (p < 0.001), height (p < 0.001), and head circumference (p < 0.001) at birth. The sibling number was higher in the non-compliant group (p = 0.011). Moreover, the non-compliant group demonstrated higher Apgar scores at 1 min and 5 min (p = 0.002 and p = 0.031, respectively). The compliant group was more likely to live in metropolitan or larger cities with a borderline significance (p = 0.056). Furthermore, the non-compliant group was less likely to suffer from respiratory distress syndrome (p < 0.001), patent ductus arteriosus (p = 0.002), retinopathy of prematurity (p = 0.007), necrotizing enterocolitis (p = 0.019), and bronchopulmonary dysplasia (p < 0.001). Moreover, it demonstrated lower postmenstrual age at discharge (p = 0.005) and a shorter length of stay in the NICU (p < 0.001). The compliance with FU appointment varied with the assigned doctor (p < 0.001). The multivariate regression analysis mentioned that the birth weight (OR = 0.903), residence in metropolitan or larger cities (OR = 1.495), and an experience of magnetic resonance imaging (OR = 1.920) were associated with compliance. The compliance to FU appointments was different according to the assigned doctor at admission (OR = 0.357). CONCLUSION: The birth weight, residence in metropolitan or larger cities, an experience of MRI, and the assigned doctors were associated with compliance to FU at a corrected age of 18-24 months.

Induction of hair growth in hair follicle cells and organ cultures upon treatment with 30 kHz frequency inaudible sound via cell proliferation and antiapoptotic effects.

Androgenic alopecia is a hair loss disease mediated by dihydrotestosterone (DHT) and is currently treated using minoxidil, finasteride, or low-level laser therapy. However, these treatments have side-effects, indicating the need for an alternative treatment. In the present study, it was demonstrated that inaudible sound at 30 kHz significantly induced proliferative and anti-apoptotic effects in human dermal papilla cells (hDPCs) and outer root sheath keratinocytes. Cell viability assay, ELISA, reverse transcription quantitative PCR and TUNEL assays were performed to evaluate the effect of inaudible sound. Inaudible sound was also demonstrated to significantly inhibit the hair loss signals induced by DHT treatment in hDPCs. Furthermore, inaudible sound significantly induced hair follicle (HF) elongation and hair matrix keratinocyte proliferation in human HF organ culture. Overall, the results suggested that inaudible sound may be effective in treating hair loss and could be used to develop a new hair loss treatment approach.

A novel glucagon analog with an extended half-life, HM15136, normalizes glucose levels in rodent models of congenital hyperinsulinism.

Congenital hyperinsulinism (CHI) is a rare genetic condition characterized by uncontrolled insulin secretion, resulting in hypoglycemia. Although glucagon has lately been regarded as a therapeutic option for CHI, its use is severely hampered by its poor solubility and stability at physiological pH, as well as its short duration of action. To address these constraints, we developed HM15136, a novel long-acting glucagon analog composed of a glucagon analog conjugated to the Fc fragment of human immunoglobulin G4 via a polyethylene glycol linker. In this study, we established that HM15136 was more soluble than natural glucagon (≥ 150 mg/mL vs 0.03 mg/mL). Next, we confirmed that HM15136 activated glucagon receptor in vitro and induced glycogenolysis and gluconeogenesis in rat primary hepatocytes. Pharmacokinetics (PK)/Pharmacodynamics (PD) analysis of HM15136 shows that HM15136 has a markedly longer half-life (36 h vs. < 5 min) and increased bioavailability (90%) compared to native glucagon in mice. Further, HM15136 could effectively reverse acute hypoglycemia induced by insulin challenge, and multiple doses of HM15136 could sustain increased blood glucose levels in CHI rats. In conclusion, our findings indicate that HM15136 promotes sustained elevation of blood glucose, demonstrating the potential for development as a once-weekly therapy for CHI.

Antenatal magnesium sulfate and intestinal morbidities in preterm infants with extremely low gestational age.

BACKGROUND: Antenatal magnesium sulfate is widely used as a tocolytic, for maternal seizures, and for seizure prophylaxis in preeclampsia. Recent studies have suggested that antenatal magnesium sulfate use is associated with favorable neurodevelopmental outcomes in preterm infants. However, there are concerns regarding the effects of antenatal magnesium sulfate on neonates, especially regarding gastrointestinal morbidities. This study aims to explore the effects of antenatal magnesium sulfate on intestinal morbidities requiring surgery in preterm infants. METHODS: This was a retrospective cohort study of 181 preterm infants who were born at less than 28 weeks of gestational age. Subjects were categorized as infants exposed to antenatal magnesium sulfate and those not exposed to antenatal magnesium sulfate. RESULTS: Antenatal magnesium sulfate was associated with a decreased risk of surgical conditions of the intestine (OR 0.393, 95% CI 0.170-0.905). The multivariate analysis showed that the duration of antenatal magnesium sulfate use was associated with surgical conditions of the intestine (adjusted OR 0.766, 95% CI 0.589-0.997). In the <26 weeks of gestational age subgroup, the use of antenatal magnesium sulfate was significantly associated with decreased intestinal morbidities requiring surgery (adjusted OR 0.234, 95% CI 0.060-0.922). CONCLUSION: Antenatal magnesium sulfate use appears to have a protective effect on intestinal morbidities requiring surgery in preterm infants in a duration-dependent manner. Association of antenatal magnesium sulfate use and decreased intestinal morbidities requiring surgery was more distinct in preterm infants <26 weeks of gestational age.

Slowed progression in models of Huntington disease by adipose stem cell transplantation.

OBJECTIVE: Adipose-derived stem cells (ASCs) are readily accessible and secrete multiple growth factors. Here, we show that ASC transplantation rescues the striatal pathology of Huntington disease (HD) models. METHODS: ASCs were isolated from human subcutaneous adipose tissue. In a quinolinic acid (QA)-induced rat model of striatal degeneration, human ASCs (1 million cells) were transplanted into the ipsilateral striatal border immediately after the QA injection. In 60-day-old R6/2 mice transgenic for HD, ASCs (0.5 million cells) were transplanted into each bilateral striata. In in vitro experiments, we treated mutant huntingtin gene-transfected cerebral neurons with ASC-conditioned media. RESULTS: In the QA model, human ASCs reduced apomorphine-induced rotation behavior, lesion volume, and striatal apoptosis. In R6/2 transgenic mice, transplantation of ASCs improved Rota-Rod performance and limb clasping, increased survival, attenuated the loss of striatal neurons, and reduced the huntingtin aggregates. ASC-transplanted R6/2 mice expressed elevated levels of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) and reactive oxygen defense enzymes and showed activation of the Akt/cAMP-response element-binding proteins. ASC-conditioned media decreased the level of N-terminal fragments of mutant huntingtin and associated apoptosis, and increased PGC-1alpha expression. INTERPRETATION: Collectively, ASC transplantation slowed striatal degeneration and behavioral deterioration of HD models, possibly via secreted factors.

Loss of EGR3 is an independent risk factor for metastatic progression in prostate cancer.

Identification of pro-metastatic genomic alterations is urgently needed to help understand and prevent the fatal course of prostate cancer. Here, we found that the transcription factor EGR3, located at chromosome 8p21.3, is a critical metastasis suppressor. Aberrant deletion of EGR3 was found in up to 59.76% (deep deletions, 16.87%; shallow deletions, 42.89%) of prostate cancer patients. In informatics analysis, EGR3 loss was associated with prostate cancer progression and low survival rates. EGR3 expression inversely correlated with the expressions of epithelial-to-mesenchymal transition (EMT) and metastasis-related gene sets in prostate cancer tissues. In prostate cancer cells, EGR3 blocked the EMT process and suppressed cell migration and invasion. In a mouse model for cancer metastasis, EGR3 overexpression significantly suppressed bone metastases of PC3 and 22Rv1 prostate cancer cells. Mechanistically, EGR3 transcriptionally activated ZFP36, GADD45B, and SOCS3 genes by directly binding to their promoter regions. The EMT-inhibitory and tumor-suppressive roles of the EGR3 downstream genes were identified through in vitro and in silico analyses. Together, our results showed that EGR3 may be a biomarker to predict clinical outcomes and that it plays an important role in the metastatic progression of prostate cancer.

The Association of Pregnancy-induced Hypertension with Bronchopulmonary Dysplasia - A Retrospective Study Based on the Korean Neonatal Network database.

The prevalence of pregnancy-induced hypertension (PIH) and preeclampsia (PE) are 5-10% and 2-4%, respectively. PIH might affect angiogenesis in preterm neonates, but its association with bronchopulmonary dysplasia (BPD) remains controversial. This study evaluated the association between PIH and BPD in very low-birth weight infants. We retrospectively analysed the maternal, perinatal, and neonatal data of preterm infants born before 30 weeks of gestation, selected from the nationwide registry of very low-birth weight infants, between January 2013 and December 2014. As a result, 1,624 infants without maternal PIH (gestational age: 27.3 ± 1.8 weeks) and 203 infants with maternal PIH (28.0 ± 1.4 weeks, p < 0.001) were included. Birth weight was higher in the non-PIH group, compared with the PIH group (1027.4 ± 250.2 vs. 876.4 ± 261.5 g, p < 0.001). Multivariate logistic regression showed that PIH was associated with BPD (adjusted OR 1.474, 95% confidence interval 1.025-2.121), after adjusting for confounders, including small-for-gestation age (SGA). The result of present study is consistent with the current concept of BPD as an early form of pulmonary vascular disease, for both PIH and BPD are attributed by abnormal vascular formation.

Fabrication and Comparison of Self-Organized Ag and Au Nanodots on Ti/MgO(001) Substrates.

We analyze and compare the differences in the dewetting phenomena and crystal structure between Ag(5.0 nm) and Au(5.0 nm) layers deposited on a Ti(1.0 nm) seed layer coated onto a MgO(001) substrate. The samples are deposited at room temperature and annealed at 350-450 °C for 5 h. The surfaces of both Ag/Ti and Au/Ti films exhibit a completely separated island structure, subsequently leading to the formation of a nanodot array after annealing. Based on atomic force microscopy (AFM) analysis, we conclude that the dewetting progression speed of Ag/Ti films is higher than that of Au/Ti films. Based on X-ray diffraction (XRD) results, the Ti thin film acts as a seed layer, assisting the epitaxial growth of fcc-Ag(001) nanodots on the MgO(001) substrate, whereas in the case of Au/Ti, the Au layer grows non-epitaxially on the MgO(001) substrate, which is related to the difference in the surface energies of Ag and Au. Furthermore, the optical absorbance spectra of the self-organized Ag and Au nanodots with the Ti seed layer are obtained in the visible light range and the optical properties of Ag and Au nanodots are compared.

BRAFV600E Transduction of an SV40-Immortalized Normal Human Thyroid Cell Line Induces Dedifferentiated Thyroid Carcinogenesis in a Mouse Xenograft Model.

Background: Despite active studies of the clinical importance of BRAFV600E, suitable research models to investigate the role of this mutation in the etiopathogenesis of human thyroid cancers are limited. Thus, we generated cell lines by transducing the simian virus (SV)-40 immortalized human thyroid cell line Nthy-ori 3-1 (Nthy) with lentiviral vectors expressing either BRAFWT (Nthy/WT) or BRAFV600E. Nthy/WT and Nthy/V600E cells were then xenografted into mice to evaluate the carcinogenic role of BRAFV600E. Methods: Each cell line was subcutaneously injected into NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice, and a pathological analysis was performed. The effects of the mutation were further verified by using a BRAFV600E-selective inhibitor (PLX-4032, vemurafenib). The transcriptome was analyzed by RNA sequencing and compared with data from The Cancer Cell Line Encyclopedia and Gene Expression Omnibus. Results: While Nthy/WT was not tumorigenic in vivo, Nthy/V600E formed tumors reaching 2784.343 mm3 in 4 weeks, on average. A pathological analysis indicated that Nthy/V600E tumors were dedifferentiated thyroid cancer. We found metastases in the lung, liver, and relevant lymph nodes. A transcriptomic analysis revealed 5512 differentially expressed genes (DEGs) between the mutant and wild-type cell lines, and more DEGs were shared with anaplastic thyroid cancer than with papillary thyroid cancer. BRAFV600E activated the cell cycle mainly by regulating G1/S phases. PLX-4032 treatment significantly inhibited tumor growth and metastasis. Conclusions: Our data show that BRAFV600E plays a pivotal role in the carcinogenic transformation of an SV40-transfected immortalized normal human thyroid cell line. This xenograft model is expected to contribute to studies of the etiopathogenesis and treatment of highly malignant thyroid cancers.