Short-Term Outcomes of Early Oral Colostrum Administration in VLBW Neonates: An Open-Label Randomized Controlled Trial.

Background: Oropharyngeal colostrum priming (OCP) has been proposed as a potential nutritional option for very low birth weight (VLBW) newborns. This study aimed to determine short-term outcomes of early oral colostrum administration in VLBW neonates. Methods: This open-label randomized controlled trial was conducted on VLBW neonates admitted to Mahdieh Hospital, Tehran, Iran, between February and December 2022. According to the protocol, all eligible neonates were randomized evenly to the intervention group, which received oral colostrum (OC), and the control group, which received no OC. Finally, short-term outcomes of early OC administration were compared between groups using the independent-samples t test, chi-square, and Fisher exact tests. Results: Of 80 randomized neonates, 37 and 39 from the intervention and control groups entered the final analysis, respectively. Neonates in the intervention and control groups did not significantly differ in terms of peripherally inserted central catheter (PICC) infection (P = 0.728), sepsis (P = 0.904), necrotizing enterocolitis (NEC) (P > 0.999), intraventricular hemorrhage (IVH) (P = 0.141), retinopathy of prematurity (ROP) (P = 0.923), and bronchopulmonary dysplasia (BPD) (P = 0.633). Furthermore, there was no significant difference between groups considering the time to reach 120 cc/kg feeds (P = 0.557), time to reach birth weight (P = 0.157), length of hospitalization (P = 0.532), and mortality rate (P = 0.628). Conclusion: The results of our study revealed that despite safety, early OC administration did not improve any of the short-term outcomes in VLBW neonates.

GSK3ß regulates epithelial-mesenchymal transition and cancer stem cell properties in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancers (TNBCs), which lack receptors for estrogen, progesterone, and amplification of epidermal growth factor receptor 2, are highly aggressive. Consequently, patients diagnosed with TNBCs have reduced overall and disease-free survival rates compared to patients with other subtypes of breast cancer. TNBCs are characterized by the presence of cancer cells with mesenchymal properties, indicating that the epithelial to mesenchymal transition (EMT) plays a major role in the progression of this disease. The EMT program has also been implicated in chemoresistance, tumor recurrence, and induction of cancer stem cell (CSC) properties. Currently, there are no targeted therapies for TNBC, and hence, it is critical to identify the novel targets to treat TNBC. METHODS: A library of compounds was screened for their ability to inhibit EMT in cells with mesenchymal phenotype as assessed using the previously described Z-cad reporters. Of the several drugs tested, GSK3ß inhibitors were identified as EMT inhibitors. The effects of GSK3ß inhibitors on the properties of TNBC cells with a mesenchymal phenotype were assessed using qRT-PCR, flow cytometry, western blot, mammosphere, and migration and cell viability assays. Publicly available datasets also were analyzed to examine if the expression of GSK3ß correlates with the overall survival of breast cancer patients. RESULTS: We identified a GSK3ß inhibitor, BIO, in a drug screen as one of the most potent inhibitors of EMT. BIO and two other GSK3ß inhibitors, TWS119 and LiCl, also decreased the expression of mesenchymal markers in several different cell lines with a mesenchymal phenotype. Further, inhibition of GSK3ß reduced EMT-related migratory properties of cells with mesenchymal properties. To determine if GSK3ß inhibitors target mesenchymal-like cells by affecting the CSC population, we employed mammosphere assays and profiled the stem cell-related cell surface marker CD44+/24- in cells after exposure to GSK3ß inhibitors. We found that GSK3ß inhibitors indeed decreased the CSC properties of cell types with mesenchymal properties. We treated cells with epithelial and mesenchymal properties with GSK3ß inhibitors and found that GSK3ß inhibitors selectively kill cells with mesenchymal attributes while sparing cells with epithelial properties. We analyzed patient data to identify genes predictive of poor clinical outcome that could serve as novel therapeutic targets for TNBC. The Wnt signaling pathway is critical to EMT, but among the various factors known to be involved in Wnt signaling, only the higher expression of GSK3ß correlated with poorer overall patient survival. CONCLUSIONS: Taken together, our data demonstrate that GSK3ß is a potential target for TNBCs and suggest that GSK3ß inhibitors could serve as selective inhibitors of EMT and CSC properties for the treatment of a subset of aggressive TNBC. GSK3ß inhibitors should be tested for use in combination with standard-of-care drugs in preclinical TNBC models.

CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer.

The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk.

Treatment of Patent Ductus Arteriosus in Premature Infants: Intravenous Paracetamol or Oral Ibuprofen?

BACKGROUND: The similarity in the mechanism of action between paracetamol and ibuprofen can cause similar side effects. However, in preterm neonates with feeding intolerance, intravenous (IV) paracetamol has replaced oral ibuprofen. Therefore, a comparison of the effectiveness and side effects is essential. METHODS: In this retrospective cohort study, the data of 118 preterm infants with a definite diagnosis of patent ductus arteriosus (PDA), including 59 patients who received oral ibuprofen and 59 patients who received IV paracetamol were analyzed. Laboratory evaluations of serum total and direct bilirubin, hemoglobin, and creatinine levels before and seven days after treatment were made. Using analysis of covariance (ANCOVA) and multiple multinomial logistic regression models, the effect of two treatment groups on the post-treatment variables as well as their efficacy comparison were evaluated. RESULTS: In both pre- and post-treatment periods, there was no significant association between echocardiography variables with treatment groups. The results from the ANCOVA model showed that the paracetamol and ibuprofen were followed by a significant decrease in the mean total bilirubin and Hct variables after treatment by 1.38 and 1.65 units, respectively. In addition, results from the Mann-Whitney U test revealed that the median Hb and K differences after and before treatment had a significant difference between the two treatment groups. Furthermore, based on the multiple multinomial logistic model results, the odds of complete arterial duct closure with IV paracetamol was 1.27 times higher than with oral ibuprofen, while in the oral ibuprofen group, the odds of closing was 1.44 times higher than the IV paracetamol group, but there was no statistically significant difference between the two groups. CONCLUSION: Intravenous paracetamol has equal efficacy compared to oral ibuprofen in the treatment of PDA. Also, it seems to be associated with a lower risk of hyperbilirubinemia following the treatment.

Potential application of foveal structural measurements in treatment decision for retinopathy of prematurity: an OCT-based study.

PURPOSE: To investigate foveal changes in infants with ROP not requiring treatment(nROP) and ROP infants needing treatment (tROP) using a handheld SD-OCT device. METHOD: We performed horizontal SD-OCT scans through the fovea in 156 eyes of 81 infants diagnosed with ROP. Foveal immaturity indices including the presence of inner retinal layers (IRL), absence of foveal outer nuclear layers widening (ONL) and attenuation of hyperreflective outer segment layers (OS), presence and type of cystoid macular edema (CME), epiretinal membrane (ERM), foveal pit depth (FPD), foveal pit width (FPW) and central foveal thickness (CFT) were calculated. The multivariate logistic regression model was used to predict the need for treatment based on OCT measurements. RESULTS: The shape of the foveolar pit was not significantly different among tROP and nROP groups (P-value = 0.287, Chi-square test). IRL extrusion was incomplete in both tROP and nROP groups (P-value = 0.0.41, Chi-square test). Nevertheless, the presence of thicker IRL was more frequent in the nROP group in comparison with the tROP group (100% vs.64.8%, P-value = 0.001). CME was observed in 29% of eyes in the tROP group and 40% of eyes in the nROP group; however, this difference was not statistically significant (P-value = 0.32, Chi-square test). ERM was detected in 15 (75%) and 84 (65.6%) eyes in the nROP and tROP groups, respectively (P-value = 0.39, Chi-square test). Multivariate logistic regression analyses showed that the need for treatment was significantly associated with gestational age (GA), CFT and FPD (P-values 0.001 and 0.002 respectively). CONCLUSIONS: This study demonstrated GA, foveal pit depth and the central foveal thickness could accurately predict the need for treatment with sensitivity, specificity, and diagnostic accuracy of 97%, 65% and 91.7% respectively.

Which Is More Accurate: Transcutaneous Bilirubin Measurement on the Forehead or Sternum?

BACKGROUND: The accuracy and reliability of noninvasive methods of neonatal jaundice assessment are not completely obvious, including which area of the body is more suitable to estimate actual bilirubin with transcutaneous bilirubinometry (TCB). METHODS: This cross-sectional study compares the accuracy of three noninvasive methods for neonatal jaundice estimation included visual estimation, TCB on the forehead, and TCB on the sternum. The mean and standard deviation describe quantitative variables. In addition to analytical analysis, we used the linear regression test to evaluate the association of different variables with the accuracy of TCB as well as paired t test for comparing the TCB results on the sternum with the forehead before and after phototherapy. For all statistical tests, a P value less than 0.05 was considered as significant. RESULTS: We enrolled 100 neonates with a mean age (±SD, standard deviation) of 6.5±1.9 days (range 2-11 days) in our study. The mean gestational age (GA) of the participants was 38.94 weeks±1.00 w SD, and their mean (±SD) weight was 3302 g (±315.60). The mean (mg/dL)±SD for bilirubin level by clinical estimation of jaundice, TCB on the forehead and TCB on the sternum were 17.35±2.88, 17.23±1.63, and 17.77±1.58, respectively. Also, comparing mean differences before and after phototherapy showed that TCB on the sternum is a good predictor for neonatal jaundice before phototherapy (0.539 vs. 0.348). CONCLUSION: TCB on the sternum is more predictive than the forehead, especially before phototherapy, to assess the need for treatment in outpatient settings.

Validation of the Postnatal Growth and Retinopathy of Prematurity (GROP) screening criteria.

Background: Retinopathy of prematurity (ROP) is a leading cause of irreversible blindness in infants. The Postnatal Growth and ROP (G-ROP) study proposed new screening criteria for ROP. This study aimed to validate the G-ROP screening criteria in a group of Iranian premature infants who were treated in the neonatal intensive care unit (NICU) for at least 40 days. Methods: In this retrospective study, we extracted the data pertaining to infants admitted to the NICU from January 2020 to December 2021. We screened all the included infants for ROP based on the Iranian national screening criteria. We applied the G-ROP criteria to our study population, and if no criterion was met, the infant was exempted from ROP screening. We determined the sensitivity and specificity of the G-ROP guidelines for ROP detection, along with its capacity for predicting the requirement for ROP treatment. Moreover, we compared the G-ROP guidelines with the Iranian and North American guidelines for ROP screening. Results: A total of 166 premature infants with complete datasets were included: 130 had ROP, of whom 61 were treated. There were 109 female infants (65.7%). The mean (standard deviation [SD]) birth weight and gestational age were 1080 (256) g and 28.28 (1.97) weeks, respectively. Applying the G-ROP criteria, 127 of 130 infants with ROP were identified (sensitivity, 97.69%; 95% confidence interval [CI], 95.11% - 100%), and of 36 infants without ROP, three were correctly excluded (specificity, 8.33%; 95% CI, 0% - 17.36%). The G-ROP criteria did not fail to identify infants who required treatment for ROP (sensitivity, 100%; 95% CI, 98.29 - 100) and had a specificity of 8.69% (95% CI, 2.04% - 15.34%). Although the Iranian and North American criteria had 100% sensitivity for infants with any stage of ROP, they could not detect infants without ROP (0% specificity). Conclusions: The G-ROP screening criteria had a sensitivity of 100% in identifying infants requiring treatment for ROP in our high-risk group; however, specificity was not sufficiently high. Further studies with larger numbers of referred infants could confirm a decrease in the burden of retinal examinations using these criteria.

Administration of breast milk cell fractions to neonates with birthweight equal to or less than 1800 g: a randomized controlled trial.

BACKGROUND: Most premature and very low birthweight infants cannot tolerate breast milk feeding in the first few days of life and are deprived of its benefits. This study evaluates the clinical outcomes of administering breast milk cell fractions to neonates with a birthweight of ≤1800 g. METHODS: We conducted a randomized controlled trial on 156 infants in the neonatal intensive care unit of Mahdieh Maternity Hospital in Tehran, Iran, from May 2019 to April 2020. All neonates with a birthweight ≤1800 g were enrolled and divided into intervention and control groups using stratified block randomization. Neonates in the intervention group received the extracted breast milk cell fractions (BMCFs) of their own mother's milk after being centrifuged in the first 6 to 12 h after birth. The control group received routine care, and breastfeeding was started as soon as tolerated in both groups. Study outcomes were necrotizing enterocolitis (NEC), death, and in-hospital complications. RESULTS: We divided participants into two groups: 75 neonates in the intervention group and 81 neonates in the control group. The mean birthweight of neonates was 1390.1 ± 314.4 g, and 19 (12.2%) neonates deceased during their in-hospital stay. The incidence of NEC was similar in both groups. After adjustment for possible confounders in the multivariable model, receiving BMCFs were independently associated with lower in-hospital mortality (5 [26.3%] vs. 70 (51.1%]; odds ratio (OR): 0.24; 95% confidence interval [CI] 0.07, 0.86). Also, in a subgroup analysis of neonates with birthweight less than 1500 g, in-hospital mortality was significantly lower in the intervention group (4 [9.5%] vs. 13 [30.2%]; OR: 0.24; 95% CI 0.07, 0.82). There were no differences in major complications such as bronchopulmonary dysplasia and retinopathy of prematurity between the two groups. No adverse effects occurred. CONCLUSIONS: Our research demonstrated a significantly lower mortality rate in neonates (with a birthweight of ≤1800 g) who received breast milk cell fractions on the first day of life. Since this is a novel method with minimal intervention, we are looking forward to developing and evaluating this method in larger studies. TRIAL REGISTRATION: IIranian Registry of Clinical Trials. Registered 25 May 2019, IRCT20190228042868N1 .

Combined inhibition of DDR1 and CDK4/6 induces synergistic effects in ER-positive, HER2-negative breast cancer with PIK3CA/AKT1 mutations.

Molecular alterations in the PI3K/AKT pathway occur frequently in hormone receptor-positive breast tumors. Patients with ER-positive, HER2-negative metastatic breast cancer are often treated with CDK4/6 inhibitors such as palbociclib in combination with endocrine therapy. Although this is an effective regimen, most patients ultimately progress. The purpose of this study was identifying synthetic lethality partners that can enhance palbociclib's antitumor efficacy in the presence of PIK3CA/AKT1 mutations. We utilized a barcoded shRNA library to determine critical targets for survival in isogenic MCF7 cells with PIK3CA/AKT1 mutations. We demonstrated that the efficacy of palbociclib is reduced in the presence of PIK3CA/AKT1 mutations. We also identified that the downregulation of discoidin domain receptor 1 (DDR1) is synthetically lethal with palbociclib. DDR1 knockdown and DDR1 pharmacological inhibitor decreased cell growth and inhibited cell cycle progression in all cell lines, while enhanced the sensitivity of PIK3CA/AKT1 mutant cells to palbociclib. Combined treatment of palbociclib and 7rh further induced cell cycle arrest in PIK3CA/AKT1 mutant cell lines. In vivo, 7rh significantly enhanced palbociclib's antitumor efficacy. Our data indicates that DDR1 inhibition can augment cell cycle suppressive effect of palbociclib and could be effective strategy for targeted therapy of ER-positive, HER2-negative breast cancers with PI3K pathway activation.

Oxidative Phosphorylation Is a Metabolic Vulnerability in Chemotherapy-Resistant Triple-Negative Breast Cancer.

Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pretreatment biopsies from patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy demonstrated that the top canonical pathway associated with worse outcome was higher expression of OXPHOS signature. IACS-10759, a novel inhibitor of OXPHOS, stabilized growth in multiple TNBC patient-derived xenografts (PDX). On gene expression profiling, all of the sensitive models displayed a basal-like 1 TNBC subtype. Expression of mitochondrial genes was significantly higher in sensitive PDXs. An in vivo functional genomics screen to identify synthetic lethal targets in tumors treated with IACS-10759 found several potential targets, including CDK4. We validated the antitumor efficacy of the combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 in vitro and in vivo. In addition, the combination of IACS-10759 and multikinase inhibitor cabozantinib had improved antitumor efficacy. Taken together, our data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens. SIGNIFICANCE: These findings suggest that triple-negative breast cancer is highly reliant on OXPHOS and that inhibiting OXPHOS may be a novel approach to enhance efficacy of several targeted therapies.

Targeting AKT for cancer therapy.

Introduction: Targeted therapies in cancer aim to inhibit specific molecular targets responsible for enhanced tumor growth. AKT/PKB (protein kinase B) is a serine threonine kinase involved in several critical cellular pathways, including survival, proliferation, invasion, apoptosis, and angiogenesis. Although phosphatidylinositol-3 kinase (PI3K) is the key regulator of AKT activation, numerous stimuli and kinases initiate pro-proliferative AKT signaling which results in the activation of AKT pathway to drive cellular growth and survival. Activating mutations and amplification of components of the AKT pathway are implicated in the pathogenesis of many cancers including breast and ovarian. Given its importance, AKT, it has been validated as a promising therapeutic target.Areas covered: This article summarizes AKT's biological function and different classes of AKT inhibitors as anticancer agents. We also explore the efficacy of AKT inhibitors as monotherapies and in combination with cytotoxic and other targeted therapies.Expert opinion: The complex mechanism following AKT inhibition requires the addition of other therapies to prevent resistance and improve clinical response. Further studies are necessary to determine additional rational combinations that can enhance efficacy of AKT inhibitors, potentially by targeting compensatory mechanisms, and/or enhancing apoptosis. The identification of biomarkers of response is essential for the development of successful therapeutics.

Silymarin Restores Regulatory T Cells (Tregs) Function in Multiple Sclerosis (MS) Patients In Vitro.

Dysregulation of the immune system and impairment in the function and number of patient-derived regulatory T cells (Treg) have an important role in multiple sclerosis (MS) pathogenesis. MS patients still receive different medications to overcome the relapses and to slow the disease progression. However, the benefits of these therapies are limited and are accompanied by different side effects. The immunoregulatory effects of Silymarin as a plant-derived flavonoid have shown in studies. In the present study, regulatory T cells (Tregs) were isolated from MS patients who diagnosed as new cases and IFN-ß-treated RRMS patients. Isolated Treg cells were cultured in the presence of different concentrations of Silymarin (50, 100, 150 µM) for 48, 72, and 120 h. Proliferation and activation of Treg cells were assessed by flow cytometry. Also, FOXP3, JAK3, and STAT5 gene expression, IL-10, and TGF-ß production by Tregs were evaluated by real-time PCR and ELISA respectively. The results showed that Silymarin promoted Treg proliferation at 100 µM concentration after 72 h. Additionally, IL-10, TGF-ß levels, and FOXP3, JAK3, and STAT5 gene expression enhanced by Silymarin dose and time dependently. Our preliminary results suggest that the induction and activation of Tregs could be an underlying mechanism of the ancient used herbal medicine Silymarin, providing effective means against autoimmune and inflammatory diseases.

The Effect of Non-Nutritive Sucking and Maternal Milk Odor on the Independent Oral Feeding in Preterm Infants.

OBJECTIVES: Given the positive effects of stimulation with breast milk odor and non-nutritive sucking (NNS) on preterm feeding skills, we examined the effect of NNS and milk odor, on the time of achieving independent oral feeding in preterm infants. MATERIALS & METHODS: This study was conducted at two Neonatal Intensive Care Units of Tehran, Iran in 2016. Overall, 32 neonates with gestational ages of 28-32 wk were enrolled in two groups; NNS with and without olfactory stimuli (breast milk odor). The simulations were performed in both groups during the first five minutes of gavage, three times per day, and over ten consecutive days. Weight gain, time of achieving oral feeding and chronological age at discharge were as measures of the effectiveness of the interventions. The results of the interventions were analyzed and compared using SPSS.18. RESULTS: NNS with breast milk odor resulted to a lower post-menstrual age at the first oral feeding, independent oral feeding and discharge from the hospital, but had no effects on their daily weight gain and weight at the time of discharge. CONCLUSION: These results show the effectiveness of combining milk odor and NNS as two important stimuli in achieving oral feeding and earlier discharge from the hospital.

Survival Outcomes by TP53 Mutation Status in Metastatic Breast Cancer.

PURPOSE: We sought to determine the significant genomic alterations in patients with metastatic breast cancer (MBC), and survival outcomes in common genotypes. PATIENTS AND METHODS: High-depth next generation sequencing was performed for 202 genes in tumor and normal DNA from 257 patients with MBC, including 165 patients with ER/PR+ HER2- (hormone receptor positive, HR+ positive), 32 patients with HER2+ and 60 patients with triple negative (ER/PR/HER2-) cancer. Kaplan Meier survival analysis was performed in our discovery set, in breast cancer patients analyzed in The Cancer Genome Atlas, and in a separate cohort of 98 patients with MBC who underwent clinical genomic testing. RESULTS: Significantly mutated genes (SMGs) varied by histology and tumor subtype, but TP53 was a SMG in all three subtypes. The most SMGs in HR+ patients included PIK3CA (32%), TP53 (29%), GATA3 (15%), CDH1 (8%), MAP3K1 (8%), PTEN (5%), TGFBR2 (4%), AKT1 (4%), and MAP2K4 (4%). TP53 mutations were associated with shorter recurrence-free survival (P=0.004), progression-free survival (P=0.00057) and overall survival (P=0.003). Further, TP53 status was prognostic among HR+ patients with PIK3CA mutations. TP53 mutations were also associated with poorer overall survival in the 442 HR+ breast cancer patients in the TCGA (P=0.042) and in an independent set of 96 HR+ MBC who underwent clinical sequencing (P=0.0004). CONCLUSIONS: SMGs differ by tumor subtype but TP53 is significantly mutated in all three breast cancer subtypes. TP53 mutations are associated with poor prognosis in HR+ breast cancer. TP53 mutations should be considered in the design and interpretation of precision oncology trials.

Frequency and Causes of Hypotonia in Neonatal Period with the Gestational Age of More Than 36 Weeks in NICU of Mofid Children Hospital, Tehran, Iran During 2012-2014.

OBJECTIVE: Hypotonia is a serious neurologic problem in neonatal period. Although hypotonia is a nonspecific clinical finding but it is the most common motor disorder in the newborn. The objective of this study was to determine the frequency of neonatal hypotonia then to ascertain of the most common causes. MATERIALS & METHODS: This cross -sectional prospective study was carried out on the 3281 term infants hospitalized in conventional and NICU of Mofid Children Hospital, Tehran, Iran during 2012-2014. Diagnosis was made by history, physical & neurological examination and accessible diagnostic tests. RESULTS: Fifty nine hypotonic neonates were identified, forty seven (79.66%) had central hypotonia (Hypoxic ischemic encephalopathy (n= 2), other causes of encephalopathy (n=2), intracranial hemorrhage (n=4), CNS abnormalities (n= 7), chromosomal disorders (n=4), syndromic-nonsyndromic (n=8), and metabolic diseases (n=8). Peripheral hypotonic recognized in 6 infants (10.17%); spinal muscular atrophy (n= 1), and myopathy (n= 5). Six cases (10.17%) remained unclassified. Twelve infants had transient hypotonia. In final study, 18 of 59 infants (30%) died, nearly 90% before one year of age. Twenty-eight (47%) infants found developmental disorders and only 13 (22%) infants achieved normal development in their follow up. CONCLUSION: Neonatal hypotonia is a common event in neonatal period. A majority of diagnosis is obtained by history and physical examination. Neuroimaging, genetic and metabolic tests were also important in diagnosis. Genetic, syndromic-nonsyndromic, and metabolic disorders were the most causes of neonatal hypotonia.

Evaluation of Initial Respiratory Support Strategies in VLBW Neonates with RDS.

BACKGROUND: Non-invasive ventilation (NIV) has brought about a significant change in care and treatment of respiratory distress syndrome (RDS) in very low birth weight (VLBW) neonates. The present study was designed and conducted to evaluate different strategies of initial respiratory support (IRS) in VLBW neonates hospitalized in the neonatal intensive care unit (NICU). METHODS: This prospective study was conducted over three years (March 21, 2011 to March 20, 2014). Each eligible VLBW baby with RDS diagnosis received a specific IRS, including room air (RA), oxygen therapy (O2 RX), n.CPAP, NIPPV, MV ± SURF, based on clinical evaluation; then, the next strategies were selected based on the disease progression. Obtained data was entered in SPSS and the groups were compared for disease consequences or death. Then, contributing factors to the failure of NIV strategies, and the need for endotracheal mechanical ventilation (eMV) were determined. RESULTS: In total, 499 neonates were included in the study. The mean birth weight was 1,125 ± 254 g and the gestational age was 29.2 ± 2.5 weeks. The IRS included: RA = 43, O2.RX = 60, n.CPAP/NIPPV = 219, INSURE = 83 and MV ± SURF = 177. In terms of the need for IRS upgrading during hospitalization, neonates not on mechanical ventilation (64.5%) were divided into three groups. In 45.3% of cases, the IRS did not change (Never upgrading); in 24.5% of cases, the level of IRS increased but there was no need for eMV in the first three days of life (Specific); in 24.8% of cases, there was need for eMV within the first three days of life (Absolute) and during hospitalization (after the first three days of life) 5.3% of cases were in need of eMV (General). In terms of correlation between the effective variables in IRS upgrading, univariable analyses showed that low gestational age, low birth weight, multiple pregnancy, maternal disease, low one-minute Apgar score, and need for surfactant therapy had significant correlation, and multivariable analysis showed that low gestational age, low birth weight and maternal disease were risk factors independently correlated to IRS upgrading, CLD and death. CONCLUSION: Early use of NIV in preterm neonates with mild to moderate respiratory distress and spontaneous breathing significantly reduced the need for intubation, surfactant, mechanical ventilation and thereby pulmonary and non-pulmonary complications and neonatal mortality.

N-BLR, a primate-specific non-coding transcript leads to colorectal cancer invasion and migration.

BACKGROUND: Non-coding RNAs have been drawing increasing attention in recent years as functional data suggest that they play important roles in key cellular processes. N-BLR is a primate-specific long non-coding RNA that modulates the epithelial-to-mesenchymal transition, facilitates cell migration, and increases colorectal cancer invasion. RESULTS: We performed multivariate analyses of data from two independent cohorts of colorectal cancer patients and show that the abundance of N-BLR is associated with tumor stage, invasion potential, and overall patient survival. Through in vitro and in vivo experiments we found that N-BLR facilitates migration primarily via crosstalk with E-cadherin and ZEB1. We showed that this crosstalk is mediated by a pyknon, a short ~20 nucleotide-long DNA motif contained in the N-BLR transcript and is targeted by members of the miR-200 family. In light of these findings, we used a microarray to investigate the expression patterns of other pyknon-containing genomic loci. We found multiple such loci that are differentially transcribed between healthy and diseased tissues in colorectal cancer and chronic lymphocytic leukemia. Moreover, we identified several new loci whose expression correlates with the colorectal cancer patients' overall survival. CONCLUSIONS: The primate-specific N-BLR is a novel molecular contributor to the complex mechanisms that underlie metastasis in colorectal cancer and a potential novel biomarker for this disease. The presence of a functional pyknon within N-BLR and the related finding that many more pyknon-containing genomic loci in the human genome exhibit tissue-specific and disease-specific expression suggests the possibility of an alternative class of biomarkers and therapeutic targets that are primate-specific.

Risk Factors and Consequent Outcomes of Placenta Previa: Report From a Referral Center.

 Because of an unknown factor, the frequency of complicated pregnancy with placenta previa has been raised during past decade. This study was designed to deepen our understanding of risk factors and outcomes of placenta previa in our country. This study investigated 694 cases of placenta previa comparing with 600 healthy pregnant women with not overlie placenta in two referral and tertiary Obstetrics and Gynecological Hospital in Iran on the basis of the clinical and para-clinical analysis, in order to find the probable risk factors for occurrence of placenta previa and its effect on maternal and neonatal complications. The most important risk factor for the occurrence of placenta previa was advanced maternal age (P<0.001) and history of stillbirth (OR=117.2, CI=58.3-236.0). In the other hand, the most substantial outcome of this disorder was a reduction of gestational age (P<0.001) and low birth weight neonatally (P<0.001). The conservative follow-up should be programmed for women with placenta previa based on the type of risk factors which can provide the best possible management to decrease the morbidity and mortality of their related complications.

Clinical outcomes based on multigene profiling in metastatic breast cancer patients.

BACKGROUND: Identifying the clinical impact of recurrent mutations can help define their role in cancer. Here, we identify frequent hotspot mutations in metastatic breast cancer (MBC) patients and associate them with clinical outcomes. PATIENTS AND METHODS: Hotspot mutation testing was conducted in 500 MBC patients using an 11 gene (N = 126) and/or 46 or 50 gene (N = 391) panel. Patients were stratified by hormone receptor (HR) and human epidermal growth factor 2 (HER2) status. Clinical outcomes were retrospectively collected. RESULTS: Hotspot mutations were most frequently detected in TP53 (30%), PIK3CA (27%) and AKT1 (4%). Triple-negative breast cancer (TNBC) patients had the highest incidence of TP53 (58%) and the lowest incidence of PIK3CA (9%) mutations. TP53 mutation was associated with shorter relapse-free survival (RFS) (median 22 vs 42months; P < 0.001) and overall survival (OS) from diagnosis of distant metastatic disease (median 26 vs 51months; P < 0.001). Conversely, PIK3CA mutation was associated with a trend towards better clinical outcomes including RFS (median 41 vs 30months; P = 0.074) and OS (52 vs 40months; P = 0.066). In HR-positive patients, TP53 mutation was again associated with shorter RFS (median 30 vs 46months; P = 0.017) and OS (median 30 vs 55months; P = 0.001). When multivariable analysis was performed for RFS and OS, TP53 but not PIK3CA mutation remained a significant predictor of outcomes in the overall cohort and in HR-positive patients. CONCLUSIONS: Clinical hotspot sequencing identifies potentially actionable mutations. In this cohort, TP53 mutation was associated with worse clinical outcomes, while PIK3CA mutation did not remain a significant predictor of outcomes after multivariable analysis.

Perinatal complications associated with preterm deliveries at 24 to 33 weeks and 6 days gestation (2011- 2012): A hospital-based retrospective study.

BACKGROUND: Morbidity and mortality of preterm babies are important issues in perinatal medicine. In developed countries, preterm delivery is the cause of about 70% of mortality and 75% of morbidity in the neonatal period, respectively. OBJECTIVE: The aim of this study was to determine the risk factors for preterm labor and the outcomes, in terms of perinatal mortality and morbidity at the time of discharge home, among preterm infants at less than 34 weeks gestation. MATERIALS AND METHODS: A retrospective study was conducted and all infants with a gestational age of 24 to 33 weeks and 6 days who were born from November 1(st), 2011 to March 31, 2012 were enrolled in this study. RESULTS: From 1185 preterm infants were born during this period, 475 (40.08%) infants with less than 34 weeks gestational age were included in the study. Our study showed the major obstetrical risk factors for preterm labor were as follows: preeclampsia (21%), premature rupture of membranes (20.3%), abruption of placenta (10%), and idiopathic cases (48.7%). The neonatal mortality rate in less than 34 weeks was 9.05%. Significant perinatal morbidity causesd in less than 34 weeks were as follows: sepsis (46.94%), respiratory distress syndrome (41.47%), patent ductus arteriosus (21.47%), retinopathy of prematurity (3.57%), necrotizing entrocolitis (1.68%), intra-ventricular hemorrhage (9%), and broncho-pulmonary dysplasia (0.84%). CONCLUSION: Preterm birth is associated with adverse perinatal outcome. This situation needs to be improved by directing appropriately increased resources for improving prenatal health services and providing advanced neonatal care.