Tumor suppressor role of cytoplasmic polyadenylation element binding protein 2 (CPEB2) in human mammary epithelial cells.

BACKGROUND: Over-expression of cyclooxygenase (COX)-2 promotes breast cancer progression by multiple mechanisms, including induction of stem-like cells (SLC). Combined gene expression and microRNA microarray analyses of empty vector vs COX-2- transfected COX-2 low MCF7 breast cancer cell line identified two COX-2-upregulated microRNAs, miR-526b and miR-655, both found to be oncogenic and SLC-promoting. Cytoplasmic Polyadenylation Element-Binding Protein 2 (CPEB2) was the single common target of both microRNAs, the functions of which remain controversial. CPEB2 has multiple isoforms (A-F), and paradoxically, a high B/A ratio was reported to impart anoikis-resistance and metastatic phenotype in triple- negative breast cancer cells. We tested whether CPEB2 is a tumor suppressor in mammary epithelial cells. METHODS: We knocked-out CPEB2 in the non-tumorigenic mammary epithelial cell line MCF10A by CRISPR/Cas9-double nickase approach, and knocked-down CPEB2 with siRNAs in the poorly malignant MCF7 cell line, both lines being high CPEB2-expressing. The resultant phenotypes for oncogenity were tested in vitro for both lines and in vivo for CPEB2KO cells. Finally, CPEB2 expression was compared between human breast cancer and non-tumor breast tissues. RESULTS: CPEB2 (isoform A) expression was inversely correlated with COX-2 or the above microRNAs in COX-2-divergent breast cancer cell lines. CPEB2KO MCF10A cells exhibited oncogenic properties including increased proliferation, migration, invasion, EMT (decreased E-Cadherin, increased Vimentin, N-Cadherin, SNAI1, and ZEB1) and SLC phenotype (increased tumorsphere formation and SLC marker-expression). Tumor-suppressor p53 protein was shown to be a novel translationally-regulated target of CPEB2, validated with polysome profiling. CPEB2KO, but not wild-type cells produced lung colonies upon intravenous injection and subcutaneous tumors and spontaneous lung metastases upon implantation at mammary sites in NOD/SCID/IL2Rϒ-null mice, identified with HLA immunostaining. Similarly, siRNA-mediated CPEB2 knockdown in MCF7 cells promoted oncogenic properties in vitro. Human breast cancer tissues (n = 105) revealed a lower mRNA expression for CPEB2 isoform A and also a lower A/B isoform ratio than in non-tumour breast tissues (n = 20), suggesting that CPEB2A accounts for the tumor-suppressor functions of CPEB2. CONCLUSIONS: CPEB2, presumably the isoform A, plays a key role in suppressing tumorigenesis in mammary epithelial cells by repressing EMT, migration, invasion, proliferation and SLC phenotype, via multiple targets, including a newly-identified translational target p53.

Evaluating arsenic contamination in northwestern Bangladesh: A GIS-Based assessment of groundwater vulnerability and human health impacts.

One of the biggest environmental worries in the world today is the risk of arsenic (As) contamination in groundwater. The Atomic Absorption Spectrometer (AAS) was used in this work to assess the As content in groundwater samples from 38 shallow (27 m) tubewells in northwest Bangladesh to determine the existing situation, potential source(s), and likely health risk of As and other important water quality parameters. The range of arsenic concentrations (µgL-1) was troublesome and greater than the WHO recommended level for drinking water, ranging from 0.50 to 164 (mean ± SD: 20.22 ± 36.46). In groundwater, the concentrations of Fe, and Mn vary from 0.04 to 52.75 mgL-1 (mean ± SD: 4.23 ± 9.68), and 0.23 to 3.27 mgL-1 (mean ± SD: 1.10 ± 0.67). The obtained groundwater samples have pH values ranging from 5.9 to 7.1, which indicates a somewhat acidic to neutral character. Major cations have an average abundance that is as follows: Ca2+ > Mg2+ > Na+ > K+, while major anions have an average abundance that is as follows: HCO3- > Cl- > SO42- > NO3-; Ca2+ and HCO3- are the main cation and anion, respectively. The groundwater in the Rajarampur village was deemed unfit for drinking or irrigation based on analyses of water quality performed using the entropy water quality index. The Ca-HCO3 type of water, in which Ca2+ and HCO3- are the main positive ions and negative ions, is suggested by the Piper tri-linear diagram. It was discovered that silicate weathering regulates the hydro-geochemical activities in groundwater using a bi-variate examination of several hydro-chemical variables. Four major clusters were observed for the water sample. According to reductive dissolution processes and principal component analysis, the arsenic in groundwater is geogenic in origin. Arsenic is discharged from sediment to groundwater by reductive dissolution of FeOOH and MnOOH, as shown by the modest connection between As, Fe, and Mn. The United Nations Environmental Protection Agency's (USEPA) suggested value for probable cancer risk assessment was 10-6, however the probable cancer risk assessment found a higher value, indicating that the population in the study region was at high risk for cancer. Remedial measures for arsenic mitigation include removing arsenic from groundwater after it is extracted, searching for alternative aquifers, and implementing various water-supply technologies such as dugwells, deep tubewells, pond-sand filters, and rainwater harvesting systems.

Origin, spatial distribution, sediment contamination, ecological and health risk evaluation of trace metals in sediments of ship breaking area of Bangladesh.

Eleven trace metals (Cd, Cr, Fe, Mn, Cu, Ni, Co, Zn, As, Pb, and Ag) in sediments of Bangladesh's ship breaking area were measured by an atomic absorption spectrometer to determine origin, contamination extent, spatial distributions, and associated ecological and human health hazards. This study found considerable quantities of Pb, Cd, Mn, Zn, and Cu when compared with standards and high levels of Pb, Cd, Zn, Cu, As, and Ag contamination according to pollution evaluation indices. Different indices indicate most of the sampling sites were highly polluted. However, spatial distribution maps indicate that trace metals were predominantly deposited in the northern and southern region. The ecological risk index revealed that Cd has the highest while Pb and As had moderate risk. Based on the health index values, Zn for both adults and children were higher than the safe limit while Mn, Pb, Cr, As, Fe, Cu, Ni, and Co for children were close to the threshold. The mean total carcinogenic risk values of Cr, As, and Ni for children and Ni for adults exceeded the permissible threshold. The cancer risk possibilities were further assessed using Monte Carlo simulation. Most trace metals have anthropogenic origins, which were attributed to ship breaking activities.

Spatial distribution, water quality, human health risk assessment, and origin of heavy metals in groundwater and seawater around the ship-breaking area of Bangladesh.

The concentrations of eleven heavy metals (Pb, Cd, Cr, Fe, Mn, Zn, Cu, Ni, Co, As, and Ag) were assessed in both groundwater and seawater collected from the ship-breaking industrial area of Bangladesh using an atomic absorption spectrometer. The investigation aimed to estimate the water quality and pollution level employing several indices, and its associated health risks for the first time in that area. This study found that Cd, Cr, Fe, Pb, Mn, and Ni were higher in both groundwater and seawater compared with WHO standards. Based on the WQI (water quality index) and EWQI (entropy water quality index) classifications, the quality of most of the groundwater is extremely poor or unsuitable for drinking purposes. Furthermore, the HPI (heavy metal pollution index), HEI (heavy metal evaluation index), and CD (degree of contamination) values of most groundwater and all seawater samples exhibit a higher degree of pollution. In addition, the results of NI (Nemerow pollution index) come to an end that both groundwater and seawater in the study area are mostly polluted by Fe, Mn, Pb, Cr, and Cd. Although the HI (hazard quotient index) values of almost all studied heavy metals in both cases of adults and children are within the safe limit, the HI value of Cr for an adult is near the threshold limit and the maximum HI value of Cr for children exceeds this limit. The carcinogenic risk reveals that Cr, Pb, As, and Cd produce detrimental effects on local people through the direct ingestion of groundwater. The pollution source is identified using principal component analysis and a Pearson correlation matrix as being primarily anthropogenic and attributed to intensive ship-breaking activities or other industries in the area.

Comparison of the clinical characteristics and outcomes associated with vancomycin-resistant Enterococcus faecalis and vancomycin-resistant E. faecium bacteremia.

In published studies, cohorts of patients with bacteremia due to vancomycin-resistant Enterococcus (VRE) have predominantly been infected with Enterococcus faecium. Little is known about the epidemiology and outcomes associated with bacteremia due to VR Enterococcus faecalis. A retrospective study of isolates obtained from January 2008 to October 2010 was conducted at Detroit Medical Center (DMC). Unique patients with blood cultures positive for VRE were reviewed. Outcomes were analyzed using logistic regression. During the study period, 105 cases of bacteremia due to VR E. faecalis and 197 cases of bacteremia due to VR E. faecium were identified. The mean age in the study cohort was 61.5 ± 15 years; 162 subjects (53.6%) were male. After controlling for a propensity score, bacteremia due to VR E. faecalis was associated with >2-fold-lower in-hospital mortality than bacteremia due to VR E. faecium. Interestingly, bacteremia due to VR E. faecalis was associated with longer hospital stay after VRE isolation, although total length of stay was similar for groups with VR E. faecalis and VR E. faecium. Bacteremia due to VR E. faecalis was associated with a >2-fold-lower risk for mortality than bacteremia due to VR E. faecium, possibly due to the availability of ß-lactam therapeutics for treatment of VR E. faecalis.

Hepatic involvement in children with acute bronchiolitis.

BACKGROUND: Respiratory syncytial virus (RSV) is a prevalent cause of lower respiratory tract infections. It may be associated with hepatocellular involvement, as indicated by increased liver enzymes aspartate aminotransferase and alanine transaminase (ALT). AIM: To evaluate the rate of increased liver enzyme levels in children with acute bronchiolitis and correlate them with clinical, laboratory, and radiological variables. METHODS: The study was a retrospective review of the medical records of children who presented with acute bronchiolitis when admitted to the Pediatric Department, Salmaniya Medical Complex, the Kingdom of Bahrain, between 2019 and 2020. We collected the demographic data, the clinical presentation, the laboratory and radiological findings, and the clinical outcomes. We compared the patients with elevated liver enzymes to those with normal levels at the time of presentation and at follow-up. RESULTS: We included 166 (57.8%) of 287 patients with acute bronchiolitis who fulfilled the inclusion criteria. Ninety-three (56%) patients were males. The median age at presentation was 3.4 (interquartile range 1.1 to 12.4) mo. Fifty-four (28%) patients tested positive for RSV, which was confirmed in 15 of them (28%) by PCR. Laboratory findings of 161 patients tested at presentation showed high ALT levels in 14 (8.7%) patients and normal ALT in 147 (91.3%). Coagulation profiles were measured in 46 (27.7%) of 166 patients. High prothrombin time was present in 15 (32.6%), a high international normalized ratio was present in 13 (28.3%), and high activated partial thromboplastin time was present in three (6.5%). Thrombin time was elevated in nine (27.3%) of 33 patients. Five (21.7%) of 23 patients with available radiological data had hepatomegaly; one of them had findings suggestive of fatty infiltration. High ALT had a significant association with lengthy hospital stays (P < 0.05) and positive urine culture (P < 0.05). Seventy (42.2%) patients had documented follow-up with liver function tests over a median follow-up period of 10.2 (IQR, 2.4-23.3) mo. Total serum protein and serum globulin levels were normalized at the follow-up time, with a significant P value of < 0.05. CONCLUSION: This study showed a low prevalence of liver function involvement in patients with acute bronchiolitis with a benign course. However, there was a rising trend in ALT during follow-up. Prolonged hospital stay and positive urine cultures were associated with elevated liver enzymes.

C-Reactive Protein Levels in Children with Acute Bronchiolitis.

Results: Of 287 patients, 229 (79.2%) were included. 132 (57.6%) were males. Median presentation age was 3.7 (interquartile range (IQR), 1.27-12.33) months. Median CRP level was 10.4 (IQR, 2.8-35.1) mg/L. CRP was high in 167 (72.9%) patients. 17.6% (33/187 patients) had confirmed bacterial coinfection. Respiratory syncytial virus (RSV) was detected in 84 (36.7%) patients. Mean CRP level was higher in RSV-negative compared to RSV-positive patients, 31.3 ± 44.3 versus 21.5 ± 27.7 mg/L, respectively (P = 0.042). Respiratory viral serology profile was positive in 34.7% (17/49 patients). 66.9% (107/160 patients) had positive chest X-ray. Antibiotics were used in 78.1% (179/227 patients). Thirteen (5.7%) patients required intensive care, five (2.2%) had surgical intervention, four (1.8%) required endotracheal intubation, and four (1.8%) died. Patients with high CRP were older at presentation (P < 0.0001) and had more fever (P < 0.0001) and cough (P = 0.002), but lower hemoglobin level (P < 0.0001) compared to those with normal CRP. Fever (P = 0.016) and hemoglobin level (P = 0.002) were independent factors. Conclusion: Most children with acute bronchiolitis had high rate of elevated CRP values that did not correlate with the rate of bacterial coinfection. High CRP levels were found in older children, those presented with more fever and cough, and had a lower hemoglobin level despite that those factors were previously reported to be associated with disease severity and bacterial coinfection. This study also showed a high overall rate of antibiotic prescriptions in mostly viral disease.

Mechanism of arsenic enrichment and mobilization in groundwater from southeastern Bangladesh: Water quality and preliminary health risks assessment.

To understand the mechanistic pathway of arsenic (As) enrichment and mobilization in groundwater (southeastern Bangladesh) and to evaluate the water quality as well as associated health risks, a suite of systematically collected groundwater samples (depth: 17-61 m) were analyzed. Arsenic concentrations (µg L-1) in the groundwater samples were ranged from 6 to 581 with a mean value of 199 which is significantly higher than the recommended values. The assessment of water quality using entropy water quality index and irrigation water quality indices revealed that the groundwater in the studied region was not recommended for drinking and irrigation, respectively with few exceptions. Dominant water types in the studied area were Ca-Mg-HCO3, Na-HCO3, and Na-Cl types. Various forms of water-rock interactions, leaching of evaporates, and the confined nature of the aquifer mostly control the hydro-chemical parameters. Fe/Mn bound As are likely to be released in the aquifer through the dissolution of carbonate minerals of Fe/Mn while the higher degree of water-rock interaction and probable oxidation of organic materials helped to elevate As concentration. The probable longer residence time of groundwater guided by topographic slope and the neighboring clayey aquitard govern the As mobilization in the aquifer. Probabilistic health risk assessment revealed that groundwaters from the studied area can cause both non-carcinogenic and carcinogenic health risks.

Calcified Prolactinoma of the Pituitary Gland: Illustrative Case Reports Highlighting Medical versus Surgical Intervention.

The presence of calcification is uncommon in pituitary adenomas, and often lends support to other diagnoses including craniopharyngioma. The majority of calcified pituitary adenomas are prolactin-secreting tumors. We report two patients with calcified macroprolactinomas, one that was treated medically with a biochemical response and partial tumor response, and one that was treated successfully via an endoscopic endonasal transsphenoidal approach. Suspected calcified prolactinomas can be initially managed medically as per standard treatment for typical prolactinomas; however, the presence of diffuse calcification may hinder tumor shrinkage. Tumors that are refractory to medical treatment can be safely managed with surgery.

Primary Hyperoxaluria Type 1 with Thrombophilia in Pregnancy: A Case Report.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease caused by a mutation in the AGXT gene, resulting in deficiency of the alanineglyoxylate:aminotransferase enzyme. It is characterized by accumulation of oxalate in the kidneys and other organs. CASE PRESENTATION: A Syrian woman with a history of nephrolithiasis and heterozygosity for factor V Leiden and prothrombin gene mutations presented with postpartum renal failure. She required initiation of renal replacement therapy at 14 weeks postpartum. Kidney biopsy showed severe acute and chronic crystalline deposition consistent with oxalate nephropathy. Genetic testing revealed a Gly170Arg mutation in the AGXT gene, confirming the diagnosis of PH1. CONCLUSIONS: The diagnosis of PH should be considered in patients with severe, recurrent calcium oxalate nephrolithiasis. Early treatment with pyridoxine reduces urinary oxalate excretion and can delay progression to end-stage renal disease (ESRD). After ESRD, intensive dialysis is needed to prevent systemic oxalate accumulation and deposition. Combined liver and kidney transplantation is curative. In our patient, we anticipate that liver transplantation will cure both the hyperoxaluria and the hypercoagulable state.

COX-2 induces oncogenic micro RNA miR655 in human breast cancer.

We show that Cyclooxygenase-2 over-expression induces an oncogenic microRNA miR655 in human breast cancer cells by activation of EP4. MiR655 expression positively correlated with COX-2 in genetically disparate breast cancer cell lines and increased in all cell lines when grown as spheroids, implicating its link with stem-like cells (SLCs). Ectopic miR655 over-expression in MCF7 and SKBR3 cells resulted in increased proliferation, migration, invasion, spheroid formation and Epithelial to Masenchymal transition (EMT). Conversely, knocking down miR655 in aggressive MCF7-COX2 and SKBR3-COX2 cells reverted these phenotypes. MCF7-miR655 cells displayed upregulated NOTCH/WNT genes; both pathway inhibitors abrogated miR655-induced spheroid formation, linking miR655 with SLC-related pathways. MiR655 expression was dependent on EP4 activity and EP4 downstream signaling pathways PI3K/AKT, ERK and NF-kB and led to TGFß resistance for Smad3 phosphorylation. Tail vein injection of MCF7-miR655 and SKBR3-miR655 cells in NOD/SCID/GUSB-null mice revealed increased lung colony growth and micrometastases to liver and spleen. MiR655 expression was significantly high in human breast tumors (n = 105) compared to non-tumor tissues (n = 20) and associated with reduced patient survival. Thus miR655 could serve as a prognostic breast cancer biomarker.

Trace metals pollution in seawater and groundwater in the ship breaking area of Sitakund Upazilla, Chittagong, Bangladesh.

This study reveals potential accumulation of trace metals in the sea and groundwater due to ship breaking activities which take place along the Bay of Bengal in Sitakund Upazilla, Chittagong, Bangladesh. When compared with WHO and Bangladesh domestic standards for water quality, it is revealed that seawater was strongly polluted by Fe and Hg, moderately by Mn and Al, and slightly by Pb and Cd. Groundwater was strongly polluted by Fe, Pb and Hg, moderately by Mn and Al, and slightly by As. Trace element concentrations of all seawater samples exceeded the average concentration of elements in the Earth's seawater. The application of Principal Components Analysis identified two sources of pollution-marine and ship breaking. The mechanism of groundwater pollution inferred that if seawater is polluted, nearby groundwater is also polluted with trace metals due to the influence of seawater intrusion.

The burden of multidrug-resistant organisms on tertiary hospitals posed by patients with recent stays in long-term acute care facilities.

BACKGROUND: Long-term acute care (LTAC) facilities admit patients with complex, advanced disease states. Study aims were to determine the burden posed on hospitals associated with LTAC exposure and analyze the differences between "present on admission" (POA) multidrug-resistant (MDR), gram-negative organisms (GNO) and POA MDR gram-positive organisms (GPO). METHODS: A multicenter retrospective study was conducted in 13 hospitals from southeast Michigan, from September 1, 2008, to August 31, 2009. Cultures obtained in the first 72 hours of hospitalization (ie, POA) of MDR-GPO and MDR-GNO were reviewed. LTAC exposures in the previous 6 months and direct admission from a LTAC were recorded. RESULTS: Overall, 5,297 patients with 7,147 MDR POA cultures were analyzed: 2,619 (36.6%) were MDR-GNO, and 4,528 (63.4%) were MDR-GPO. LTAC exposure in the past 6 months was present in 251 (5.2%) infectious episodes and was significantly more common among POA MDR-GNO than MDR-GPO (158 [8.6%] and 94 [3.1%], respectively, odds ratio, 2.87; P < .001). Recent LTAC exposure was strongly associated with both carbapenem-resistant Enterobacteriaceae (CRE) (31.6% of all CRE cases, P < .001) and Acinetobacter baumannii (14.9% of all A baumannii cases, P < .001). CONCLUSION: Nearly 10% of MDR-GNO POA had recent LTAC exposure. Hospital efforts to control the spread of MDR-GNO should focus on collaborations and communications with referring LTACs and interventions targeted towards patients with recent LTAC exposure.