Molecular Epidemiology, Risk Factors and Clinical Outcomes of Carbapenem-Nonsusceptible Enterobacter cloacae Complex Infections in a Taiwan University Hospital.

The genus Enterobacter is a member of the ESKAPE group, which contains the major resistant bacterial pathogens. Enterobacter cloacae complex (ECC) has emerged as a clinically significant cause of a wide variety of nosocomial infections. Carbapenem-nonsusceptible Enterobacter cloacae complex (CnsECC) has become an emerging threat to public health but there is still a lack of comprehensive molecular and clinical epidemiological analysis. A total of 157 CnsECC isolates were recovered during October 2011 to August 2017. hsp60 gene sequencing and pulsed-field gel electrophoresis (PFGE) were applied to discriminate the species, genetic clusters and clonal relatedness. All the isolates were subjected to polymerase chain reaction (PCR) analysis for carbapenemase, AmpC-type ß-lactamase, and extended spectrum ß-lactamase (ESBL) genes. Clinical data were collected on all patients for comparing clinical risks and outcomes between patients with carbapenemase-producing (CP)-CnsECC compared with non-CP-CnsECC infection. The most commonly identified species was E. hormaechei subsp. hoffmannii (47.1%), followed by E. hormaechei subsp. steigerwaltii (24.8%). Different species of CnsECC isolates showed heterogeneity in resistance patterns to piperacillin/tazobactam, cefepime and levofloxacin. In the present study, we observed that E. hormaechei subsp. hoffmannii was characterized with higher cefepime and levofloxacin resistance rate but lower piperacillin/tazobactam resistance rate relative to other species of CnsECC. CP-CnsECC comprised 41.1% (65 isolates) and all of these isolates carried IMP-8. In this study, 98% of patients had antimicrobial therapy prior to culture, with a total of 57/150 (38%) patients being exposed to carbapenems. Chronic pulmonary disease (OR: 2.51, 95% CI: 1.25-5.06), received ventilator support (OR: 5.54, 95% CI: 2.25-12.03), steroid exposure (OR: 3.88, 95% CI: 1.91-7.88) and carbapenems exposure (OR: 2.17, 95% CI: 1.10-4.25) were considered risk factors associated with CP-CnsECC infection. The results suggest that CP-CnsECC are associated with poorer outcomes including in-hospital mortality, 30-day mortality and 100-day mortality. Our study provides insights into the epidemic potential of IMP-8-producing E. cloacae for healthcare-associated infections and underscores the importance of understanding underlying resistance mechanisms of CnsECC to direct antibiotic treatment decisions.

Compound mutations in human anion exchanger 1 are associated with complete distal renal tubular acidosis and hereditary spherocytosis.

Missense, nonsense, and frameshift mutations in the human anion exchanger 1 have been associated with inherited distal renal tubular acidosis and hereditary spherocytosis. These two disorders, however, are almost always mutually exclusive. We have found an important and unusual exception: a novel combination of heterozygous E522K and G701D mutations in the anion exchanger 1 manifested as complete distal renal tubular acidosis and severe hereditary spherocytosis in an affected patient. Analysis of protein trafficking and subcellular localization of the wild-type kidney isoform of human anion exchanger 1 and these mutants transfected into MDCK cells showed they formed homodimers or heterodimers with each other. Homodimers of the wild-type and E522K mutant were found at the plasma membrane, whereas the G701D mutant largely remained in the cytoplasm. Heterodimers of either E522K or G701D and the wild-type exchanger were located in the plasma membrane, whereas E522K/G701D heterodimers remained in the cytoplasm. Our study shows that the compound E522K/G701D mutation of human anion exchanger 1 causes a trafficking defect in kidney cells, and this may explain the complete distal renal tubular acidosis of the patient.

MicroRNA-373 (miR-373) post-transcriptionally regulates large tumor suppressor, homolog 2 (LATS2) and stimulates proliferation in human esophageal cancer.

LATS2 is a member of the LATS tumor suppressor family. It has been implicated in regulation of the cell cycle and apoptosis. Frequent loss of heterozygosity (LOH) of LATS2 has been reported in human esophageal cancer. But, the LATS2 gene expression and its regulatory mechanism in esophageal cancer remain unclear. The present study has shown that LATS2 protein expression was mediated by miR-373 at the post-transcriptional level and inversely correlated with miR-373 amounts in esophageal cancer cell lines. Furthermore, we demonstrated that the direct inhibition of LATS2 protein was mediated by miR-373 and manipulated the expression of miR-373 to affect esophageal cancer cells growth. Moreover, this correlation was supported by data collected ex vivo, in which esophageal cancer tissues from esophageal squamous cell carcinoma (ESCC) patients were analyzed. Finally, by miRNA microarray analysis, four miRNAs including miR-373 were over-expressed in ESCC samples. Our findings reveal that miR-373 would be a potential oncogene and it participates in the carcinogenesis of human esophageal cancer by suppressing LATS2 expression.