Identification of a Novel GRHL3/HOPX/Wnt/ß-Catenin Proto-oncogenic Axis in Squamous Cell Carcinoma of the Esophagus.

BACKGROUND & AIMS: Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with a poor long-term prognosis. The molecular mechanisms underlying the initiation and progression of this tumor are largely unknown. The transcription factor GRHL3 functions as a potent tumor suppressor in SCC of skin, head, and neck. This study aims to determine whether GRHL3 also plays a role in the homeostasis of the esophageal epithelium and in the development of ESCC. METHODS: The effects of Grhl3 deletion on squamous epithelial homeostasis in embryos and adult mice were examined using immunohistochemistry, transmission electron microscopy, and real-time polymerase chain reaction. The conditionally deleted mice were subsequently used to determine susceptibility to ESCC. Whole-transcriptome sequencing (RNA-seq) was performed on ESCC in wild-type and Grhl3 deleted animals. To decipher the signaling pathways, real-time polymerase chain reaction, immunohistochemistry, analysis of chromatin immunoprecipitation sequencing, chromatin immunoprecipitation-polymerase chain reaction, and RNA seq datasets were used. Primary human samples were used to validate the findings in the mouse model. RESULTS: Loss of Grhl3 perturbs the proliferation-differentiation balance in the esophageal epithelium, thereby increasing the susceptibility to esophageal carcinogenesis in adult mice. Grhl3 imparts its tumor suppressor function by regulating the expression of HOPX. We have identified the Wnt/ß-catenin pathway as the downstream effectors of GRHL3 and HOPX through our integrated approach using patient-derived ESCC samples and mouse models. CONCLUSIONS: GRHL3 conveys its tumor suppressor function in ESCC through regulating its target gene HOPX, which limits Wnt/ß-catenin signaling. Targeted therapies to inhibit this pathway could be a potential treatment strategy for ESCC patients with reduced GRHL3 expression.

Antimicrobial Sensitivity Pattern from Hospitalized Pneumonia Patients in National Referral Infectious Disease Hospital in Indonesia.

Background: Pneumonia is still a major global problem with high morbidity and mortality. The increasing number of pneumonia cases caused by bacteria, especially multidrug-resistant pathogens, increasing age of the population, patients with chronic disease (comorbid), and inappropriate antimicrobial therapy at initial administration make the treatment become less effective. These issues finally contribute to higher morbidity and mortality in cases of hospitalized pneumonia patients. Therefore, it is crucial to know the microbial pattern and select the therapy according to local antimicrobial sensitivity patterns. Method: A cross-sectional study was conducted for hospitalized pneumonia patients between January 2015 and December 2016 in Indonesia National Referral Infectious Disease Hospital. Data were collected from medical records to show patient characteristics, antimicrobial treatment data, culture examination, and bacterial sensitivity. Results: A total of 99 pneumonia patients required hospitalization and underwent sputum culture examination. The patients were mostly above 65 years old (32.3%) and male (57.6%). The most common comorbidities were pulmonary tuberculosis (21%), and the others were heart failure, chronic obstructive pulmonary disease (COPD), and HIV/AIDS. Based on the sputum culture, fungi were identified in most specimens (56%), while the bacteria identified were Klebsiella pneumoniae (14%), Acinetobacter sp. (12%), and Pseudomonas sp. (8%). Third-generation cephalosporin, such as ceftriaxone (50%), was commonly used as an antibiotic for pneumonia treatment. Conclusion: Most common bacteria isolated from sputum culture were Klebsiella pneumoniae which were more sensitive to the beta-lactam and aminoglycoside groups. The higher risk factors were age above 65 years old, being male, and having tuberculosis.