An activation of LC3A-mediated autophagy contributes to de novo and acquired resistance to EGFR tyrosine kinase inhibitors in lung adenocarcinoma.

The development of therapeutic resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs, ie erlotinib or gefitinib) has been the major clinical problem when treating lung adenocarcinoma patients with these agents. However, its mechanisms have not necessarily been well studied to this date. Autophagy has been recently considered to play pivotal roles in escaping from the effects of anti-neoplastic agents. Therefore, in this study, we examined its roles in the development of resistance to EGFR-TKIs in lung adenocarcinoma. We first established erlotinib-resistant cell lines (PC9/ER) from parental PC9 cells by exposing the cells to erlotinib. In PC9/ER, autophagy-related LC3A expression came to be up-regulated and constitutive activation of LC3A-mediated autophagy became more pronounced through the process of acquiring therapeutic resistance. In addition, inhibition of LC3A or autophagy restores sensitivity to EGFR-TKIs in PC9/ER. LC3A was also activated at the transcriptional level in de novo resistant cells via demethylation of the MAP1LC3A gene. We then evaluated the status of LC3A in 169 lung adenocarcinoma patients using immunohistochemistry. LC3A immunoreactivity was only detected in carcinoma cells (89/169 patients), not in non-tumoural cells. In addition, LC3A immunoreactivity was significantly correlated with progression-free survival (p = 0.0039) and overall survival (p = 0.0040) of 35 patients treated with EGFR-TKIs. The results of our present study demonstrated that LC3A-mediated autophagy in carcinoma cells was involved in the development of resistance to EGFR-TKIs, and that LC3A could serve as a promising therapeutic target for overcoming resistance to EGFR-TKIs and a novel predictor of response to EGFR-TKIs in lung adenocarcinoma patients.

Escherichia coli pneumonia in combination with fungal sinusitis and meningitis in a tsunami survivor after the Great East Japan Earthquake.

Individuals who survive near drowning often suffer from complicated infections, including multi-organ and polymicrobial events. This pattern may be especially pronounced among patients exposed to infectious agents during catastrophic events like that of the Great East Japan Earthquake and the associated tsunami disaster. We report here on a patient who presented with Escherichia coli (E. coli) pneumonia in combination with fungal sinusitis and meningitis. A 73-year-old woman survived the tsunami that engulfed the Sanriku coast. By the time of hospital admission, the patient exhibited high fever, severe cough, and sputum production. Chest X-ray and CT scan showed consolidation in the left upper lobe. Administration of an antibacterial agent improved this pneumonia. However, the patient's consciousness was increasingly impaired. Brain CT showed the low-density lesions and partial high-density spot in the sinus, which suggests the fungal infection. MRI showed the inflammation in the sinus spread into the central nerve system. The examination of the cerebrospinal fluid showed the low glucose level, high mononuclear cell count, and highß-D glucan level, the findings of which supported the diagnosis of fungal meningitis. Although the patient improved temporarily in response to combination treatment with anti-fungal agents, no further improvement was seen. In conclusion, this patient, who suffered from infections of pneumonia, sinusitis, and meningitis, presented a quite rare clinical progress. We propose that fungal infection should be taken into consideration in individuals who suffered near drowning, a profile expected to be frequent among tsunami survivors.

Anterior gradient 2 is correlated with EGFR mutation in lung adenocarcinoma tissues.

BACKGROUND: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) has demonstrated a promising therapeutic response in lung adenocarcinoma patients with EGFR gene mutations. However, the predictive factors for this therapy have not been established, except for the EGFR gene mutation status of carcinoma cells. METHODS: We first performed microarray analysis in EGFR-TKI-sensitive lung adenocarcinoma cell lines. The results indicated anterior gradient 2 (AGR2) as a potential surrogate marker of EGFR-TKI. Therefore, we then evaluated the correlation between the status of AGR2 immunoreactivity and clinicopathological factors including overall survival (OS), progression-free survival (PFS) and clinical response to EGFR-TKI, in 147 cases of surgically resected lung adenocarcinoma. The biological significance of AGR2 was further evaluated by transfecting small interfering RNA (siRNA) against AGR2 in these cells. RESULTS: The status of AGR2 immunoreactivity was significantly higher in lung adenocarcinoma cases with EGFR gene mutations than in those with the wild type (p<0.0001), but there were no significant differences in OS, PFS and response of EGFR-TKI between the AGR2 high and low carcinoma cases. Knockdown of AGR2 gene expression following siRNA transfection resulted in a significantly lower response to EGFR-TKI in EGFR-mutated PC-3. CONCLUSIONS: AGR2 could serve as an adjunctive surrogate protein marker possibly reflecting EGFR gene mutations in lung adenocarcinoma patients. Results from in vitro analysis indicated that AGR2 could be a potential clinical biomarker of EGFR-TKI therapeutic sensitivity in lung adenocarcinoma cells.

Two cases of acute respiratory distress syndrome with high values of Chlamydophila pneumoniae-specific antibodies.

We herein report two cases of acute respiratory distress syndrome (ARDS) with high values of Chlamydophila pneumoniae-specific antibodies. In the first case (a 65-year-old man), high levels of anti-C. pneumoniae antibodies (IgG and IgA) were detected on admission, and the anti-C. pneumoniae IgA level rose by Day 30. The patient was successfully treated with quinolone and steroids. In the second case (an 85-year-old man), abnormally high levels of anti-C. pneumoniae IgM were detected on admission. The patient did not recover, despite receiving treatment with several antibiotics and anti-inflammatory agents. Neither of the patients displayed other pathogen-specific antigens or antibodies. Chlamydophila pneumonia is usually mild, although it can cause severe interstitial pneumonia and ARDS in reinfected patients and the elderly.