FAM167A is a key molecule to induce BCR-ABL-independent TKI resistance in CML via noncanonical NF-κB signaling activation

Abstract Background BCR-ABL-independent drug resistance is a barrier to curative treatment of chronic myeloid leukemia (CML). However, the molecular pathways underlying BCR-ABL-independent tyrosine kinase inhibitor (TKI) resistance remain unclear. Methods In silico bioinformatic analysis was performed to identify the most active transcription factor and its inducer that contribute to BCR-ABL-independent TKI resistance. Tandem mass spectrometry analysis was performed to identify the receptor for the noncanonical NF-κB activator FAM167A. In vitro and in vivo mouse experiments revealed detailed molecular insights into the functional role of the FAM167A-desmoglein-1 (DSG1) axis in BCL-ABL-independent TKI resistance. CML cells derived from CML patients were analyzed using quantitative reverse transcription PCR and flow cytometry. Results We found that NF-κB had the greatest effect on differential gene expression of BCR-ABL-independent TKI-resistant CML cells. Moreover, we found that the previously uncharacterized protein FAM167A activates the noncanonical NF-κB pathway and induces BCR-ABL-independent TKI resistance. Molecular analyses revealed that FAM167A activates the noncanonical NF-κB pathway by binding to the cell adhesion protein DSG1 to upregulate NF-κB-inducing kinase (NIK) by blocking its ubiquitination. Neutralization of FAM167A in a mouse tumor model reduced noncanonical NF-κB activity and restored sensitivity of cells to TKIs. Furthermore, FAM167A and surface DSG1 levels were highly upregulated in CD34+ CML cells from patients with BCR-ABL-independent TKI-resistant disease. Conclusions These results reveal that FAM167A acts as an essential factor for BCR-ABL-independent TKI resistance in CML by activating the noncanonical NF-κB pathway. In addition, FAM167A may serve as an important target and biomarker for BCR-ABL-independent TKI resistance

Pulmonary hypertension due to obstructive sleep apnea in a child with Rubinstein-Taybi syndrome

Rubinstein-Taybi syndrome (RTS) is characterized by peculiar facies, mental retardation, broad thumbs, and great toes. Approximately one-third of the affected individuals have a variety of congenital heart diseases. They can also have upper airway obstruction during sleep, due to hypotonia and the anatomy of the oropharynx and airway, which make these patients susceptible to obstructive sleep apnea (OSA). In our case, pulmonary hypertension was caused, successively, by congenital heart defects (a large patent ductus arteriosus and arch hypoplasia) and obstructive sleep apnea during early infancy. The congenital heart defects were surgically corrected, but persistent pulmonary hypertension was identified 2 months after the operation. This pulmonary hypertension was due to OSA, and it was relieved by nasal continuous positive airway pressure. This case is the first report of pulmonary hypertension from OSA in a young infant with RTS

A Case of Disseminated and Fulminant Plasmacytomas That Developed during Bortezomib Treatment

Multiple myeloma is an incurable and slow growing plasma cell neoplasm. The introduction of new drugs has increased the number of treatment options. Bortezomib, the first-in-class proteasome inhibitor, has been shown to have a significant antitumor activity in the treatment of relapse/refractory patients with multiple myeloma. Additionally, plasmacytomas have shown significant response to bortezomib. In this case report, we describe a patient who developed disseminated and fulminant extramedullary plasmacytomas during combination chemotherapy treatment with bortezomib within a short period, after having shown clinical improvement

Subconjuctival Loa loa with Calabar Swelling

Loa loa is unique among the human filariae in that adult worms are occasionally visible during subconjuntival migration. A 29-yr-old African female student, living in Korea for the past 5 yr without ever visiting her home country, presented with acute eyelid swelling and a sensation of motion on the left eyeball. Her symptoms started one day earlier and became worse over time. Examination revealed a threadlike worm beneath the left upper bulbar conjunctiva with mild eyelid swelling as well as painless swelling of the right forearm. Upon exposure to slit-lamp illumination, a sudden movement of the worm toward the fornix was noted. After surgical extraction, parasitologic analysis confirmed the worm to be a female adult Loa loa with the vulva at the extreme anterior end. On blood smear, the microfilariae had characteristic features of Loa loa, including sheath and body nuclei up to the tip of the tail. The patient also showed eosinophilia (37%) measuring 4,100/µL. She took ivermectin (200 µg/kg) as a single dose and suffered from a mild fever and chills for one day. This patient, to the best of our knowledge, is the first case of subconjunctival loiasis with Calabar swelling in Korea

Impairment of Instrumental Activities of Daily Living in Patients with Mild Cognitive Impairment

ObjectiveaaThis study was conducted to examine the following: whether patients with mild cognitive impairment (MCI) show impairments in instrumental activities of daily living (IADL) as compared to controls; to identify the functional sub-domains of instrumental activities of daily living (IADL) that are affected in MCI and, finally, to identify the Seoul-Instrumental Activities of Daily Living (S-IADL) scale cut-off score that best differentiated between MCI and controls. MethodsaaThis study was carried out at the geropsychiatry clinic, university hospital. The study participants included 66 patients with MCI and 61 normal elderly. The S-IADL and Seoul-Activities of Daily Living (S-ADL) scales were administered to the main caregivers of all participants in order to assess everyday functioning. ResultsaaThe total S-IADL score was significantly higher in the patients with MCI [mean (SD) score=4.47 (2.06)] than in the controls [mean (SD) score=1.44 (1.65)] (p<0.001). The patients with MCI performed significantly worse on IADLs, such as the ability to use the telephone, prepare meals, take medication, manage belongings, keep appointments, talk about recent events, and perform leisure activities/hobbies (p<0.05). The S-IADL scal

The inhibition of inflammatory molecule expression on 3T3-L1 adipocytes by berberine is not mediated by leptin signaling

In our previous study, we have shown that berberine has both anti-adipogenic and anti-inflammatory effects on 3T3-L1 adipocytes, and the anti-adipogenic effect is due to the down-regulation of adipogenic enzymes and transcription factors. Here we focused more on anti-inflammatory effect of berberine using real time RT-PCR and found it changes expressions of adipokines. We hypothesized that anti-adipogenicity of berberine mediates anti-inflammtory effect and explored leptin as a candidate mediator of this signaling. We studied this hypothesis by western blot analysis, but our results showed that berberine has no effect on the phosphorylations of STAT-3 and ERK which have important roles on leptin signaling. These results led us to conclude that the anti-inflammatory effect of berberine is not mediated by the inhibition of leptin signal transduction. Moreover, we have found that berberine down-regulates NF-κB signaling, one of the inflammation-related signaling pathway, through western blot analysis. Taken together, the anti-inflammatory effect of berberine is not mediated by leptin, and berberine induces anti-inflammatory effect independent of leptin signaling