Picropodophyllotoxin Inhibits Cell Growth and Induces Apoptosis in Gefitinib-Resistant Non-Small Lung Cancer Cells by Dual-Targeting EGFR and MET

Patients with non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) amplification or sensitive muta-tions initially respond to the tyrosine kinase inhibitor gefitinib, however, the treatment becomes less effective over time by resis-tance mechanism including mesenchymal-epithelial transition (MET) overexpression. A therapeutic strategy targeting MET and EGFR may be a means to overcoming resistance to gefitinib. In the present study, we found that picropodophyllotoxin (PPT), derived from the roots of Podophyllum hexandrum, inhibited both EGFR and MET in NSCLC cells. The antitumor efficacy of PPT in gefitinib-resistant NSCLC cells (HCC827GR), was confirmed by suppression of cell proliferation and anchorage-independent colony growth. In the targeting of EGFR and MET, PPT bound with EGFR and MET, ex vivo, and blocked both kinases activity. The binding sites between PPT and EGFR or MET in the computational docking model were predicted at Gly772/Met769 and Arg1086/Tyr1230 of each ATP-binding pocket, respectively. PPT treatment of HCC827GR cells increased the number of annexin V-positive and subG1 cells. PPT also caused G2/M cell-cycle arrest together with related protein regulation. The inhibition of EGFR and MET by PPT treatment led to decreases in the phosphorylation of the downstream-proteins, AKT and ERK. In addition, PPT induced reactive oxygen species (ROS) production and GRP78, CHOP, DR5, and DR4 expression, mitochondrial dysfunc-tion, and regulated involving signal-proteins. Taken together, PPT alleviated gefitinib-resistant NSCLC cell growth and induced apoptosis by reducing EGFR and MET activity. Therefore, our results suggest that PPT can be a promising therapeutic agent for gefitinib-resistant NSCLC.

Corrigendum: Efficacy of a Knee Walker for Foot and Ankle Patients: Comparative Study with an Axillary Crutch / 대한족부족관절학회지

This correction is being published to correct the corresponding author's name and information in the article.

Efficacy of a Knee Walker for Foot and Ankle Patients: Comparative Study with an Axillary Crutch / 대한족부족관절학회지

PURPOSE: An axillary crutch is the most commonly used assistive device in foot and ankle patients who require nonweightbearing. On the other hand, its use frequently induces axillary or wrist pain and critical neurovascular injuries have been reported in several studies. This study compared the clinical outcomes of patients using the knee walker and axillary crutch. MATERIALS AND METHODS: A retrospective analysis was performed comparing the utility of a knee walker and axillary crutch as a nonweightbearing ambulatory aid for 62 foot and ankle patients treated between November 2016 and March 2018. A comparative study of the two orthosis could be performed because all the patients temporarily used an axillary crutch before or after the use of a knee walker. A demographic study and comparative analysis based on the visual analogue scale (VAS) satisfaction score (0~100), complications, and fall down history were evaluated. Furthermore, under the assumption of having retreatment, their preference of orthosis between the knee walker and axillary crutch was investigated. RESULTS: The mean age of the patients was 36.5 and the mean duration of ambulation with a knee walker and axillary crutch were 5.2 and 2.4 weeks. The VAS satisfaction score of the knee walker and crutch was 88.8 and 27.5, respectively (p < 0.05). The most frequent complications of the knee walker and crutch were ipsilateral knee pain (6 cases) and axillary or wrist pain (56 cases), respectively. No case of falling down occurred during knee walker ambulation, but there were two cases of crutch ambulation. Fifty-eight patients (93.5%) preferred the knee walker and four patients (6.5%) preferred a crutch. CONCLUSION: Compared to the axillary crutch, the knee walker afforded lower complication and higher satisfaction. Most patients preferred the knee walker to a crutch. Therefore, the knee walker is an efficient and safe orthosis for foot and ankle patients who require nonweightbearing.

A Case of Occipital Neuralgia in the Greater and Lesser Occipital Nerves Treated with Neurectomy by Using Transcranial Doppler Sonography: Technical Aspects

Occipital neuralgia is usually defined as paroxysmal stabbing pain in the greater or lesser occipital nerve (GON or LON) distribution. In occipital neuralgia patients, surgical considerations are carefully taken into account if medical management is ineffective. However, identification of the occipital artery by palpation in patients with thick necks or small occipital arteries can be technically difficult. Therefore, we established a new technique using transcranial Doppler (TCD) sonography for more accurate and rapid identification. The patient was a 64-year-old man who had undergone C1-C3 screw fixation and presented with intractable stabbing pain in the bilateral GON and LON distributions. In cases in which pain management was performed using medication, physical therapy, nerve block, or radiofrequency thermocoagulation, substantial pain relief was not consistently achieved, and recurrence of pain was reported. Therefore, we performed occipital neurectomy of the bilateral GON and LON by using TCD sonography, which helped detect the greater occipital artery easily. After the operation, the patient's headache disappeared gradually, although he had discontinued all medication except antidepressants. We believe that this new technique of occipital neurectomy via a small skin incision performed using TCD sonography is easy and reliable, has a short operative time, and provides rapid pain relief.

A Case of Occipital Neuralgia in the Greater and Lesser Occipital Nerves Treated with Neurectomy by Using Transcranial Doppler Sonography: Technical Aspects / 대한통증학회지

Occipital neuralgia is usually defined as paroxysmal stabbing pain in the greater or lesser occipital nerve (GON or LON) distribution. In occipital neuralgia patients, surgical considerations are carefully taken into account if medical management is ineffective. However, identification of the occipital artery by palpation in patients with thick necks or small occipital arteries can be technically difficult. Therefore, we established a new technique using transcranial Doppler (TCD) sonography for more accurate and rapid identification. The patient was a 64-year-old man who had undergone C1-C3 screw fixation and presented with intractable stabbing pain in the bilateral GON and LON distributions. In cases in which pain management was performed using medication, physical therapy, nerve block, or radiofrequency thermocoagulation, substantial pain relief was not consistently achieved, and recurrence of pain was reported. Therefore, we performed occipital neurectomy of the bilateral GON and LON by using TCD sonography, which helped detect the greater occipital artery easily. After the operation, the patient's headache disappeared gradually, although he had discontinued all medication except antidepressants. We believe that this new technique of occipital neurectomy via a small skin incision performed using TCD sonography is easy and reliable, has a short operative time, and provides rapid pain relief.