Hemorrhagic Complications Following Ultrasound-Guided Breast Biopsy: A Prospective Patient-Centered Study.

OBJECTIVE: We aimed to evaluate the clinical and imaging factors associated with hemorrhagic complications and patient discomfort following ultrasound (US)-guided breast biopsy. MATERIALS AND METHODS: We prospectively enrolled 94 patients who were referred to our hospital between June 2022 and December 2022 for US-guided breast biopsy. After obtaining informed consent, two breast radiologists independently performed US-guided breast biopsy and evaluated the imaging findings. A hemorrhagic complication was defined as the presence of bleeding or hematoma on US. The patients rated symptoms of pain, febrile sensation, swelling at the biopsy site, and dyspnea immediately, 20 minutes, and 2 weeks after the procedure on a visual analog scale, with 0 for none and 10 for the most severe symptoms. Additional details recorded included those of nausea, vomiting, bleeding, bruising, and overall satisfaction score. We compared the clinical symptoms, imaging characteristics, and procedural features between patients with and those without hemorrhagic complications. RESULTS: Of 94 patients, 7 (7%) developed hemorrhagic complications, while 87 (93%) did not. The complication resolved with 20 minutes of manual compression, and no further intervention was required. Vascularity on Doppler examination (P = 0.008), needle type (P = 0.043), and lesion location (P < 0.001) were significantly different between the groups. Patients with hemorrhagic complications reported more frequent nausea or vomiting than those without hemorrhagic complications (29% [2/7] vs. 2% [2/87], respectively; P = 0.027). The overall satisfaction scores did not differ between the two groups (P = 0.396). After 2 weeks, all symptoms subsided, except bruising (50% 2/4 in the complication group and 25% [16/65] in the no-complication group). CONCLUSION: US-guided breast biopsy is a safe procedure with a low complication rate. Radiologists should be aware of hemorrhagic complications, patient discomfort, and overall satisfaction related to this procedure.

Primary Ciliogenesis by 2-Isopropylmalic Acid Prevents PM2.5-Induced Inflammatory Response and MMP-1 Activation in Human Dermal Fibroblasts and a 3-D-Skin Model.

Particulate matters (PMs) increase oxidative stress and inflammatory response in different tissues. PMs disrupt the formation of primary cilia in various skin cells, including keratinocytes and melanocytes. In this study, we found that 2-isopropylmalic acid (2-IPMA) promoted primary ciliogenesis and restored the PM2.5-induced dysgenesis of primary cilia in dermal fibroblasts. Moreover, 2-IPMA inhibited the generation of excessive reactive oxygen species and the activation of stress kinase in PM2.5-treated dermal fibroblasts. Further, 2-IPMA inhibited the production of pro-inflammatory cytokines, including IL-6 and TNF-α, which were upregulated by PM2.5. However, the inhibition of primary ciliogenesis by IFT88 depletion reversed the downregulated cytokines by 2-IPMA. Moreover, we found that PM2.5 treatment increased the MMP-1 expression in dermal fibroblasts and a human 3-D-skin model. The reduced MMP-1 expression by 2-IPMA was further reversed by IFT88 depletion in PM2.5-treated dermal fibroblasts. These findings suggest that 2-IPMA ameliorates PM2.5-induced inflammation by promoting primary ciliogenesis in dermal fibroblasts.

Does central sensitization affect hyperalgesia after staged bilateral total knee arthroplasty? A randomized controlled trial.

OBJECTIVE: Osteoarthritis (OA) patients who undergo staged bilateral total knee arthroplasty (TKA) feel postoperative hyperalgesia in the second operated knee compared with the first knee. Ketamine is an important drug for central temporal summation and inhibition of secondary mechanical hyperalgesia. This study investigated whether central sensitization has a significant effect on hyperalgesia after consecutive operations. METHODS: Seventy-one of 80 OA patients were randomly allocated to the ketamine or saline group. A bolus of ketamine (group K) or saline (group C) (0.5 mg/kg) was injected before induction and at an infusion rate of 3 µg/kg/minute during surgery. A visual analog scale (VAS) was used to assess resting and moving pain and opioid consumption on postoperative days 1, 2, and 3. RESULTS: The difference in the VAS score between stages 1 and 2 (DV2-V1) was higher in the ketamine compared with the saline group. DV2-V1 for movement between the two groups was not inferior for all periods. Ketamine did not show a large analgesic effect on second-operated knee hyperalgesia in staged bilateral TKAs. CONCLUSIONS: We could not confirm that hyperalgesia was only related to central sensitization with low-dose ketamine. Other factors might be also associated with the hyperexcitability of nociceptive stimuli.Clinical Research Information Service (CRIS) trial registry no: KCT0001481.

Acute mental change as the presenting sign of posthepatectomy hepatic failure: A case report.

RATIONALE: Hepatectomy is a treatment to increase survival and curability of patients with intrahepatic lesions or malignant tumors. However, posthepatectomy liver failure (PHLF) can occur. This case is a patient showing acute mental change in postanesthetic care unit (PACU) as an uncommon symptom of PHLF after extended right hepatectomy. PATIENT CONCERNS: A 68-year-old male patient was admitted for surgery of Klatskin tumor. He had hypertension and atrial fibrillation. His model for end-stage liver disease score was 16 pts. His serum bilirubin and ammonia levels were 4.75 mg/dL and 132.8 mcg/dL, respectively. Other laboratory data were nonspecific. He underwent extended right hepatic lobectomy including segments IV-VIII for 9 hours. Weight of liver specimen was 1028 g which was about 58% of total liver volume based on computed tomographic volumetry. The patient was extubated and moved to the PACU with stable vital sign and regular self-breathing. He could obey verbal commands. Fifteen minutes after admission to the PACU, the patient showed abruptly decreasing mental status and self-breathing. DIAGNOSES: Brain computed tomography, blood culture, and sputum culture were performed to diagnose brain lesions and sepsis for evaluating the sudden onset comatous mental status. Results showed nonspecific finding. INTERVENTIONS: He was intubated for securing airway and applying ventilatory care. The patient was moved to the intensive care unit. He received intensive conservative therapy including continuous renal replacement therapy and broad-spectrum antibiotics. OUTCOMES: The patient's condition was worsened. He expired on postoperative day 3. LESSONS: Acute mental change is uncommon and rare as initial symptoms of PHLF. Therefore, clinician may overlook the diagnosis of PHLF in patients with acute mental change after hepatectomy. Thus, clinician should plan an aggressive treatment for PHLF including liver transplantation by recognizing any suspicious symptom, although such symptom is rare.

Prognosis after wedge resection in patients with 8th edition TNM stage IA1 and IA2 non-small cell lung cancer.

BACKGROUND: According to the 8th edition TNM classification for non-small cell lung cancer (NSCLC), tumor stage (T) is determined by the maximum size of the invasive component, without the lepidic component, and the T category has been further subdivided. We investigated the indications for wedge resection using the 8th edition TNM staging system, which measures only the size of the invasive component in tumor size. METHODS: We compared 5-year disease-free survival (DFS) rates in 429 consecutive patients with 8th edition stage IA1 and IA2 NSCLC who underwent lobectomy or wedge resection from 2007 to 2017. We also analyzed the risk factors for recurrence after surgical resection. RESULTS: There were no significant differences in clinicopathological factors or 5-year DFS in patients with stage IA1 disease (5-year DFS 95.0%, lobectomy, vs. 91.6%, wedge resection; P=0.435). For patients with stage IA2 tumors, the 5-year DFS was 88.3% after lobectomy and 74.0% after wedge resection (P=0.118). There were significant differences in clinicopathological characteristics between lobectomy and wedge resection groups in stage IA2 NSCLC. On multivariate analysis, serum CEA level [hazard ratio (HR) =1.040, P=0.046] and lymphovascular invasion (HR =2.664, P=0.027), but not wedge resection, were significant risk factors for recurrence in stage IA2 NSCLC. On multivariate analysis for recurrence risk after wedge resection in stage IA1 and stage IA2 NSCLC, only the width of the resection margin was associated with recurrence. CONCLUSIONS: Wedge resection may be an acceptable procedure in stage IA1 NSCLC. When performing wedge resection, it is necessary to ensure a sufficient resection margin distance.

Inhibition of VEGF-dependent angiogenesis and tumor angiogenesis by an optimized antibody targeting CLEC14a.

The C-type lectin-like domain of CLEC14a (CLEC14a-C-type lectin-like domain [CTLD]) is a key domain that mediates endothelial cell-cell contacts in angiogenesis. However, the role of CLEC14a-CTLD in pathological angiogenesis has not yet been clearly elucidated. In this study, through complementarity-determining region grafting, consecutive deglycosylation, and functional isolation, we generated a novel anti-angiogenic human monoclonal antibody that specifically targets CLEC14a-CTLD and that shows improved stability and homogeneity relative to the parental antibody. We found that this antibody directly inhibits CLEC14a-CTLD-mediated endothelial cell-cell contact and simultaneously downregulates expression of CLEC14a on the surface of endothelial cells. Using various in vitro and in vivo functional assays, we demonstrated that this antibody effectively suppresses vascular endothelial growth factor (VEGF)-dependent angiogenesis and tumor angiogenesis of SNU182 human hepatocellular carcinoma, CFPAC-1 human pancreatic cancer, and U87 human glioma cells. Furthermore, we also found that this antibody significantly inhibits tumor angiogenesis of HCT116 and bevacizumab-adapted HCT116 human colorectal cancer cells. These findings suggest that antibody targeting of CLEC14a-CTLD has the potential to suppress VEGF-dependent angiogenesis and tumor angiogenesis and that CLEC14a-CTLD may be a novel anti-angiogenic target for VEGF-dependent angiogenesis and tumor angiogenesis.

Primary Cilia Negatively Regulate Melanogenesis in Melanocytes and Pigmentation in a Human Skin Model.

The primary cilium is an organelle protruding from the cell body that senses external stimuli including chemical, mechanical, light, osmotic, fluid flow, and gravitational signals. Skin is always exposed to the external environment and responds to external stimuli. Therefore, it is possible that primary cilia have an important role in skin. Ciliogenesis was reported to be involved in developmental processes in skin, such as keratinocyte differentiation and hair formation. However, the relation between skin pigmentation and primary cilia is largely unknown. Here, we observed that increased melanogenesis in melanocytes treated with a melanogenic inducer was inhibited by a ciliogenesis inducer, cytochalasin D, and serum-free culture. However, these inhibitory effects disappeared in GLI2 knockdown cells. In addition, activation of sonic hedgehog (SHH)-smoothened (Smo) signaling pathway by a Smo agonist, SAG inhibited melanin synthesis in melanocytes and pigmentation in a human skin model. On the contrary, an inhibitor of primary cilium formation, ciliobrevin A1, activated melanogenesis in melanocytes. These results suggest that skin pigmentation may be regulated partly by the induction of ciliogenesis through Smo-GLI2 signaling.

Conditioned Media from Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Inhibits Melanogenesis by Promoting Proteasomal Degradation of MITF.

Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) secrete various beneficial molecules, which have anti-apoptotic activity and cell proliferation. However, the effect of hUCB-MSCs in melanogenesis is largely unclear. In this study, we show that conditioned media (CM) derived from hUCB-MSCs inhibit melanogenesis by regulating microphthalmia-associated transcription factor (MITF) expression via the ERK signalling pathway. Treatment of hUCB-MSC-CM strongly inhibited the alpha-melanocyte stimulating hormone-induced hyperpigmentation in melanoma cells as well as melanocytes. Treatment of hUCB-MSC-CM induced ERK1/2 activation in melanocytes. In addition, inhibition of ERK1/2 suppressed the anti-pigmentation activity of the hUCB-MSC-CM in melanocytes and in vitro artificial skin models. We also found that the expression of MITF was appreciably diminished while expression of phosphorylated MITF, which leads to its proteasomal degradation, was increased in cells treated with hUCB-MSC-CM. These results suggested that hUCB-MSC-CM significantly suppresses melanin synthesis via MITF degradation by the ERK pathway activation.

A prospective randomized controlled trial of the laryngeal mask airway versus the endotracheal intubation in the thyroid surgery: evaluation of postoperative voice, and laryngopharyngeal symptom.

BACKGROUND: The present study was performed to determine whether thyroidectomy patients undergoing general anesthesia provided with a laryngeal mask airway (LMA) have a lower risk of voice-related complications and laryngopharyngeal symptoms than those undergoing endotracheal intubation (ETI). MATERIALS AND METHODS: In a prospective, double-blinded, randomized clinical trial, we studied 64 patients undergoing elective thyroid lobectomy between July 2013 and February 2014. Acoustic analyses were performed preoperatively and at 48 h and 2 weeks postoperatively. The voice handicap index (VHI), M.D. Anderson dysphagia index (MDADI), and laryngopharyngeal symptom score (LPS) were determined preoperatively and at 24 h, 48 h, 1 week, and 2 weeks post-thyroidectomy. RESULTS: In acoustic analysis, jitter, shimmer and noise-to-harmonic ratio showed significantly better results in the LMA group than the ETI group 48 h after surgery, but there was no difference at 2 weeks. The incidence of postoperative lower-pitched voice in the LMA group was also significantly lower than that in the ETI group. In the LMA group, the VHI, MDADI, and LPS were better compared to those in the ETI group at 24 h postoperatively, and improved to the preoperative state within 1 week. However, those in the ETI group remained poorer than the preoperative values 1 week after surgery. CONCLUSIONS: Use of the LMA in general anesthesia for thyroid surgery has advantages over the ETI in decreasing patients' subjective and objective voice symptoms, reducing the duration of symptoms, and relieving the laryngopharyngeal symptoms.

Comparison of the size 3 and size 4 ProSeal™ laryngeal mask airway in anesthetized, non-paralyzed women: a randomized controlled trial.

PURPOSE: Based on experimental results, various authors have advocated a size 4 ProSeal™ laryngeal mask airway (PLMA) in preference to a size 3 PLMA for women given a neuromuscular blocking agent because the larger size provided a better airway seal. However, spontaneously breathing patients may be ventilated adequately with a lower seal pressure than that needed for mechanical ventilation. Therefore, a smaller size might be preferable as its reduced bulk possibly induces less mucosal damage in non-paralyzed patients. METHODS: A total of 152 females undergoing general anesthesia for short outpatient gynecological surgeries were randomly allocated in equal numbers to insertion of a size 3 or 4 PLMA. The insertion time, success rate, seal pressure, hemodynamic variables, and complications, such as blood staining and sore throat, were evaluated. RESULTS: The incidence of blood staining was lower with the size 3 PLMA compared to the size 4 PLMA (18 vs. 36 %; P = 0.028). Compared with the size 3 LMA, the size 4 PLMA resulted in higher fluctuations in both blood pressure (P = 0.003) and heart rate (P = 0.01). The insertion time was shorter with the size 3 PLMA (9 vs. 16 s; P < 0.001). The airway seal pressure with the size 3 PLMA, although lower than that of the size 4 PLMA (23 vs. 28 cmH2O; P = 0.001), was sufficient for spontaneous ventilation. CONCLUSIONS: Due to the reduced incidence of mucosal injury and greater hemodynamic stability, the size 3 PLMA may be preferable to the size 4 PLMA for non-paralyzed females.

Therapeutic robot-assisted neck dissection via a retroauricular or modified facelift approach in head and neck cancer: a comparative study with conventional transcervical neck dissection.

BACKGROUND: In a previous study of robot-assisted neck dissection (RAND), we limited the indication for neck dissection in clinical N0 head and neck cancer. The purpose of this study was for us to present the comparison of the results of therapeutic RAND via a retroauricular or modified facelift approach with outcomes from conventional neck dissection in clinical node-positive head and neck cancer. METHODS: This study involved a total of 53 patients who underwent neck dissection for head and neck cancer. Operative and pathologic parameters were assessed. RESULTS: The RAND and the conventional neck dissection group consisted of 20 and 33 patients, respectively. The mean operative time for the RAND group was significantly longer than that of the conventional neck dissection group. The mean number of retrieved lymph nodes in the RAND group was not significantly different from the conventional neck dissection group. CONCLUSION: Therapeutic RAND via a retroauricular or modified facelift approach was successful with satisfactory esthetic results in patients with node-positive head and neck cancer.

Suppression of Cpn10 increases mitochondrial fission and dysfunction in neuroblastoma cells.

To date, several regulatory proteins involved in mitochondrial dynamics have been identified. However, the precise mechanism coordinating these complex processes remains unclear. Mitochondrial chaperones regulate mitochondrial function and structure. Chaperonin 10 (Cpn10) interacts with heat shock protein 60 (HSP60) and functions as a co-chaperone. In this study, we found that down-regulation of Cpn10 highly promoted mitochondrial fragmentation in SK-N-MC and SH-SY5Y neuroblastoma cells. Both genetic and chemical inhibition of Drp1 suppressed the mitochondrial fragmentation induced by Cpn10 reduction. Reactive oxygen species (ROS) generation in 3-NP-treated cells was markedly enhanced by Cpn10 knock down. Depletion of Cpn10 synergistically increased cell death in response to 3-NP treatment. Furthermore, inhibition of Drp1 recovered Cpn10-mediated mitochondrial dysfunction in 3-NP-treated cells. Moreover, an ROS scavenger suppressed cell death mediated by Cpn10 knockdown in 3-NP-treated cells. Taken together, these results showed that down-regulation of Cpn10 increased mitochondrial fragmentation and potentiated 3-NP-mediated mitochondrial dysfunction in neuroblastoma cells.

Mitochondrial dynamics regulate melanogenesis through proteasomal degradation of MITF via ROS-ERK activation.

Mitochondrial dynamics control mitochondrial functions as well as their morphology. However, the role of mitochondrial dynamics in melanogenesis is largely unknown. Here, we show that mitochondrial dynamics regulate melanogenesis by modulating the ROS-ERK signaling pathway. Genetic and chemical inhibition of Drp1, a mitochondrial fission protein, increased melanin production and mitochondrial elongation in melanocytes and melanoma cells. In contrast, down-regulation of OPA1, a mitochondria fusion regulator, suppressed melanogensis but induced massive mitochondrial fragmentation in hyperpigmented cells. Consistently, treatment with CCCP, a mitochondrial fission chemical inducer, also efficiently repressed melanogenesis. Furthermore, we found that ROS production and ERK phosphorylation were increased in cells with fragmented mitochondria. And inhibition of ROS or ERK suppressed the antimelanogenic effect of mitochondrial fission in α-MSH-treated cells. In addition, the activation of ROS-ERK pathway by mitochondrial fission induced phosphorylation of serine73 on MITF accelerating its proteasomal degradation. In conclusion, mitochondrial dynamics may regulate melanogenesis by modulating ROS-ERK signaling pathway.

Robot-assisted neck dissection via a transaxillary and retroauricular approach versus a conventional transcervical approach in papillary thyroid cancer with cervical lymph node metastases.

BACKGROUND: Recently, robot-assisted neck dissection (ND) using a transaxillary approach in thyroid cancer patients with lateral neck metastases (LNM) was demonstrated to be feasible. The aim of this study was to compare the surgical outcomes of a modified transaxillary and retroauricular (TARA) versus a conventional transcervical approach in papillary thyroid carcinoma (PTC) patients with LNM. PATIENTS AND METHODS: In total, 47 patients with PTC underwent total thyroidectomy with central compartment ND and modified radical ND except Level I. Twenty-two NDs were performed via the TARA approach, and 25 unilateral NDs were performed via the conventional transcervical approach. RESULTS: The TARA and the open ND groups consisted of 22 and 25 patients, respectively. The operation time for ND in the TARA group was longer than that in the open ND group (209.4±38.2 minutes versus 143.1±30.5 minutes; P=.000). The mean scar satisfaction score in the TARA group was higher than in the conventional ND group (3.9±1.0 versus 2.8±1.0; P=.000). There were no differences in the mean number of retrieved lymph nodes. CONCLUSIONS: The robot-assisted ND via the TARA approach can be an alternative option that produces excellent esthetic results for the management of LNM in PTC patients.

Cervical subcutaneous emphysema and pneumomediastinum after septorhinoplasty.

Cervical and facial subcutaneous emphysema is mainly caused by maxillofacial trauma or head and neck surgery. There are only 2 cases of subcutaneous emphysema after septorhinoplasty in the English literature. We report a case of subcutaneous emphysema and pneumomediastinum after a septorhinoplasty.A healthy 35-year-old man with nasal obstruction and dissatisfaction with the shape of his nose was referred to our outpatient clinic. The patient had a septorhinoplasty including bilateral medial and lateral osteotomy under general anesthesia. On the fifth day after the surgery, the patient visited the emergency department with swelling and pain in the right submandibular area and cheek. On computed tomographic (CT) scans, air was observed in the right temporal space, masticator space, submandibular space, and superior mediastinal space. He was immediately hospitalized for administration of intravenous antibiotics and bed rest.On the fifth day after the hospitalization, follow-up CT scans were performed. Subcutaneous emphysema and pneumomediastinum were markedly decreased. The patient was discharged on the fifth day.

Autophagy induced by resveratrol suppresses α-MSH-induced melanogenesis.

Autophagy degrades cellular components and organelles through a cooperative process involving autophagosomes and lysosomes. Although autophagy is known to mainly regulate the turnover of cellular components, the role of autophagy in melanogenesis has not been well addressed. Here, we show that inhibition of autophagy suppresses the antimelanogenesis activity of resveratrol (RSV), a well-known antimelanogenic agent. RSV strongly increased autophagy in melanocytes. However, the depletion of ATG5 significantly suppressed RSV-mediated antimelanogenesis as well as RSV-induced autophagy in melanocytes. Moreover, suppression of ATG5 retrieved the RSV-mediated downregulation of tyrosinase and TRP1 in α-MSH-treated cells. Most importantly, electron microscopy analysis revealed that autophagosomes engulfed melanin or melanosomes after combined treatment of α-MSH and RSV. Taken together, these results suggest that RSV-mediated autophagy regulates melanogenesis.

Down-regulation of mortalin exacerbates Aß-mediated mitochondrial fragmentation and dysfunction.

Mitochondrial dynamics greatly influence the biogenesis and morphology of mitochondria. Mitochondria are particularly important in neurons, which have a high demand for energy. Therefore, mitochondrial dysfunction is strongly associated with neurodegenerative diseases. Until now various post-translational modifications for mitochondrial dynamic proteins and several regulatory proteins have explained complex mitochondrial dynamics. However, the precise mechanism that coordinates these complex processes remains unclear. To further understand the regulatory machinery of mitochondrial dynamics, we screened a mitochondrial siRNA library and identified mortalin as a potential regulatory protein. Both genetic and chemical inhibition of mortalin strongly induced mitochondrial fragmentation and synergistically increased Aß-mediated cytotoxicity as well as mitochondrial dysfunction. Importantly we determined that the expression of mortalin in Alzheimer disease (AD) patients and in the triple transgenic-AD mouse model was considerably decreased. In contrast, overexpression of mortalin significantly suppressed Aß-mediated mitochondrial fragmentation and cell death. Taken together, our results suggest that down-regulation of mortalin may potentiate Aß-mediated mitochondrial fragmentation and dysfunction in AD.

ARP101 inhibits α-MSH-stimulated melanogenesis by regulation of autophagy in melanocytes.

Autophagy is a cooperative process between autophagosomes and lysosomes that degrades cellular organelles. Although autophagy regulates the turnover of cellular components, its role in melanogenesis is not clearly established. Previously, we reported that ARP101 induces autophagy in various cancer cells. Here, we show that ARP101 inhibits melanogenesis by regulation of autophagy. ARP101 inhibited α-MSH-stimulated melanin synthesis and suppressed the expression of tyrosinase and TRP1 in immortalized mouse melanocytes. ARP101 also induced autophagy in melanocytes. Knockdown of ATG5 reduced both anti-melanogenic activity and autophagy mediated by ARP101 in α-MSH treated melanocytes. Electron microscopy analysis further revealed that autophagosomes engulf melanin or melanosome in α-MSH and ARP101-treated cells. Collectively, our results suggest that ARP101 inhibits α-MSH-stimulated melanogenesis through the activation of autophagy in melanocytes.

Autophagy mediates anti-melanogenic activity of 3'-ODI in B16F1 melanoma cells.

Autophagy is a cellular degradation process for cellular aggregates and unneeded cellular compartments including damaged mitochondria, ER, and peroxisomes. Melanosome is cellular organelle that is the cellular site of generation, storage and transports of melanin in melanocytes. Despite potential importance of autophagy, the role of autophagy in melanogenesis and melanosome autophagy are largely unknown. In here, we identified 3'-hydroxydaidzein (3'-ODI) as an autophagy inducer from a phytochemical library screening. Treatment with 3'-ODI significantly reduced α-MSH-mediated melanogenesis but efficiently increased autophagy both in melanoma cells and melanocytes. Furthermore, inhibition of autophagy significantly reduced the anti-melanogenic effects of 3'-ODI in α-MSH-stimulated melanoma cells. Taken together, these results suggest that autophagy mediates anti-melanogenic activity of 3'-ODI.

Down-Regulation of Survivin by Nemadipine-A Sensitizes Cancer Cells to TRAIL-Induced Apoptosis.

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family of cytokines. TRAIL selectively induces apoptotic cell death in various tumors and cancer cells, but it has little or no toxicity in normal cells. Agonism of TRAIL receptors has been considered to be a valuable cancer-therapeutic strategy. However, more than 85% of primary tumors are resistant to TRAIL, emphasizing the importance of investigating how to overcome TRAIL resistance. In this report, we have found that nemadipine-A, a cell-permeable L-type calcium channel inhibitor, sensitizes TRAIL-resistant cancer cells to this ligand. Combination treatments using TRAIL with nemadipine-A synergistically induced both the caspase cascade and apoptotic cell death, which were blocked by a pan caspase inhibitor (zVAD) but not by autophagy or a necrosis inhibitor. We further found that nemadipine-A, either alone or in combination with TRAIL, notably reduced the expression of survivin, an inhibitor of the apoptosis protein (IAP) family of proteins. Depletion of survivin by small RNA interference (siRNA) resulted in increased cell death and caspase activation by TRAIL treatment. These results suggest that nemadipine-A potentiates TRAIL-induced apoptosis by down-regulation of survivin expression in TRAIL resistant cells. Thus, combination of TRAIL with nemadipine-A may serve a new therapeutic scheme for the treatment of TRAIL resistant cancer cells, suggesting that a detailed study of this combination would be useful.