Targeting phosphorylation circuits on CREB and CRTCs as the strategy to prevent acquired skin hyperpigmentation.

Background: The cAMP response element-binding protein (CREB) and CREB-regulated transcription coactivators (CRTCs) cooperate in the transcriptional activation of microphthalmia-associated transcription factor subtype M (MITF-M) that is a master regulator in the biogenesis, pigmentation and transfer of melanosomes at epidermal melanocytes. Here, we propose the targeting of phosphorylation circuits on CREB and CRTCs in the expression of MITF-M as the rationale to prevent skin hyperpigmentation by elucidating the inhibitory activity and mechanism of yakuchinone A (Yaku A) on facultative melanogenesis. Methods: We employed human epidermal melanocyte cell, mouse skin, and mouse melanoma cell, and applied Western blotting, reverse transcription-polymerase chain reaction, immunoprecipitation and confocal microscopy to conduct this study. Results: This study suggested that α-melanocyte stimulating hormone (α-MSH)-induced melanogenic programs could switch on the axis of protein kinase A-salt inducible kinases (PKA-SIKs) rather than that of PKA-AMP activated protein kinase (PKA-AMPK) during the dephosphorylation of CRTCs in the expression of MITF-M. SIK inhibitors rather than AMPK inhibitors stimulated melanin production in melanocyte cultures in the absence of extracellular melanogenic stimuli, wherein SIK inhibitors increased the dephosphorylation of CRTCs but bypassed the phosphorylation of CREB for the expression of MITF-M. Treatment with Yaku A prevented ultraviolet B (UV-B)-irradiated skin hyperpigmentation in mice and inhibited melanin production in α-MSH- or SIK inhibitor-activated melanocyte cultures. Mechanistically, Yaku A suppressed the expression of MITF-M via dually targeting the i) cAMP-dependent dissociation of PKA holoenzyme at the upstream from PKA-catalyzed phosphorylation of CREB coupled with PKA-SIKs axis-mediated dephosphorylation of CRTCs in α-MSH-induced melanogenic programs, and ii) nuclear import of CRTCs after SIK inhibitor-induced dephosphorylation of CRTCs. Conclusions: Taken together, the targeting phosphorylation circuits on CREB and CRTCs in the expression of MITF-M could be a suitable strategy to prevent pigmentary disorders in the skin.

An Innovative Ultrasound Technique for Evaluation of Tumor Vascularity in Breast Cancers: Superb Micro-Vascular Imaging.

Tumor vascularity is an important indicator for differential diagnosis, tumor growth, and prognosis. Superb micro-vascular imaging (SMI) is an innovative ultrasound technique for vascular examination that uses a multidimensional filter to eliminate clutter and preserve extremely low-velocity flows. Theoretically, SMI could depict more vessels and more detailed vascular morphology, due to the increased sensitivity of slow blood flow. Here, we report the early experience of using SMI in 21 breast cancer patients. We evaluated tumor vascular features in breast cancer and compared SMI and conventional color or power Doppler imaging. SMI was superior to color or power Doppler imaging in detecting tumor vessels, the details of vessel morphology, and both peripheral and central vascular distribution. In conclusion, SMI is a promising ultrasound technique for evaluating microvascular information of breast cancers.

Functional magnetic resonance cholangiography with Gd-EOB-DTPA: a study in healthy volunteers.

PURPOSE: To describe the patterns of bile distribution in the biliary tree, duodenum, jejunum, and stomach, and to determine the gallbladder ejection fraction (GBEF) by using functional magnetic resonance cholangiography (MRC) with gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) in healthy volunteers. MATERIALS AND METHODS: Forty subjects were included in this study. After conventional MRC, pre-fatty meal MRC (PRFM) was obtained at 30, 40, 50, and 60min after contrast agent injection. Then, post-fatty meal MRC (POFM) was obtained every 10min for 1h. We assessed the PRFM and POFM for opacification of contrast agent in the first- and second-order intrahepatic ducts (IHDs) and the common bile duct (CBD). Contrast agent opacification in the cystic duct was assessed, and the percentage volume of contrast agent filling in the gallbladder (GB) was calculated on PRFM. We calculated the GBEF and assessed the presence of contrast agent in the GB, duodenum, jejunum, and stomach. RESULTS: Thirty-six (90%) subjects showed grade 3 CBD opacification (visible contrast and well-defined bile duct border) on 60-min PRFM. Thirty-four (85%) subjects showed grade 3 first-order IHD opacification on 60-min PRFM. All (100%) subjects showed cystic duct opacification of contrast agent, and the average percentage volume of contrast agent filling in the GB was 68.81%±16.84% on 60-min PRFM. The GBEF at 30-min POFM was 35.00%±18.26%. Ten (25%) subjects had no contrast agent in the stomach and small bowel on all PRFMs. Twelve (30%) subjects had contrast medium in the stomach on PRFM and/or POFM. CONCLUSIONS: Functional MRC with Gd-EOB-DTPA can allow determining the distribution of bile in the biliary tree and small intestine, as well as the GBEF.

Diagnosis of acute cholecystitis: value of contrast agent in the gallbladder and cystic duct on Gd-EOB-DTPA enhanced MR cholangiography.

To evaluate value of %volume of contrast agent in gallbladder and contrast in cystic duct in diagnosis of acute cholecysititis with Gd-EOB-DTPA MRC obtained 60 min after contrast injection (T1-MRC60min). We included 16 acute cholecystitis (AC), 23 chronic cholecystitis (CC), and 40 healthy volunteers. Receiver operating characteristic analysis showed cutoff value of 30.5% as predictor of AC comparing with healthy volunteers (sensitivity 93.8%, specificity 100%, AUC 0.958) and cutoff of 0% as predictor of AC comparing CC (sensitivity 81.2%, specificity 82.6%, AUC 0.823). In AC absent or obliterated cystic duct on T1-MRC60min showed 81.3%, 100%, sensitivity and specificity, respectively. These can be helpful for diagnosis of AC.

Biliary reflux detection in anomalous union of the pancreatico-biliary duct patients.

AIM: To demonstrate the imaging findings of biliopancreatic and pancreatico-biliary reflux in patients with anomalous union of the pancreatico-biliary duct (AUPBD) on gadoxetic acid-enhanced functional magnetic resonance cholangiography (fMRC). METHODS: This study included six consecutive patients (two men and four women; mean age 47.5 years) with AUPBD. All subjects underwent endoscopic retrograde cholangiopancreatography (ERCP); one subject also underwent bile sampling of the common bile duct (CBD) to measure the amylase level because his gadoxetic acid-enhanced fMRC images showed evidence of pancreatico-biliary reflux of pancreatic secretions. Of the five patients with choledochal cysts, four underwent pylorus-preserving pancreaticoduodenectomy. RESULTS: The five cases of choledochal cysts were classified as Todani classification I. In three of the six patients with AUPBD, injected contrast media reached the distal CBD and pancreatic duct on delay images, suggesting biliopancreatic reflux. In two of these six patients, a band-like filling defect was noted in the CBD on pre-fatty meal images, which decreased in size on delayed post-fatty meal images, suggesting pancreatico-biliary reflux of pancreatic secretions, and the bile sampled from the CBD in one patient had an amylase level of 113,000 IU/L. In one of the six patients with AUPBD, contrast media did not reach the distal CBD due to multiple CBD stones. CONCLUSION: Gadoxetic acid-enhanced fMRC successfully demonstrated biliopancreatic reflux of bile and pancreatico-biliary reflux of pancreatic secretions in patients with AUPBD with and without choledochal cysts.

Spinal cord stimulation for intractable post-thoracotomy pain syndrome: A case report.

Post-thoracotomy syndrome is a condition characterized by pain that continues for more than 2 months after a thoracotomic procedure. Some patients suffer from devastating chest pain despite receiving multimodal treatment such as analgesics, antidepressants, anticonvulsants and nerve blockers. Spinal cord stimulation has been reported to be a promising relief for the intractable neuropathic pain. A 60-year-old man who had been suffering from post-thoracotomy pain for 20 years showed relief of pain after spinal cord stimulation. Spinal cord stimulation thus seems to be a viable option for patients who do not respond to conventional pain management therapy.