Combined Antitumor Effect of the Serine Protease Urokinase Inhibitor Upamostat and the Sphingosine Kinase 2 Inhibitor Opaganib on Cholangiocarcinoma Patient-Derived Xenografts.

Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the urokinase-type plasminogen activator (uPA). These enzymes are expressed in many cancers, especially during tissue remodeling and subsequent tumor cell invasion. Opaganib (ABC294640), a novel, orally available small molecule is a selective inhibitor of the phosphorylation of sphingosine to sphingosine-1-phosphate (S-1-P) by sphingosine kinase 2 (SPHK2). Both sphingosine kinase 1 (SPHK1) and SPHK2 are known to regulate the proliferation-inducing compound S-1-P. However, SPHK2 is more critical in cancer pathogenesis. The goal of this project was to investigate the potential antitumor effects of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) xenografts in nude mice. PAX165, a patient-derived xenograft (PDX) from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2, and PRSS3. Four groups of 18 mice each were treated with upamostat, opaganib, both, or vehicle. Mouse weights and PAX165 tumor volumes were measured. Tumor volumes in the upamostat, opaganib, and upamostat plus opaganib groups were significantly decreased compared to the control group.

Reaching New Heights: A Comprehensive Study of Hand Transplantations in Korea after Institutionalization of Hand Transplantation Law.

PURPOSE: With the revision of the Organ and Transplantation Act in 2018, the hand has become legal as an area of transplantable organs in Korea. In January 2021, the first hand allotransplantation since legalization was successfully performed, and we have performed a total of three successful hand transplantation since then. By comparing and incorporating our experiences, this study aimed to provide a comprehensive reconstructive solution for hand amputation in Korea. MATERIALS AND METHODS: Recipients were selected through a structured preoperative evaluation, and hand transplantations were performed at the distal forearm level. Postoperatively, patients were treated with three-drug immunosuppressive regimen, and functional outcomes were monitored. RESULTS: The hand transplantations were performed without intraoperative complications. All patients had partial skin necrosis and underwent additional surgical procedures in 2 months after transplantation. After additional operations, no further severe complications were observed. Also, patients developed acute rejection within 3 months of surgery, but all resolved within 2 weeks after steroid pulse therapy. Motor and sensory function improved dramatically, and patients were very satisfied with the appearance and function of their transplanted hands. CONCLUSION: Hand transplantation is a viable reconstructive option, and patients have shown positive functional and psychological outcomes. Although this study has limitations, such as the small number of patients and short follow-up period, we should focus on continued recovery of hand function, and be careful not to develop side effects from immunosuppressive drugs. Through the present study, we will continue to strive for a bright future regarding hand transplantation in Korea.

Prevention of Postoperative Complications by Prepectoral versus Subpectoral Breast Reconstruction: A Systematic Review and Meta-Analysis.

BACKGROUND: Implant-based breast reconstruction has evolved over time. However, the effects of prepectoral breast reconstruction (PBR) compared with those of subpectoral breast reconstruction (SBR) have not been clearly defined. Therefore, this study aimed to compare the occurrence of surgical complications between PBR and SBR to determine the procedure that is effective and relatively safe. METHODS: The PubMed, Cochrane Library, and EMBASE databases were searched for studies published until April of 2021 comparing PBR and SBR following mastectomy. Two authors independently assessed the risk of bias. General information on the studies and surgical outcomes were extracted. Among 857 studies, 34 and 29 were included in the systematic review and meta-analysis, respectively. Subgroup analysis was performed to clearly compare the results of patients who underwent postmastectomy radiation therapy. RESULTS: Pooled results showed that prevention of capsular contracture (OR, 0.57; 95% CI, 0.41 to 0.79) and infection control (OR, 0.73; 95% CI, 0.58 to 0.92) were better with PBR than with SBR. Rates of hematoma, implant loss, seroma, skin-flap necrosis, and wound dehiscence were not significantly different between PBR and SBR. PBR considerably improved postoperative pain, BREAST-Q score, and upper arm function compared with SBR. Among postmastectomy radiation therapy patients, the incidence rates of capsular contracture were significantly lower in the PBR group than in the SBR group (OR, 0.14; 95% CI, 0.05 to 0.35). CONCLUSIONS: The results showed that PBR had fewer postoperative complications than SBR. The authors' meta-analysis suggests that PBR could be used as an alternative technique for breast reconstruction in appropriate patients.

Ulmus davidiana 60% edible ethanolic extract for prevention of pericyte apoptosis in diabetic retinopathy.

Diabetic retinopathy (DR) is a disease that causes visual deficiency owing to vascular leakage or abnormal angiogenesis. Pericyte apoptosis is considered one of the main causes of vascular leakage in diabetic retina, but there are few known therapeutic agents that prevent it. Ulmus davidiana is a safe natural product that has been used in traditional medicine and is attracting attention as a potential treatment for various diseases, but its effect on pericyte loss or vascular leakage in DR is not known at all. In the present study, we investigated on the effects of 60% edible ethanolic extract of U. davidiana (U60E) and catechin 7-O-ß-D-apiofuranoside (C7A), a compound of U. davidiana, on pericyte survival and endothelial permeability. U60E and C7A prevented pericyte apoptosis by inhibiting the activation of p38 and JNK induced by increased glucose and tumor necrosis factor alpha (TNF-α) levels in diabetic retina. Moreover, U60E and C7A reduced endothelial permeability by preventing pericyte apoptosis in co-cultures of pericytes and endothelial cells. These results suggest that U60E and C7A could be a potential therapeutic agent for reducing vascular leakage by preventing pericyte apoptosis in DR.

Effects of oral ß-cryptoxanthin administration on the transcriptomes of peripheral neutrophil and liver tissue using microarray analysis in post-weaned Holstein calves.

We investigated the effects of oral administration of ß-cryptoxanthin (ß-CRX), a precursor of vitamin A synthesis, on the transcriptomes of peripheral neutrophils and liver tissue in post-weaned Holstein calves with immature immunity. A single oral administration of ß-CRX (0.2 mg/kg body weight) was performed in eight Holstein calves (4.0 ± 0.8 months of age; 117 ± 10 kg) on Day 0. Peripheral neutrophils (n = 4) and liver tissue (n = 4) were collected on Days 0 and 7. Neutrophils were isolated by density gradient centrifugation and treated with the TRIzol reagent. mRNA expression profiles were examined by microarray and differentially expressed genes were investigated using the Ingenuity Pathway Analysis software. The differentially expressed candidate genes identified in neutrophils (COL3A1, DCN, and CCL2) and liver tissue (ACTA1) were involved in enhanced bacterial killing and maintenance of cellular homoeostasis respectively. The changes in the expression of six of the eight common genes encoding enzymes (ADH5 and SQLE) and transcription regulators (RARRES1, COBLL1, RTKN, and HES1) were in the same direction in neutrophils and liver tissue. ADH5 and SQLE are involved in the maintenance of cellular homoeostasis by increasing the availability of substrates, and RARRES1, COBLL1, RTKN, and HES1 are associated with the suppression of apoptosis and carcinogenesis. An in silico analysis revealed that MYC, which is related to the regulation of cellular differentiation and apoptosis, was the most significant upstream regulator in neutrophils and liver tissue. Transcription regulators such as CDKN2A (cell growth suppressor) and SP1 (cell apoptosis enhancer) were significantly inhibited and activated, respectively, in neutrophils and liver tissue. These results suggest that oral administration of ß-CRX promotes the expression of candidate genes related to bactericidal ability and regulation of cellular processes in peripheral neutrophils and liver cells in response to the immune-enhancing function of ß-CRX in post-weaned Holstein calves.

Parturition and postpartum dietary change altered ruminal pH and the predicted functions of rumen bacterial communities but did not alter the bacterial composition in Holstein cows.

We investigated the temporal dynamics of ruminal pH and the composition and predicted functions of the rumen bacterial community in Holstein cows during the periparturient period. Eight multiparous Holstein cows (body weight; 707.4 ± 29.9 kg, parity; 3.6 ± 0.6) were used for continuous reticulo-ruminal pH measurement, among which five were also used for bacterial community analysis. Rumen fluid samples were collected at 3 weeks before and 2 and 6 weeks after parturition, and blood samples were collected 3 weeks before and 0, 2, 4, and 6 weeks after parturition. After the parturition, reduction in the 1-h mean reticulo-ruminal pH was associated with a significant (P < 0.05) increase in total volatile fatty acid concentration. However, with the exception of a significant change in an unclassified genus of Prevotellaceae (P < 0.05), we detected no significant changes in the compositions of major bacterial phyla or genera or diversity indices during the periparturient period. On the basis of predicted functional analysis, we identified a total of 53 MetaCyc pathways (45 upregulated), 200 enzyme commissions (184 upregulated), and 714 Kyoto Encyclopedia of Genes and Genomes orthologs (667 upregulated) at 6 weeks postpartum that were significantly (P < 0.05) different to those at 3 weeks prepartum. Among the 14 MetaCyc pathways (P < 0.05) in which pyruvate is an end product, PWY-3661 [log2-fold change (FC) = 5.49, false discovery rate (FDR) corrected P < 0.001] was the most highly upregulated pyruvate-producing pathway. In addition, P381-PWY [adenosylcobalamin biosynthesis II (aerobic); FC = 5.48, FDR corrected P < 0.001] was the second most upregulated adenosylcobalamin (Vitamin B12)-producing pathway. In contrast, PWY-2221 (FC = -4.54, FDR corrected P = 0.003), predominantly found in pectinolytic bacteria, was the most downregulated pathway. Our findings indicate that changes in rumen bacterial community structure are not strictly associated with transitions in parturition or diet; however, we did observe changes in reticulo-ruminal pH and the metabolic adaptation of predicted functional pathways. Consequently, predictive analysis of postpartum functional pathways may enable us to gain insights into the underlying functional adaptations of bacterial communities in Holstein cows during the periparturient period.

Surface Modification of Matrimid® 5218 Polyimide Membrane with Fluorine-Containing Diamines for Efficient Gas Separation.

Polyimide membranes have been widely investigated in gas separation applications due to their high separation abilities, excellent processability, relatively low cost, and stabilities. Unfortunately, it is extremely challenging to simultaneously achieve both improved gas permeability and selectivity due to the trade-off relationship in common polymer membranes. Diamine modification is a simple strategy to tune the separation performance of polyimide membranes, but an excessive loss in permeability is also generally observed. In the present work, we reported the effects of diamine type (i.e., non-fluorinated and fluorinated) on the physicochemical properties and the corresponding separation performance of a modified membrane using a commercial Matrimid® 5218 polyimide. Detailed spectroscopic, thermal, and surface analyses reveal that the bulky fluorine groups are responsible for the balanced chain packing modes in the resulting Matrimid membranes compared to the non-fluorinated diamines. Consequently, the modified Matrimid membranes using fluorinated diamines exhibit both higher gas permeability and selectivity than those of pristine Matrimid, making them especially effective for improving the separation performance towards H2/CH4 and CO2/CH4 pairs. The results indicate that the use of fluorinated modifiers may offer new opportunities to tune the gas transport properties of polyimide membranes.

Effect of Food on the Pharmacokinetics and Pharmacodynamics of a Single Oral Dose of Tegoprazan.

PURPOSE: Tegoprazan is a potassium-competitive acid blocker (P-CAB) that is designed to treat acid-related diseases through a fundamentally different mechanism than that of proton pump inhibitors (PPIs). Because PPIs inhibit only activated parietal cell H+/K+ adenosine triphosphatase, stimulation of parietal cells by a meal is necessary for optimal results. In contrast, P-CABs can inactivate proton pumps without acid activation and bind to both activated and inactivated adenosine triphosphatase. This study evaluates the effect of food consumption on the pharmacokinetic and pharmacodynamic properties of tegoprazan after a single oral dose in healthy men. METHODS: In this open-label, 2-period crossover study, 24 healthy men were randomized to 1 of 2 treatment sequence groups: administration of tegoprazan under the fasting condition and administration of tegoprazan under the fed condition. The dosing periods of both sequence groups were separated by a washout period of 7 days. At each dosing period, the participants received a single dose of 200 mg of tegoprazan followed by pharmacokinetic and pharmacodynamic analysis. FINDINGS: After the oral administration of 200 mg tegoprazan, the Cmax was decreased and delayed under the fed condition compared with that of the fasting condition. However, no significant differences were observed in the AUC and the time of gastric acid suppression (inhibition of integrated acidity) during 24 hours. IMPLICATIONS: The pharmacokinetic and pharmacodynamic properties of tegoprazan are independent of food effect; thus, tegoprazan could be administered regardless of the timing of food consumption in patients. ClinicalTrials.gov identifier: NCT01830309.

Changes in peripheral blood oxidative stress markers and hepatic gene expression related to oxidative stress in Holstein cows with and without subacute ruminal acidosis during the periparturient period.

We investigated changes in peripheral blood metabolites, oxidative stress markers (malondialdehyde, potential antioxidant capacity, and glutathione peroxidase [GPX]), and hepatic gene expression related to oxidative stress in Holstein cows with and without subacute ruminal acidosis (SARA) during the periparturient period. Eighteen multiparous Holstein cows were categorized into SARA (n=9) or non-SARA (n=9) groups depending on whether they developed SARA; reticulo-ruminal pH was <5.6 for more than 3 hr per day, during the 2 weeks after parturition. Blood and liver tissue samples were collected 3 weeks prepartum and 2 and 6 weeks postpartum, with an additional blood sample collected 0 and 4 weeks postpartum. Blood aspartate transaminase (AST) and nonesterified fatty acid (NEFA) increased significantly (P<0.05) after parturition in both groups. GPX activity decreased gradually after parturition in the SARA group. In the SARA group, gene expression of GPX 1 and microsomal glutathione S-transferase 3 (MGST3) decreased significantly (P<0.05), and expression of metallothionein 2A increased significantly (P<0.05) after parturition in the SARA group. Superoxide dismutase 1 and MGST3 decreased significantly (P<0.05) 2 weeks postpartum in the non-SARA group. Gene expression related to oxidative stress was negatively correlated with AST, NEFA and total ketone body levels. Therefore, the hepatic gene expression related to oxidative stress might change associated with a negative energy balance, and might relate the high oxidative stress in the SARA group during periparturient period.

Femoral arteriovenous fistula associated with surgery of proximal femoral fracture: a systematic review of the literature and case presentation.

BACKGROUND: Proximal femoral fracture (PFF), such as intertrochanteric femoral fracture or femur neck fracture, and its management are crucial issues to surgeons. PFF has been dramatically is becoming exponentially prevalent, and it is at high risk of complication and mortality because it is frequently associated with serious trauma and advanced age, especially in patients treated with anticoagulants or antiplatelet agents. Surgical management is essential for the treatment of PFF. Unfortunately, current surgical procedures have been related to accompanied by vascular complications, including laceration, hemorrhage, thrombosis, embolism, intimal flap tear and pseudoaneurysm. Furthermore, these vascular injuries following surgical management of PFF are potentially limb- and life-threatening. Of the complications after operation of PFF, femoral arteriovenous fistula (AVF) is rare, but remains a challenging problem because it is frequently associated with significantly high mortality and morbidity and is very difficult to treat. METHODS: A systematic literature review was conducted using the PRISMA guidelines with no language restriction. We searched scientific publications via PubMed, Embase, Cochrane central register of controlled trial, Google Scholar, the KoreaMed and the Research Information Sharing Service database. The goal of this study was to report on the incidence, clinical presentation, diagnosis, treatment, associated complications, morbidity and mortality of femoral AVF caused by PFF and to draw special attention to its prevention and management. RESULTS: A total of 7 case reports on femoral AVF associated with operation of PFF were identified, and one our case was added to the systematic analysis. Of the 8 cases, 4 were male and 4 were female under the age of 67.87±18.44; 6 (75.0%) survived without any events, 1 (12.5%) survived with a sequela of peroneal nerve impairment, and 1 (12.5%) died of multi-organ failure and hypovolemia. CONCLUSIONS: The incidence of femoral AVF associated with PFF is extremely low, though it appears to increase with the rising frequency of PFF. With a very few exceptions, complications following internal fixation are potentially limb- and life-threatening. There is still no definite consensus on the standardized diagnostic or therapeutic modalities. Therefore, surgeons should keep in mind that this serious complication requires early diagnosis and prompt treatment, which should not be underestimated. Femoral AVF following operation of PFF should be meticulously managed, because untreated fistulae result in serious unexpected complications including renin-mediated hypertension, high-output heart failure and venous and/or arterial insufficiency. Surgical treatment is still the gold standard for such cases, but in limited cases endovascular procedures using embolization and closure device can be a good treatment option.

JNK suppresses melanogenesis by interfering with CREB-regulated transcription coactivator 3-dependent MITF expression.

Melanogenesis is a critical self-defense mechanism against ultraviolet radiation (UVR)-induced skin damage and carcinogenesis; however, dysregulation of melanin production and distribution causes skin-disfiguring pigmentary disorders. Melanogenesis is initiated by UVR-induced cAMP generation and ensuing activation of transcription factor CREB, which induces expression of the master melanogenic regulator MITF. Recent studies have demonstrated that recruitment of CRTCs to the CREB transcription complex is also required for UVR-stimulated melanogenesis. Therefore, modulation of cAMP-CRTC/CREB-MITF signaling may be a useful therapeutic strategy for UVR-associated skin pigmentary disorders. Methods: We identified the small-molecule Ro31-8220 from CREB/CRTC activity screening and examined its melanogenic activity in cultured mouse and human melanocytes as well as in human skin. Molecular mechanisms were deciphered by immunoblotting, RT-PCR, promoter assays, tyrosinase activity assays, immunofluorescent examination of CRTC3 subcellular localization, and shRNA-based knockdown. Results: Ro31-8220 suppressed basal and cAMP-stimulated melanin production in melanocytes and human melanocyte co-culture as well as UVR-stimulated melanin accumulation in human skin through downregulation of MITF and tyrosinase expression. Mechanistically, down regulation of MITF expression by Ro31-8220 was due to inhibition of transcriptional activity of CREB, which was resulted from phosphorylation-dependent blockade of nuclear translocation of CRTC3 via JNK activation. The selective JNK activator anisomycin also inhibited melanin production through phosphoinhibition of CRTC3, while JNK inhibition enhanced melanogenesis by stimulating CRTC3 dephosphorylation and nuclear migration. Conclusions: Melanogenesis can be enhanced or suppressed via pharmacological modulation of a previously unidentified JNK-CRTC/CREB-MITF signaling axis. As Ro31-8220 potently inhibits UVR-stimulated melanin accumulation in human skin, suggesting that small-molecule JNK-CRTC signaling modulators may provide therapeutic benefit for pigmentation disorders.

Randomised clinical trial: safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of tegoprazan (CJ-12420), a novel potassium-competitive acid blocker, in healthy male subjects.

BACKGROUND: Tegoprazan (CJ-12420) is a potassium-competitive acid blocker (P-CAB) with therapeutic potential for gastro-oesophageal reflux disease (GERD) by reversibly suppressing gastric H+ /K+ -ATPase. AIMS: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of tegoprazan METHODS: A phase I, randomised, double-blind and placebo-controlled clinical trial was conducted in 56 healthy male subjects without Helicobacter pylori infection. In the single ascending dose study, 50, 100, 200 and 400 mg tegoprazan were administered to 32 subjects. In the multiple ascending dose study, 100 and 200 mg tegoprazan were administered every 24 hours to each of the eight subjects for 7 days. In the comparative pharmacodynamics study, 40 mg esomeprazole was administered to eight subjects every 24 hours for 7 days. The assessment included safety, tolerability, pharmacodynamics through monitoring of 24-hour gastric pH and pharmacokinetics of tegoprazan in plasma and urine. RESULTS: Tegoprazan was generally well tolerated. Most adverse events reported in the study were mild in intensity and resolved without any sequelae. Exposure to tegoprazan increased in a dose-proportional manner. Multiple dosing with tegoprazan showed no accumulation in plasma on day 7. The pharmacodynamic analysis revealed that tegoprazan showed rapid, dose-dependent gastric acid suppression. CONCLUSIONS: Tegoprazan was well tolerated and showed rapid and potent gastric acid suppression. This supports the further development of tegoprazan as a treatment for acid-related disorders.

Computed tomography-guided percutaneous hook wire localization of pulmonary nodular lesions before video-assisted thoracoscopic surgery: Highlighting technical aspects.

OBJECTIVE: Confirming the histologic diagnosis of small pulmonary nodules or Ground-glass opacity nodules (GGNs) of unknown origin is difficult. These nodules are not always appropriate for percutaneous transthoracic needle biopsy. Preoperative localization of pulmonary lesions provides more precise target points to ensure complete surgical excision. The goal of the present study was to evaluate the validity and effectiveness of computed tomography-guided preoperative hook wire localization with our technique for video-assisted thoracoscopic surgery (VATS). METHODS: We retrospectively investigated 113 patients who had undergone preoperative hook wire localization before VATS resection for newly present or growing pulmonary nodular lesions between May 2007 and December 2016. Procedural and perioperative outcomes were assessed to evaluate the safety and efficacy of preoperative localization technique. RESULTS: A total of 113 pulmonary nodules were localized and successfully resected in all 113 patients. The mean diameter of nodules was 10.8 ± 6.1 mm (range, 3-28). The mean distance from the pleural surface was 20.2 ± 12.4 mm (range, 5-55). The mean procedure time of localization was 23.7 ± 6.3 min. Asymptomatic minimal pneumothorax and mild parenchymal hemorrhage occurred in 26 (23.0%) and 8 (7.1%) patients, respectively. There were 32 (28.3%) deep lung nodules, in which the distance to pleural surface was more than 25 mm. Wire dislodgement occurred in 4 (3.5%) patients. Complete resection of all lung lesions was achieved, and definite histological diagnosis was obtained in all patients. Pathologic examination revealed 42 (37.2%) primary lung cancers, 2 (1.8%) lymphomas, 53 (46.9%) metastases, 16 (14.1%) benign lesions. CONCLUSIONS: Preoperative percutaneous hook wire localization is a dependable and useful technique to facilitate positioning small and deep pulmonary nodules for thoracoscopic complete excision and accurate diagnosis.

Spontaneous lumbar artery rupture and massive retroperitoneal hematoma, successfully treated with arteriographic embolization.

BACKGROUND AND OBJECTIVE: Massive retroperitoneal hematoma caused by lumbar artery rupture is generally associated with trauma or retroperitoneal malignancy. However, despite recent advances in technologies and tools, spontaneous lumbar artery rupture is a very rare disease entity but remains a challenging problem because it is frequently associated with significantly high mortality and morbidity and is very difficult to make a correct diagnosis. METHODS: We evaluated the databases of the PubMed, Embase, Cochrane Central Register of Controlled Trial, Google Scholar, the KoreaMed and the Research Information Sharing Service databases, and a detailed systematic review was performed by searching in PubMed. The initial search was performed on 3 February 2018 and a second search conducted in 29 January 2019. RESULTS: A total of 10 case reports on massive hemoperitoneum caused by spontaneous lumbar artery rupture were identified. Of the 10 case reports involving 14 patients, eight were male and six were female under 62.71 ± 13.93. Of the 14 patients, 9 (64.3%) surviving with transcatheter arterial embolization, three (21.4%) died of multi-organ failure or hypovolemia, and two (14.3%) had no definite records on survival or death. CONCLUSIONS: A massive retroperitoneal hematoma caused by lumbar artery rupture should be considered in patients with late-onset shock accompanied by blunt abdominal/pelvic trauma. Furthermore, early detection and urgent embolization would prevent further complications and eliminate the need for surgical interventions.

L-765,314 Suppresses Melanin Synthesis by Regulating Tyrosinase Activity.

Although melanin production is a key self-defense mechanism against ultraviolet radiation (UVR)-induced skin damage, uneven or excessive deposition of melanin causes hyperpigmentary disorders. Currently available whitening agents are unsatisfactory because of issues with efficacy and safety. To develop more effective depigmenting agents, we performed high-throughput melanin content assay screening using the B16F10 melanoma cell line and identified L-765,314 as a drug that suppressed melanin production in cultured melanocytes in a dose-dependent manner as well as cAMP- or 12-O-tetradecanoylphorbol 13-acetate (TPA)-stimulated melanin production without cytotoxicity. Interestingly, melanogenic gene expression was not altered by L-765,314. Rather, diminished melanin production by L-765,314 appeared to be caused by downregulation of tyrosinase activity via inhibition of protein kinase C (PKC). Because L-765,314 did not show any adverse effect in melanocytes, altogether our data suggest that L-765,314 could be a potential therapeutic candidate for skin hyperpigmentary disorders and further discovery of selective inhibitors targeting PKC might be a promising strategy for the development of depigmenting agents to treat hyperpigmentary disorders.

Experimental Investigation on the Tissue Response Induced by Face-Lifting Mesh Suspension Thread in Rats.

BACKGROUND: Face-lifting procedures are often performed to hide the effects of aging. Thread-lifting, a minimally invasive technique for the correction of facial aging, has become increasingly popular, and various materials for the procedure have been developed. OBJECTIVE: This study compared tissue responses to two types of threading sutures placed under rat skin: polypropylene (PP) monofilament mesh suspension thread (a novel face-lifting material) and polydioxanone (PDO) barbed thread. METHODS: Eight rats each were assigned to the PP monofilament mesh suspension, PDO barbed thread, and control groups. Tissue reactions were evaluated 28 days after subcutaneous loading of the materials. RESULTS: Significant increases in tensile strength and the mean area occupied by collagen fibers were evident in skin loaded with PDO barbed thread and PP monofilament mesh suspension thread compared to control skin (p<0.05). Compared to sites loaded with PDO barbed thread, those loaded with PP monofilament mesh suspension thread showed a significant increase in the number of collagen fibers and a lower grade of inflammation (p<0.05). CONCLUSION: PP monofilament mesh suspension thread has skin-rejuvenating effects comparable to those of PDO barbed thread, but induces a less severe inflammatory response. This indicates that it is a safe and effective material for use in thread-lifting procedures on aging skin.

Postoperative chest tube placement after thoracoscopic wedge resection of lung for primary spontaneous pneumothorax: is it mandatory?

BACKGROUND: The goal of present study is to assess the efficiency and feasibility of postoperative care without positioning of chest tube after video-assisted thoracoscopic surgery (VATS) in patients with primary spontaneous pneumothorax (PSP). METHODS: We conducted a prospective randomized trial of patients who have undergone video-assisted thoracoscopic wedge resection surgery for PSP. During the period of April 2015 until December 2016, 119 eligible patients undergoing VATS for PSP were consecutively included. We divided the patients into two groups at random: (I) avoiding chest tube (ACT) group, comprising 58 patients in whom chest tube was not placed intra or postoperatively, and (II) indwelling chest tube (ICT) group, comprising 61 patients in whom chest tube was placed conventionally. Primary end point was to evaluate and analyze the postoperative clinical data and relevant morbidities between two groups. RESULTS: The mean postoperative length of hospital stay (3.57±0.79 vs. 5.39±0.97 days) and postoperative pain (1.37±0.78 vs. 2.53±0.63) in ACT group were significantly lower than in the ICT group (P<0.05). However, there were no statistical differences between two groups regarding other clinical data and postoperative morbidities. There were no patients who experienced significant adverse events postoperatively. CONCLUSIONS: Postoperative management without chest tube placement is safe and feasible approach for patients undergoing thoracoscopic wedge resection for PSP.

NEDD4L limits cAMP signaling through ubiquitination of CREB-regulated transcription coactivator 3.

The transcription factor cAMP-responsive element-binding protein (CREB) is involved in a variety of physiologic processes. Although its activity appears to be largely correlated with its phosphorylation status, cAMP-mediated dephosphorylation and the subsequent nuclear migration of the CREB-regulated transcription factors (CRTCs) are required to stimulate CREB transcriptional activity. Among the 3 identified mammalian homologs of CRTCs, CRTC3 has been shown to be expressed predominantly in adipose tissues in response to catecholamine signals that regulate lipid metabolism. Here, we show that prolonged cAMP signaling down-regulates CRTC3 in a proteasome-dependent manner and that neural precursor cell-expressed developmentally down-regulated gene 4-like (NEDD4L), a specific ubiquitin ligase for CRTC3, is responsible for this process. By recognizing the PY motif of CRTC3, NEDD4L interacts with CRTC3 and promotes its polyubiquitination. Interaction between NEDD4L and CRTC3 is further boosted by cAMP signaling, and this enhanced interaction appears to be dependent on the cAMP-mediated phosphorylation of NEDD4L at the Ser448 site. Furthermore, we show that food withdrawal stimulates NEDD4L phosphorylation in mice, which then show a decrease of adipose tissue CRTC3 protein levels. Together, these results suggest that NEDD4L plays a key role in the feedback regulation of cAMP signaling by limiting CRTC3 protein levels.-Kim, Y.-H., Yoo, H., Hong, A.-R., Kwon, M., Kang, S.-W., Kim, K., Song, Y. NEDD4L limits cAMP signaling through ubiquitination of CREB-regulated transcription coactivator 3.

The management of chemical pleurodesis with viscum album in patients with persistent air leakage.

BACKGROUND: Persistent air leak (PAL) after major pulmonary resection or involved with secondary lung disease is prevalent and associated with significant morbidity. Chemical pleurodesis is a practical therapeutic tool to manage the patients with PAL. Among various sclerosing substances, viscum album (fraxini) is considered effective and safe. The aim of this study was to evaluate the efficacy and safety of viscum album pleurodesis in patients with intractable prolonged air leakage. METHODS: Between February 2013 and February 2015, 73 consecutive patients who underwent pleurodesis due to PAL were enrolled in this study. Pleurodesis was performed using 100 mg of viscum album (fraxini) at 1 time through the indwelling chest tube. Main studied outcomes were focused on success rate of pleurodesis assessed on chest radiography and cessation of the air leak after procedure. RESULTS: The study population was predominantly male (n=64, 87.7%). The overall success rate was 90.4%. One patient died of pneumonia not related to the viscum album pleurodesis. The mean length of stoppage to air leakage was 28.00±22.19 hours. The mean duration of chest tube drainage after pleurodesis was 2.78±1.35 days. The mean number of pleurodesis was 1.38±0.75. Thirty-six patients (49.3%) complained of chest pain requiring a prescription for pain control. There were no major relevant complications or mortalities. CONCLUSIONS: Air leaks remain an important cause of morbidity. This viscum album pleurodesis could be considered as an option for the treatment of prolonged air leak patients, associated with acceptable side effects.

Extramedullary Hematopoiesis Mimicking Mediastinal Tumor in a Patient with Hereditary Spherocytosis: Case report.

INTRODUCTION: Extramedullary hematopoiesis (EMH) is a rare disorder, defined as the appearance of hematopoietic elements outside the bone marrow or peripheral blood. The exact mechanism of this development is still unknown. We herein report a case of intrathoracic EMH, manifesting as a posterior mediastinal tumor in a patient with hereditary spherocytosis. PRESENTATION OF CASE: A 45-year-old man who presented with anemia, jaundice and abdominal pain was diagnosed with hereditary spherocytosis. A 2.6cm homogeneous right paravertebral (at the level of T8) round mass of soft tissue density was discovered incidentally on computed tomography. We performed a complete excision of mass lesion by video-assisted thoracoscopic surgery (VATS) to confirm the diagnosis. It appeared to be well encapsulated and contained bloody, fragile material. A pathological result disclosed a normal diffuse hematopoiesis consisting of megakaryocytes, immature granulocytic and myeloid precursor cells, and finally confirmed a diagnosis of EMH. Furthermore, laparoscopic splenectomy and cholecystectomy surgery was accomplished uneventfully as well. DISCUSSION: It was very significant to differentiate posterior mediastinal neurogenic tumor from EMH, as it can be clinically confused with other tumors of the mediastinum. Radiological examination has limitations, so definite diagnostic confirmation by surgical approach should be considered. CONCLUSION: We successfully performed a complete removal of intrathoracic mediastinal mass and confirmed a diagnosis of extramedullary hematopoiesis (EMH) which is mimicking mediastinal neoplasm.