Optimal Timing of Expander-to-Implant Exchange after Irradiation in Immediate Two-Stage Breast Reconstruction.

BACKGROUND: Time intervals for expander-to-implant exchange from radiation therapy have been reported to reduce device failure. This study investigated the optimal timing of expander-to-implant exchange after irradiation in terms of short- and long-term outcomes. METHODS: This retrospective review enrolled consecutive patients who underwent immediate two-stage breast reconstruction and radiation therapy to tissue expanders from 2010 to 2019. Receiver operating characteristic curves and the Youden index were used to estimate the optimal time from radiation therapy to implant placement in terms of 49-day (early) and 2-year (late) complications. Logistic regression analysis was performed to identify the risk factors for each complication. RESULTS: Of the 1675 patients, 133 were included. The 49-day and 2-year complication rates were 8.3 percent and 29.7 percent, respectively. Capsular contracture was the most common 2-year complication. The Youden index indicated that implant placement at 131 days after radiation therapy was most effective in reducing the 49-day complications, but that the 2-year complication was less significant, with lower sensitivity and area under the curve. Modified radical mastectomy, expander fill volume at radiation therapy, and size of permanent implant increased the odds of 49-day complications; none of them was associated with the odds of 2-year complications. CONCLUSIONS: To reduce short-term complications, the best time point for permanent implant placement was 131 days after radiation therapy. However, there was no significant time interval for reducing long-term complications. Capsular contracture was an irreversible complication of radiation injury that was not modified by postirradiation variables including the time from irradiation or size of permanent implant. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

The Interchondral Joints of Thorax in Microtia Surgery: Classification and Fabrication Strategies.

BACKGROUND: The interchondral joint between the sixth and seventh costal cartilages, called synchondrosis, assists in harvesting and fabricating the microtia framework. However, its looseness often complicates the microtia surgery. We aimed to classify the interchondral joints based on looseness and identify predictors for each subtype. METHODS: Electronic chart and intraoperative photographs were reviewed for consecutive microtia patients who underwent costal cartilage graft for ear reconstruction from June 2001 to February 2020. The sixth and seventh costal interchondral joint was classified in the ascending order of looseness-direct cartilaginous fusion (class I), synovial joint (class II), and loose tissue (class III)-with a minor modification from the cadaveric study of Dr. Briscoe in 1925. χ2 Tests compared the incidence of each subtype in terms of patient variables including age, sex, chest laterality, and radiologic chest deformity. Multivariate logistic regression was used for identifying independent predictors for each subtype. RESULTS: Seven hundred thirty-three graft specimens were enrolled (mean age 12.1 years). Class I joint was seen in 137 (18.7%) grafts, class II in 544 (74.2%), and class III in 52 (7.1%). Female predilection was found for cartilaginous fusion (class I) (adjusted odds ratio, 1.691; P = 0.007). The incidence of loose joint (class III) was comparable, ranging from 4.6% to 12.5%, in terms of all the patient variables. CONCLUSIONS: Loose interchondral joints were not uncommon in microtia surgery. Patient variables were less likely to predict this anatomical variation, necessitating some knowledge of managing the framework instability. Female patients were more likely to enable easy fabrication with directly fused costal cartilages.

Retrospective multicenter cohort analysis of 621 cases of BellaGel silicone breast implants with study of physicochemical properties and surface topography.

This study aimed to assess the effectiveness and safety of BellaGel implants after implantation in Asian women and inform surgeons of another option for use in breast augmentation and reconstruction. This study was conducted in eight hospitals from November 27, 2015 to April 30, 2018. All patients underwent augmentation mammoplasty or implant-based breast reconstruction with BellaGel implants. Complication rates were compared between groups, and the cumulative hazard function was compared using the Kaplan-Meier survival analysis. Implants were grouped by surface type, and the cumulative hazard functions of total complication cases were compared. The biomechanical properties of the BellaGel implant and other company representative implants were tested using a mechanical testing machine, and surface topography was analyzed using a 3D laser scanning confocal microscope. There was a significant difference in the incidence of complications between the reconstruction (17.1%) and augmentation (4.7%) groups, but no significant difference in the complication rates of each group. There was no difference in the reoperation or revision rates between the groups. The log rank test showed a statistically significant difference in cumulative hazard function between the groups. Among the three types of implants (smooth, textured, and microtextured), the microtextured type had the lowest complication rate. The BellaGel microtexture implant had the highest maximal tensile load and displacement value. The BellaGel and Silksurface implants had the highest stored energy, although there was no significant difference. BellaGel implants can serve as a criterion for the selection of safe and effective implants among currently available implants.

The Impact of Fibrin Sealant Volume on Skin Graft Contraction in a Full-Thickness Skin Graft Model.

BACKGROUND: Fibrin sealant has been used for skin grafting in anatomically difficult facial areas. Although biodegradable, an excess of fibrin sealant may inhibit skin graft healing by inhibiting diffusion at the graft-recipient bed interface. The impact of fibrin sealant volume on graft healing was examined in a rat full-thickness skin graft model. METHODS: Seventy-two full-thickness 2.5 × 2.5-cm skin grafts were used on the dorsum of male Sprague-Dawley rats. The grafts were treated with three different volumes of fibrin sealant placed onto the recipient bed: 0.0 mL or normal saline (group 1), 0.1 mL (group 2), and 0.4 mL (group 3). Graft healing and complications were assessed using digital photographs and necropsies on postoperative days 3, 7, and 21. RESULTS: Group 3 showed the greatest graft contraction on days 3 and 21, while group 2 showed the least contraction on all 3 postoperative days (P = 0.002, 0.004, and <0.001, respectively). Histopathologic analysis showed inflammatory foreign body reactions in group 3 on days 3 and 7, and less vascular density on day 21 (P = 0.003). Group 1 showed the highest incidence of hematoma (P = 0.004). CONCLUSION: An excess volume of fibrin sealant may produce pathologic wound contraction in skin grafting because a skin graft lacks a vascular pedicle and is highly dependent on diffusion from the host environment. Before using fibrin sealant for skin grafting in facial areas where the aesthetic outcome is important, the appropriate volume to use can be determined.

Risk Factors for Delayed Resorption of Costal Cartilage Framework Following Microtia Reconstruction.

Background: Resorption of the cartilage framework results from hematoma or infection, deteriorating outcomes in microtia reconstruction. Delayed resorption still occurs for unclear reasons in patients without adverse events. The risk factors for delayed framework resorption were explored in this 20-year microtia cohort. Methods: Patients who underwent auricular elevation >5 years ago were reviewed from January 2001 to March 2019. Bilateral microtia, infection, and hematoma cases were excluded. Framework resorption was graded on the last photographs as none to minimal (grade 1), blunted but all components present (grade 2), loss of either the helical or antihelical component (grade 3), and loss of all components (grade 4). Logistic regression was used to evaluate independent risk factors for grade 3 and 4 resorption. Results: Of the 367 patients, 132 revisited our institution with a mean postoperative duration of 8.0 years. Grade 1 resorption was seen in 37.1%, 2 in 31.8%, 3 in 24.2%, and 4 in 6.8%. Canalplasty increased the risk of resorption regardless of timing (before auricular elevation, p = 0.017; after auricular elevation, p = 0.011). Body mass index at the time of cartilage harvest lowered the risk of resorption (p = 0.057) with clinical significance. Conclusions: Canalplasty may be avoided given the risk of framework resorption or may be performed with antiresorption strategies if the expected hearing outcome is superior. Our timing of harvest at the age of 10 years may have ensured cartilage maturation, both in terms of size and biomechanics, resulting in the resistance to resorption.

Review of 602 Microtia Reconstructions: Revisions and Specific Recommendations for Each Subtype.

BACKGROUND: Congenital microtia is highly variable in its clinical presentation, leading to many technical modifications to and controversies over treatment. The authors evaluated how surgical revisions and interdisciplinary interventions were involved in microtia reconstruction according to each subtype. METHODS: Congenital unilateral microtia patients who underwent two-stage microtia reconstruction from June of 2001 to June of 2019 were reviewed. Patient and surgical variables were collected, including the type, number, and timing of surgical revisions, canaloplasty, and jaw operations. Data were presented in relation to each subtype of microtia (i.e., anotia, small/atypical but usable lobule, typical lobule, concha, and scapha). RESULTS: From a total of 602 patients, 407 (67.6 percent) underwent some form of revisions and/or interventions in addition to the two stages of microtia reconstruction, with an average number of 2.2. The majority of small/atypical lobule cases underwent revisions to improve aesthetics, with lobule and inferior sulcus as the most problematic regions. Skin flap necrosis, with an overall rate of 4.0 percent, was most commonly found in the concha type. Except for anotia and small/atypical lobule, nearly one-third of all subtypes underwent canaloplasty, necessitating protective strategies against the circulation-threatening condition. A very small number of jaw operations (up to 7 percent) were performed in all subtypes. CONCLUSIONS: Over the two-decade cohort study of microtia reconstruction, revision and interdisciplinary operations were used differently for each subtype. An optimal management plan will be established with respect to type-specific conditions, including the level of difficulty in elevating the subcutaneous pedicle, usable vestige, and later effect of canaloplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Serial measurements of facial asymmetry using a wooden tongue depressor in patients with congenital microtia.

BACKGROUND AND OBJECTIVES: Congenital microtia may be associated with hemifacial microsomia, but little is known about their correlation and development with aging. Historically, facial asymmetry is easily assessed by observing the occlusal cant using a tongue depressor. We serially measured the occlusal cant in children with microtia to evaluate change in facial asymmetry with growth. METHODS: Since 2011, frontal photographs of patients with congenital microtia biting a tongue depressor were obtained and reviewed. The occlusal angle was compared between the baseline and final photographs, and the change was compared between cant-positive (>3° at baseline) and cant-negative (<3° at baseline) groups. Multivariate analysis was conducted to determine variables associated with the change in occlusal angle. RESULTS: Overall, 105 patients were enrolled. With a mean age of 5.4 years at baseline and a mean follow-up of 3.9 years, clinically significant aggravation was observed in 15.4% and 24.2% of cant-positive and cant-negative patients, respectively. Hemifacial microsomia (OR, 4.825; p = 0.005) and occlusal angle at baseline (OR, 0.821; p = 0.045) were associated with aggravation, but the severity of microtia showed no significant association. CONCLUSIONS: When hemifacial microsomia was present, the occlusal cant seemed to be aggravated in children with microtia at later ages. When the occlusal cant was present without noticeable hemifacial microsomia, some compensation in facial asymmetry was expected. The use of a wooden tongue depressor is a simple, non-invasive, and radiologic hazard-free aid to detect notable change in facial asymmetry in children with microtia.

BellaGel breast implant: 6-Year results of a prospective cohort study.

BACKGROUND: This is the first clinical study conducted among Asian women using breast implants manufactured by an Asian company. Four-year data regarding the safety and efficacy of BellaGel breast implants have already been published, and we now report 6-year data. METHODS: This study was designed to take place over 10 years. It included 103 patients who underwent breast reconstruction or augmentation using BellaGel breast implants. The rates of implant rupture and capsular contracture were measured and analyzed to evaluate the effectiveness of the breast implant. RESULTS: At patients' 6-year postoperative visits, the implant rupture and capsular contracture rates were 1.15% and 2.30%, respectively. The implant rupture rate was 3.77% among reconstruction cases and 0% among augmentation cases. The capsular contracture rate was 5.66% among reconstruction cases and 0.83% among augmentation cases. CONCLUSIONS: The 6-year data from this planned 10-year study suggest that the BellaGel cohesive silicone gel-filled breast implant is an effective and safe medical device that can be used in breast reconstruction and augmentation.

Minimally invasive salvage of infected breast tissue expanders: A continuous closed irrigation technique based on surface biofilm disruption.

BACKGROUND: Removal of the infected device has been the general treatment for device-associated infection in antibiotic failure. There have been anecdotal attempts to salvage infected medical devices by introducing a continuous closed irrigation system. OBJECTIVE: This study examines whether continuous closed irrigation of an infected device is a successful alternative to removal in patients with recalcitrant device-associated infection. METHODS: Patients who were diagnosed with recalcitrant periexpander infections during the course of expander-implant breast reconstruction from 2010 to 2018 were enrolled in a retrospective case-control study. Patients who failed antibiotics before 2017 underwent expander removal, but patients since 2017 underwent continuous closed irrigation of the infected expanders. Treatment details and clinical outcomes were compared. Rationale for expander irrigation was based on review of the current literature on biofilm research. RESULTS: During the study period, 21 out of the 1176 patients were diagnosed with periexpander infection recalcitrant to antibiotic therapy. Among the 21 patients, 16 underwent expander removal and five underwent expander irrigation. Clinical outcomes were comparable in terms of resolution of infection signs. The irrigation group showed fewer patients who abandoned reconstruction after infection treatment (removal = 11/16, irrigation = 1/5). Literature review revealed that expander irrigation might have induced hydrodynamic disruption of the biofilm structure. CONCLUSION: Expander irrigation was less invasive than removal and effective in suppressing severe recalcitrant periexpander infection. Continuous closed irrigation of infected expander devices may be a successful antibiofilm strategy in treating device-associated infections in select patients.

Atypical proliferative nodule in congenital melanocytic nevus with dural invasion: a case report.

Here we report a case of a focal atypical proliferative nodule (PN) arising from a congenital melanocytic nevus (CMN). Diagnosis was challenging because it had both benign and malignant clinical features. Unusual histopathology, immunohistochemistry, and intraoperative findings of this atypical PN are discussed. A 5-year-old girl was admitted for a congenital 5× 5 cm sized scalp mass. This hemangioma-like soft mass showed biphasic characteristics such as a slow, gradual, and benign increase in size but worrisome dural invasion with cranial bone defect. We removed the scalp mass with clear resection margins. Interoperatively, we found that the cranial bone defect had already filled. Histopathologic examination showed CMN with focal atypical PN. The nodule showed sharp demarcation and cellular pleomorphism. However, in immunohistochemical study, Ki-67 proliferation index and expression levels of protein S-100 and Melan-A were very low. These were unusual findings of atypical PNs. Despite her worrisome preoperative radiologic features, she showed an indolent clinical course compatible with previously reported biologic behavior. The patient underwent follow-up inspection with magnetic resonance imaging every 6 months for up to 3 years. The nodule appeared to be stationary at the last visit.

Evaluation of Donor Morbidity following Single-Stage Latissimus Dorsi Neuromuscular Transfer for Facial Reanimation.

BACKGROUND: Single-stage latissimus dorsi neuromuscular transfer has been a valuable option for dynamic smile reanimation. However, there is a paucity of studies evaluating the potential donor morbidity in such cases. The present study aimed to comprehensively analyze the donor morbidity following functional latissimus dorsi muscle transfer. METHODS: Patients who underwent single-stage functional latissimus dorsi muscle transfer for smile reanimation between 2002 and 2016 were reviewed. Postoperative complications and functional impairments at the donor sites were evaluated. The Quick-Disabilities of the Arm, Shoulder and Hand questionnaire was used for assessing postoperative donor-site function. RESULTS: Sixty patients, including 12 pediatric (18 years or younger) patients, were analyzed. Mean length of a harvested thoracodorsal nerve was 14.9 cm. Fourteen patients were treated with a dual innervation technique, in which both a descending and a transverse branch of the thoracodorsal nerve were harvested. Donor complications were observed in seven cases; all of them were seromas and resolved by simple aspiration. No other complications including scoliosis and sensory and/or motor disturbances in the upper extremities were encountered. Fifty patients responded to the Quick-Disabilities of the Arm, Shoulder and Hand questionnaire at a median follow-up of 51 months. The average score was 2.64, and all but three patients scored less than 10. No variables, including patient age (pediatric versus adult) and the use of a dual-innervation technique, affected the donor morbidities, including the functional deficits. CONCLUSION: Single-stage latissimus dorsi neuromuscular transfer for facial reanimation might be associated with a low rate of complications and minimal functional morbidity at the donor site. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

In Situ Solid-Gas Reactivity of Nanoscaled Metal Borides from Molten Salt Synthesis.

Metal borides have mostly been studied as bulk materials. The nanoscale provides new opportunities to investigate the properties of these materials, e.g., nanoscale hardening and surface reactivity. Metal borides are often considered stable solids because of their covalent character, but little is known on their behavior under a reactive atmosphere, especially reductive gases. We use molten salt synthesis at 750 °C to provide cobalt monoboride (CoB) nanocrystals embedded in an amorphous layer of cobalt(II) and partially oxidized boron as a model platform to study morphological, chemical, and structural evolutions of the boride and the superficial layer exposed to argon, dihydrogen (H2), and a mixture of H2 and carbon dioxide (CO2) through a multiscale in situ approach: environmental transmission electron microscopy, synchrotron-based near-ambient-pressure X-ray photoelectron spectroscopy, and near-edge X-ray absorption spectroscopy. Although the material is stable under argon, H2 triggers at 400 °C decomposition of CoB, leading to cobalt(0) nanoparticles. We then show that H2 activates CoB for the catalysis of CO2 methanation. A similar decomposition process is also observed on NiB nanocrystals under oxidizing conditions at 300 °C. Our work highlights the instability under reactive atmospheres of nanocrystalline cobalt and nickel borides obtained from molten salt synthesis. Therefore, we question the general stability of metal borides with distinct compositions under such conditions. These results shed light on the actual species in metal boride catalysis and provide the framework for future applications of metal borides in their stability domains.

Intraoperative Assessment of Facial Nerve Trunk Width in Early Childhood With Cervicofacial Lymphatic Malformation.

BACKGROUND: Facial nerve damage during head and neck surgery has long been an important issue. However, few publications on the gross anatomy of the facial nerve are available in the young population. The aim of this study was to provide in vivo measurements of the facial nerve trunk during lymphatic malformation (LM) resection and to determine the association between the trunk width and patient- and disease-related variables. METHODS: We conducted a retrospective analysis of 11 consecutive pediatric patients (11 facial nerve trunks) who underwent cervicofacial LM resection. The facial nerve of the affected side was dissected, and its trunk width at bifurcation was measured using calipers under a microscope during the operation. RESULTS: Eleven patients younger than 6 years were enrolled. The median width of the facial nerve in patients younger than 1 year was 1.15 mm; it was 2.5 mm in those older than 1 year. Trunk width was significantly greater in patients older than 1 year than those younger than 1 year, whereas no statistical significance was found when comparing other age groups. Patient weight was positively correlated with trunk width, whereas LM grade and diameter showed no significant correlation. CONCLUSIONS: The significantly greater width of the facial nerve trunk in LM patients older than 1 year than those younger than 1 year suggests that the age of 1 may be a threshold for facial nerve hypertrophy and growth acceleration. This study provides informative in vivo data to help understand facial nerve characteristics in young patients.

Suppression of PPARγ-mediated monoacylglycerol O-acyltransferase 1 expression ameliorates alcoholic hepatic steatosis.

Alcohol consumption is one of the major causes of hepatic steatosis, fibrosis, cirrhosis, and superimposed hepatocellular carcinoma. Ethanol metabolism alters the NAD(+)/NADH ratio, thereby suppressing the activity of sirtuin family proteins, which may affect lipid metabolism in liver cells. However, it is not clear how long-term ingestion of ethanol eventually causes lipid accumulation in liver. Here, we demonstrate that chronic ethanol ingestion activates peroxisome proliferator-activated receptor γ (PPARγ) and its target gene, monoacylglycerol O-acyltransferase 1 (MGAT1). During ethanol metabolism, a low NAD(+)/NADH ratio repressed NAD-dependent deacetylase sirtuin 1 (SIRT1) activity, concomitantly resulting in increased acetylated PPARγ with high transcriptional activity. Accordingly, SIRT1 transgenic mice exhibited a low level of acetylated PPARγ and were protected from hepatic steatosis driven by alcohol or PPARγ2 overexpression, suggesting that ethanol metabolism causes lipid accumulation through activation of PPARγ through acetylation. Among the genes induced by PPARγ upon alcohol consumption, MGAT1 has been shown to be involved in triglyceride synthesis. Thus, we tested the effect of MGAT1 knockdown in mice following ethanol consumption, and found a significant reduction in alcohol-induced hepatic lipid accumulation. These results suggest that MGAT1 may afford a promising approach to the treatment of fatty liver disease.

Postoperative pain control by preventive intercostal nerve block under direct vision followed by catheter-based infusion of local analgesics in rib cartilage harvest for auricular reconstruction in children with microtia: A randomized controlled trial.

BACKGROUND: Children with microtia complain of severe postoperative pain during early postoperative days after rib cartilage harvest for auricular reconstruction. The purpose of this study was to evaluate the effects of preventive donor site wound analgesia by intercostal nerve block (ICNB) and catheter-based infusion of local analgesics on postoperative pain after rib cartilage graft for auricular reconstruction in children with microtia. METHODS: In this prospective randomized study, 66 children underwent postoperative pain control using either preventive ICNB followed by catheter-based infusion (33 patients, study group) or intravenous (IV) analgesia alone (33 patients, control group). ICNB was performed under direct vision by the surgeon by injecting 0.5% bupivacaine into each of the three intercostal spaces before perichondrial dissection. Catheters were placed in three subchondral spaces before wound closure, and 0.5% bupivacaine was infused every 12 h for 48 h postoperatively. Pain degrees were recorded every 4 h during the first 48 postoperative hours using a visual analogue scale. RESULTS: The study group showed significantly lower mean pain scores of the chest at rest (3.7 vs. 5.1, p = 0.001), the chest during coughing (4.3 vs. 5.8, p = 0.006), and the ear (3.0 vs. 4.1, p = 0.001) than the control group. The amount of use of rescue IV ketorolac was smaller in the study group (p = 0.026) than in the control group. No side effects related to the intervention were noted. CONCLUSIONS: Preventive ICNB followed by catheter-based infusion is effective and safe in postoperative pain relief in rib cartilage graft for auricular reconstruction. (The clinical trial registration number: WHO ICTRP, apps.who.int/trialsearch (KCT0001668)).

Comprehensive Analysis of Donor-Site Morbidity following Free Thoracodorsal Artery Perforator Flap Harvest.

BACKGROUND: The authors evaluated donor-site morbidity following free thoracodorsal artery perforator flap harvest comprehensively and investigated patient-and operation-related factors that might contribute to adverse outcomes. METHODS: A retrospective analysis was conducted for all cases of free thoracodorsal artery perforator flap reconstruction performed between January of 2002 and December of 2014. Donor-site morbidity was evaluated in three aspects: postoperative complications, scar-related problems, and functional impairment. The Quick-Disabilities of the Arm, Shoulder and Hand questionnaire was administered postoperatively to assess donor-site function. RESULTS: A total of 293 patients were analyzed. The median follow-up period was 19.0 months. Donor-site complications developed in 33 patients (11.3 percent). Wound dehiscence (7.4 percent) and seroma (3.0 percent) were the most common complications. Harvesting thoracodorsal artery perforator flaps on multiple perforators or segmental latissimus dorsi muscle-chimeric flaps increased the rate of seroma formation but did not affect other donor-site morbidities significantly. Patient American Society of Anesthesiologists classification was a significant predictor of wound dehiscence and overall donor-site complications. Thirty-one patients (10.6 percent) had scar-related problems, including 18 hypertrophic and 13 widened scars. A transverse skin paddle design had a significant protective effect on developing scar-related problems, compared with the nontransverse design. The mean Quick-Disabilities of the Arm, Shoulder and Hand questionnaire score was 2.68 (range, 0 to 18.2), and 90 percent of patients scored less than 10. Flap dimensions were positively correlated with the questionnaire score. CONCLUSIONS: The present study suggests that the free thoracodorsal artery perforator flap is associated with low donor-site morbidity and minimal dysfunction. Careful consideration of patient condition and thoughtful planning could further minimize donor-site morbidity. CLINICAL QUESTION/LEVEVL OF EVIDENCE: Therapeutic, IV.

Caffeine inhibits adipogenesis through modulation of mitotic clonal expansion and the AKT/GSK3 pathway in 3T3-L1 adipocytes.

Caffeine has been proposed to have several beneficial effects on obesity and its related metabolic diseases; however, how caffeine affects adipocyte differentiation has not been elucidated. In this study, we demonstrated that caffeine suppressed 3T3-L1 adipocyte differentiation and inhibited the expression of CCAAT/enhancer binding protein (C/EBP)α and peroxisome proliferator-activated receptor (PPAR)γ, two main adipogenic transcription factors. Anti-adipogenic markers, such as preadipocyte secreted factor (Pref)-1 and Krüppel-like factor 2, remained to be expressed in the presence of caffeine. Furthermore, 3T3-L1 cells failed to undergo typical mitotic clonal expansion in the presence of caffeine. Investigation of hormonal signaling revealed that caffeine inhibited the activation of AKT and glycogen synthase kinase (GSK) 3 in a dose-dependent manner, but not extracellular signal-regulated kinase (ERK). Our data show that caffeine is an anti-adipogenic bioactive compound involved in the modulation of mitotic clonal expansion during adipocyte differentiation through the AKT/GSK3 pathway. [BMB Reports 2016; 49(2): 111-115].

Mitochondrial respiratory function induces endogenous hypoxia.

Hypoxia influences many key biological functions. In cancer, it is generally believed that hypoxic condition is generated deep inside the tumor because of the lack of oxygen supply. However, consumption of oxygen by cancer should be one of the key means of regulating oxygen concentration to induce hypoxia but has not been well studied. Here, we provide direct evidence of the mitochondrial role in the induction of intracellular hypoxia. We used Acetylacetonatobis [2-(2'-benzothienyl) pyridinato-kN, kC3'] iridium (III) (BTP), a novel oxygen sensor, to detect intracellular hypoxia in living cells via microscopy. The well-differentiated cancer cell lines, LNCaP and MCF-7, showed intracellular hypoxia without exogenous hypoxia in an open environment. This may be caused by high oxygen consumption, low oxygen diffusion in water, and low oxygen incorporation to the cells. In contrast, the poorly-differentiated cancer cell lines: PC-3 and MDAMB231 exhibited intracellular normoxia by low oxygen consumption. The specific complex I inhibitor, rotenone, and the reduction of mitochondrial DNA (mtDNA) content reduced intracellular hypoxia, indicating that intracellular oxygen concentration is regulated by the consumption of oxygen by mitochondria. HIF-1α was activated in endogenously hypoxic LNCaP and the activation was dependent on mitochondrial respiratory function. Intracellular hypoxic status is regulated by glucose by parabolic dose response. The low concentration of glucose (0.045 mg/ml) induced strongest intracellular hypoxia possibly because of the Crabtree effect. Addition of FCS to the media induced intracellular hypoxia in LNCaP, and this effect was partially mimicked by an androgen analog, R1881, and inhibited by the anti-androgen, flutamide. These results indicate that mitochondrial respiratory function determines intracellular hypoxic status and may regulate oxygen-dependent biological functions.