An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance.

The Hippo pathway is a key growth control pathway that is conserved across species. The downstream effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs (transcriptional enhanced associate domain) are central to their transcriptional activities, we discovered a potent small-molecule inhibitor (SMI), GNE-7883, that allosterically blocks the interactions between YAP/TAZ and all human TEAD paralogs through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models and achieves strong antitumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes both intrinsic and acquired resistance to KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors in diverse preclinical models through the inhibition of YAP/TAZ activation. Taken together, this work demonstrates the activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.

The economic damage of COVID-19 on regional economies: an application of a spatial computable general equilibrium model to South Korea.

We developed a spatial computable general equilibrium model of South Korea to assess the spatial spillover effects of the COVID-19 pandemic on South Korea's regional economic growth patterns. The model measures a wide range of economic losses, including human health costs at the city and county level, through an analysis of regional producers' profit maximization on the supply side and regional households' utility maximization on the demand side. The model's findings showed that if the level of spatial interaction decreases by 10% as a result of social distancing policies, the national gross domestic product drops by 0.815-0.864%. This loss in economic growth can be further decomposed into 0.729% loss in agglomeration effect, 0.080-0.130% loss in health effect associated with medical treatment and premature mortality, and 0.005% loss in labor effect. The results of the models and simulations shed light on not only the epidemiological effects of social distancing interventions, but also their resultant economic consequences. This ex-ante evaluation of social distancing measures' effects can serve as a guide for future policy decisions made at both the national and regional level, providing policymakers with the tools for tailored solutions that address both regional economic circumstances and the spatial distribution of COVID-19 cases.

Association of Unilateral Latissimus Dorsi Muscle Harvest for Breast Reconstruction with Postoperative Spinal Posture.

BACKGROUND: The latissimus dorsi muscle originates from the lower thoracic spine with broad attachment and plays a subsidiary role in spinal postural stability. The authors investigated whether harvesting unilateral latissimus dorsi muscle for breast reconstruction could influence spinal posture in the long term. METHODS: Patients who underwent immediate unilateral breast reconstruction between 2002 and 2010 were reviewed. They were grouped according to reconstruction methods: latissimus dorsi muscle flap and tissue expander/implant. The Cobb angle was assessed twice at each of five different time points (preoperatively and 2, 4, 6, and 8 years postoperatively) by an independent physician blinded to the reconstruction modality. Postoperative scoliosis was defined as a mean Cobb angle greater than 10 degrees at 8 years postoperatively. The trends of changes in Cobb angle over time and the rates of postoperative scoliosis were compared between reconstruction methods. RESULTS: In total, 153 women were analyzed, including 102 using latissimus dorsi muscle flap and 51 using tissue expander/implant, with a median follow-up of 103 months. The latissimus dorsi flap group showed enhanced trends of increasing postoperative Cobb angles as compared with the tissue expander/implant group, and the difference remained significant after adjusting for other variables ( p = 0.001). The rate of postoperative scoliosis was significantly higher in the latissimus dorsi flap group than in the control group ( p = 0.029). Multivariable analyses revealed that use of the latissimus dorsi flap was associated with a significantly increased rate of postoperative scoliosis. CONCLUSION: Unilateral latissimus dorsi muscle flap harvest for breast reconstruction might be associated with changes in spinal posture in the long term.

AK2 is an AMP-sensing negative regulator of BRAF in tumorigenesis.

The RAS-BRAF signaling is a major pathway of cell proliferation and their mutations are frequently found in human cancers. Adenylate kinase 2 (AK2), which modulates balance of adenine nucleotide pool, has been implicated in cell death and cell proliferation independently of its enzyme activity. Recently, the role of AK2 in tumorigenesis was in part elucidated in some cancer types including lung adenocarcinoma and breast cancer, but the underlying mechanism is not clear. Here, we show that AK2 is a BRAF-suppressor. In in vitro assays and cell model, AK2 interacted with BRAF and inhibited BRAF activity and downstream ERK phosphorylation. Energy-deprived conditions in cell model and the addition of AMP to cell lysates strengthened the AK2-BRAF interaction, suggesting that AK2 is involved in the regulation of BRAF activity in response to cell metabolic state. AMP facilitated the AK2-BRAF complex formation through binding to AK2. In a panel of HCC cell lines, AK2 expression was inversely correlated with ERK/MAPK activation, and AK2-knockdown or -knockout increased BRAF activity and promoted cell proliferation. Tumors from HCC patients showed low-AK2 protein expression and increased ERK activation compared to non-tumor tissues and the downregulation of AK2 was also verified by two microarray datasets (TCGA-LIHC and GSE14520). Moreover, AK2/BRAF interaction was abrogated by RAS activation in in vitro assay and cell model and in a mouse model of HRASG12V-driven HCC, and AK2 ablation promoted tumor growth and BRAF activity. AK2 also bound to BRAF inhibitor-insensitive BRAF mutants and attenuated their activities. These findings indicate that AK2 monitoring cellular AMP levels is indeed a negative regulator of BRAF, linking the metabolic status to tumor growth.

Machine-Learning and Chemicogenomics Approach Defines and Predicts Cross-Talk of Hippo and MAPK Pathways.

Hippo pathway dysregulation occurs in multiple cancers through genetic and nongenetic alterations, resulting in translocation of YAP to the nucleus and activation of the TEAD family of transcription factors. Unlike other oncogenic pathways such as RAS, defining tumors that are Hippo pathway-dependent is far more complex due to the lack of hotspot genetic alterations. Here, we developed a machine-learning framework to identify a robust, cancer type-agnostic gene expression signature to quantitate Hippo pathway activity and cross-talk as well as predict YAP/TEAD dependency across cancers. Further, through chemical genetic interaction screens and multiomics analyses, we discover a direct interaction between MAPK signaling and TEAD stability such that knockdown of YAP combined with MEK inhibition results in robust inhibition of tumor cell growth in Hippo dysregulated tumors. This multifaceted approach underscores how computational models combined with experimental studies can inform precision medicine approaches including predictive diagnostics and combination strategies. SIGNIFICANCE: An integrated chemicogenomics strategy was developed to identify a lineage-independent signature for the Hippo pathway in cancers. Evaluating transcriptional profiles using a machine-learning method led to identification of a relationship between YAP/TAZ dependency and MAPK pathway activity. The results help to nominate potential combination therapies with Hippo pathway inhibition.This article is highlighted in the In This Issue feature, p. 521.

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.

Immunopathogenesis of ANCA-Associated Vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder which affects small- and, to a lesser degree, medium-sized vessels. ANCA-associated vasculitis encompasses three disease phenotypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). This classification is largely based on clinical presentations and has several limitations. Recent research provided evidence that genetic background, risk of relapse, prognosis, and co-morbidities are more closely related to the ANCA serotype, proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, compared to the disease phenotypes GPA or MPA. This finding has been extended to the investigation of biomarkers predicting disease activity, which again more closely relate to the ANCA serotype. Discoveries related to the immunopathogenesis translated into clinical practice as targeted therapies are on the rise. This review will summarize the current understanding of the immunopathogenesis of ANCA-associated vasculitis and the interplay between ANCA serotype and proposed disease biomarkers and illustrate how the extending knowledge of the immunopathogenesis will likely translate into development of a personalized medicine approach in the management of ANCA-associated vasculitis.

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.

Assessment of the risk of bulge/hernia formation after abdomen-based microsurgical breast reconstruction with the aid of preoperative computed tomographic angiography-derived morphometric measurements.

BACKGROUND: No preoperative risk assessment tool is available to predict postoperative bulge formation after abdomen-based breast reconstruction. The authors evaluated the association between clinical variables and morphometric measurements on preoperative computed tomographic (CT) angiography and postoperative abdominal wall morbidity. METHODS: The authors evaluated all cases of postoperative bulge/hernia and normal controls in patients who underwent preoperative CT angiography and abdomen-based microsurgical breast reconstruction between July 2009 and January 2018. CT-based abdominal wall profiles, including abdominal wall protrusion, abdominopelvic cavity cross-sectional area (CSA), and abdominopelvic cavity-to-total body CSA ratio, were obtained and analyzed. A novel risk stratification scoring system to stratify the risk of bulge/hernia was developed. RESULTS: Among 463 patients who underwent abdomen-based breast reconstruction, 23 were diagnosed as having a bulge/hernia. Age (OR 2.912; 95% CI 1.157-7.333), lateral row perforator (OR 5.065; 95% CI 1.834-13.986), and abdominal wall protrusion (OR 3.687; 95% CI 1.494-9.100) were significant risk factors associated with postoperative bulge/hernia in the multivariate analysis. Using the risk stratification scoring system, the incidence rates of postoperative bulge/hernia were 1.7%, 4.8%, and 19.0% for low-, intermediate-, and high-risk patients, respectively (p<0.001). CONCLUSIONS: Age, lateral row perforator, and abdominal wall protrusion were significantly associated with postoperative bulge/hernia formation after abdomen-based microsurgical breast reconstruction. The authors' risk score based on the three variables may help predict and minimize donor-site morbidity.

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.

A method to prevent cerebrospinal fluid leakage: Reinforcing acellular dermal matrix.

In neurosurgical cases, problems related to wound healing can vary from simple wound dehiscence to multilayer defects. This study demonstrates an effective method to prevent persistent cerebrospinal fluid (CSF) leakage using reinforcing acellular dermal matrix in neurosurgical patients with wound dehiscence. A 52-year-old woman was admitted for management of recurrent glioblastoma. After tumor removal surgery, the patient experienced sustained CSF leakage from the wound despite reparative attempts. The plastic surgery team performed wound repair procedure after remnant tumor removal by the neurosurgery team. Acellular dermal matrix was applied over the mesh plate to prevent CSF leakage and the postoperative status of the patient was evaluated. No sign of CSF leakage was found in the immediate postoperative period. After 3 years, there were no complications including CSF leakage, wound dehiscence, and infection. We hereby propose this method as a feasible therapeutic alternative for preventing CSF leakage in patients experiencing wound problem after neurosurgical procedures.

The Tumor Suppressor BAP1 Regulates the Hippo Pathway in Pancreatic Ductal Adenocarcinoma.

The deubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with a high risk for mesothelioma and melanocytic tumors. Here, we show that pancreatic intraepithelial neoplasia driven by oncogenic mutant KrasG12D progressed to pancreatic adenocarcinoma in the absence of BAP1. The Hippo pathway was deregulated in BAP1-deficient pancreatic tumors, with the tumor suppressor LATS exhibiting enhanced ubiquitin-dependent proteasomal degradation. Therefore, BAP1 may limit tumor progression by stabilizing LATS and thereby promoting activity of the Hippo tumor suppressor pathway. SIGNIFICANCE: BAP1 is mutated in a broad spectrum of tumors. Pancreatic Bap1 deficiency causes acinar atrophy but combines with oncogenic Ras to produce pancreatic tumors. BAP1-deficient tumors exhibit deregulation of the Hippo pathway.See related commentary by Brekken, p. 1624.

Impact of overweight/obesity on the development of hematoma following tissue expander-based breast reconstruction.

BACKGROUND: Overweight and obesity are well-known risk factors for postoperative complications; however, their impacts on hematoma formation have not been clarified. Several studies have suggested that overweight/obesity could have procoagulative effects, potentially reducing a risk for developing postoperative bleeding complications. This study aimed to investigate the effects of overweight/obesity on hematoma formation following tissue expander-based breast reconstruction. METHOD: Patients who underwent immediate tissue expander-based unilateral breast reconstruction between January 2010 and November 2018 were reviewed. They were categorized into four groups according to body mass index (BMI): underweight (<18.5 kg/m2), normal weight (18.5-25.0 kg/m2), overweight (25.0-30.0 kg/m2), and obesity (>30.0 kg/m2). The outcome was major postoperative hematoma, defined as one requiring emergent surgical intervention. Independent impacts of variables on hematoma development were evaluated via uni- and multivariable analyses. RESULTS: A total of 1,431 patients were analyzed, including 133 cases (9.3%) with underweight, 952 (66.5%) with normal weight, 302 (21.1%) with overweight, and 44 (3.1%) with obesity. Postoperative major hematoma developed in 29 cases (2.0%). The rate of hematoma formation was 2.3%, 2.6%, 0.3%, and 0% in the underweight, normal weight, overweight, and obesity groups, respectively, showing a significantly decreasing trend (p = 0.009), while those of other complications including seroma and mastectomy flap necrosis revealed the opposite trends, being significantly elevated as patient BMI increased. Multivariate analyses found overweight to be an independent protector against major hematoma compared with normal weight (p = 0.014; odds ratio=0.071). CONCLUSION: Overweight/obesity might have a protective effect on development of major bleeding complications following tissue expander-based breast reconstruction.

Management of Congenital Melanocytic Nevus on Face Using Multiple Re-expansion Method: Aesthetic and Psychosocial Results.

BACKGROUND: Congenital giant melanocytic nevus on the face is a challenging condition, especially in the pediatric population. It can produce significant cosmetic deformity with negative psychosocial effects in pediatric patients even after treatment. The objective of this study was to report aesthetic and psychosocial results in the management of congenital melanocytic nevus on the face using multiple reexpansion. METHODS: Data of 6 patients with congenital melanocytic nevus on the face who underwent excision and multiple reexpansion at our center from September 2004 to August 2017, were retrospectively reviewed. To evaluate aesthetic outcomes, preoperative and final photographs of each patient were reviewed by 3 other plastic surgeons and 4 laypersons. For comparison, 6 other patients who were treated with conventional surgery during the same period were reviewed. After final reconstruction surgery, the authors surveyed patients' satisfaction via telephone. RESULTS: Six patients were followed up for an average of 87.66 months (range, 55-123 months). The mean number of tissue expander insertions was 3.33 and the mean number of total expanders inserted was 4.83. Complication associated with expander exposure occurred in 1 patient during the fifth expansion. The average score of aesthetic outcome in the multiple reexpansion group was superior to that of the conventional group (2.60 versus 2.10, P = 0.03). During the telephone survey, patients did not rate their appearance as positive, although they were comparatively satisfied with the surgical procedure. CONCLUSION: Considering the low rate of malignancy involving congenital melanocytic nevus in childhood, multiple reexpansion is an attractive option to obtain better results compared with other reconstructive methods.

DR4-Ser424 O-GlcNAcylation Promotes Sensitization of TRAIL-Tolerant Persisters and TRAIL-Resistant Cancer Cells to Death.

TNF-related apoptosis-inducing ligand (TRAIL) resistance, including nongenetically acquired tolerance in cancer persister cells, is a major obstacle to translating TRAIL therapy into patients with cancer. However, the underlying mechanisms remain to be elucidated. Here, we show that DR4/TRAIL-R1 is O-GlcNAcylated at Ser424 in its death domain to mediate both apoptosis and necrosis upon TRAIL ligation. We found that DR4-Ser424 mutations, identified from our cell-based functional screen using a cancer patient-derived cDNA expression library and from The Cancer Genome Atlas, caused TRAIL resistance in various human cancer cell lines. Using O-GlcNAc transferase knockdown cells, DR4-preferred versus DR5-preferred cancer cells, and a DR5-neutralizing antibody, we evaluated the essential role of DR4-specific O-GlcNAc modification in TRAIL cytotoxicity. In contrast to DR4, DR5 was not O-GlcNAcylated by TRAIL treatment, discriminating DR4 from DR5-mediated signaling. Apart from genetic changes in DR4-Ser424, we further classified various cancer cell lines originated from stomach, colon, lung, and glioblastoma according to their sensitivity to and receptor preference upon TRAIL death signaling and generated TRAIL-tolerant persister-derived DLD-1PER cells. Among these, we discovered that DR4 was not modified by O-GlcNAc in most of the TRAIL-resistant cancer cells and DLD-1PER cells. Interestingly, promoting DR4 O-GlcNAcylation intentionally using 2-deoxy-d-glucose or a high concentration of glucose sensitized those resistant cancer cells to TRAIL. The O-GlcNAcylation-defective DR4 failed to form DISC/necrosome and could not translocate to aggregated platforms for receptor clustering. Our findings demonstrate that DR4 O-GlcNAcylation is crucial for TRAIL death signaling, providing new opportunities for TRAIL therapy overcoming TRAIL resistance in cancers. SIGNIFICANCE: This study reports that a novel posttranslational modification by O-GlcNAcylation of one of the two human TRAIL receptors with a death domain, TRAIL-R1 (DR4), plays a crucial role in enabling both apoptotic and necroptotic cell death induction by TRAIL.

Muscle-splitting approach to thoracoacromial vein for superdrainage in deep inferior epigastric artery perforator flap breast reconstruction.

BACKGROUND: Thoracoacromial vein (TAv) is seldomly considered as a secondary outflow recipient option when venous congestion of deep inferior epigastric artery perforator (DIEP) flap is encountered. The purpose of this study was to present a computed tomography (CT)-based anatomy and a method of approaching TAv in performing superdrainage using superficial inferior epigastric vein (SIEV) in DIEP flap breast reconstruction. METHODS: For CT-based anatomical study, 42 thoracoacromial vessels (TAV) of 21 patients who underwent DIEP flap breast reconstruction were analyzed. From November 2016 to May 2018, pectoralis major (PM) muscle splitting approach to TAv in the first intercostal space was applied to 7 patients who required superdrainage via SIEV. RESULTS: TAVs at mid-first intercostal space (ICS) were located 83.5 ± 9.8 mm lateral to the sternal border (H), 41.5 ± 12.9 mm below the clavicle (V), and 11.7 ± 3.2 mm deep to the outer surface of PM muscle (D). Mean oblique distances from TAV to internal mammary vessels in the 2nd and 3rd ICS were 75.7 ± 9.7 mm and 98.2 ± 10.9 mm, respectively. Seven DIEP flaps presenting intraoperative venous congestion were successfully salvaged intraoperatively with superdrainge procedure. TAvs were harvested without cutting the PM muscle in any patient. Their mean size at anastomosis was 1.61 ± 3.2 mm (range, 0.9-2.5 mm). All flaps survived without perfusion-related complications including fat necrosis. CONCLUSIONS: Harvest of TAv by muscle-splitting approach is an alternative option when additional venous anastomosis using SIEV is mandated for managing venous congestion of DIEP flap.

The tumor suppressor BAP1 cooperates with BRAFV600E to promote tumor formation in cutaneous melanoma.

The deubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with a high risk of mesothelioma and melanocytic tumors. Here, we show that Bap1 deletion in melanocytes cooperates with the constitutively active, oncogenic form of BRAF (BRAFV600E ) and UV to cause melanoma in mice, albeit at very low frequency. In addition, Bap1-null melanoma cells derived from mouse tumors are more aggressive and colonize and grow at distant sites more than their wild-type counterparts. Molecularly, Bap1-null melanoma cell lines have increased DNA damage measured by γH2aX and hyperubiquitination of histone H2a. Therapeutically, these Bap1-null tumors are completely responsive to BRAF- and MEK-targeted therapies. Therefore, BAP1 functions as a tumor suppressor and limits tumor progression in melanoma.

The Hippo pathway effector TAZ induces TEAD-dependent liver inflammation and tumors.

The Hippo signaling pathway regulates organ size and plays critical roles in maintaining tissue growth, homeostasis, and regeneration. Dysregulated in a wide spectrum of cancers, in mammals, this pathway is regulated by two key effectors, YAP and TAZ, that may functionally overlap. We found that TAZ promoted liver inflammation and tumor development. The expression of TAZ, but not YAP, in human liver tumors positively correlated with the expression of proinflammatory cytokines. Hyperactivated TAZ induced substantial myeloid cell infiltration into the liver and the secretion of proinflammatory cytokines through a TEAD-dependent mechanism. Furthermore, tumors with hyperactivated YAP and TAZ had distinct transcriptional signatures, which included the increased expression of inflammatory cytokines in TAZ-driven tumors. Our study elucidated a previously uncharacterized link between TAZ activity and inflammatory responses that influence tumor development in the liver.

Mortality, liver transplantation and hepatic complications in patients with treatment-naïve chronic hepatitis B treated with entecavir vs tenofovir.

Few studies have directly compared the long-term clinical outcomes of entecavir (ETV) and tenofovir disoproxil fumarate (TDF). This study aimed to compare the risk of mortality, liver transplantation and hepatic complications including hepatocellular carcinoma (HCC) and hepatic decompensation between these drugs in treatment-naïve chronic hepatitis B (CHB). We performed a longitudinal observational analysis of data from 1325 consecutive adult CHB patients with a cumulative adherence of ≥80% to treatment with ETV (n = 721) or TDF (n = 604) at a tertiary referral hospital in Ulsan, Korea, from 1 January 2007 through 31 April 2017. Among the patients, 708 were analysed using propensity score matching with a ratio of 1:1. In the follow-up period of up to 5 years, five patients (0.4%) died, three patients (0.2%) underwent liver transplantation (LT) and 54 patients (4.1%) developed HCC. Hepatic decompensation occurred in 24 (1.8%) patients. ETV therapy did not significantly differ from TDF therapy regarding the risk of liver-related death or LT (HR 0.96; 95% CI, 0.23-4.07; log-rank P = 0.955), HCC (HR, 1.36; 95% CI, 0.72-2.56; log-rank P = 0.340) and hepatic decompensation (HR, 1.64; 95% CI, 0.67-4.00; log-rank P = 0.276). In the 708 propensity-matched pairs, ETV and TDF were also not significantly different with respect to the risk of mortality, LT and hepatic complications. In this longitudinal observational study of 1325 patients with CHB, ETV and TDF therapies were not significantly different regarding the risk of mortality, HCC, LT and hepatic decompensation.