Efficacy of 24 hours versus 5 days of prophylactic antibiotics for the prevention of surgical site infection in outpatient elective facial plastic surgery.

Background: The discovery of penicillin marked a paradigm shift in medicine with the ability to treat previously life-threatening infections. Increasing antibiotic resistance as well as the risk of adverse reactions to antibiotics, however, creates pressures for judicious use. There continues to be debate about the role of prophylactic antibiotics in facial plastic surgery. This study explores the role of prophylactic antibiotic administration in elective outpatient facial plastic surgery by comparing 5 days versus 24 hours of antibiotic prophylaxis. Method: A retrospective cohort study of all consecutive patients undergoing cosmetic procedures at an outpatient facial plastic surgical center who received either 5 days or 24 hours of prophylactic antibiotics was performed. The primary outcome was the need for postoperative antibiotics within 6 weeks of surgery. Results: 204 patients met the inclusion criteria: 104 in the 5-day group and 100 in the 24-hour prophylaxis group. The overall infection rate was 3.4%: 3% in the 24-hour group and 3.8% in the 5-day group (p = 0.77). Subgroup analysis of clean-contaminated cases (n = 85) showed the rate of postoperative infections was 4.3%, all within the 5-day group. In clean cases (n = 119), the rate of postoperative infections was 4.2% (n = 5): 4.8% (n = 3) in the 24-hour group versus 3.5% (n = 2) in the 5-day group. Conclusions: The results show that decreasing the duration of antibiotics was not associated with an increased risk of postoperative infection. Given that antibiotics are an increasingly precious commodity with rising rates of resistance, this study supports the use of decreasing postoperative antibiotics to 24 hours.

BARD1 germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma.

BACKGROUND: High-risk neuroblastoma is a complex genetic disease that is lethal in more than 50% of patients despite intense multimodal therapy. Through genome-wide association studies (GWAS) and next-generation sequencing, we have identified common single nucleotide polymorphisms and rare, pathogenic or likely pathogenic germline loss-of-function variants in BARD1 enriched in neuroblastoma patients. The functional implications of these findings remain poorly understood. METHODS: We correlated BARD1 genotype with expression in normal tissues and neuroblastomas, along with the burden of DNA damage in tumors. To validate the functional consequences of germline pathogenic or likely pathogenic BARD1 variants, we used CRISPR-Cas9 to generate isogenic neuroblastoma (IMR-5) and control (RPE1) cellular models harboring heterozygous BARD1 loss-of-function variants (R112*, R150*, E287fs, and Q564*) and quantified genomic instability in these cells via next-generation sequencing and with functional assays measuring the efficiency of DNA repair. RESULTS: Both common and rare neuroblastoma-associated BARD1 germline variants were associated with lower levels of BARD1 mRNA and an increased burden of DNA damage. Using isogenic heterozygous BARD1 loss-of-function variant cellular models, we functionally validated this association with inefficient DNA repair. BARD1 loss-of-function variant isogenic cells exhibited reduced efficiency in repairing Cas9-induced DNA damage, ineffective RAD51 focus formation at DNA double-strand break sites, and enhanced sensitivity to cisplatin and poly (ADP-ribose) polymerase (PARP) inhibition both in vitro and in vivo. CONCLUSIONS: Taken together, we demonstrate that germline BARD1 variants disrupt DNA repair fidelity. This is a fundamental molecular mechanism contributing to neuroblastoma initiation that may have important therapeutic implications.

Germline pathogenic variants in neuroblastoma patients are enriched in BARD1 and predict worse survival.

BACKGROUND: Neuroblastoma is an embryonal cancer of the developing sympathetic nervous system. The genetic contribution of rare pathogenic or likely pathogenic germline variants in patients without a family history remains unclear. METHODS: Germline DNA sequencing was performed on 786 neuroblastoma patients. The frequency of rare cancer predisposition gene pathogenic or likely pathogenic variants in patients was compared with 2 cancer-free control cohorts. Matched tumor DNA sequencing was evaluated for second hits, and germline DNA array data from 5585 neuroblastoma patients and 23 505 cancer-free control children were analyzed to identify rare germline copy number variants. Patients with germline pathogenic or likely pathogenic variants were compared with those without to test for association with clinical characteristics, tumor features, and survival. RESULTS: We observed 116 pathogenic or likely pathogenic variants involving 13.9% (109 of 786) of neuroblastoma patients, representing a statistically significant excess burden compared with cancer-free participants (odds ratio [OR] = 1.60, 95% confidence interval [CI] = 1.27 to 2.00). BARD1 harbored the most statistically significant enrichment of pathogenic or likely pathogenic variants (OR = 32.30, 95% CI = 6.44 to 310.35). Rare germline copy number variants disrupting BARD1 were identified in patients but absent in cancer-free participants (OR = 29.47, 95% CI = 1.52 to 570.70). Patients harboring a germline pathogenic or likely pathogenic variant had a worse overall survival compared with those without (P = 8.6 x 10-3). CONCLUSIONS: BARD1 is an important neuroblastoma predisposition gene harboring both common and rare germline pathogenic or likely pathogenic variations. The presence of any germline pathogenic or likely pathogenic variant in a cancer predisposition gene was independently predictive of worse overall survival. As centers move toward paired tumor-normal sequencing at diagnosis, efforts should be made to centralize data and provide an infrastructure to support cooperative longitudinal prospective studies of germline pathogenic variation.

The Simons Observatory: A fully remote controlled calibration system with a sparse wire grid for cosmic microwave background telescopes.

For cosmic microwave background (CMB) polarization observations, calibration of detector polarization angles is essential. We have developed a fully remote controlled calibration system with a sparse wire grid that reflects linearly polarized light along the wire direction. The new feature is a remote-controlled system for regular calibration, which has not been possible in sparse wire grid calibrators in past experiments. The remote control can be achieved by two electric linear actuators that load or unload the sparse wire grid into a position centered on the optical axis of a telescope between the calibration time and CMB observation. Furthermore, the sparse wire grid can be rotated by using a motor. A rotary encoder and a gravity sensor are installed on the sparse wire grid to monitor the wire direction. They allow us to achieve detector polarization angle calibration with an expected systematic error of 0.08°. The calibration system will be installed in small-aperture telescopes at Simons Observatory.

Optimizing Treatment for Relapsed/Refractory Classic Hodgkin Lymphoma in the Era of Immunotherapy.

Most patients with classic Hodgkin lymphoma (cHL) are cured with combination chemotherapy, but approximately 10-20% will relapse, and another 5-10% will have primary refractory disease. The treatment landscape of relapsed/refractory (R/R) cHL has evolved significantly over the past decade following the approval of brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, and the PD-1 inhibitors nivolumab and pembrolizumab. These agents have significantly expanded options for salvage therapy prior to autologous hematopoietic cell transplantation (AHCT), post-transplant maintenance, and treatment of relapse after AHCT, which have led to improved survival in the modern era. In this review, we highlight our approach to the management of R/R cHL in 2023 with a focus on choosing first salvage therapy, post-transplant maintenance, and treatment of relapse after AHCT. We also discuss the management of older adults and transplant-ineligible patients, who require a separate approach. Finally, we review novel immunotherapy approaches in clinical trials, including combinations of PD-1 inhibitors with other immune-activating agents as well as novel antibody-drug conjugates, bispecific antibodies, and cellular immunotherapies. Ongoing studies assessing biomarkers of response to immunotherapy and dynamic biomarkers such as circulating tumor DNA may further inform treatment decisions and enable a more personalized approach in the future.

The Management of Low-Risk Myelodysplastic Syndromes-Current Standards and Recent Advances.

ABSTRACT: The myelodysplastic syndromes (MDSs) are a heterogeneous group of hematologic neoplasms with varied natural histories and prognoses. Specific to this review, treatment of low-risk MDS most often focuses on improving quality of life by correcting cytopenias, as opposed to urgent disease modification to avoid acute myeloid leukemia. These treatments include transfusion support with iron chelation when necessary, growth factors including novel maturation agents such as luspatercept, lenalidomide for del(5q) disease, and, increasingly, low-dose hypomethylating agents. Recent advances in the understanding of the genetic lesions that drive MDS have prompted a reassessment of how low-risk disease is defined and helped to identify a subset of low-risk MDS patients who may benefit from a more aggressive treatment paradigm, including hematopoietic stem cell transplantation.

Germline pathogenic variants in 786 neuroblastoma patients.

Importance: Neuroblastoma accounts for 12% of childhood cancer deaths. The genetic contribution of rare pathogenic germline variation in patients without a family history remains unclear. Objective: To define the prevalence, spectrum, and clinical significance of pathogenic germline variation in cancer predisposition genes (CPGs) in neuroblastoma patients. Design Setting and Participants: Germline DNA sequencing was performed on the peripheral blood from 786 neuroblastoma patients unselected for family history. Rare variants mapping to CPGs were evaluated for pathogenicity and the percentage of cases harboring pathogenic (P) or likely pathogenic (LP) variants was quantified. The frequency of CPG P-LP variants in neuroblastoma cases was compared to two distinct cancer-free control cohorts to assess enrichment. Matched tumor DNA sequencing was evaluated for "second hits" at CPGs and germline DNA array data from 5,585 neuroblastoma cases and 23,505 cancer-free control children was analyzed to identify rare germline copy number variants (CNVs) affecting genes with an excess burden of P-LP variants in neuroblastoma. Neuroblastoma patients with germline P-LP variants were compared to those without P-LP variants to test for association with clinical characteristics, tumor features, and patient survival. Main Outcomes and Measures: Rare variant prevalence, pathogenicity, enrichment, and association with clinical characteristics, tumor features, and patient survival. Results: We observed 116 P-LP variants in CPGs involving 13.9% (109/786) of patients, representing a significant excess burden of P-LP variants compared to controls (9.1%; P = 5.14 × 10-5, Odds Ratio: 1.60, 95% confidence interval: 1.27-2.00). BARD1 harbored the most significant burden of P-LP variants compared to controls (1.0% vs. 0.03%; P = 8.18 × 10-7; Odds Ratio: 32.30, 95% confidence interval: 6.44-310.35). Rare germline CNVs disrupting BARD1 were also identified in neuroblastoma patients (0.05%) but absent in controls (P = 7.08 × 10-3; Odds Ratio: 29.47, 95% confidence interval: 1.52 - 570.70). Overall, P-LP variants in DNA repair genes in this study were enriched in cases compared to controls (8.1% vs. 5.7%; P = 0.01; Odds Ratio: 1.45, 95% confidence interval: 1.08-1.92). Neuroblastoma patients harboring a germline P-LP variant had a worse overall survival when compared to patients without P-LP variants (P = 8.6 × 10-3), and this remained significant in a multivariate Cox proportional-hazards model (P = 0.01). Conclusions and Relevance: Neuroblastoma patients harboring germline P-LP variants in CPGs have worse overall survival and BARD1 is an important predisposition gene affected by both common and rare pathogenic variation. Germline sequencing should be performed for all neuroblastoma patients at diagnosis to inform genetic counseling and support future longitudinal and mechanistic studies. Patients with a germline P-LP variant should be closely monitored, regardless of risk group assignment.

BARD1 germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma.

Importance: High-risk neuroblastoma is a complex genetic disease that is lethal in 50% of patients despite intense multimodal therapy. Our genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) within the BARD1 gene showing the most significant enrichment in neuroblastoma patients, and also discovered pathogenic (P) or likely pathogenic (LP) rare germline loss-of-function variants in this gene. The functional implications of these findings remain poorly understood. Objective: To define the functional relevance of BARD1 germline variation in children with neuroblastoma. Design: We correlated BARD1 genotype with BARD1 expression in normal and tumor cells and the cellular burden of DNA damage in tumors. To validate the functional consequences of rare germline P-LP BARD1 variants, we generated isogenic cellular models harboring heterozygous BARD1 loss-of-function (LOF) variants and conducted multiple complementary assays to measure the efficiency of DNA repair. Setting: (N/A). Participants: (N/A). Interventions/Exposures: (N/A). Main Outcomes and Measures: BARD1 expression, efficiency of DNA repair, and genome-wide burden of DNA damage in neuroblastoma tumors and cellular models harboring disease-associated BARD1 germline variants. Results: Both common and rare neuroblastoma associated BARD1 germline variants were significantly associated with lower levels of BARD1 mRNA and an increased burden of DNA damage. Using neuroblastoma cellular models engineered to harbor disease-associated heterozygous BARD1 LOF variants, we functionally validated this association with inefficient DNA repair. These BARD1 LOF variant isogenic models exhibited reduced efficiency in repairing Cas9-induced DNA damage, ineffective RAD51 focus formation at DNA doublestrand break sites, and enhanced sensitivity to cisplatin and poly-ADP ribose polymerase (PARP) inhibition. Conclusions and Relevance: Considering that at least 1 in 10 children diagnosed with cancer carry a predicted pathogenic mutation in a cancer predisposition gene, it is critically important to understand their functional relevance. Here, we demonstrate that germline BARD1 variants disrupt DNA repair fidelity. This is a fundamental molecular mechanism contributing to neuroblastoma initiation that may have important therapeutic implications, and these findings may also extend to other cancers harboring germline variants in genes essential for DNA damage repair. Key Points: Question: How do neuroblastoma patient BRCA1-associated RING domain 1 ( BARD1 ) germline variants impact DNA repair? Findings: Neuroblastoma-associated germline BARD1 variants disrupt DNA repair fidelity. Common risk variants correlate with decreased BARD1 expression and increased DNA double-strand breaks in neuroblastoma tumors and rare heterozygous loss-of-function variants induce BARD1 haploinsufficiency, resulting in defective DNA repair and genomic instability in neuroblastoma cellular models. Meaning: Germline variation in BARD1 contributes to neuroblastoma pathogenesis via dysregulation of critical cellular DNA repair functions, with implications for neuroblastoma treatment, risk stratification, and cancer predisposition.

The RhinoCEROS Guidelines: A Practical Tool for Reporting Nasal Anatomy on Computed Tomography Pertaining to Rhinoplasty.

Cone-beam computed tomography (CT) is gaining popularity worldwide due to an increasingly diffuse and affordable in-office availability. It is becoming more commonplace for rhinoplasty surgeons to utilize this imaging as tool for preoperative assessment; however, there is inconsistency among radiologists commenting on specific structures of the nose or nasal cavity as there is currently no standardized reporting protocol. The goal of this article is to present clear guidelines for radiologists to report relevant nasal anatomy in the context of preoperative rhinoplasty evaluation. We have proposed the RhinoCEROS Guidelines, which stands for: Rhinoplasty Cephalometric Evaluation for Radiologic pre-Operative Systematization. This guideline highlights the primary aspects of nasal anatomy on CT that affect rhinoplasty outcomes and will provide radiologists with a straightforward template for reporting this increasingly popular use for CT scan.

The Simons Observatory: A large-diameter truss for a refracting telescope cooled to 1 K.

We present the design and measured performance of a new carbon fiber strut design that is used in a cryogenically cooled truss for the Simons Observatory small aperture telescope. The truss consists of two aluminum 6061 rings separated by 24 struts. Each strut consists of a central carbon fiber tube fitted with two aluminum end caps. We tested the performance of the strut and truss by (i) cryogenically cycling and destructively pull-testing strut samples, (ii) non-destructively pull-testing the final truss, and (iii) measuring the thermal conductivity of the carbon fiber tubes. We found that the strut strength is limited by the mounting fasteners and the strut end caps, not the epoxy adhesive or the carbon fiber tube. This result is consistent with our numerical predictions. Our thermal measurements suggest that the conductive heat load through the struts (from 4 to 1 K) will be less than 1 mW. This strut design may be a promising candidate for use in other cryogenic support structures.

Does metformin affect outcomes in COVID-19 patients with new or pre-existing diabetes mellitus? A systematic review and meta-analysis.

AIMS: The COVID-19 pandemic is a global public health emergency and patients with diabetes mellitus (DM) are disproportionately affected, exhibiting more severe outcomes. Recent studies have shown that metformin is associated with improved outcomes in patients with COVID-19 and DM and may be a potential candidate for drug repurposing. We aimed to investigate the effects of metformin on outcomes in patients with COVID-19 and DM. METHODS: Databases (PubMed, Scopus, Web of Science, EMBASE, Clinicaltrials.gov and Cochrane library) were searched up to 10 April 2021 for studies reporting data on metformin use in COVID-19 patients with DM. The risk of bias was assessed using the Newcastle-Ottawa scale. Certainty of evidence was rated using the GRADE approach. The primary outcome was mortality reported as odds ratio (OR). A random-effects meta-analysis was carried out on both unadjusted and adjusted ORs. This study is registered with PROSPERO, CRD42020221842. RESULTS: In total, 2 916 231 patients from 32 cohort studies were included in the quantitative and qualitative synthesis. The meta-analysis showed that metformin was significantly associated with lower mortality in COVID-19 patients with DM in both unadjusted (OR 0.61 [95% confidence interval: 0.53-0.71], P < .00001, I2  = 70%) and adjusted (OR 0.78 [95% confidence interval: 0.69-0.88], P < .00001, I2  = 67%) models. CONCLUSION: Poor outcomes in COVID-19 patients with DM can be attributed to inadequate glycaemic control and weakened immune responses. Metformin has multiple effects that can improve outcomes in patients with DM and our findings highlight a possible role of its use. However, robust randomised trials are needed to thoroughly assess its use.

A Systematic Review of Closure Techniques in Lateral Skull Base Tumor Surgery.

Introduction Tumors of the lateral skull base often require collaboration between neurosurgeons and neurotologists for the surgical approach. The three main transosseous surgical approaches are retrosigmoid (RS), translabyrinthine (TL), and middle fossa (MF). The literature reflects a relative paucity regarding the various closure techniques for these approaches and the postoperative complications. We have performed a systematic review comparing closure techniques from each approach. Methods A systematic review was performed using Ovid MEDLINE (1990-2016) on closure technique and postoperative complications for patients undergoing lateral skull base surgery via the TL, RS, or MF approach. Studies were included if they contained at least 10 patients, described their closure technique, and provided data on postoperative complications. Results A total of 1,403 studies were reviewed. Of these, 53 studies met inclusion criteria yielding a total of 10,466 subjects in this analysis. The average rate of cerebrospinal fluid leak was 5.3% in the TL approach, 9% in the RS approach, and 6.2% in the MF approach. There was no significant effect of various closure techniques on postoperative wound complications in the MF approach. Multiple factors were identified which affected postoperative wound complication in the RS and TL approaches. Conclusion There are a plethora of closure techniques for lateral skull base surgery. Several techniques were identified in this review that may affect the postoperative wound complication rates in lateral skull base surgery.

An Integrated Dyspepsia Module for First-year Pharmacy Students.

Objective. To design an integrated dyspepsia module for first year pharmacy students that combines clinical and professional practice with fundamental sciences in five different science subject areas. Methods. The approaches used in designing this module are described with emphasis on strategies adopted to integrate science and practice, and the new ways of working adopted by the design team. Students' views and experiences of the module and its integration were explored using questionnaires. Results. A high proportion of students reported positive views and experiences of the module, the integration and its impact (as self-reported) on their learning and practice. The assessment of student performance indicated learning and attainment was at an appropriate level for a first-year module. Both the student grades and research results indicate a positive student learning experience. Conclusion. The dyspepsia module provides a flexible and effective template for the integration of science and practice in theme-based modules, with students reporting positively about the integration, including their perception of its contribution to improving their learning and understanding. New and more collaborative ways of working are required when designing integrated modules.

A KRAS wild type mutational status confers a survival advantage in pancreatic ductal adenocarcinoma.

BACKGROUND: The KRAS oncogene is a driver mutation and is present in greater than 90% of pancreatic ductal adenocarcinomas (PDAC). A subset of these tumors, however, do not harbor mutations in KRAS (wild type KRAS). Studies have shown that patients with mutated KRAS have a poorer survival on first-line gemcitabine-based chemotherapy compared to wild type KRAS. In this study, we examined a cohort of patients with PDAC at our institution who were either wild type or mutant for the KRAS gene and assessed for differences in survival and response to different chemotherapeutic regimens. METHODS: We examined clinical records of patients treated at the Abramson Cancer Center of the University of Pennsylvania from 2013 to 2017. Patients with a pancreatic mass and a histologic diagnosis of pancreatic or pancreaticobiliary adenocarcinoma were identified. Thirty-nine patients with PDAC who underwent tumor sequencing at Penn Medicine's Center for Personalized Diagnostics (CPD) were selected for further study. Twelve patients were identified whose tumors were KRAS wild type. Twenty-seven patients with PDAC whose tumors harbored KRAS mutations were selected as controls (KRAS mutant). RESULTS: We noted a longer overall survival (OS) among KRAS wild type patients compared to KRAS mutant patients (P=0.026). This was independent of the age at diagnosis, patient gender, stage of diagnosis, tumor morphology, mismatch repair (MMR) status, and chemotherapeutic regimen. CONCLUSIONS: Similar to previously reported studies, PDAC with a KRAS wild type mutational profile has a better prognosis with a longer OS. This improved prognosis is independent of the protocol utilized in therapy for these patients. Our findings suggest that future clinical trials in pancreatic cancer should take into consideration the presence of KRAS mutations in their pre-planned analysis when assessing the efficacy of a novel therapeutic approach. This may be a crucial factor in trial concepts and outcomes.

Genetic susceptibility to neuroblastoma: current knowledge and future directions.

Neuroblastoma, a malignancy of the developing peripheral nervous system that affects infants and young children, is a complex genetic disease. Over the past two decades, significant progress has been made toward understanding the genetic determinants that predispose to this often lethal childhood cancer. Approximately 1-2% of neuroblastomas are inherited in an autosomal dominant fashion and a combination of co-morbidity and linkage studies has led to the identification of germline mutations in PHOX2B and ALK as the major genetic contributors to this familial neuroblastoma subset. The genetic basis of "sporadic" neuroblastoma is being studied through a large genome-wide association study (GWAS). These efforts have led to the discovery of many common susceptibility alleles, each with modest effect size, associated with the development and progression of sporadic neuroblastoma. More recently, next-generation sequencing efforts have expanded the list of potential neuroblastoma-predisposing mutations to include rare germline variants with a predicted larger effect size. The evolving characterization of neuroblastoma's genetic basis has led to a deeper understanding of the molecular events driving tumorigenesis, more precise risk stratification and prognostics and novel therapeutic strategies. This review details the contemporary understanding of neuroblastoma's genetic predisposition, including recent advances and discusses ongoing efforts to address gaps in our knowledge regarding this malignancy's complex genetic underpinnings.

Changes in Transcranial Ultrasound Velocities in Children with Sickle Cell Disease Undergoing Adenotonsillectomy.

Objectives (1) To assess for changes in cerebral blood flow velocity in children with sickle cell disease and obstructive sleep apnea (OSA) following adenotonsillectomy. (2) To determine if clinical factors such as OSA severity affect cerebral blood flow velocity values. Study Design Case series with chart review over 10 years. Settings Two tertiary children's hospitals. Subjects and Methods Children aged 2 to 18 years with a history of sickle cell disease and OSA, as defined by an apnea hypopnea index (AHI) >1 on polysomnography, were eligible for inclusion. Transcranial Doppler ultrasonography was used to assess cerebral blood flow velocity before and after adenotonsillectomy. Results Fifteen patients met inclusion criteria; 73% (n = 11) were female. The mean preoperative AHI was 8.9 (range, 1.2-22.2). Six (40%) patients had severe OSA (AHI >10). Following adenotonsillectomy, there was a significant reduction in mean (95% CI) cerebral blood flow velocities of the left terminal internal cerebral artery, 91.2 (79.4-103.1) to 75.7 (61.7-89.8; P = .018), and the right middle cerebral artery, 134.3 (119.2-149.3) to 116.5 (106.5-126.5; P = .003). There was not a significant correlation between baseline AHI and change in cerebral blood flow velocities. Conclusion Adenotonsillectomy may result in a reduction in some cerebral blood flow velocities. Further research is needed to determine if changes in cerebral velocities as assessed by transcranial Doppler ultrasonography translate into a reduced risk of stroke for children with sickle cell disease and OSA.

Axin phosphorylation in both Wnt-off and Wnt-on states requires the tumor suppressor APC.

The aberrant activation of Wnt signal transduction initiates the development of 90% of colorectal cancers, the majority of which arise from inactivation of the tumor suppressor Adenomatous polyposis coli (APC). In the classical model for Wnt signaling, the primary role of APC is to act, together with the concentration-limiting scaffold protein Axin, in a "destruction complex" that directs the phosphorylation and consequent proteasomal degradation of the transcriptional activator ß-catenin, thereby preventing signaling in the Wnt-off state. Following Wnt stimulation, Axin is recruited to a multiprotein "signalosome" required for pathway activation. Whereas it is well-documented that APC is essential in the destruction complex, APC's role in this complex remains elusive. Here, we demonstrate in Drosophila that Axin exists in two distinct phosphorylation states in Wnt-off and Wnt-on conditions, respectively, that underlie its roles in the destruction complex and signalosome. These two Axin phosphorylation states are catalyzed by glycogen synthase kinase 3 (GSK3), and unexpectedly, completely dependent on APC in both unstimulated and Wnt-stimulated conditions. In a major revision of the classical model, we show that APC is essential not only in the destruction complex, but also for the rapid transition in Axin that occurs after Wnt stimulation and Axin's subsequent association with the Wnt co-receptor LRP6/Arrow, one of the earliest steps in pathway activation. We propose that this novel requirement for APC in Axin regulation through phosphorylation both prevents signaling in the Wnt-off state and promotes signaling immediately following Wnt stimulation.