A Virtual Wellness and Learning Communities Program for Medical Students during the COVID-19 Pandemic.

OBJECTIVES: Numerous studies have demonstrated the high risk for burnout and mental illness in medical students. Because of the coronavirus disease 2019 (COVID-19) pandemic, our medical school transitioned to an all-virtual learning environment from March to June 2020, which raised concerns among student leaders and administrators, as reduced interpersonal attachments have known associations with decreased mental health. In an effort to facilitate student well-being during the pandemic, the Virtual Wellness and Learning Communities (VWLC) program was established. VWLC consisted of hour-long events that offered students the opportunity to engage with their peers online. METHODS: More than 20 events and workshops were conducted from March to June 2020, including trivia nights, song and guitar performances, sketching, video editing tutorials, chess lessons, yoga, and personal investing tips. An institutional review board-approved survey to assess the efficacy of the VWLC program was sent to medical student participants and nonparticipants. RESULTS: The overall response rate of this study was 43% (53/123). The response rate for students who attended a VWLC event was 51% (33/65), and the response rate for students who did not attend a VWLC event was 34% (20/58). Of all of the respondents, 85% (45/53) reported a decreased sense of connectivity with peers because of the pandemic, and 40% (21/53) reported a decrease in their sense of wellness. After attending a VWLC event, 79% (26/33) reported an increased sense of peer connectivity, 61% (20/33) reported improved wellness, and 55% (18/33) believed that these events should continue postpandemic to supplement in-person programming. Those who did not attend a virtual event stated that the main barriers to attending were unfamiliarity with attendees and screen fatigue. CONCLUSIONS: The COVID-19 pandemic has worsened medical student well-being and sense of community. VWLC programming may be an effective strategy for promoting medical student wellness and community while social distancing during the COVID-19 pandemic. To our knowledge, this is the first virtual wellness program for promotion of medical student mental health during the COVID-19 pandemic to be described in the literature.

Passenger deletions generate therapeutic vulnerabilities in cancer.

Inactivation of tumour-suppressor genes by homozygous deletion is a prototypic event in the cancer genome, yet such deletions often encompass neighbouring genes. We propose that homozygous deletions in such passenger genes can expose cancer-specific therapeutic vulnerabilities when the collaterally deleted gene is a member of a functionally redundant family of genes carrying out an essential function. The glycolytic gene enolase 1 (ENO1) in the 1p36 locus is deleted in glioblastoma (GBM), which is tolerated by the expression of ENO2. Here we show that short-hairpin-RNA-mediated silencing of ENO2 selectively inhibits growth, survival and the tumorigenic potential of ENO1-deleted GBM cells, and that the enolase inhibitor phosphonoacetohydroxamate is selectively toxic to ENO1-deleted GBM cells relative to ENO1-intact GBM cells or normal astrocytes. The principle of collateral vulnerability should be applicable to other passenger-deleted genes encoding functionally redundant essential activities and provide an effective treatment strategy for cancers containing such genomic events.

Postoperative Pain and Perioperative Antibiotic Management in Functional Rhinoplasty.

Post-rhinoplasty pain control should use a multimodal regimen. Evidence suggests decreasing routine prescriptions of narcotics is reasonable for most individuals, and acetaminophen and nonsteroidal antiinflammatory drug combinations may be equivalent to as-needed opioids for postsurgical pain management. Preoperative pain counseling is important to set post-rhinoplasty pain expectations and reduce opioid use. A single intravenous dose of prophylactic antibiotics before incision is sufficient for most cases of functional rhinoplasty. Additional considerations are given to complex revision cases, use of allogenic grafts or implants, external osteotomies, or patients with immunosuppression or at risk of endocarditis.

Prophylactic Antibiotic Use in Reconstruction of Nasal Mohs Defects.

OBJECTIVE: To evaluate the effect of prophylactic antibiotics on outcomes and complications following surgical reconstructions of nasal Mohs defects in the outpatient setting. STUDY DESIGN: Retrospective cohort study. SETTING: Single tertiary care center, July 2021 to June 2023. METHODS: All adult patients who underwent reconstruction of nasal Mohs defects in an outpatient office setting were examined. Patient demographics, surgical details, prophylactic postprocedural antibiotic use, and postprocedural complications (infection, flap or graft necrosis, wound dehiscence) were collected. Outcomes and complications were compared between patients who received and did not receive prophylactic antibiotics using χ2, Kruskal-Wallis, and multivariable logistic regression. RESULTS: A total of 211 patients met inclusion criteria. A majority of reconstructions utilized a local flap (70%), followed by a skin or composite graft (22%), then an interpolated flap (8%). Over half of patients (55%) were prescribed prophylactic antibiotics. Postprocedural complications were documented in 16 patients (7.6%), including infection (3.3%) and flap or graft loss or necrosis (1.4%). The rate of complications did not differ based on receipt of antibiotics. The only factors independently associated with the development of complications were history of chemoradiation and reconstruction with skin or composite grafts. CONCLUSION: Prophylactic antibiotics after nasal Mohs reconstructions performed in the office setting were not associated with any differences in the rate of postprocedural complications, including surgical site infections.

Bilateral Longus Colli Abscesses as a Complication of Advanced Bacterial Rhinosinusitis.

Known complications of acute bacterial rhinosinusitis include retropharyngeal abscess, cavernous sinus thrombosis, intracranial abscess, and associated sequelae. We describe the case of a patient with longus colli abscess formation resulting from acute pansinusitis, complicated by bilateral cavernous sinus thrombosis in the setting of concurrent viral pneumonitis, severe sepsis, and a large area cerebral infarction. The bilateral longus colli abscesses were drained via stereotactic image-guided endonasal sinus surgery, yielding Staphylococcus hominis in culture. The described disease progressed rapidly over a 2-week course amid the COVID-19 pandemic.

Utility of PET-CT in Newly Diagnosed HPV-Associated Oropharyngeal Squamous Cell Carcinoma.

OBJECTIVE: To compare the utility of positron emission tomography-computed tomography (PET-CT) versus contrasted CT neck combined with routine chest imaging for disease staging and treatment planning in human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) with clinically evident sites of primary disease. METHODS: All adult patients with primary HPV-associated OPSCC at a single quaternary care cancer center from 2018 to 2019 were reviewed, and those with images available for re-review were included. Primary outcomes included concordance in clinical staging between the 2 imaging modalities of interest (PET-CT vs CT), as well as independent agreement of each with pathologic staging. Analysis was performed via ordinal logistic regression. A secondary outcome was treatment selection after diagnostic imaging, analyzed via chi-squared testing. RESULTS: In total, 100 patients were included for evaluation, of which 89% were male, 91% Caucasian, and mean age was 61.2 years (SD 9.6). Clinical disease staging agreed between imaging modalities in 95% of cases (54 of 57 patients). Pathologic staging agreed with clinical staging from CT neck in 93% of cases (25 of 27 patients; P = .004), and with PET-CT in 82% (14 of 17 patients; P =.003). No differences were observed between the 2 imaging modalities for subsequent treatment selection (P = .39). CONCLUSION: In uncomplicated HPV-associated OPSCC, CT offers equivalent diagnostic accuracy to that of combined whole-body PET-CT for clinical staging, and has no appreciable impact on treatment selection. A reduced reliance on routine PET-CT during initial workup of HPV-associated OPSCC may be favorable for otherwise healthy patients with clinically evident sites of primary disease.

Impact of Preoperative Risk Factors on Inpatient Stay and Facility Discharge After Free Flap Reconstruction.

OBJECTIVE: To determine the preoperative risk factors most predictive of prolonged length of stay (LOS) or admission to a skilled nursing facility (SNF) or inpatient rehabilitation center (IPR) after free flap reconstruction of the head and neck. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary academic medical center. METHODS: Retrospective review of 1008 patients who underwent tumor resection and free flap reconstruction of the head and neck at a tertiary referral center from 2002 to 2019. RESULTS: Of 1008 patients (65.7% male; mean age of 61.4 years, SD 14.0 years), 161 (15.6%) were discharged to SNF/IPR, and the median LOS was 7 days. In multiple linear regression analysis, Charlson Comorbidity Index (CCI; P < .001), American Society of Anesthesiologists (ASA) classification (P = .021), female gender (P = .023), and inability to tolerate oral diet preoperatively (P = .006) were statistically significantly related to increased LOS, whereas age, body mass index (BMI), modified frailty index (MFI), a history of prior radiation or chemotherapy, and home oxygen use were not. Multiple logistic regression analysis demonstrated that CCI (odds ratio [OR] = 1.119, confidence interval [CI] 1.023-1.223), age (OR = 1.082, CI 1.056-1.108), and BMI <19.0 (OR = 2.141, CI 1.159-3.807) were the only variables statistically significantly related to posthospital placement in an SNF or IPR. CONCLUSION: Common tools for assessing frailty and need for additional care may be inadequate in a head and neck reconstructive population. CCI appears to be the best of the aggregate metrics assessed, with significant relationships to both LOS and placement in SNF/IPR.

Red Blood Cell Distribution Width and Pediatric Community-Acquired Pneumonia Disease Severity.

BACKGROUND AND OBJECTIVES: No standardized risk assessment tool exists for community-acquired pneumonia (CAP) in children. This study aims to investigate the association between red blood cell distribution width (RDW) and pediatric CAP. METHODS: Data prospectively collected by the Etiology of Pneumonia in the Community study (2010-2012) was used. Study population was pediatric patients admitted to tertiary care hospitals in Nashville and Memphis, Tennessee with clinically and radiographically confirmed CAP. The earliest measured RDW value on admission was used, in quintiles and also as a continuous variable. Outcomes analyzed were: severe CAP (requiring ICU, mechanical ventilation, vasopressor support, or death) or moderate CAP (hospital admission only). Analysis used multivariable logistic regression and restricted cubic splines modeling. RESULTS: In 1459 eligible children, the median age was 29 months (interquartile range: 12-73), median RDW was 13.3% (interquartile range: 12.5-14.3), and 289 patients (19.8%) developed severe disease. In comparison with the lowest RDW quintile (Q1), the adjusted odds ratio (95% CI) for severe CAP in subsequent quintiles were, Q2: 1.20 (0.72-1.99); Q3: 1.28 (0.76-2.14); Q4: 1.69 (1.01-2.82); Q5: 1.25 (0.73-2.13). Consistently, RDW restricted cubic splines demonstrated an independent, nonlinear, positive association with CAP severity (P = .027), with rapid increases in the risk of severe CAP with RDW values up to 15%. CONCLUSIONS: Higher presenting RDW was associated with an increased risk of severe CAP in hospitalized children. Widely available and inexpensive, RDW can serve as an objective data point to help with clinical assessments.

Socioeconomic Influences on Short-term Postoperative Outcomes in Patients With Oral Cavity Cancer Undergoing Free Flap Reconstruction.

OBJECTIVE: To evaluate the associations between median household income (MHI) and area deprivation index (ADI) on postoperative outcomes in oral cavity cancer. STUDY DESIGN: Retrospective review (2000-2019). SETTING: Single-institution tertiary medical center. METHODS: MHI and ADI were matched from home zip codes. Main postoperative outcomes of interest were length of tracheostomy use, length of hospital stay, return to oral intake, discharge disposition, and 60-day readmissions. Linear and logistic regression controlled for age, sex, race, body mass index, tobacco and alcohol use history, primary tumor location, disease staging at presentation, and length of surgery. A secondary outcome was clinical disease staging (I-IV) at time of presentation. RESULTS: The cohort (N = 681) was 91.3% White and 38.0% female, and 51.7% presented with stage IV disease. The median age at the time of surgery was 62 years (interquartile range [IQR], 53-71). The median MHI was $47,659 (IQR, $39,324-$58,917), and the median ADI was 67 (IQR, 48-79). ADI and MHI were independently associated with time to return of oral intake (ß = 0.130, P = .022; ß = -0.092, P = .045, respectively). Neither was associated with length of tracheostomy, hospital stay, discharge disposition, or readmissions. MHI quartiles were associated with a lower risk of presenting with more advanced disease (Q3 vs Q1: adjusted odds ratio, 0.56 [95% CI, 0.32-0.97]). CONCLUSION: MHI is associated with oral cavity cancer staging at the time of presentation. MHI and ADI are independently associated with postoperative return to oral intake following intraoral tumor resection and free flap reconstruction.

Improving annual albuminuria testing for individuals with diabetes.

BACKGROUND: Annual albuminuria screening detects the early stages of nephropathy in individuals with diabetes. Because early detection of albuminuria allows for interventions that lower the risk of developing chronic kidney disease, guidelines recommend annual testing for all individuals with type 2 diabetes mellitus and for those with type 1 diabetes for at least 5 years. However, at the Eskind Diabetes Clinic at the Vanderbilt University Medical Center, testing occurred less frequently than desired. METHODS: A quality improvement team first analysed the clinic's processes, identifying the lack of a systematic approach to testing as the likely cause for the low rate. The team then implemented two successive interventions in a pilot of patients seen by nurse practitioners in the clinic. In the first intervention, staff used a dashboard within the electronic health record while triaging each patient, pending an albuminuria order if testing had not been done within the past year. In the second intervention, clinic leadership sent daily reminders to the triage staff. A statistical process control chart tracked monthly testing rates. RESULTS: After 6 months, annual albuminuria testing increased from a baseline of 69% to 82%, with multiple special-cause signals in the control chart. CONCLUSIONS: This project demonstrates that a series of simple interventions can significantly impact annual albuminuria testing. This project's success likely hinged on using an existing workflow to systematically determine if a patient was due for testing and prompting the provider to sign a pended order for an albuminuria test. Other diabetes/endocrinology and primary care clinics can likely implement a similar process and so improve testing rates in other settings. When coupled with appropriate interventions to reduce the development of chronic kidney disease, such interventions would improve patient outcomes, in addition to better adhering to an established quality metric.

A Four-Week Otolaryngology Virtual Educational Curriculum for Prospective Applicants.

The COVID-19 pandemic led to a suspension of visiting student rotations across the United States. For senior medical students applying into surgical subspecialties, such as otolaryngology, these away rotations serve a vital role in the residency application process. Prior to the pandemic, there was not a virtual alternative to in-person visiting student rotations for applicants. We developed a replicable and expandable program focused on helping prospective otolaryngology applicants (fourth-year medical students) gain exposure to the experiences typically offered via in-person rotations. The goal was to improve otolaryngology-specific knowledge and to help applicants demonstrate specific program interest, without the financial and logistical challenges associated with in-person away rotations.

The Reality of Hearing Preservation in Cochlear Implantation: Who Is Utilizing EAS?

OBJECTIVE: To report the proportion of subjects successfully fit with combined electroacoustic stimulation (EAS) compared with those with preserved hearing (HP) after cochlear implantation (CI). In addition, to 1) report the trends in HP and EAS fit rates over time and 2) identify and characterize those patients who preferred the electric only condition. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary referral center. PATIENTS: Two hundred five postlingually deafened adults with bilateral SNHL and a preoperative low-frequency pure-tone average 80 dB HL or better in the ear to be implanted. INTERVENTIONS: Subjects underwent CI from 2013 to 2018 with routine pre- and postoperative audiometric testing performed at 6- and 12-months. MAIN OUTCOME MEASURES: Percentage of patients fit with EAS, low-frequency pure-tone average, and threshold shift. RESULTS: Overall, 141 patients (78.6%) had HP at activation and 42.6% were fit with EAS. Rates of EAS fitting improved from 36.4% in 2013 to 69.0% in 2018. 93.5% of patients had hearing preserved in 2018 compared with 57.9% in 2013. Six patients rejected EAS after a trial period either because of discomfort or poor sound quality. Eight patients had EAS removed because of loss of aidable hearing over time (between activation to 12 mo). CONCLUSIONS: Despite the high percentages of HP in the literature, EAS may be under-utilized in the adult CI population. Moving toward a universal definition of HP across institutions may better represent the potential for EAS fitting and a clinical measure capable of identifying patients best suited to benefit from EAS.

Risk factors for unchanged ventricles during pediatric shunt malfunction.

OBJECTIVE: Children whose ventricles do not change during shunt malfunction present a diagnostic dilemma. This study was performed to identify risk factors for unchanged ventricular size at shunt malfunction. METHODS: This retrospective 1:1 age-matched case-control study identified children with shunted hydrocephalus who underwent shunt revision with intraoperative evidence of malfunction at one of the three participating institutions from 1997 to 2019. Cases were defined as patients with a change of < 0.05 in the frontal-occipital horn ratio (FOR) between malfunction and baseline, and controls included patients with FOR changes ≥ 0.05. The presence of infection, abdominal pseudocyst, pseudomeningocele, or wound drainage and lack of baseline cranial imaging at the time of malfunction warranted exclusion. RESULTS: Of 450 included patients, 60% were male, 73% were Caucasian, and 67% had an occipital shunt. The median age was 4.3 (IQR 0.97-9.21) years at malfunction. On univariable analysis, unchanged ventricles at malfunction were associated with a frontal shunt (41% vs 28%, p < 0.001), programmable valve (17% vs 9%, p = 0.011), nonsiphoning shunt (85% vs 66%, p < 0.001), larger baseline FOR (0.44 ± 0.12 vs 0.38 ± 0.11, p < 0.001), no prior shunt infection (87% vs 76%, p = 0.003), and no prior shunt revisions (68% vs 52%, p < 0.001). On multivariable analysis with collinear variables removed, patients with a frontal shunt (OR 1.67, 95% CI 1.08-2.70, p = 0.037), programmable valve (OR 2.63, 95% CI 1.32-5.26, p = 0.007), nonsiphoning shunt at malfunction (OR 2.76, 95% CI 1.63-4.67, p < 0.001), larger baseline FOR (OR 3.13, 95% CI 2.21-4.43, p < 0.001), and no prior shunt infection (OR 2.34, 95% CI 1.27-4.30, p = 0.007) were more likely to have unchanged ventricles at malfunction. CONCLUSIONS: In a multicenter cohort of children with shunt malfunction, those with a frontal shunt, programmable valve, nonsiphoning shunt, baseline large ventricles, and no prior shunt infection were more likely than others to have unchanged ventricles at shunt failure.

Association of Social Determinants of Health with Time to Diagnosis and Treatment Outcomes in Idiopathic Subglottic Stenosis.

OBJECTIVES: To examine whether social determinants of health (SDH) factors are associated with time to diagnosis, treatment selection, and time to recurrent surgical intervention in idiopathic subglottic stenosis (iSGS) patients. METHODS: Adult patients with diagnosed iSGS were recruited prospectively (2015-2017) via clinical providers as part of the North American Airway Collaborative (NoAAC) and via an online iSGS support community on Facebook. Patient-specific SDH factors included highest educational attainment (self-reported), median household income (matched from home zip code via U.S. Census data), and number of close friends (self-reported) as a measure of social support. Main outcomes of interest were time to disease diagnosis (years from symptom onset), treatment selection (endoscopic dilation [ED] vs cricotracheal resection [CTR] vs endoscopic resection with adjuvant medical therapy [ERMT]), and time to recurrent surgical intervention (number of days from initial surgical procedure) as a surrogate for disease recurrence. RESULTS: The total 810 participants were 98.5% female, 97.2% Caucasian, and had a median age of 50 years (IQR, 43-58). The cohort had a median household income of $62 307 (IQR, $50 345-$79 773), a median of 7 close friends (IQR, 4-10), and 64.7% of patients completed college or graduate school. Education, income, and number of friends were not associated with time to diagnosis via multivariable linear regression modeling. Univariable multinominal logistic regression demonstrated an association between education and income for selecting ED versus ERMT, but no associations were noted for CTR. No associations were noted for time to recurrent surgical procedure via Kaplan Meier modeling and Cox proportional hazards regression. CONCLUSIONS: Patient education, income, and social support were not associated with time to diagnosis or time to disease recurrence. This suggests additional patient, procedure, or disease-specific factors contribute to the observed variations in iSGS surgical outcomes.

Child Pain Intensity and Parental Attitudes toward Complementary and Alternative Medicine Predict Post-Tonsillectomy Analgesic Use.

Parental attitudes regarding pain interventions and perceptions of their child's pain intensity likely influence the decision to administer postoperative analgesics. Our study examined the impact of daily fluctuations in child pain intensity and parental attitudes regarding complementary and alternative medicine (CAM) on analgesic administration following pediatric tonsillectomy. Parents of children undergoing tonsillectomy (n = 33) completed a survey assessing CAM attitudes and a 7-day postoperative electronic daily diary to record their child's daily pain intensity and analgesic medications (acetaminophen, ibuprofen, or oxycodone). Generalized linear mixed models with Poisson distributions evaluated the effects of within-person (child's daily pain intensity) and between-person (average postoperative pain, parental CAM attitudes) components on the number of medication doses administered. Higher daily pain intensity was associated with more oxycodone doses administered on a given day, but not acetaminophen or ibuprofen. Positive parental CAM attitudes were associated with less oxycodone use, beyond the variations accounted for by the child's daily pain intensity and average postoperative pain. Both parental CAM attitudes and their child's daily pain intensity were independently associated with parental decisions to administer opioids following tonsillectomy. Understanding factors influencing individual variability in analgesic use could help optimize children's postoperative pain management.

FOXO protects against age-progressive axonal degeneration.

Neurodegeneration resulting in cognitive and motor impairment is an inevitable consequence of aging. Little is known about the genetic regulation of this process despite its overriding importance in normal aging. Here, we identify the Forkhead Box O (FOXO) transcription factor 1, 3, and 4 isoforms as a guardian of neuronal integrity by inhibiting age-progressive axonal degeneration in mammals. FOXO expression progressively increased in aging human and mouse brains. The nervous system-specific deletion of Foxo transcription factors in mice accelerates aging-related axonal tract degeneration, which is followed by motor dysfunction. This accelerated neurodegeneration is accompanied by levels of white matter astrogliosis and microgliosis in middle-aged Foxo knockout mice that are typically only observed in very old wild-type mice and other aged mammals, including humans. Mechanistically, axonal degeneration in nerve-specific Foxo knockout mice is associated with elevated mTORC1 activity and accompanying proteotoxic stress due to decreased Sestrin3 expression. Inhibition of mTORC1 by rapamycin treatment mimics FOXO action and prevented axonal degeneration in Foxo knockout mice with accelerated nervous system aging. Defining this central role for FOXO in neuroprotection during mammalian aging offers an invaluable window into the aging process itself.

ZNF652, a novel zinc finger protein, interacts with the putative breast tumor suppressor CBFA2T3 to repress transcription.

The transcriptional repressor CBFA2T3 is a putative breast tumor suppressor. To define the role of CBFA2T3, we used a segment of this protein as bait in a yeast two-hybrid screen and identified a novel uncharacterized protein, ZNF652. In general, primary tumors and cancer cell lines showed lower expression of ZNF652 than normal tissues. Together with the location of this gene on the long arm of chromosome 17q, a region of frequent loss of heterozygosity in cancer, these results suggest a possible role of ZNF652 in tumorigenesis. In silico analysis of this protein revealed that it contains multiple classic zinc finger domains that are predicted to bind DNA. Coimmunoprecipitation assays showed that ZNF652 strongly interacts with CBFA2T3 and this interaction occurs through the COOH-terminal 109 amino acids of ZNF652. In contrast, there was a weak interaction of ZNF652 with CBFA2T1 and CBFA2T2, the other two members of this ETO family. Transcriptional reporter assays further confirmed the strength and selectivity of the ZNF652-CBFA2T3 interaction. The transcriptional repression of growth factor independent-1 (GFI-1), a previously characterized ETO effector zinc finger protein, was shown to be enhanced by CBFA2T1, but to a lesser extent by CBFA2T2 and CBFA2T3. We therefore suggest that each of the various gene effector zinc finger proteins may specifically interact with one or more of the ETO proteins to generate a defined range of transcriptional repressor complexes.

FBXO31 is the chromosome 16q24.3 senescence gene, a candidate breast tumor suppressor, and a component of an SCF complex.

A BAC located in the 16q24.3 breast cancer loss of heterozygosity region was previously shown to restore cellular senescence when transferred into breast tumor cell lines. We have shown that FBXO31, although located just distal to this BAC, can induce cellular senescence in the breast cancer cell line MCF-7 and is the likely candidate senescence gene. FBXO31 has properties consistent with a tumor suppressor, because ectopic expression of FBXO31 in two breast cancer cell lines inhibited colony growth on plastic and inhibited cell proliferation in the MCF-7 cell line. In addition, compared with the relative expression in normal breast, levels of FBXO31 were down-regulated in breast tumor cell lines and primary tumors. FBXO31 was cell cycle regulated in the breast cell lines MCF-10A and SKBR3 with maximal expression from late G(2) to early G(1) phase. Ectopic expression of FBXO31 in the breast cancer cell line MDA-MB-468 resulted in the accumulation of cells at the G(1) phase of the cell cycle. FBXO31 contains an F-box domain and is associated with the proteins Skp1, Roc-1, and Cullin-1, suggesting that FBXO31 is a component of a SCF ubiquitination complex. We propose that FBXO31 functions as a tumor suppressor by generating SCF(FBXO31) complexes that target particular substrates, critical for the normal execution of the cell cycle, for ubiquitination and subsequent degradation.

The intraflagellar transport protein IFT27 promotes BBSome exit from cilia through the GTPase ARL6/BBS3.

The sorting of signaling receptors into and out of cilia relies on the BBSome, a complex of Bardet-Biedl syndrome (BBS) proteins, and on the intraflagellar transport (IFT) machinery. GTP loading onto the Arf-like GTPase ARL6/BBS3 drives assembly of a membrane-apposed BBSome coat that promotes cargo entry into cilia, yet how and where ARL6 is activated remains elusive. Here, we show that the Rab-like GTPase IFT27/RABL4, a known component of IFT complex B, promotes the exit of BBSome and associated cargoes from cilia. Unbiased proteomics and biochemical reconstitution assays show that, upon disengagement from the rest of IFT-B, IFT27 directly interacts with the nucleotide-free form of ARL6. Furthermore, IFT27 prevents aggregation of nucleotide-free ARL6 in solution. Thus, we propose that IFT27 separates from IFT-B inside cilia to promote ARL6 activation, BBSome coat assembly, and subsequent ciliary exit, mirroring the process by which BBSome mediates cargo entry into cilia.