Type I interferon regulation by USP18 is a key vulnerability in cancer.

Precise regulation of Type I interferon signaling is crucial for combating infection and cancer while avoiding autoimmunity. Type I interferon signaling is negatively regulated by USP18. USP18 cleaves ISG15, an interferon-induced ubiquitin-like modification, via its canonical catalytic function, and inhibits Type I interferon receptor activity through its scaffold role. USP18 loss-of-function dramatically impacts immune regulation, pathogen susceptibility, and tumor growth. However, prior studies have reached conflicting conclusions regarding the relative importance of catalytic versus scaffold function. Here, we develop biochemical and cellular methods to systematically define the physiological role of USP18. By comparing a patient-derived mutation impairing scaffold function (I60N) to a mutation disrupting catalytic activity (C64S), we demonstrate that scaffold function is critical for cancer cell vulnerability to Type I interferon. Surprisingly, we discovered that human USP18 exhibits minimal catalytic activity, in stark contrast to mouse USP18. These findings resolve human USP18's mechanism-of-action and enable USP18-targeted therapeutics.

Evaluating the safety of same-day discharge following pediatric pyeloplasty and ureteral reimplantation; A NSQIP analysis 2012-2020.

INTRODUCTION: Same-day discharge (SDD) is a safe option for several adult urologic surgeries, benefiting patients and hospitals. By decreasing length of stay while maintaining patient safety, SDD is in-line with recent goals to provide high value care while minimizing costs. Literature on SDD in the pediatric population, however, is scarce, and no study has identified the efficacy of SDD for pediatric pyeloplasty (PP) and ureteral reimplantation (UR). OBJECTIVE: The aim of this study was to identify trends in the usage of SDD as well as its efficacy and safety based on surgical outcomes for pediatric PP and UR. STUDY DESIGN: The 2012-2020 files of the American College of Surgeon's National Surgical Quality Improvement Project pediatric database were queried for PP and UR. Patients were stratified as SDD or standard-length discharge (SLD). Trends in SDD usage, differences in baseline characteristics, surgical approach, and surgical outcomes including 30-day readmission, complication, and reoperation rates were analyzed between SDD and SLD groups. RESULTS: 8213 PP (SDD: 202 [2.46%]) and 10,866 UR (469 [4.32%]) were included in analysis. There were no significant changes in SDD rates between 2012 and 2020, averaging 2.39% (PP), and 4.39% (UR). For both procedures, SDD was associated with higher rates of open versus minimally invasive (MIS) surgical approach and with shorter operative and anesthesia durations. For PP, there were no differences in readmission, complication, or reoperation rates in the SDD group. For UR, there was a 1.69% increase in CD I/II complications in those receiving SDD, correlating to 1.96-fold higher odds of CD I/II in all SDD patients compared to SLD patients. DISCUSSION: These results suggest that while the rate of SDD has not increased in recent years, the current screening methods for SDD have been generally effective in maintaining the safety of SDD for pediatric procedures. Though SDD for UR did show a very small increase in minor complications, this may be due to less strict screening protocols, and may be alleviated via MIS surgical approach. While this is the first paper to investigate SDD for pediatric urology procedures, these results are similar to those found for adult procedures. This study is limited by the lack of clinical data reported in the database. CONCLUSION: SDD is a generally safe option for pediatric PP and UR, and further research should identify proper screening protocols to continue to allow for safe SDD.

Urology case report: Multifactorial bladder dysfunction in the setting of down syndrome.

A 16-year-old male patient with Down syndrome diagnosed with AKI and urinary tract infection was treated with meropenem for ESBL-positive E. coli in urine culture. Persistently elevated creatinine and persistent post-void residual (PVR) of >300 mL led to further testing, which revealed urethral stricture and a lower sacral Tarlov cyst. Due to no complete improvement with urethral dilatation, he underwent laminectomy and Tarlov cyst fenestration. Creatinine normalized, with increased urine output and robust flow. Due to a PVR of >100 mL, he received behavioral therapy, including sitting and timed voiding, and the PVR was reduced to <5 mL.

Mentorship in Urology Residency Programs in the United States.

OBJECTIVE: To characterize the status of mentorship programs for Urology residencies in the United States, highlight the importance of mentorship in the career of a urology resident, and identify the obstacles of implementing a mentorship program. METHODS: With Internal Review Board exemption and approval from the Society of Academic Urologists, a survey was sent to the Program Directors of the Urology Residency programs in the United States containing questions about the presence and structure of a mentorship program in their department. RESULTS: Response rate was 54%. Seventy-five percent of respondents approved of formal mentorship programs. Fifty-eight percent of respondents had 1 established. Five percent of programs had an official training course for faculty mentors. Thirty-eight percent of programs had no requirement on mentor and/or mentee meeting frequency. The most common reason for not having a formal mentorship program was because the program felt that informal mentorship sufficed. CONCLUSION: While the vast majority of Program Directors for Urology Residency programs in the United States approve of formal mentorship programs, only a little over half have 1 established. Programs should strive to create a formal mentorship program in their residency programs due to their recognized importance.

Optimized protocols for studying the NLRP3 inflammasome and assessment of potential targets of CP-453,773 in undifferentiated THP1 cells.

The NLRP3 inflammasome is a complex multimeric signaling apparatus that regulates production of the pro-inflammatory cytokine IL-1ß. To overcome both the variability among primary immune cells and the limitations of genetic manipulation of differentiated human or murine macrophages, we developed a simplified, reliable and relevant cell-based model for studying the NLRP3 inflammasome using the undifferentiated human myelomonocytic cell line THP1. Undifferentiated THP1 cells constitutively express NLRP3, and NLRP3 inflammasome activation occurred in response to canonical NLRP3 activation stimuli including nigericin, ATP, and urea crystals, culminating in pro-IL-1ß cleavage, extracellular release of mature IL-1ß, and pyroptosis. We used this THP1 cell system to investigate potential targets of the potent, NLRP3 inflammasome selective inhibitor CP-456,773. We optimized a viral shRNA transduction method for gene expression knockdown (KD), and the KD of NLRP3 itself eliminated inflammasome activation and IL-1ß production. NLRP3 inflammasome activation and CP-453,773 pharmacology were not altered in ABCb7- or ABCb10-deficient THP1 cells, eliminating these gene products as candidate pharmacological targets of CP-453,773. For ABCb10, we confirmed our results using CRISPR/CAS9-mediated ABCb10 knockout (KO) THP1 sub-lines. In summary, undifferentiated THP1 cells are fully competent for activation of the NLRP3 inflammasome and production of IL-1ß, without differentiation into macrophages, and we describe optimized KD and KO methodologies to manipulate gene expression in these cells. As an example of the utility of undifferentiated THP1 cells for investigations into the biology of the NLRP3 inflammasome, we have used this cell system to rule out ABCb7 and ABCb10 as potential targets of the NLRP3 inflammasome inhibitor CP-453,773.

Solving Congestion in the Plastic Surgery Match: A Game Theory Analysis.

Plastic and reconstructive surgery is among the most competitive specialties in the residency match. Applicants seeking to maximize their chances of a successful match often submit numerous applications to the National Residency Matching Program. It is not uncommon for those applying to plastic and reconstructive surgery to apply to every program. The high application volume imparts significant time and financial burden for applicants and programs alike. Furthermore, it makes distinguishing between applicants with a genuine interest in a specific program and those who are merely hoping to improve their chances vastly more difficult. The authors sought to characterize trends in the match rate, as the number of integrated plastic and reconstructive surgery programs continues to increase. Furthermore, they reviewed the literature on game theory for possible solutions to residency application congestion. The authors propose the use of the game theory model to explain the observed results and show why an application limit is the most reasonable approach to address this issue.

A mouse model for evaluation of efficacy and concomitant toxicity of anti-human CXCR4 therapeutics.

The development of therapeutic monoclonal antibodies through mouse immunization often originates drug candidates that are not cross-reactive to the mouse ortholog. In such cases, and particularly in oncology, drug efficacy studies are performed on human tumor xenografts or with "surrogate" anti-mouse ortholog antibodies if targeting tumor host cells. Safety assessment of drug candidate(s) is performed at a later development stage in healthy non-human primates. While the latter remains necessary before a drug advances into human subjects, it precludes evaluation of safety in disease conditions and drug de-risking during early development. Therefore, mouse models that allow concomitant evaluation of drug efficacy and safety are highly desirable. The C-X-C motif chemokine receptor 4 (CXCR4) is an attractive target for tumor-targeted and immuno-oncology therapeutics, with multiple mouse immunization-derived antibodies undergoing clinical trials. Given the pleiotropic role of CXCR4 in cancer biology, we anticipate continuous interest in this target, particularly in the testing of therapeutic combinations for immuno-oncology. Here, we describe the generation and validation of the first mouse knock-in of the whole coding region of human CXCR4. Homozygous human CXCR4 knock-in (hereafter designated as HuCXCR4KI) mice were viable and outwardly healthy, reproduced normally and nursed their young. The expression pattern of human CXCR4 in this model was similar to that of CXCR4 expression in normal human tissues. The human CXCR4 knock-in gene was expressed as a biologically active protein, thereby allowing normal animal development and adequate"homing" of leukocytes to the bone marrow. To further validate our model, we used an in vivo functional assay of leukocyte mobilization from bone marrow to peripheral blood by blocking CXCR4 signaling. Both an anti-human CXCR4 -specific blocking antibody and the small molecule CXCR4 inhibitor AMD3100 induced increased leukocyte counts in peripheral blood, whereas an anti-mouse CXCR4 -specific blocking antibody had no effect. This new mouse model is useful to evaluate efficacy and safety of anti-human CXCR4 -specific drugs as single agents or in combination therapies, particularly in the oncology, immuno-oncology, wound healing and chronic inflammation therapeutic areas.