A contemporary comparison of laparoscopic versus open partial nephrectomy for renal cell carcinoma.

PURPOSE: To analyze surgical and oncologic outcomes of patients undergoing open partial nephrectomy (OPN) versus laparoscopic partial nephrectomy (LPN) for treatment of renal cell carcinoma (RCC). METHODS: We retrospectively investigated our institutional RCC database for patients who underwent PN for RCC from 1997 to 2018. Decision for technique was at the discretion of the operating urologist, following practice patterns and training history. Outcomes analyzed included pre/peri/post-operative parameters, pathologic outcomes, and disease recurrence rates. RESULTS: 1088 patients underwent PN from 1997 to 2018. After exclusionary criteria, 631 patients who underwent 647 unique PNs for a total of 162 OPN and 485 LPN remained. Baseline, pre-op, and pathologic characteristics were not statistically different. Surgical time was lower in laparoscopic cases [185 vs. 205 min] (p = 0.013). Margin involvement was not statistically different; LPN had lower estimated blood loss (EBL) [150 vs. 250 mL] (p < 0.001) and longer ischemia time [21 vs. 19 min] (p = 0.005). LPN had shorter length of stay [2 vs. 4 days] (p < 0.001), fewer overall complications (p < 0.001), and no significant difference in high-grade complications [2.89 vs. 4.32%] (p = 0.379). Fewer LPN patients developed metastases [1.65 vs. 4.94%] (p = 0.0499). Local recurrence rates were not statistically different [1.24 vs. 3.09%] (p = 0.193). Renal function was equivalent between cohorts post-operatively. CONCLUSION: Long-term oncologic outcomes were not significantly different between LPN versus OPN, with no statistical difference in patient and tumor characteristics. LPN was associated with lower EBL, shorter length of stay, and lower overall complication risk. Renal function was not significantly different between cohorts.

Speech and Swallowing Outcomes of Surgically Managed Cervical Chordoma: A Case Series.

OBJECTIVES: Cervical chordoma is a rare, low-grade primary bone tumor occurring in the axial skeleton. Due to challenges in surgical exposure caused by anatomic location, patients may experience dysfunction in speech and swallowing. The objective of this study was to characterize speech and swallowing outcomes for patients undergoing surgical resection of cervical chordoma. Moreover, we detail in-depth two cases with similar initial presentations to compare prognostic factors and management strategies. METHODS: Eleven patients with histologically confirmed cervical chordoma treated between 1993 and 2020 were included in this retrospective case series. Outcomes measured included overall survival, disease-free survival, need for enteral feeds, as well as results of modified barium swallow study (MBSS) and fiberoptic laryngoscopy. RESULTS: The mean age at diagnosis was 55.9 years. The patient population was 81.8% male. Mean survival after diagnosis was 96 months. Four (36.4%) patients required post-operative MBSS and demonstrated aspiration. All four of these patients presented with tumors in the superior cervical spine and received surgeries utilizing anterior approaches. Of the four, 2 required enteral feeds long-term. Four (36.4%) patients endorsed dysphonia. One patient developed post-operative right vocal fold paresis. The remaining three patients experienced stable dysphonia pre- and post-operatively. Additionally, three (27%) patients required tracheostomy placement, two of which remained in place long-term. CONCLUSIONS: Dysphagia is a common side effect of cervical chordoma resection. It is associated with the use of an anterior approach during resection and with tumors located in the superior cervical spine. Patients with postoperative dysphagia should receive early multidisciplinary swallow rehabilitation. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

PLK1 and its substrate MISP facilitate intrahepatic cholangiocarcinoma progression by promoting lymphatic invasion and impairing E-cadherin adherens junctions.

Intrahepatic cholangiocarcinoma (iCCA) is a subtype of CCA and has a high mortality rate and a relatively poor prognosis. However, studies focusing on increased cell motility and loss of epithelial integrity during iCCA progression remain relatively scarce. We collected seven fresh tumor samples from four patients to perform RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) to determine the transcriptome profile and chromatin accessibility of iCCA. The increased expression of cell cycle regulators, including PLK1 and its substrate MISP, was identified. Ninety-one iCCA patients were used to validate the clinical significance of PLK1 and MISP. The upregulation of PLK1 and MISP was determined in iCCA tissues. Increased expression of PLK1 and MISP was significantly correlated with tumor number, N stage, and lymphatic invasion in an iCCA cohort. Knockdown of PLK1 or MISP reduced trans-lymphatic endothelial migration and wound healing and affected focal adhesions in vitro. In cell‒cell junctions, MISP localized to adherens junctions and suppressed E-cadherin dimerization. PLK1 disrupted adherens junctions in a myosin-dependent manner. Furthermore, PLK1 and MISP promoted cell proliferation in vitro and tumorigenesis in vivo. In iCCA, PLK1 and MISP promote aggressiveness by increasing lymphatic invasion, tumor growth, and motility through the repression of E-cadherin adherens junctions.

At the Intersection of Intersectionality: Race and Gender Diversity Among Surgical Faculty and Trainees.

OBJECTIVE: To compare the representation of intersectional (ie, racial/ethnic and gender) identities among surgical faculty versus medical students. BACKGROUND: Health disparities are pervasive in medicine, but diverse physicians may help the medical profession achieve health equity. METHODS: Data from the Association of American Medical Colleges for 140 programs (2011/2012-2019/2020) were analyzed for students and full-time surgical faculty. Underrepresented in medicine (URiM) was defined as Black/African American, American Indian/Alaskan Native, Hispanic/Latino/Spanish Origin, or Native Hawaiian/Other Pacific Islander. Non-White included URiM plus Asian, multiracial, and non-citizen permanent residents. Linear regression was used to estimate the association of year and proportions of URiM and non-White female and male faculty with proportions of URiM and non-White students. RESULTS: Medical students were comprised of more White (25.2% vs 14.4%), non-White (18.8% vs 6.6%), and URiM (9.6% vs 2.8%) women and concomitantly fewer men across all groups versus faculty (all P < 0.01). Although the proportion of White and non-White female faculty increased over time (both P ≤ 0.001), there was no significant change among non-White URiM female faculty, nor among non-White male faculty, regardless of whether they were URiM or not. Having more URiM male faculty was associated with having more non-White female students (estimate = +14.5% students/100% increase in faculty, 95% CI: 1.0% to 8.1%, P = 0.04), and this association was especially pronounced for URiM female students (estimate = +46.6% students/100% increase in faculty, 95% CI: 36.9% to 56.3%, P < 0.001). CONCLUSIONS: URiM faculty representation has not improved despite a positive association between having more URiM male faculty and having more diverse students.

Targeting of RRM2 suppresses DNA damage response and activates apoptosis in atypical teratoid rhabdoid tumor.

BACKGROUND: Atypical teratoid rhabdoid tumors (ATRT) is a rare but aggressive malignancy in the central nervous system, predominantly occurring in early childhood. Despite aggressive treatment, the prognosis of ATRT patients remains poor. RRM2, a subunit of ribonucleotide reductase, has been reported as a biomarker for aggressiveness and poor prognostic conditions in several cancers. However, little is known about the role of RRM2 in ATRT. Uncovering the role of RRM2 in ATRT will further promote the development of feasible strategies and effective drugs to treat ATRT. METHODS: Expression of RRM2 was evaluated by molecular profiling analysis and was confirmed by IHC in both ATRT patients and PDX tissues. Follow-up in vitro studies used shRNA knockdown RRM2 in three different ATRT cells to elucidate the oncogenic role of RRM2. The efficacy of COH29, an RRM2 inhibitor, was assessed in vitro and in vivo. Western blot and RNA-sequencing were used to determine the mechanisms of RRM2 transcriptional activation in ATRT. RESULTS: RRM2 was found to be significantly overexpressed in multiple independent ATRT clinical cohorts through comprehensive bioinformatics and clinical data analysis in this study. The expression level of RRM2 was strongly correlated with poor survival rates in patients. In addition, we employed shRNAs to silence RRM2, which led to significantly decrease in ATRT colony formation, cell proliferation, and migration. In vitro experiments showed that treatment with COH29 resulted in similar but more pronounced inhibitory effect. Therefore, ATRT orthotopic mouse model was utilized to validate this finding, and COH29 treatment showed significant tumor growth suppression and prolong overall survival. Moreover, we provide evidence that COH29 treatment led to genomic instability, suppressed homologous recombinant DNA damage repair, and subsequently induced ATRT cell death through apoptosis in ATRT cells. CONCLUSIONS: Collectively, our study uncovers the oncogenic functions of RRM2 in ATRT cell lines, and highlights the therapeutic potential of targeting RRM2 in ATRT. The promising effect of COH29 on ATRT suggests its potential suitability for clinical trials as a novel therapeutic approach for ATRT.

Globo H ceramide is an independent prognostic marker for gallbladder cancer.

In recent studies, there has been growing interest in developing cancer therapeutics targeting Globo H ceramide, which is considered as the most prevalent tumor-associated carbohydrate antigen in epithelial cancers. In this study, we aimed to evaluate the expression of Globo H and investigate its prognostic significance in gallbladder cancer (GBC). The tumor specimens and clinical characteristics of GBC patients were collected from the tumor bank and database of Chang Gung Memorial Hospital. Globo H in tumor specimens was detected by immunohistochemistry (IHC) and mass spectrometry analysis. Through data mining, it was discovered that FUT1 and FUT2, which are key enzymes involved in the biosynthesis of Globo H, were significantly up-regulated in human gallbladder cancer (GBC). Consistent with this finding, Globo H expression was detected in 86% (128 out of 149) of GBC specimens using immunohistochemical (IHC) staining. This was the highest frequency among Globo H expressing cancers. Patients with tumors exhibiting higher Globo H expression (H-score ≥ 80) demonstrated significantly shorter disease-free survival (DFS) and overall survival (OS) (P = 0.0001 and P = 0.0004, respectively). In a multivariable Cox regression analysis, elevated Globo H expression was identified as an independent unfavorable predictor for DFS and OS (hazard ratio: 2.29 and 2.32, respectively, P = 0.008 and 0.001) in primary GBC. Globo H is an independent prognostic marker for GBC.

Priming of macrophage by glycosphingolipids from extracellular vesicles facilitates immune tolerance for embryo-maternal crosstalk.

Glycosphingolipids (GSLs) display diverse functions during embryonic development. Here, we examined the GSL profiles of extracellular vesicles (EVs) secreted from human embryonic stem cells (hESCs) and investigated their functions in priming macrophages to enhance immune tolerance of embryo implantation. When peripheral blood mononuclear cells were incubated with ESC-secreted EVs, globo-series GSLs (GHCer, SSEA3Cer, and SSEA4Cer) were transferred via EVs into monocytes/macrophages. Incubation of monocytes during their differentiation into macrophages with either EVs or synthetic globo-series GSLs induced macrophages to exhibit phenotypic features that imitate immune receptivity, i.e., macrophage polarization, augmented phagocytic activity, suppression of T cell proliferation, and the increased trophoblast invasion. It was also demonstrated that decidual macrophages in first-trimester tissues expressed globo-series GSLs. These findings highlight the role of globo-series GSLs via transfer from EVs in priming macrophages to display decidual macrophage phenotypes, which may facilitate healthy pregnancy.

Racial, Ethnic, and Gender Diversity Among Academic Surgical Leaders in the US.

Importance: Surgical department chairs remain conspicuously nondiverse despite the recognized importance of diverse physician workforces. However, the extent of diversity among non-chair leadership remains underexplored. Objective: To evaluate racial, ethnic, and gender diversity of surgical department chairs, vice chairs (VCs), and division chiefs (DCs) in the US. Design, Setting, and Participants: For this cross-sectional study, publicly accessible medical school and affiliated hospital websites in the US and Puerto Rico were searched from January 15 to July 15, 2022, to collect demographic and leadership data about surgical faculty. Two independent reviewers abstracted demographic data, with up to 2 additional reviewers assisting with coding resolution as necessary. In all, 2165 faculty were included in the analyses. Main Outcomes and Measures: Proportions of racial, ethnic, and gender diversity among chairs, VCs, and DCs in general surgery and 5 surgical specialties (neurosurgery, obstetrics and gynecology, ophthalmology, orthopedics, and otolaryngology). Results: A total of 2165 faculty (1815 males [83.8%] and 350 females [16.2%]; 109 [5.0%] African American or Black individuals; 347 [16.0%] Asian individuals; 83 [3.8%] Hispanic, Latino, or individuals of Spanish origin; and 1624 [75.0%] White individuals as well as 2 individuals [0.1%] of other race or ethnicity) at 154 surgical departments affiliated with 146 medical schools in the US and Puerto Rico were included in the analysis. There were more males than females in leadership positions at all levels-chairs (85.9% vs 14.1%), VCs (68.4% vs 31.6%), and DCs (87.1% vs 12.9%)-and only 192 leaders (8.9%) were from racial or ethnic groups that are underrepresented in medicine (URiM). Females occupied more VC than chair or DC positions both overall (31.6% vs 14.1% and 12.9%, respectively) and within racial and ethnic groups (African American or Black females, 4.0% VC vs 1.5% chair and 0.6% DC positions; P < .001). URiM individuals were most commonly VCs of diversity, equity, and inclusion (DEI, 51.6%) or faculty development (17.9%). Vice chairs of faculty development were split equally between males and females, while 64.5% of VCs for DEI were female. All other VCs were predominantly male. Among DC roles, URiM representation was greatest in transplant surgery (13.8%) and lowest in oral and maxillofacial surgery (5.0%). Except for breast and endocrine surgery (63.6% female), females comprised less than 20% of DC roles. Nearly half of DCs (6 of 13 [46.2%]) and VCs (4 of 9 [44.4%]) had no female URiM leaders, and notably, no American Indian, Alaska Native, or Native Hawaiian or Other Pacific Islander individuals were identified in any surgical leadership positions. Conclusions and Relevance: While it is unclear whether promotion from VC to chair or from DC to chair is more likely, these findings of similar gender distribution between chairs and DCs suggest the latter and may partially explain persistent nondiversity among surgical chairs. Female and URiM surgical leaders are disproportionately clustered in roles (eg, VCs of DEI or faculty development) that may not translate into future promotion to department chairs.

Effectiveness of perioperative chemotherapy and radical cystectomy in treating bladder cancer.

BACKGROUND: Despite abundant evidence supporting the use of perioperative chemotherapy from clinical trials, no study to date has comprehensively evaluated its use in the treatment of muscle-invasive bladder cancer (MIBC) in the real-world setting. Little is known regarding the impact of pretreatment disease stage and real-world factors such as patient comorbidities preventing timely completion of therapy on its effectiveness. This study aims to assess the usage of perioperative chemotherapy and examines its impact on pathologic downstaging rates and recurrence free survival in patients undergoing radical cystectomy. METHODS: A retrospective review was conducted in 805 patients with muscle invasive bladder cancer undergoing radical cystectomy with no perioperative chemotherapy, 761 with presurgical chemotherapy followed by radical cystectomy, and 134 radical cystectomy followed by adjuvant chemotherapy. Relevant clinicopathologic features were reviewed. Recurrence-free survival and Overall Survival probability estimates were calculated using the Kaplan-Meier method and compared using the Log-rank or Gehan-Breslow tests. The prognostic effects of presurgical chemotherapy and adjuvant chemotherapy regimens were evaluated by estimating hazard ratio and 95% confidence interval from an adjusted Cox proportional hazards model. Statistical tests were 2-sided, and significance was defined as P-value < 0.05. RESULTS: In this contemporary, real-world cohort, 5-yr RFS was found to be 65.6% in pT0, 59.1%in pT2, and 10.8% in pN+ patients. Presurgical chemotherapy increased pathologic downstaging rates from 27.5% to 41.1% in patients with ≥cT2 BCa. Stratified by clinical T-stage, only cT2 patients derived recurrence-free survival (Median 45.3 months vs. 29.0 months, P < 0.01) and overall survival (Median 62.3 months vs. 41.9 months, P < 0.001) benefits.  In patients with adverse pathologic features (≥pT3 or pN+), adjuvant chemotherapy improved recurrence-free survival (Median 22.8 months vs. 10.0 months, P < 0.0001) and overall survival (Median OS 32.4 months vs. 16.3 months, P < 0.0001). CONCLUSIONS: We report real-world outcomes from a large cohort of muscle-invasive bladder cancer patients undergoing surgical treatment with/out perioperative chemotherapy. Pathologic response rates to pre-surgical chemotherapy were modest and led to clinical benefit only in cT2 patients. Adjuvant chemotherapy provided survival benefit for pathologically advanced MIBC patients irrespective of pT/N staging.

Current Challenges of Asian National Children's Cancer Study Groups on Behalf of Asian Pediatric Hematology and Oncology Group.

In Asia, a few countries have a long and established history of collaborative clinical trials successfully formed national children's cancer study groups, but many still do not have such groups. The process of forming national children's cancer groups is fraught with many hurdles, which varies among the countries. One of the basic requirements for running clinical trials is an affordable health care system in which most of the children with cancer can receive the proposed treatment. The health insurance coverage for children with cancer varies from <20% to as high as 100% among Asian countries, and the operation of clinical trials must also be adjusted accordingly. Shortage of research personnel is common, including medical, nursing, research coordinators, and data managers. The establishment of the Asian Pediatric Hematology and Oncology Group aims to provide a good platform for promotion of international clinical trials in the Asian countries.

Understanding the valuation of paediatric health-related quality of life: a qualitative study protocol.

INTRODUCTION: There is evidence from previous studies that adults value paediatric health-related quality of life (HRQoL) and adult HRQoL differently. Less is known about how adolescents value paediatric HRQoL and whether their valuation and decision-making processes differ from those of adults. Discrete choice experiments (DCEs) are widely used to develop value sets for measures of HRQoL, but there is still much to understand about whether and how the methods choices in the implementation of DCE valuation tasks, such as format, presentation and perspective, affect the decision-making process of participants. This paper describes the protocol for a qualitative study that aims to explore the decision-making process of adults and adolescents when completing DCE valuation tasks. The study will also explore the impact of methodological choices in the design of DCE studies (including decisions about format and presentation) on participants' thinking process. METHODS AND ANALYSIS: An interview protocol has been developed using DCE valuation tasks. Interviews will be conducted online via Zoom with both an adolescent and adult sample. In the interview, the participant will be asked to go through some DCE valuation tasks while 'thinking aloud'. After completion of the survey, participants will then be asked some predetermined questions in relation to various aspects of the DCE tasks. Interviews will be recorded and transcribed and analysed using a thematic analysis approach. ETHICS AND DISSEMINATION: Ethics approval for this study has been received for the adult sample (UTS ETH20-9632) as well as the youth sample (UTS ETH22-6970) from the University of Technology Sydney Human Research Ethics Committee. Results from this study will inform the methods to be used in development of value sets for use in the health technology assessment of paediatric interventions and treatments. Findings from this study will also be disseminated through national/international conferences and peer-reviewed journals.

Whole genomic analysis reveals atypical non-homologous off-target large structural variants induced by CRISPR-Cas9-mediated genome editing.

CRISPR-Cas9 genome editing has promising therapeutic potential for genetic diseases and cancers, but safety could be a concern. Here we use whole genomic analysis by 10x linked-read sequencing and optical genome mapping to interrogate the genome integrity after editing and in comparison to four parental cell lines. In addition to the previously reported large structural variants at on-target sites, we identify heretofore unexpected large chromosomal deletions (91.2 and 136 Kb) at atypical non-homologous off-target sites without sequence similarity to the sgRNA in two edited lines. The observed large structural variants induced by CRISPR-Cas9 editing in dividing cells may result in pathogenic consequences and thus limit the usefulness of the CRISPR-Cas9 editing system for disease modeling and gene therapy. In this work, our whole genomic analysis may provide a valuable strategy to ensure genome integrity after genomic editing to minimize the risk of unintended effects in research and clinical applications.

Protein and Peptide-Based Nanotechnology for Enhancing Stability, Bioactivity, and Delivery of Anthocyanins.

Anthocyanin, a unique natural polyphenol, is abundant in plants and widely utilized in biomedicine, cosmetics, and the food industry due to its excellent antioxidant, anticancer, antiaging, antimicrobial, and anti-inflammatory properties. However, the degradation of anthocyanin in an extreme environment, such as alkali pH, high temperatures, and metal ions, limits its physiochemical stabilities and bioavailabilities. Encapsulation and combining anthocyanin with biomaterials could efficiently stabilize anthocyanin for protection. Promisingly, natural or artificially designed proteins and peptides with favorable stabilities, excellent biocapacity, and wide sources are potential candidates to stabilize anthocyanin. This review focuses on recent progress, strategies, and perspectives on protein and peptide for anthocyanin functionalization and delivery, i.e., formulation technologies, physicochemical stability enhancement, cellular uptake, bioavailabilities, and biological activities development. Interestingly, due to the simplicity and diversity of peptide structure, the interaction mechanisms between peptide and anthocyanin could be illustrated. This work sheds light on the mechanism of protein/peptide-anthocyanin nanoparticle construction and expands on potential applications of anthocyanin in nutrition and biomedicine.

Survey Study of Clerkship Curriculum on Learner's Choice to Pursue Surgery: Positive Impact of Extracurricular Opportunities.

OBJECTIVE: Prior studies have focused on the role of the learning environment on students' decisions to pursue surgery, but few have analyzed the impact of the clerkship curriculum. This study assessed surgical clerkship curricula across United States (US) medical schools and their impact on students' likelihood of pursuing a surgical residency. DESIGN: A cross-sectional survey was developed to assess surgery clerkship characteristics. Questions included clerkship duration, number of offered and required surgical services, method of service assignment, and number of advanced clinical electives (e.g., fourth-year sub-internships) and additional surgical clinical opportunities (e.g., surgical elective rotations). Survey results were merged by the Association of American Medical Colleges with the percentages of students who matched into a surgical specialty. Linear regression models estimated the association of covariates with the percentage of students who (1) matched in surgical specialties, (2) were interested in surgery at medical school matriculation and ultimately matched into surgical residency (retention rate), and (3) were not interested in surgery at medical school matriculation but ultimately matched into surgical residency (recruitment rate). SETTING: The survey was distributed to clerkship directors and coordinators at 66 medical schools through the Association for Surgical Education (ASE) from 5/1/2021 to 8/1/2021. PARTICIPANTS: All US medical schools in the ASE. RESULTS: A total of 21 medical schools responded (34.8% response rate). The overall retention rate was 36.4%, and the overall recruitment rate was 25.0%. Clerkships were 4 to 12 weeks. In 81% of programs, students submitted preferences and were assigned services. The percentage of students applying to surgical specialties was not associated with clerkship duration (p=0.79) or the number of required services (p=0.15), subspecialty services offered (p=0.33), or advanced clinical electives (p=0.24) but was associated with a program's having additional surgical clinical opportunities (p=0.02). Most of these factors were not associated with retention or recruitment rates. CONCLUSIONS: Offering more extracurricular surgical clinical opportunities was associated with having more students pursue surgical careers. Though limited by a relatively small sample size, our findings suggest that having shorter clerkships or limited subspecialty offerings may not have a significant influence on students' career choices.

Prevalence and antimicrobial resistance profiles of Vibrio spp. and Enterococcus spp. in retail shrimp in Northern California.

Shrimp is one of the most consumed seafood products globally. Antimicrobial drugs play an integral role in disease mitigation in aquaculture settings, but their prevalent use raises public health concerns on the emergence and spread of antimicrobial resistant microorganisms. Vibrio spp., as the most common causative agents of seafood-borne infections in humans, and Enterococcus spp., as an indicator organism, are focal bacteria of interest for the monitoring of antimicrobial resistance (AMR) in seafood. In this study, 400 samples of retail shrimp were collected from randomly selected grocery stores in the Greater Sacramento, California, area between September 2019 and June 2020. The prevalence of Vibrio spp. and Enterococcus spp. was 60.25% (241/400) and 89.75% (359/400), respectively. Subsamples of Vibrio (n = 110) and Enterococcus (n = 110) isolates were subjected to antimicrobial susceptibility testing (AST). Vibrio isolates had high phenotypic resistance to ampicillin (52/110, 47.27%) and cefoxitin (39/110, 35.45%). Enterococcus were most frequently resistant to lincomycin (106/110, 96.36%), quinupristin-dalfopristin (96/110, 87.27%), ciprofloxacin (93/110, 84.55%), linezolid (86/110, 78.18%), and erythromycin (58/110, 52.73%). For both Vibrio and Enterococcus, no significant associations were observed between multidrug resistance (MDR, resistance to ≥3 drug classes) in isolates from farm raised and wild caught shrimp (p > 0.05) and in isolates of domestic and imported origin (p > 0.05). Whole genome sequencing (WGS) of a subset of Vibrio isolates (n = 42) speciated isolates as primarily V. metschnikovii (24/42; 57.14%) and V. parahaemolyticus (12/42; 28.57%), and detected 27 unique antimicrobial resistance genes (ARGs) across these isolates, most commonly qnrVC6 (19.05%, 8/42), dfrA31 (11.90%, 5/42), dfrA6 (9.5%, 4/42), qnrVC1 (9.5%, 4/42). Additionally, WGS predicted phenotypic resistance in Vibrio isolates with an overall sensitivity of 11.54% and specificity of 96.05%. This study provides insights on the prevalence and distribution of AMR in Vibrio spp. and Enterococcus spp. from retail shrimp in California which are important for food safety and public health and exemplifies the value of surveillance in monitoring the spread of AMR and its genetic determinants.

High expression of embryonic stem cell marker SSEA3 confers poor prognosis and promotes epithelial mesenchymal transition in hepatocellular carcinoma.

BACKGROUND: Malignant cells may arise from dedifferentiation of mature cells and acquire features of the progenitor cells. Definitive endoderm from which liver is derived, expresses glycosphingolipids (GSLs) such as stage-specific embryonic antigen 3 (SSEA3), Globo H, and stage-specific embryonic antigen 4 (SSEA4). Herein, we evaluated the potential prognosis value of the three GSLs and biological functions of SSEA3 in hepatocellular carcinoma (HCC). METHODS: The expression of SSEA3, Globo H, and SSEA4 in tumor tissues obtained from 328 patients with resectable HCC was examined by immunohistochemistry staining. Epithelial mesenchymal transition (EMT) and their related genes were analyzed by transwell assay and qRT-PCR, respectively. RESULTS: Kaplan Meier survival analysis showed significantly shorter relapse-free survival (RFS) for those with higher expression of SSEA3 (p < 0.001), Globo H (p < 0.001), and SSEA4 (p = 0.005) and worse overall survival (OS) for those with high expression of either SSEA3 (p < 0.001) or SSEA4 (p = 0.01). Furthermore, multivariable Cox regression analysis identified the SSEA3 as an independent predictor for RFS (HR: 2.68, 95% CI: 1.93-3.72, p < 0.001) and OS (HR: 2.99, 95% CI: 1.81-4.96, p < 0.001) in HCC. Additionally, SSEA3-ceramide enhanced the EMT of HCC cells, as reflected by its ability to increase migration, invasion and upregulate the expression of CDH2, vimentin, fibronectin, and MMP2, along with ZEB1. Moreover, ZEB1 silencing abrogated the EMT-enhancing effects of SSEA3-ceramide. CONCLUSIONS: Higher expression of SSEA3 was an independent predictor for RFS and OS in HCC and promoted EMT of HCC via upregulation of ZEB1.

Leadership and Impostor Syndrome in Surgery.

BACKGROUND: Impostor syndrome is an internalized sense of incompetence and not belonging. We examined associations between impostor syndrome and holding leadership positions in medicine. STUDY DESIGN: A cross-sectional survey was distributed to US physicians from June 2021 to December 2021 through medical schools and professional organizations. Differences were tested with the chi-square test and t -test for categorical and continuous variables, respectively. Logistic regression was used to identify factors associated with holding leadership positions and experiencing impostor syndrome. RESULTS: A total of 2,183 attending and retired physicians were included in the analytic cohort; 1,471 (67.4%) were in leadership roles and 712 (32.6%) were not. After adjustment, male physicians were more likely than women to hold leadership positions (odds ratio 1.4; 95% CI 1.16 to 1.69; p < 0.001). Non-US citizens (permanent resident or visa holder) were less likely to hold leadership positions than US citizens (odds ratio 0.3; 95% CI 0.16 to 0.55; p < 0.001). Having a leadership position was associated with lower odds of impostor syndrome (odds ratio 0.54; 95% CI 0.43 to 0.68; p < 0.001). Female surgeons were more likely to report impostor syndrome compared to male surgeons (90.0% vs 67.7%; p < 0.001), an association that persisted even when female surgeons held leadership roles. Similar trends were appreciated for female and male nonsurgeons. Impostor syndrome rates did not differ by race and ethnicity, including among those underrepresented in medicine, even after adjustment for gender and leadership role. CONCLUSIONS: Female physicians were more likely to experience impostor syndrome than men, regardless of specialty or leadership role. Although several identity-based gaps persist in leadership, impostor syndrome among racially minoritized groups may not be a significant contributor.

Mucin 4 Confers Gemcitabine Resistance and an Unfavorable Prognosis in Patients with Cholangiocarcinoma via AKT Activation.

Cholangiocarcinoma (CCA) exhibits aggressive biological behavior and a poor prognosis. Gemcitabine (GEM)-based chemotherapy is the first-line chemotherapy for advanced CCA but has a response rate of only 20-30%. Therefore, investigating treatments to overcome GEM resistance in advanced CCA is crucial. Among mucin (MUC) family members, MUC4 showed the greatest increase in the resistant versus parental sublines. MUC4 was upregulated in whole-cell lysates and conditioned media from gemcitabine-resistant (GR) CCA sublines. MUC4 mediated GEM resistance by activating AKT signaling in GR CCA cells. The MUC4-AKT axis induced BAX S184 phosphorylation to inhibit apoptosis and downregulated GEM transporter human equilibrative nucleoside transporter 1 (hENT1) expression. The combination of AKT inhibitors and GEM or afatinib overcame GEM resistance in CCA. In vivo, capivasertib (an AKT inhibitor) increased GEM sensitivity in GR cells. MUC4 promoted EGFR and HER2 activation to mediate GEM resistance. Finally, MUC4 expression in patient plasma correlated with MUC4 expression. Paraffin-embedded specimens from non-responders expressed significantly more MUC4 than did those from responders, and this upregulation was associated with poor progression-free survival and overall survival. In GR CCA, high MUC4 expression promotes sustained EGFR/HER2 signaling and AKT activation. The combination of AKT inhibitors with GEM or afatinib might overcome GEM resistance.

Targeting macrophage Syk enhances responses to immune checkpoint blockade and radiotherapy in high-risk neuroblastoma.

Background: Neuroblastoma (NB) is considered an immunologically cold tumor and is usually less responsive to immune checkpoint blockade (ICB). Tumor-associated macrophages (TAMs) are highly infiltrated in NB tumors and promote immune escape and resistance to ICB. Hence therapeutic strategies targeting immunosuppressive TAMs can improve responses to ICB in NB. We recently discovered that spleen tyrosine kinase (Syk) reprograms TAMs toward an immunostimulatory phenotype and enhances T-cell responses in the lung adenocarcinoma model. Here we investigated if Syk is an immune-oncology target in NB and tested whether a novel immunotherapeutic approach utilizing Syk inhibitor together with radiation and ICB could provide a durable anti-tumor immune response in an MYCN amplified murine model of NB. Methods: Myeloid Syk KO mice and syngeneic MYCN-amplified cell lines were used to elucidate the effect of myeloid Syk on the NB tumor microenvironment (TME). In addition, the effect of Syk inhibitor, R788, on anti-tumor immunity alone or in combination with anti-PDL1 mAb and radiation was also determined in murine NB models. The underlying mechanism of action of this novel therapeutic combination was also investigated. Results: Herein, we report that Syk is a marker of NB-associated macrophages and plays a crucial role in promoting immunosuppression in the NB TME. We found that the blockade of Syk in NB-bearing mice markedly impairs tumor growth. This effect is facilitated by macrophages that become immunogenic in the absence of Syk, skewing the suppressive TME towards immunostimulation and activating anti-tumor immune responses. Moreover, combining FDA-approved Syk inhibitor, R788 (fostamatinib) along with anti-PDL1 mAb provides a synergistic effect leading to complete tumor regression and durable anti-tumor immunity in mice bearing small tumors (50 mm3) but not larger tumors (250 mm3). However, combining radiation to R788 and anti-PDL1 mAb prolongs the survival of mice bearing large NB9464 tumors. Conclusion: Collectively, our findings demonstrate the central role of macrophage Syk in NB progression and demonstrate that Syk blockade can "reeducate" TAMs towards immunostimulatory phenotype, leading to enhanced T cell responses. These findings further support the clinical evaluation of fostamatinib alone or with radiation and ICB, as a novel therapeutic intervention in neuroblastoma.