Financial Relationships in General Surgery Education: Recent Trends in Industry Payments to General Surgery Residency Leadership.

INTRODUCTION: Residency programs and their directors frequently receive funding from industry payers. Both general surgery residency program directors (PDs) and assistant program directors (APDs) receive industry funding for various reasons, including educational advancement. This study investigates recent trends in industry payments to both PDs and APDs to better understand the financial relationships among leaders in residency education. METHODS: We compared industry payments to general surgery residency PDs and APDs from 2019 to 2021 utilizing the U.S. Centers for Medicare & Medicaid Services (CMS) open payments database. In addition, secondary analyses were performed among PDs to assess differences based on gender, practicing surgical specialty, and geographical region. RESULTS: During the study period (2019-2021), PDs received payments amounting to 2,882,821 USD. PDs were found to receive more funding than APDs, with each receiving average funding of 10,045 vs. 323 USD (p < 0.01), respectively, over the study period. There was a significant decrease in total payments from 2019 to 2020 (1,512,190 vs. 868,811 USD; p < 0.01). Total payments made in 2021 were similar compared to 2020 (905,836 vs. 868,811 USD; p = 0.1). We found that male PDs received significantly more in-industry payments when compared to female PDs (11,702 USD per PD vs. 3971 USD per PD, p < 0.01). CONCLUSION: This study presents initial data that residency program leadership has robust biomedical industry relationships, and further research is warranted to investigate the impacts of these payments on program resources, educational opportunities for residents, and program outcomes. Male PDs received significantly more industry payments when compared to female PDs. Leaders in the surgical training community must cautiously ensure that these industry relationships are appropriately navigated.

Cerebrospinal fluid liver pseudocyst: A bizarre long-term complication of ventriculoperitoneal shunt: A case report.

BACKGROUND: Ventriculoperitoneal (VP) shunt placement has become a standard of care procedure in managing hydrocephalus for drainage and absorption of cerebrospinal fluid (CSF) into the peritoneum. Abdominal pseudocysts containing CSF are the common long-term complication of this frequently performed procedure, mainly because VP shunts have significantly prolonged survival. Of these, liver CSF pseudocysts are rare entities that may cause shunt dysfunction, affect normal organ function, and therefore pose therapeutic challenges. CASE SUMMARY: A 49-year-old man with history of congenital hydrocephalus status post bilateral VP shunt placement presented with progressively worsening dyspnea on exertion, abdominal discomfort/distention. Abdominal computed tomography (CT) scan revealed a large CSF pseudocyst in the right hepatic lobe with the tip of VP shunt catheter into the hepatic cyst cavity. Patient underwent robotic laparoscopic cyst fenestration with a partial hepatectomy, and repositioning of VP shunt catheter to the right lower quadrant of the abdomen. Follow-up CT demonstrated a significant reduction in hepatic CSF pseudocyst. CONCLUSION: A high index of clinical suspicion is required for early detection of liver CSF pseudocysts since their presentation is often asymptomatic and cunning early in the course. Late-stage liver CSF pseudocysts could have adverse outcomes on the treatment course of hydrocephalus as well as on hepatobiliary dysfunction. There is paucity of data to define the management of liver CSF pseudocyst in current guidelines due to rare nature of this entity. The reported occurrences have been managed by laparotomy with debridement, paracentesis, radiological imaging guided fluid aspiration and laparoscopic-associated cyst fenestration. Robotic surgery is an additional minimally invasive option in the management of hepatic CSF pseudocyst; however, its use is limited by lack of widespread availability and cost of surgery.

Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia.

Children of Hispanic/Latino ancestry have increased incidence of high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) with poor prognosis. This leukemia is characterized by a single-copy deletion of the IKZF1 (IKAROS) tumor suppressor and increased activation of the PI3K/AKT/mTOR pathway. This identifies mTOR as an attractive therapeutic target in HR B-ALL. Here, we report that IKAROS represses MTOR transcription and IKAROS' ability to repress MTOR in leukemia is impaired by oncogenic CK2 kinase. Treatment with the CK2 inhibitor, CX-4945, enhances IKAROS activity as a repressor of MTOR, resulting in reduced expression of MTOR in HR B-ALL. Thus, we designed a novel therapeutic approach that implements dual targeting of mTOR: direct inhibition of the mTOR protein (with rapamycin), in combination with IKAROS-mediated transcriptional repression of the MTOR gene (using the CK2 inhibitor, CX-4945). Combination treatment with rapamycin and CX-4945 shows synergistic therapeutic effects in vitro and in patient-derived xenografts from Hispanic/Latino children with HR B-ALL. These data suggest that such therapy has the potential to reduce the health disparity in HR B-ALL among Hispanic/Latino children. The dual targeting of oncogene transcription, combined with inhibition of the corresponding oncoprotein provides a paradigm for a novel precision medicine approach for treating hematological malignancies.

Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2.

IKAROS, encoded by the IKZF1 gene, is a DNA-binding protein that functions as a tumor suppressor in T cell acute lymphoblastic leukemia (T-ALL). Recent studies have identified IKAROS's novel function in the epigenetic regulation of gene expression in T-ALL and uncovered many genes that are likely to be directly regulated by IKAROS. Here, we report the transcriptional regulation of two genes, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) and phosphoinositide kinase, FYVE-type zinc finger containing (PIKFYVE), by IKAROS in T-ALL. PIK3CD encodes the protein p110δ subunit of phosphoinositide 3-kinase (PI3K). The PI3K/AKT pathway is frequently dysregulated in cancers, including T-ALL. IKAROS binds to the promoter regions of PIK3CD and PIKFYVE and reduces their transcription in primary T-ALL. Functional analysis demonstrates that IKAROS functions as a transcriptional repressor of both PIK3CD and PIKFYVE. Protein kinase CK2 (CK2) is a pro-oncogenic kinase that is overexpressed in T-ALL. CK2 phosphorylates IKAROS, impairs IKAROS's DNA-binding ability, and functions as a repressor of PIK3CD and PIKFYVE. CK2 inhibition results in increased IKAROS binding to the promoters of PIK3CD and PIKFYVE and the transcriptional repression of both these genes. Overall, the presented data demonstrate for the first time that in T-ALL, CK2 hyperactivity contributes to PI3K signaling pathway upregulation, at least in part, through impaired IKAROS transcriptional regulation of PIK3CD and PIKFYVE. Targeting CK2 restores IKAROS's regulatory effects on the PI3K oncogenic signaling pathway.

Metabolic Engineering Strategies of Industrial Hemp (Cannabis sativa L.): A Brief Review of the Advances and Challenges.

Industrial hemp (Cannabis sativa L.) is a diploid (2n = 20), dioecious plant that is grown for fiber, seed, and oil. Recently, there has been a renewed interest in this crop because of its panoply of cannabinoids, terpenes, and other phenolic compounds. Specifically, hemp contains terpenophenolic compounds such as cannabidiol (CBD) and cannabigerol (CBG), which act on cannabinoid receptors and positively regulate various human metabolic, immunological, and physiological functions. CBD and CBG have an effect on the cytokine metabolism, which has led to the examination of cannabinoids on the treatment of viral diseases, including COVID-19. Based on genomic, transcriptomic, and metabolomic studies, several synthetic pathways of hemp secondary metabolite production have been elucidated. Nevertheless, there are few reports on hemp metabolic engineering despite obvious impact on scientific and industrial sectors. In this article, recent status and current perspectives on hemp metabolic engineering are reviewed. Three distinct approaches to expedite phytochemical yield are discussed. Special emphasis has been placed on transgenic and transient gene delivery systems, which are critical for successful metabolic engineering of hemp. The advent of new tools in synthetic biology, particularly the CRISPR/Cas systems, enables environment-friendly metabolic engineering to increase the production of desirable hemp phytochemicals while eliminating the psychoactive compounds, such as tetrahydrocannabinol (THC).

A novel G6PD deleterious variant identified in three families with severe glucose-6-phosphate dehydrogenase deficiency.

BACKGROUND: Glucose-6-phosphate dehydrogenase deficiency (D-G6PD) is an X-linked recessive disorder resulted from deleterious variants in the housekeeping gene Glucose-6-phosphate 1-dehydrogenase (G6PD), causing impaired response to oxidizing agents. Screening for new variations of the gene helps with early diagnosis of D-G6PD resulting in a reduction of disease related complications and ultimately increased life expectancy of the patients. METHODS: One thousand five hundred sixty-five infants with pathological jaundice were screened for G6PD variants by Sanger sequencing all of the 13 exons, and the junctions of exons and introns of the G6PD gene. RESULTS: We detected G6PD variants in 439 (28.1%) of the 1565 infants with pathological jaundice. In total, 9 types of G6PD variants were identified in our cohort; and a novel G6PD missense variant c.1118 T > C, p.Phe373Ser in exon 9 of the G6PD gene was detected in three families. Infants with this novel variant showed decreased activity of G6PD, severe anemia, and pathological jaundice, consistent with Class I G6PD deleterious variants. Analysis of the resulting protein's structure revealed this novel variant affects G6PD protein stability, which could be responsible for the pathogenesis of D-G6PD in these patients. CONCLUSIONS: High rates of G6PD variants were detected in infants with pathological jaundice, and a novel Class I G6PD deleterious variants was identified in our cohort. Our data reveal that variant analysis is helpful for the diagnosis of D-G6PD in patients, and also for the expansion of the spectrum of known G6PD variants used for carrier detection and prenatal diagnosis.

Targeting NAT10 Induces Apoptosis Associated With Enhancing Endoplasmic Reticulum Stress in Acute Myeloid Leukemia Cells.

N-acetyltransferase 10 (NAT10) has oncogenic properties in many tumors through its role in different cellular biological processes. NAT10 is also a potential biomarker in acute myeloid leukemia (AML); however, the mechanisms underlying NAT10's contribution to disease states and the effect of targeting NAT10 as a therapeutic target remain unclear. NAT10 was found to be highly expressed in patients with AML, and increased NAT10 expression was associated with poor outcomes. Additionally, targeting NAT10 via the shRNA knockdown and its pharmacotherapeutic inhibitor resulted in inhibition of cell proliferation, induction of cell cycle arrest in the G1 phase, and apoptosis in AML cells. Moreover, NAT10 induces cell cycle arrest by decreasing expression of CDK2, CDK4, CyclinD1, Cyclin E while simultaneously increasing the expression of p16 and p21. Targeting NAT10 induces ER stress through the increased expression of GRP78 and the cleavage of caspase 12, which are classical markers of ER stress. This triggered the Unfolded Protein Response (UPR) pathway by consequently increasing IRE1, CHOP, and PERK expression, all of which play crucial roles in the UPR pathway. Targeting NAT10 also activated the classical apoptotic pathway through the upregulation of the Bax/bak and the concurrent downregulation of Bcl-2. In summary, our data indicate that targeting NAT10 promotes ER stress, triggers the UPR pathway, and activates the Bax/Bcl-2 axis in AML cells. Our results thus indicate a novel mechanism underlying the induction of NAT10 inhibition-mediated apoptosis and reveal the potential for the therapeutic effect of a NAT10 specific inhibitor in AML.

Cellular signaling and epigenetic regulation of gene expression in leukemia.

Alterations in normal regulation of gene expression is one of the key features of hematopoietic malignancies. In order to gain insight into the mechanisms that regulate gene expression in these diseases, we dissected the role of the Ikaros protein in leukemia. Ikaros is a DNA-binding, zinc finger protein that functions as a transcriptional regulator and a tumor suppressor in leukemia. The use of ChIP-seq, RNA-seq, and ATAC-seq-coupled with functional experiments-revealed that Ikaros regulates both the global epigenomic landscape and epigenetic signature at promoter regions of its target genes. Casein kinase II (CK2), an oncogenic kinase that is overexpressed in leukemia, directly phosphorylates Ikaros at multiple, evolutionarily-conserved residues. Phosphorylation of Ikaros impairs the protein's ability to regulate both the transcription of its target genes and global epigenetic landscape in leukemia. Treatment of leukemia cells with a specific inhibitor of CK2 restores Ikaros function, resulting in cytotoxicity of leukemia cells. Here, we review the mechanisms through which the CK2-Ikaros signaling axis regulates the global epigenomic landscape and expression of genes that control cellular proliferation in leukemia.