MGA deletion leads to Richter's transformation by modulating mitochondrial OXPHOS.

Richter's transformation (RT) is a progression of chronic lymphocytic leukemia (CLL) to aggressive lymphoma. MGA (Max gene associated), a functional MYC suppressor, is mutated at 3% in CLL and 36% in RT. However, genetic models and molecular mechanisms of MGA deletion that drive CLL to RT remain elusive. We established an RT mouse model by knockout of Mga in the Sf3b1/Mdr CLL model using CRISPR-Cas9 to determine the role of Mga in RT. Murine RT cells exhibited mitochondrial aberrations with elevated oxidative phosphorylation (OXPHOS). Through RNA sequencing and functional characterization, we identified Nme1 (nucleoside diphosphate kinase) as an Mga target, which drives RT by modulating OXPHOS. Given that NME1 is also a known MYC target without targetable compounds, we found that concurrent inhibition of MYC and electron transport chain complex II substantially prolongs the survival of RT mice in vivo. Our results suggest that the Mga-Nme1 axis drives murine CLL-to-RT transition via modulating OXPHOS, highlighting a potential therapeutic avenue for RT.

Co-shared genomic alterations within tumors from patients with both myeloproliferative neoplasms and lymphoma.

Not available.

MiR-17∼92 is involved in NF-κB activation via targeting the ubiquitin-editing proteins to mediate RIP1 complex polyubiquitinations in ABC-DLBCL.

Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive lymphoma characterized by constitutive NF-κB activation, but whether miR-17∼92 contributes to this activation remains unclear. Herein, we sought to evaluate the role of miR-17∼92 in the process of NF-κB activation in ABC-DLBCL. We found that the expression of miR-17∼92 primary transcript was positively correlated with NF-κB activity, miR-17∼92 activated the NF-κB signaling in ABC-DLBCL, and its over-expression promoted ABC-DLBCL cell growth, accelerated cell G1 to S phase transition and enhanced cell resistance to NF-κB inhibitor. Importantly, miR-17∼92 promoted NF-κB activation through directly targeting multiple ubiquitin-editing regulators to lead to increase the K63-linked polyubiquitination and decrease the K48-linked polyubiquitination of RIP1 complex in ABC-DLBCL. We further found that miR-17∼92 selectively activated IκB-α and NF-κB p65 but not NF-κB p52/p100, and high miR-17∼92 expression was also associated with poorer outcome in ABC-DLBCL patients. Overall, our results showed that miR-17∼92 selectively activated the canonical NF-κB signaling via targeting ubiquitin-editing regulators to lead to constitutively NF-κB activation and poorer outcome in ABC-DLBCL. These findings uncovered an innovative function of miR-17∼92 and previously unappreciated regulatory mechanism of NF-κB activation in ABC-DLBCL. Targeting miR-17∼92 may thus provide a novel bio-therapeutic strategy for ABC-DLBCL patients.

Association between anaesthesia-surgery team sex diversity and major morbidity.

BACKGROUND: Team diversity is recognized not only as an equity issue but also a catalyst for improved performance through diversity in knowledge and practices. However, team diversity data in healthcare are limited and it is not known whether it may affect outcomes in surgery. This study examined the association between anaesthesia-surgery team sex diversity and postoperative outcomes. METHODS: This was a population-based retrospective cohort study of adults undergoing major inpatient procedures between 2009 and 2019. The exposure was the hospital percentage of female anaesthetists and surgeons in the year of surgery. The outcome was 90-day major morbidity. Restricted cubic splines were used to identify a clinically meaningful dichotomization of team sex diversity, with over 35% female anaesthetists and surgeons representing higher diversity. The association with outcomes was examined using multivariable logistic regression. RESULTS: Of 709 899 index operations performed at 88 hospitals, 90-day major morbidity occurred in 14.4%. The median proportion of female anaesthetists and surgeons was 28 (interquartile range 25-31)% per hospital per year. Care in hospitals with higher sex diversity (over 35% female) was associated with reduced odds of 90-day major morbidity (OR 0.97, 95% c.i. 0.95 to 0.99; P = 0.02) after adjustment. The magnitude of this association was greater for patients treated by female anaesthetists (OR 0.92, 0.88 to 0.97; P = 0.002) and female surgeons (OR 0.83, 0.76 to 0.90; P < 0.001). CONCLUSION: Care in hospitals with greater anaesthesia-surgery team sex diversity was associated with better postoperative outcomes. Care in a hospital reaching a critical mass with over 35% female anaesthetists and surgeons, representing higher team sex-diversity, was associated with a 3% lower odds of 90-day major morbidity.

A population-based analysis of the management of symptoms of depression among patients with stage IV non-small cell lung cancer (NSCLC) in Ontario, Canada.

PURPOSE: Patients with lung cancer can experience significant psychological morbidities including depression. We characterize patterns and factors associated with interventions for symptoms of depression in stage IV non-small cell lung cancer (NSCLC). METHODS: We conducted a population-based cohort study using health services administrative data in Ontario, Canada of stage IV NSCLC diagnosed from January 2007 to September 2018. A positive symptom of depression score was defined by reporting at least one ESAS (Edmonton Symptom Assessment System) depression score ≥ 2 following diagnosis until the end of follow-up (September 2019). Patient factors included age, sex, comorbidity burden, rurality of residence, and neighbourhood income quintile. Interventions included psychiatry assessment, psychology referral, social work referral and anti-depressant medical therapy (for patients ≥ 65 years with universal drug coverage). Multivariable modified Poisson regression models were used to examine the association between patient factors and intervention use for patients who reported symptoms of depression. RESULTS: In the cohort of 13,159 patients with stage IV NSCLC lung cancer, symptoms of depression were prevalent (71.4%, n = 9,397). Patients who reported symptoms of depression were more likely to receive psychiatry assessment/psychology referral (7.8% vs 3.5%; SD [standardized difference] 0.19), social work referral (17.4% vs 11.9%; SD 0.16) and anti-depressant prescriptions (23.8% vs 13.8%; SD 0.26) when compared to patients who did not report symptoms of depression respectively. In multivariable analyses, older patients were less likely to receive any intervention. Females were more likely to obtain a psychiatry assessment/psychology referral or social work referral. In addition, patients from non-major urban or rural residences were less likely to receive psychiatry assessment/psychology referral or social work referral, however patients from rural residences were more likely to be prescribed anti-depressants. CONCLUSIONS: There is high prevalence of symptoms of depression in stage IV NSCLC. We identify patient populations, including older patients and rural patients, who are less likely to receive interventions that will help identifying and screening for symptoms of depression.

Motive and opportunity: MYC rearrangements in high-grade B-cell lymphoma with MYC and BCL2 rearrangements (an LLMPP study).

ABSTRACT: Rearrangements that place the oncogenes MYC, BCL2, or BCL6 adjacent to superenhancers are common in mature B-cell lymphomas. Lymphomas with diffuse large B-cell lymphoma (DLBCL) or high-grade morphology with both MYC and BCL2 rearrangements are classified as high-grade B-cell lymphoma with MYC and BCL2 rearrangements ("double hit"; HGBCL-DH-BCL2) and are associated with aggressive disease and poor outcomes. Although it is established that MYC rearrangements involving immunoglobulin (IG) loci are associated with inferior outcomes relative to those involving other non-IG superenhancers, the frequency of and mechanisms driving IG vs non-IG MYC rearrangements have not been elucidated. Here, we used custom targeted capture and/or whole-genome sequencing to characterize oncogene rearrangements across 883 mature B-cell lymphomas including Burkitt lymphoma, follicular lymphoma, DLBCL, and HGBCL-DH-BCL2 tumors. We demonstrate that, although BCL2 rearrangement topology is consistent across entities, HGBCL-DH-BCL2 have distinct MYC rearrangement architecture relative to tumors with single MYC rearrangements or with both MYC and BCL6 rearrangements (HGBCL-DH-BCL6), including both a higher frequency of non-IG rearrangements and different architecture of MYC::IGH rearrangements. The distinct MYC rearrangement patterns in HGBCL-DH-BCL2 occur on the background of high levels of somatic hypermutation across MYC partner loci in HGBCL-DH-BCL2, creating more opportunity to form these rearrangements. Furthermore, because 1 IGH allele is already disrupted by the existing BCL2 rearrangement, the MYC rearrangement architecture in HGBCL-DH-BCL2 likely reflects selective pressure to preserve both BCL2 and B-cell receptor expression. These data provide new mechanistic explanations for the distinct patterns of MYC rearrangements observed across different lymphoma entities.

Risk of Cesarean Delivery Among People With Inflammatory Bowel Disease According to Disease Characteristics: A Population-Based Study.

OBJECTIVES: It is unclear if use of cesarean delivery in people with inflammatory bowel disease (IBD) is guideline-concordant. We compared the odds of cesarean delivery among primiparous individuals with IBD versus without, overall, and by disease characteristics, as well as time to subsequent delivery. METHODS: Retrospective matched population-based cohort study between 1 April 1994 and 31 March 2020. Primiparous individuals aged 15-55 years with IBD were matched to those without IBD on age, year, hospital, and number of newborns delivered. Primary outcome was cesarean delivery versus vaginal delivery. Multivariable conditional logistic regression analyses were performed to estimate the odds of cesarean delivery among individuals with and without IBD as a binary exposure, and a categorical exposure based on IBD-related indications for cesarean delivery. Time to subsequent delivery was evaluated using a Cox proportional hazard model. RESULTS: We matched 7472 individuals with IBD to 37 360 individuals without (99.02% match rate). Individuals with IBD were categorised as having perianal (PA) disease (IBD-PA, n = 764, 10.2%), prior ileal pouch-anal anastomosis (n = 212, 2.8%), or IBD-Other (n = 6496, 86.9%). Cesarean delivery rates were 35.4% in the IBD group versus 30.4% in their controls (adjusted odds ratio 1.27; 95% CI 1.20-1.34). IBD-ileal pouch-anal anastomosis had a cesarean delivery rate of 66.5%, compared to 49.9% in IBD-PA and 32.7% in IBD-Other. There was no significant difference in the rate of subsequent delivery in those with and without IBD (adjusted hazard ratio 1.03; 95% CI 1-1.07). CONCLUSIONS: The higher risk of cesarean delivery in people with IBD reflects guideline-concordant use. Individuals with and without IBD were equally likely to have a subsequent delivery with similar timing.

MYC overexpression in natural killer cell lymphoma: prognostic and therapeutic implications.

The current clinical management of Extranodal NK/T-cell lymphoma (ENKTL) primarily depends on conventional chemotherapy and radiotherapy, underscoring the need for innovative therapeutic strategies. This study explores the clinical significance and therapeutic implication of c-MYC (MYC) in ENKTL. Initially, we identified MYC protein overexpression in approximately 75% of cases within a large cohort of 111 patients. MYC overexpression was strongly correlated with lymphoma cell proliferation and poor clinical outcomes. Intriguingly, integrating MYC expression into the PINK-E prognostic model significantly enhanced its predictive power. Subsequently, we implemented MYC knockdown (KD) in NK malignancy cell lines with MYC overexpression, resulting in significant viability reduction. RNA-sequencing (RNA-seq) used to determine MYC function revealed a high overlap with canonical MYC-regulated genes and enrichment in metabolism and cell cycle regulation. Integrative analysis of the RNA-seq data upon MYC KD with gene expression profiles of primary ENKTL cases identified a subset of genes closely associated with MYC overexpression. Among these, CDK4 emerged as a potential therapeutic target, and its inhibition not only abrogated MYC function but also decreased MYC expression in NK malignancy cells. Furthermore, the clinical-grade CDK4/6 inhibitor palbociclib exhibited a potent anti-tumor effect in xenograft mouse models, especially when combined with gemcitabine. In summary, our study firmly establishes MYC as an oncogene with prognostic significance in ENKTL and highlights CDK4 inhibition as a promising therapeutic strategy for treating ENKTL with MYC overexpression.