Faculty Bibliography

MYCN amplification, a characteristic of aggressive neuroblastoma, presents therapeutic challenges. This study uncovered the potential effects of a fructose metabolite, acetate, on the transcriptional regulation of MYCN expression, which is still largely unexplored. We elucidated the pivotal role of acyl-coenzyme A (acyl-CoA) synthetase short-chain family member 2 (ACSS2), found to be heightened in MYCN-amplified neuroblastoma. We demonstrated that ACSS2 enhanced MYCN gene transcription and growth of MYCN-amplified neuroblastoma. Our results revealed a new mechanism wherein ACSS2 orchestrates MYCN transcription by escalating acetyl-CoA levels and histone acetylation, hinting at a metabolic participation in forcibly dictating MYCN regulation. We further demonstrated that fructose or acetate exacerbated neuroblastoma growth, which can be halted by the ACSS2 inhibitor. We further identified the Nogo-B receptor (NgBR) as the trigger for ACSS2 induction through the Akt-SREBP-1 pathway. Our findings propose NgBR as a novel therapeutic target, emphasizing the promising potential of metabolic therapies for managing aggressive MYCN-amplified neuroblastoma.

A key treatment for patients with multiple myeloma is high-dose melphalan followed by autologous stem cell transplant (ASCT). It can provide a deep response with long-term remission. However, some patients progress quickly, and it is not clear why that is. Here, we performed single-cell RNA and T-cell receptor (TCR) sequencing of the immune microenvironment of 40 patients before and after ASCT to determine if differences in the immune composition could define those who would progress. Clear differences in cell populations were identified in progressors, including increased T-cell infiltration, decreased TCR diversity, and decreased frequency of monocytes and CD56bright NK cells. We identified cell interactions that predicted progression including increased frequency of CD8+ exhausted T cells and stromal cells and decreased frequency of CD56bright NK cells and plasmacytoid dendritic cells. We propose and validate a model of progression that can also be determined by flow cytometry. Together these data highlight the importance of the immune microenvironment in understanding responses to ASCT.

BACKGROUND:The prolonged turnaround time for next-generation sequencing (NGS) results may be a barrier to the timely selection of therapeutics in myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) with mutated TP53. Biomarker validation for early detection of TP53 mutation may have a significant impact on clinical decision-making. METHODS:In this study, p53 immunohistochemistry (IHC) (index test) and TP53 NGS (referent test) were performed on 145 bone marrow specimens from 82 unique patients with TP53-mutant MDS or AML to validate IHC as an early surrogate for NGS, and to assess the prognostic relevance of IHC. RESULTS:p53 IHC testing was able to correctly identify 95.5% of patients with TP53-mutant MDS and 100% of patients with TP53-mutant AML in this cohort. The mean p53 stain positivity was higher for AML compared to MDS (28% ± 3.67% vs. 8.8% ± 1.61%; p < .001), as well as for multihit TP53 compared to monoallelic TP53. Bootstrap analysis with 2000 iterations showed that a p53 IHC of 7% was the threshold best associated with multihit TP53. False-negative results were obtained with IHC in all TP53 sole nonsense or frameshift mutations. IHC positivity was inversely correlated with overall survival (OS), with the highest quintile of p53 positivity showing a median OS of just 2.53 months. CONCLUSIONS:IHC is a useful biomarker for the early detection of TP53-mutant MDS or AML and for prediction of TP53 allelic state. The results suggest a role for IHC across global markets, especially in geographic areas with inaccessibility to NGS testing.

BACKGROUND:Routine collection and use of sexual orientation and gender identity data can assist in understanding and addressing the health disparities that affect lesbian, gay, bisexual, transgender, queer+ (LGBTQ+), also known as sexual and gender minority, individuals and communities. This study explored the implementation of a culturally relevant sexual and gender minority/sexual orientation and gender identity training program at a National Cancer Institute (NCI)-Designated Comprehensive Cancer Center. METHODS:The training consisted of 6 in-person 15-minute modules or 3 virtual 30-minute modules that occurred during established high-reliability organization huddles attended by oncology faculty and staff. Module topics were (1) Building LGBTQ+ Knowledge & LGBTQ+ Cancer Disparities, (2) Creating an Inclusive Environment, (3) Recovering From Misgendering/Making Assumptions, (4) How to Receive & Respond to Feedback, (5) Witnessing & Responding to Discrimination, and (6) Making and Sustaining a Change. All high-reliability organization attendees were considered eligible for participation and were provided with pretraining and post-training surveys. Survey items included comfort caring for sexual and gender minority patients, practice collecting sexual orientation and gender identity data, knowledge of sexual and gender minority health, and demographics. RESULTS:A total of 344 individuals completed the presurvey and 187 completed the postsurvey. Postsurvey results demonstrated a statistically significant improvement in self-perceived knowledge about sexual and gender minority health (scale: 0-100, with 100 = highest; presurvey vs postsurvey, 69 vs 84; P < .001). Respondents also reported statistically significant improvements in confidence in engaging with sexual orientation and gender identity questions (53 vs 79, P < .001) as well as intention to collect patient sexual orientation and gender identity information (49 vs 75, P < .001). Notably, sexual orientation and gender identity data collection tracking demonstrated a 311% increase in sexual orientation and 262% in gender identity disclosure during the study period. CONCLUSION/CONCLUSIONS:Despite the availability of sexual orientation and gender identity data fields within electronic health records, sexual orientation and gender identity disclosure remains an ongoing nationwide problem. Use of culturally relevant sexual and gender minority/sexual orientation and gender identity training can help improve oncology staff and clinician sexual and gender minority knowledge and confidence when engaging patients with and subsequent documentation of sexual orientation and gender identity data, resulting in improvement of data completion.

Acetate is the end product of alcohol metabolism. Acyl-CoA synthetase short-chain family member 2 (ACSS2) converts acetate to acetyl-CoA, involving metabolic pathways and epigenetic regulation. However, the function of ACSS2-mediated epigenetic control in alcoholic liver disease (ALD) remains incompletely understood. We demonstrate that alcohol downregulates hepatic ACSS2, causing acetate accumulation in the liver and serum. This disrupts iron metabolism and hepatic ferroptosis, triggering liver injury and inflammation. Mechanistically, ACSS2 binds CREB binding protein (CBP) to mediate histone acetylation and regulate hepcidin antimicrobial peptide 1/2 (HAMP1/2) transcription. ACSS2 deficiency downregulates HAMP1/2, causing systemic iron dyshomeostasis and ferroptosis, which is restored by overexpression of HAMP1/2. Iron chelators or ferroptosis inhibitors attenuates alcohol-induced liver injury in ACSS2-deficient mice. Our study uncovers the epigenetic mechanisms of ACSS2-mediated ferroptosis and its role in ALD progression.

BACKGROUND: While prior studies have recommended immediate flap coverage within 72 hours of injury for soft tissue reconstruction for traumatic extremity injuries, recent evidence in the setting of advanced wound care techniques de-emphasizes the need for immediate coverage. Negative-pressure wound therapy (NPWT) has been an essential tool for extending the time to definitive soft tissue coverage. This study sought to elucidate the impact of preoperative NPWT use on the success of microsurgical reconstruction. METHODS: A literature search was conducted using the following databases from their inception up to February 2023: PubMed, OVID databases (Embase and Cochrane Library), Web of Science, and Scopus. Of 801 identified articles, 648 were assessed and 24 were included. Cases were divided based on whether NPWT was used preoperatively or not. Timing to definitive coverage, injury details, and basic demographics were recorded. Rates of flap failure, infection, bone nonunion, reoperation, and complications were compared between groups. RESULTS: A total of 1,027 patients and 1,047 flaps were included, of which 894 (85.39%) received preflap NPWT. The average time to definitive coverage for the NPWT and non-NPWT groups was 16 and 18 days, respectively. The NPWT group experienced lower postoperative complication rates than the non-NPWT group in all reported complications except for deep infections. Compared with the non-NPWT group, the NPWT group experienced lower rates of any flap failure (3.69 vs. 9.80%) and partial flap failure (2.24 vs. 6.54%). CONCLUSION/CONCLUSIONS: Preoperative NPWT was associated with reduced postoperative complications, most importantly flap failure rates. This merits further investigation into the decision-making process for traumatic extremity reconstruction. Future prospective studies adopting standardized protocols with longer follow-up are required to better understand the potentially beneficial role of preoperative NPWT use in soft tissue reconstruction.

Nomenclature for the disease widely known as Sjögren syndrome has proven unsatisfactory. Patients have perceived 'syndrome' as indicative of a vague collection of symptoms, prompting the Sjögren's Foundation to abandon the term. Furthermore, the traditional distinction between 'primary' and 'secondary' forms fails to account for the complex interplay between overlapping autoimmune diseases. Following a bibliometric analysis, systematic literature review and a Delphi consensus process with equal involvement of professional and patient representatives, five recommendations are now issued. First, the term 'Sjögren disease' should replace 'Sjögren syndrome'. Second, the acronym 'SjD' should be used as an abbreviation for 'Sjögren disease'. Third, the descriptor 'associated' should be used in lieu of 'secondary' for Sjögren disease occurring in association with a second systemic autoimmune disease for which classification criteria are fulfilled. Fourth, Sjögren disease is the preferred terminology in common parlance and in clinical diagnosis, without differentiation as to primary and associated forms. Fifth, the differentiation between primary and associated Sjögren is recommended for scientific studies to define a homogeneous population. In conclusion, the consensus endorses 'Sjögren disease' as the official nomenclature to acknowledge the distinct pathogenesis of this disorder and to improve clarity in both clinical practice and research.

BACKGROUND:High fasting plasma glucose (HFPG) plays an important role in the progression of breast cancer. This study aims to assess the global time trends of female breast cancer attributable to HFPG from 1990 to 2021 and projections to 2046. METHODS:This study obtained the number and age-standardised rate of deaths and disability-adjusted life years (DALYs) of female breast cancer burden attributable to HFPG by age, region, country, and socio-demographic index (SDI) from 1990 to 2021. Average Annual Percentage Change (AAPC) was analysed to assess time trends in female breast cancer burden attributable to HFPG. The age-period-cohort model was used to project the global burden by 2046. RESULTS:In 2021, 4.62% of female breast cancer deaths (30,000) and 4.04% of DALYs (820,000) globally were attributed to HFPG. Compared with 1990, the age-standardised mortality rate (ASMR) and age-standardised DALY rate (ASDR) increased, with AAPCs of 0.76 (95% CI: 0.71, 0.89) and 0.86 (95% CI: 0.84, 0.98), respectively. The burden of breast cancer attributable to HFPG was higher in the elderly and low SDI regions. Additionally, the burden of female breast cancer attributable to HFPG is projected to continue to increase through 2046. CONCLUSIONS:The burden of female breast cancer attributable to HFPG has increased over the past three decades and will continue to increase over the next 25 years. Therefore, it is important to control blood sugar to reduce the burden of breast cancer.

The objective of this prospective, longitudinal cohort study was to evaluate the pilot effects of a 24-month exercise and nutrition intervention, called the Lifestyle Intervention for Fibroid Elimination Program (LIFE), at NYU Langone Health's Center for Fibroid Care. Specifically, we evaluate the impact on quality of life (QOL), symptom severity (SS), and clinical lab markers in 22 fibroid patients. Patients who underwent a procedure within 3 months of the start of the LIFE Program and completed up to 12 months of the program were included in this study. Participants were excluded if currently pregnant, postmenopausal, or had dietary restrictions or physical constraints that prevented them from participating fully in the intervention. This intervention required participants to follow a prescribed nutrition and exercise regimen for up to 12 months and attend at least 2 office visits with a physician. Participants also completed two quality of life questionnaires and regular ultrasound imaging. The demographic breakdown of our study cohort was 63.6% Black and 18.2% Hispanic/LatinX. A clinically meaningful improvement in QOL and symptom severity was found within the first year of the LIFE program. The QOL sub-scale scores that showed the greatest improvement were concern and energy/mood. Vitamin D lab values also showed a clinically meaningful improvement. The LIFE Program was associated with a reduction in symptom burden and an improvement in quality of life up to 12 months after a procedural fibroid intervention, yielding insight into how a lifestyle intervention may be an effective adjunct in improving patient quality of life.

Microangiopathy is a major complication of SARS-CoV-2 infection and contributes to the acute and chronic complications of the disease¹. Endotheliopathy and dysregulated blood coagulation are prominent in COVID-19 and are considered to be major causes of microvascular obstruction^1,2. Here we demonstrate extensive endothelial cell (EC) death in the microvasculature of COVID-19 organs. Notably, EC death was not associated with fibrin formation or platelet deposition, but was linked to microvascular red blood cell (RBC) haemolysis. Importantly, this RBC microangiopathy was associated with ischaemia-reperfusion injury, and was prominent in the microvasculature of humans with myocardial infarction, gut ischaemia, stroke, and septic and cardiogenic shock. Mechanistically, ischaemia induced MLKL-dependent EC necroptosis and complement-dependent RBC haemolysis. Deposition of haemolysed RBC membranes at sites of EC death resulted in the development of a previously unrecognized haemostatic mechanism preventing microvascular bleeding. Exaggeration of this haemolytic response promoted RBC aggregation and microvascular obstruction. Genetic deletion of Mlkl from ECs decreased RBC haemolysis, microvascular obstruction and reduced ischaemic organ injury. Our studies demonstrate the existence of a RBC haemostatic mechanism induced by dying ECs, functioning independently of platelets and fibrin. Therapeutic targeting of this haemolytic process may reduce microvascular obstruction in COVID-19, and other major human diseases associated with organ ischaemia.