Characterizing cancer metabolism from bulk and single-cell RNA-seq data using METAFlux.

Cells often alter metabolic strategies under nutrient-deprived conditions to support their survival and growth. Characterizing metabolic reprogramming in the tumor microenvironment (TME) is of emerging importance in cancer research and patient care. However, recent technologies only measure a subset of metabolites and cannot provide in situ measurements. Computational methods such as flux balance analysis (FBA) have been developed to estimate metabolic flux from bulk RNA-seq data and can potentially be extended to single-cell RNA-seq (scRNA-seq) data. However, it is unclear how reliable current methods are, particularly in TME characterization. Here, we present a computational framework METAFlux (METAbolic Flux balance analysis) to infer metabolic fluxes from bulk or single-cell transcriptomic data. Large-scale experiments using cell-lines, the cancer genome atlas (TCGA), and scRNA-seq data obtained from diverse cancer and immunotherapeutic contexts, including CAR-NK cell therapy, have validated METAFlux's capability to characterize metabolic heterogeneity and metabolic interaction amongst cell types.

An Evaluation of Peer-Rated Surgical Skill and its Relationship With Detrusor Muscle Sampling in Transurethral Resection of Bladder Tumor.

OBJECTIVE: To assess the reliability of peer-review of TURBT videos as a means to evaluate surgeon skill and its relationship to detrusor sampling. METHODS: Urologists from an academic health system submitted TURBT videos in 2019. Ten blinded peers evaluated each surgeon's performance using a 10-item scoring instrument to quantify surgeon skill. Normalized composite skill scores for each surgeon were calculated using peer ratings. For surgeons submitting videos, we retrospectively reviewed all TURBT pathology results (2018-2019) to assess surgeon-specific detrusor sampling. A hierarchical logistic regression model was fit to evaluate the association between skill and detrusor sampling, adjusting for patient and surgeon factors. RESULTS: Surgeon skill scores and detrusor sampling rates were determined for 13 surgeons performing 245 TURBTs. Skill scores varied from -6.0 to 5.1 [mean: 0; standard deviation (SD): 2.40]. Muscle was sampled in 72% of cases, varying considerably across surgeons (mean: 64.5%; SD: 30.7%). Among 8 surgeons performing >5 TURBTs during the study period, adjusted detrusor sampling rate was associated with sending separate deep specimens (odds ratio [OR]: 1.97; 95% confidence interval [CI]: 1.02-3.81, P = .045) but not skill (OR: 0.81; 95% CI: 0.57-1.17, P = .191). CONCLUSION: Surgeon skill was not associated with detrusor sampling, suggesting there may be other drivers of variability of detrusor sampling in TURBT.

It's all in the name: Does nomenclature for indolent prostate cancer impact management and anxiety?

BACKGROUND: Despite consensus guidelines, many men with low-grade prostate cancer are not managed with active surveillance. Patient perception of the nomenclature used to describe low-grade prostate cancers may partly explain this discrepancy. METHODS: A randomized online survey was administered to men without a history of prostate cancer, presenting a hypothetical clinical scenario in which they are given a new diagnosis of low-grade prostate cancer. The authors determined whether diagnosis nomenclature was associated with management preference and diagnosis-related anxiety using ratings given on a scale from 1 to 100, adjusting for participant characteristics through multivariable linear regression. RESULTS: The survey was completed by 718 men. Compared with Gleason 6 out of 10 prostate cancer, the term grade group 1 out of 5 prostate cancer was associated with lower preference for immediate treatment versus active surveillance (ß = -9.3; 95% CI, -14.4, -4.2; P < .001), lower diagnosis-related anxiety (ß = -8.3; 95% CI, -12.8, -3.8; P < .001), and lower perceived disease severity (ß = -12.3; 95% CI, -16.5, -8.1; P < .001) at the time of initial diagnosis. Differences decreased as participants received more disease-specific education. Indolent lesion of epithelial origin, a suggested alternative term for indolent tumors, was not associated with differences in anxiety or preference for active surveillance. CONCLUSIONS: Within a hypothetical clinical scenario, nomenclature for low-grade prostate cancer affects initial perception of the disease and may alter subsequent decision making, including preference for active surveillance. Disease-specific education reduces the differential impact of nomenclature use, reaffirming the importance of comprehensive counseling and clear communication between the clinician and patient.

Nucleostemin Modulates Outcomes of Hepatocellular Carcinoma via a Tumor Adaptive Mechanism to Genomic Stress.

Hepatocellular carcinomas (HCC) are adapted to survive extreme genomic stress conditions imposed by hyperactive DNA replication and genotoxic drug treatment. The underlying mechanisms remain unclear, but may involve intensified DNA damage response/repair programs. Here, we investigate a new role of nucleostemin (NS) in allowing HCC to survive its own malignancy, as NS was previously shown to promote liver regeneration via a damage repair mechanism. We first established that a higher NS transcript level correlates with high-HCC grades and poor prognostic signatures, and is an independent predictor of shorter overall and progression-free survival specifically for HCC and kidney cancer but not for others. Immunostaining confirmed that NS is most abundantly expressed in high-grade and metastatic HCCs. Genome-wide analyses revealed that NS is coenriched with MYC target and homologous recombination (HR) repair genes in human HCC samples and functionally intersects with those involved in replication stress response and HR repair in yeasts. In support, NS-high HCCs are more reliant on the replicative/oxidative stress response pathways, whereas NS-low HCCs depend more on the mTOR pathway. Perturbation studies showed NS function in protecting human HCC cells from replication- and drug-induced DNA damage. Notably, NS depletion in HCC cells increases the amounts of physical DNA damage and cytosolic double-stranded DNA, leading to a reactive increase of cytokines and PD-L1. This study shows that NS provides an essential mechanism for HCC to adapt to high genomic stress for oncogenic maintenance and propagation. NS deficiency sensitizes HCC cells to chemotherapy but also triggers tumor immune responses. IMPLICATIONS: HCC employs a novel, nucleostemin (NS)-mediated-mediated adaptive mechanism to survive high genomic stress conditions, a deficiency of which sensitizes HCC cells to chemotherapy but also triggers tumor immune responses.

Willingness to Participate in Home Screening for Urologic Cancers in the General Population: An Online Survey of Over 1400 Adults.

OBJECTIVE: To assess willingness of adults to undergo home screening for urologic cancers via urine dipstick and determine the effect of an educational pamphlet on hematuria on screening willingness and knowledge of hematuria. MATERIALS AND METHODS: We performed an online survey of adult volunteers throughout the United States from September 25, 2018 to October 15, 2018. The primary outcome was pretest willingness to undergo home screening for hematuria with urine dipstick (4 or 5 out of 5-point Likert). Secondary outcomes included changes in willingness to screen and knowledge on hematuria after exposure to an educational pamphlet. RESULTS: Of 1442 participants, 54% were male and 87% were White. Median age was 48. Pretest willingness to home screen was high (90%). Older age was associated with an increased willingness to screen (per 10-year increase: odds ratio 1.47, 95% confidence interval 1.28-1.68, P <.001). Participants who had not previously discussed hematuria with a health care provider were less willing to screen (odds ratio 0.50, 95% confidence interval 0.27-0.94, P = .033). Patients with risk factors for urologic cancers (ie, smoking and occupational exposures) were equally willing to screen. After pamphlet exposure hematuria knowledge increased (P <.001) while willingness to screen did not change (P = .15). CONCLUSION: Willingness to perform home-based screening for urologic cancers by assessing for hematuria is high in an adult population, including those with risk factors. Knowledge of hematuria improves significantly after exposure to an educational pamphlet.

The Influence of Decision Aids on Prostate Cancer Screening Preferences: A Randomized Survey Study.

PURPOSE: Shared decision making is recommended in regard to prostate cancer screening. Decision aids may facilitate this process but the impact of decision aids on screening preferences is poorly understood. MATERIALS AND METHODS: In an online survey we randomized a national sample of adults to the online decision aids of 1 of 6 professional societies. We compared survey responses before and after decision aid exposure. The primary outcome was the change in participant likelihood of undergoing or recommending prostate cancer screening on a scale of 1-unlikely to 100-extremely likely. Secondary outcomes included change in participant comfort with prostate cancer screening based on the average of 6, 5-point Likert-scale questions. RESULTS: Median age was 53 years in the 1,336 participants and 50% were men. The randomized groups did not differ significantly by race, age, gender, income, marital status or education level. The likelihood of undergoing or recommending prostate cancer screening decreased from 83 to 78 following decision aid exposure (p <0.001). Reviewing the decision aid from the Centers for Disease Control or the American Academy of Family Physicians did not alter the likelihood (each p >0.2). However, the decision aid from the United States Preventive Services Task Force was associated with the largest decrease in screening preference (-16.0, p <0.001). Participants reported increased comfort (from 3.5 to 4.1 of 5) with the decision making process of prostate cancer screening following exposure to a decision aid (p <0.001). CONCLUSIONS: Exposure to a decision aid decreased the participant likelihood of undergoing or recommending prostate cancer screening and increased comfort with the screening process.