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Accurate ancestry inference is critical for identifying genetic contributors of cancer disparities among populations. Although methods to infer genetic ancestry have historically relied upon genome-wide markers, the adaptation to targeted clinical sequencing panels presents an opportunity to incorporate ancestry inference into routine diagnostic workflows. We show that global ancestral contributions and admixture of continental populations can be quantitatively inferred using markers captured by the MSK-IMPACT clinical panel. In a pan-cancer cohort of 45,157 patients, we observed differences by ancestry in the frequency of somatic alterations, recapitulating known associations and revealing novel associations. Despite the comparable overall prevalence of driver alterations by ancestry group, the proportion of patients with clinically actionable alterations was lower for African (30%) compared with European (33%) ancestry. Although this result is largely explained by population-specific cancer subtype differences, it reveals an inequity in the degree to which different populations are served by existing precision oncology interventions. Significance: We performed a comprehensive analysis of ancestral associations with somatic mutations in a real-world pan-cancer cohort, including >5,000 non-European individuals. Using an FDA-authorized tumor sequencing panel and an FDA-recognized oncology knowledge base, we detected differences in the prevalence of clinically actionable alterations, potentially contributing to health care disparities affecting underrepresented populations. This article is highlighted in the In This Issue feature, p. 2483

Supplementary Figure from Genetic Ancestry Correlates with Somatic Differences in a Real-World Clinical Cancer Sequencing Cohort

Accurate ancestry inference is critical for identifying genetic contributors of cancer disparities among populations. Although methods to infer genetic ancestry have historically relied upon genome-wide markers, the adaptation to targeted clinical sequencing panels presents an opportunity to incorporate ancestry inference into routine diagnostic workflows. We show that global ancestral contributions and admixture of continental populations can be quantitatively inferred using markers captured by the MSK-IMPACT clinical panel. In a pan-cancer cohort of 45,157 patients, we observed differences by ancestry in the frequency of somatic alterations, recapitulating known associations and revealing novel associations. Despite the comparable overall prevalence of driver alterations by ancestry group, the proportion of patients with clinically actionable alterations was lower for African (30%) compared with European (33%) ancestry. Although this result is largely explained by population-specific cancer subtype differences, it reveals an inequity in the degree to which different populations are served by existing precision oncology interventions.Significance:We performed a comprehensive analysis of ancestral associations with somatic mutations in a real-world pan-cancer cohort, including >5,000 non-European individuals. Using an FDA-authorized tumor sequencing panel and an FDA-recognized oncology knowledge base, we detected differences in the prevalence of clinically actionable alterations, potentially contributing to health care disparities affecting underrepresented populations.This article is highlighted in the In This Issue feature, p. 2483

Supplementary Data from Genetic Ancestry Correlates with Somatic Differences in a Real-World Clinical Cancer Sequencing Cohort

Compact cardiomyocytes that make up the ventricular wall of the adult heart represent an important therapeutic target population for modeling and treating cardiovascular diseases. Here, we established a differentiation strategy that promotes the specification, proliferation and maturation of compact ventricular cardiomyocytes from human pluripotent stem cells (hPSCs). The cardiomyocytes generated under these conditions display the ability to use fatty acids as an energy source, a high mitochondrial mass, well-defined sarcomere structures and enhanced contraction force. These ventricular cells undergo metabolic changes indicative of those associated with heart failure when challenged in vitro with pathological stimuli and were found to generate grafts consisting of more mature cells than those derived from immature cardiomyocytes following transplantation into infarcted rat hearts. hPSC-derived atrial cardiomyocytes also responded to the maturation cues identified in this study, indicating that the approach is broadly applicable to different subtypes of the heart. Collectively, these findings highlight the power of recapitulating key aspects of embryonic and postnatal development for generating therapeutically relevant cell types from hPSCs., Cardiomyocytes of heart ventricles consist of subpopulations of trabecular and compact subtypes. Here the authors describe the generation of structurally, metabolically and functionally mature compact ventricular cardiomyocytes as well as mature atrial cardiomyocytes from human pluripotent stem cells.

Anticancer therapy changes tumor physiology and genomics, making it a key variable in cancer studies. Although antineoplastics given at a single institution may be available in research-ready format, treatment at external institutions prior to receiving care at academic medical centers, common among patients at these centers, is often only described in free-text clinical notes, necessitating manual curation for downstream analysis. To overcome this bottleneck, we trained and validated natural language processing (NLP) models using initial consult notes to identify whether patients had received treatment at external institutions and studied the impact of these putative treatments on tumor genomics. Training data were derived from the AACR Project GENIE Biopharma Collaborative (BPC) for 2,663 patients at Memorial Sloan Kettering (MSK) across four cancer types. For each patient, we selected initial visits with medical and radiation oncologists based on an a priori note prioritization scheme and determined “ground-truth” prior external medications based on manually curated BPC administration records, whitelisting MSK-given medications. We trained logistic regression and clinical longformer models to identify external treatment receipt and evaluated model performance with 5-fold cross-validation. The clinical longformer model performed best across evaluation metrics, with an average area under the receiver operating characteristic curve of 0.972, macro-averaged precision/recall of 0.854/0.902 and macro-averaged F1 score of 0.876. Re-review of discrepant cases suggested that 75% of “false positives” may be due to curation error. We used our model to infer treatment status in a pan-cancer cohort with tumor genomic profiling using our institutional sequencing platform. Out of 48,447 patients, 11,900 were predicted to have received external treatment. Patients with putative external treatment had higher alteration frequencies in resistance-related genes than untreated patients and comparable to known pre-treated patients, including ESR1 in patients with breast cancer, AR in patients with prostate cancer, and EGFR T790M in patients with EGFR-mutated non-small cell lung cancer. Patients with putative external treatments, similar to known pre-treated patients, had shorter survival compared to treatment-naïve patients of the same cancer type. NLP can abstract external treatment status from clinical notes. When applied at scale, our model could help mitigate confounding variables and identify relationships between clinicogenomic variables and anticancer therapy. Citation Format: Thinh N. Tran, Karl B. Pichotta, Si-Yang Liu, Christopher Fong, Anisha Luthra, Brooke Mastrogiacomo, Steven Maron, Deborah Schrag, Sohrab P. Shah, Pedram Razavi, Bob T. Li, Gregory J. Riely, Nikolaus Schultz, Justin Jee. Identification of anti-neoplastic therapy given before initial visit at a referral center using natural language processing applied to medical oncology initial consultation notes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4259.

The brain consists of thousands of neuronal types that are generated by stem cells producing different neuronal types as they age. In Drosophila, this temporal patterning is driven by the successive expression of temporal transcription factors (tTFs)(1-3) We used single-cell mRNA sequencing to identify the complete series of tTFs that specify most Drosophila optic lobe neurons. We verify that tTFs regulate the progression of the series by activating the next tTF(s) and repressing the previous one(s), and also identify more complex regulations. Moreover, we establish the temporal window of origin and birth order of each neuronal type in the medulla and provide evidence that these tTFs are sufficient to explain the generation of all the neuronal diversity in this brain region. Finally, we describe the first steps of neuronal differentiation. We find that terminal differentiation genes, such as neurotransmitter-related genes, are present as transcripts, but not as proteins, in immature larval neurons; we show that these steps are conserved in humans. This comprehensive analysis of a temporal series of tTFs in the optic lobe offers mechanistic insights into how tTF series are regulated, and how they can lead to the generation of a complete set of neurons.

The emergence of interlayer excitons (IEs) from atomic layered transition metal dichalcogenides (TMDCs) heterostructures has drawn tremendous attention due to their unique and exotic optoelectronic properties. Coupling the IEs into optical cavities provides distinctive electromagnetic environments which plays an important role in controlling multiple optical processes such as optical nonlinear generation or photoluminescence enhancement. Here, the integration of IEs in TMDCs into plasmonic nanocavities based on a nanocube on a metallic mirror is reported. Spectroscopic studies reveal an order of magnitude enhancement of the IE at room temperature and a 5-time enhancement in fluorescence at cryogenic temperatures. Cavity modeling reveals that the enhancement of the emission is attributed to both increased excitation efficiency and Purcell effect from the cavity. The results show a novel method to control the excitonic processes in TMDC heterostructures to build high performance photonics and optoelectronics devices.

Cell cycle duration changes dramatically during development, starting out fast to generate cells quickly and slowing down over time as the organism matures. The cell cycle can also act as a transcriptional filter to control the expression of long gene transcripts, which are partially transcribed in short cycles. Using mathematical simulations of cell proliferation, we identify an emergent property that this filter can act as a tuning knob to control gene transcript expression, cell diversity, and the number and proportion of different cell types in a tissue. Our predictions are supported by comparison to single-cell RNA-seq data captured over embryonic development. Additionally, evolutionary genome analysis shows that fast-developing organisms have a narrow genomic distribution of gene lengths while slower developers have an expanded number of long genes. Our results support the idea that cell cycle dynamics may be important across multicellular animals for controlling gene transcript expression and cell fate.

Netropsin is one of the first ligands to be discovered that selectively binds to the minor groove of DNA and is actively used as a scaffold for developing potential anticancer and antibiotic agents. The mechanism by which netropsin binds to hairpin DNA remains controversial with two competing mechanisms having been proposed. In one mechanism, netropsin binding induces a hairpin-to-duplex DNA transition. Alternatively, netropsin binds in two thermodynamically different modes at a single duplexed AATT site. Here, results from native mass spectrometry (MS) with nanoscale ion emitters indicate that netropsin can simultaneously and sequentially bind to both hairpin and duplex DNA. Duplex DNA was not detected using conventional MS with larger emitters because nanoscale emitters significantly reduce the extent of salt adduction to ligand-DNA complex ions, including in the presence of relatively high concentrations of nonvolatile salts. Based on native MS and polyacrylamide gel electrophoresis results, the abundances of hairpin and duplex DNA are unaffected by the addition of netropsin. By native MS, the binding affinities for five ligand-DNA and DNA-DNA interactions can be rapidly obtained simultaneously. This research indicates a "simultaneous binding mechanism" for the interactions of netropsin with DNA.

Electrospray ionization (ESI) mass spectrometry (MS) is a crucial method for rapidly determining the interactions between small molecules and proteins with ultrahigh sensitivity. However, nonvolatile molecules and salts that are often necessary to stabilize the native structures of protein–ligand complexes can readily adduct to protein ions, broaden spectral peaks, and lower signal-to-noise ratios in native MS. ESI emitters with narrow tip diameters (∼250 nm) were used to significantly reduce the extent of adduction of salt and nonvolatile molecules to protein complexes to more accurately measure ligand–protein binding constants than by use of conventional larger-bore emitters under these conditions. As a result of decreased salt adduction, peaks corresponding to protein–ligand complexes that differ in relative molecular weight by as low as 0.06% can be readily resolved. For low-molecular-weight anion ligands formed from sodium salts, anion-bound and unbound protein ions that differ in relative mass by 0.2% were completely baseline resolved using nanoscale emitters, which was not possible under these conditions using conventional emitters. Owing to the improved spectral resolution obtained using narrow-bore emitters and an analytically derived equation, Kd values were simultaneously obtained for at least six ligands to a single druggable protein target from one spectrum for the first time. This research suggests that ligand–protein binding constants can be directly and accurately measured from solutions with high concentrations of nonvolatile buffers and salts by native MS., Nanoscale emitters in native MS significantly improve measurements of ligand−protein interactions. The binding affinities of six ligands can be rapidly obtained simultaneously with high sensitivity.

Hexagonal boron nitride (hBN) is gaining interest for potential applications in integrated quantum nanophotonics. Yet, to establish hBN as an integrated photonic platform several cornerstones must be established, including the integration and coupling of quantum emitters to photonic waveguides. Supported by simulations, we study the approach of monolithic integration, which is expected to have coupling efficiencies that are ∼4 times higher than those of a conventional hybrid stacking strategy. We then demonstrate the fabrication of such devices from hBN and showcase the successful integration of hBN single photon emitters with a monolithic waveguide. We demonstrate the coupling of single photons from the quantum emitters to the waveguide modes and collection from on-chip grating couplers. Our results build a general framework for monolithically integrated hBN single photon emitter and will facilitate future works toward on-chip integrated quantum photonics with hBN.

Accurate ancestry inference is crucial for identifying genetic determinants of cancer disparities among specific populations. While methods to infer genetic ancestry and admixture have historically relied upon genome-wide markers from broad-scale next-generation sequencing (NGS), the adaptation to targeted NGS panels presents an opportunity to prospectively incorporate ancestry inference as part of routine clinical diagnosis. Here we show that global ancestral contributions and admixture of African (AFR), European (EUR), East Asian (EAS), Native American (NAM) and South Asian (SAS) populations can be reliably inferred using markers from genomic regions covered by the FDA-authorized clinical NGS panel, MSK-IMPACT. We also show that individuals with Ashkenazi Jewish (ASJ) ancestry can be inferred with 97% accuracy using a set of ASJ ancestry-informative markers. We apply these methods to infer genetic ancestry for over 45,000 patients from the AACR GENIE v10.0-public cohort who were profiled using MSK-IMPACT. We observed 98% concordance between self-reported race and genetic ancestry for non-admixed individuals and were able to quantitatively infer ancestral contributions for individuals from recently admixed populations such as African American and Latin American. Of the discordant cases, manual review of clinical and family histories revealed the vast majority to represent clinical encoding errors where the inferred ancestry was confirmed correct. As self-reported race is not available for 17% of patients in the GENIE cohort, the ability to accurately infer genetic ancestry enables broader analysis of population-specific genomic and clinical features. We systematically evaluated the frequency of somatic and germline alterations in up to 468 genes for each cancer type and recapitulated known differences among ancestral populations. For example, we observed significantly higher frequency of EGFR somatic alterations in EAS (65%) and SAS (66%) compared to non-ASJ EUR (21%) with lung adenocarcinoma, a difference that remained significant even when limiting to never-smokers. Additionally, we found that the frequency of harboring at least one known BRCA founder mutation (BRCA1 68_69delAG, BRCA1 5266dupC, or BRCA2 5946delT) was 26x higher in genetically determined ASJ (5.1%) compared to non-ASJ (0.2%). Strikingly, while the overall rate of driver alterations in solid tumors was similar across different populations, we found that the proportion of patients with clinically actionable somatic alterations (OncoKB Level 1, 2, 3A, or 3B) was lowest in AFR (47%) patients compared to EUR, EAS and SAS (50% each). While this result is partially explained by different cancer type and subtype distributions in different populations in this real-world cohort, it highlights the urgency for greater equity in drug development programs to target alterations represented across all diverse populations. Citation Format: Kanika Arora, Thinh N. Tran, Yelena M. Kemel, Miika Mehine, Ying Liu, Shaleigh A. Smith, Subhiksha Nandakumar, Irina Ostrovnaya, Thomas C. Reynolds, Kenneth Offit, David Solit, Marc Ladanyi, Nikolaus Schultz, Ahmet Zehir, Carol L. Brown, Debyani Chakravarty, Zsofia K. Stadler, Chaitanya Bandlamudi, Michael F. Berger. Ancestry inference and population-specific disparities in a real-world clinical sequencing cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2182.

Valley polarization is among the most critical attributes of atomically thin materials. However, increasing contrast from monolayer transition metal dichalcogenides (TMDs) has so far been challenging. In this work, a large degree of circular polarization up to 45% from a monolayer WS2 is achieved at room temperature by using a single chiral plasmonic nanoparticle. The increased contrast is attributed to the selective enhancement of both the excitation and the emission rate having one particular handedness of the circular polarization, together with accelerated radiative recombination of valley excitons due to the Purcell effect. The experimental results are corroborated by the optical simulation using the finite-difference time-domain (FDTD) method. Additionally, the single chiral nanoparticle enables the observation of valley-polarized luminescence with a linear excitation. The results provide a promising pathway to enhance valley contrast from monolayer TMDs and utilize them for nanophotonic devices.

Nanoscale optical thermometry is a promising non-contact route for measuring local temperature with both high sensitivity and spatial resolution. In this work, we present a deterministic optical thermometry technique based on quantum emitters in nanoscale hexagonal boron-nitride. We show that these nanothermometers exhibit better performance than that of homologous, all-optical nanothermometers both in sensitivity and range of working temperature. We demonstrate their effectiveness as nanothermometers by monitoring the local temperature at specific locations in a variety of custom-built micro-circuits. This work opens new avenues for nanoscale temperature measurements and heat flow studies in miniaturized, integrated devices.

Cell cycle duration changes dramatically during development, starting out fast to generate cells quickly and slowing down over time as the organism matures. The cell cycle can also act as a transcriptional filter to control the expression of long genes which are partially transcribed in short cycles. Using mathematical simulations of cell proliferation, we identify an emergent property, that this filter can act as a tuning knob to control cell fate, cell diversity and the number and proportion of different cell types in a tissue. Our predictions are supported by comparison to single-cell RNA-seq data captured over embryonic development. Evolutionary genome analysis shows that fast developing organisms have a narrow genomic distribution of gene lengths while slower developers have an expanded number of long genes. Our results support the idea that cell cycle dynamics may be important across multicellular animals for controlling gene expression and cell fate.