Shuang Gao

Among many ethylene glycol (EG) synthetic methods, the ethylene carbonate (EC) route is preferred due to its extremely high EG selectivity and low H₂O/EC ratio. In this work, a variety of layered double hydroxides (LDHs) and layered double oxides (LDOs) were synthesized by the co‐precipitation method and evaluated as catalysts for this reaction. The Zn₃Al‐LDO showed the highest catalytic activity under low H₂O/EC ratio and mild conditions, and the EG yield of 93 %–99 % could be obtained at 100 °C for 3–4 h. This superior performance is attributed to the absence of the “memory effect”, allowing Zn₃Al‐LDO to retain a significant number of base sites in the hydrolysis system. The active sites inhibition experiment proved that Zn₃Al‐LDO is an acid‐base synergistic catalyst and the base sites are dominant. The catalyst can be recycled at least five times with calcination and activation to maintain excellent catalytic activity.

The cleavage and functionalization of C–S bonds have become a rapidly growing field for the design or discovery of new transformations. However, it is usually difficult to achieve in a direct and selective fashion due to the intrinsic inertness and catalyst-poisonous character. Herein, for the first time, we report a novel and efficient protocol that enables direct oxidative cleavage and cyanation of organosulfur compounds by heterogeneous nonprecious-metal Co-N-C catalyst comprising graphene encapsulated Co nanoparticles and Co-Nx sites using oxygen as environmentally benign oxidant and ammonia as nitrogen source. A wide variety of thiols, sulfides, sulfoxides, sulfones, sulfonamides, and sulfonyl chlorides are viable in this reaction, enabling access to diverse nitriles under cyanide-free conditions. Moreover, modifying the reaction conditions also allows for the cleavage and amidation of organosulfur compounds to deliver amides. This protocol features excellent functional group tolerance, facile scalability, cost-effective and recyclable catalyst, and broad substrate scope. Characterization and mechanistic studies reveal that the remarkable effectiveness of the synergistic catalysis of Co nanoparticles and Co-Nx sites is crucial for achieving outstanding catalytic performance.

The cleavage/functionalization of C–C bonds in alcohols has emerged as a robust tool for exploration of new conversion. Herein, a Mn(OAc)2-catalyzed oxidative cleavage/ammoxidation of a wide range of alcohols to amides has been developed. The practicality of this transformation was demonstrated by a scale-up experiment and an amidation of mixed alcohols in a one-pot fashion. Moreover, a plausible mechanism was proposed based on a series of control experiments.

Background: Homologous recombination deficiency (HRD), broadly defined as a loss of the cellular mechanism underlying homologous recombination, is often observed in breast cancer. HRD causes distinctive perturbations to tumor genomic architecture that allow for its molecular identification, while also rendering HRD+ cancers vulnerable to specific chemotherapeutic interventions. This makes the molecular identification of HRD a promising avenue in precision medicine of breast cancer. Specific features of HRD include the presence of large-scale transitions (LST), telomeric allelic imbalance (TAI) and Loss of Heterozygosity (LOH). Each are readily detectable via targeted next generation sequencing (tNGS) or via array-based genotyping. However, genome-wide approaches for HRD detection using cost-effective methods, such as low-pass sequencing (LP-WGS), remain relatively under-explored. Here, we investigated whether HRD signals can be successfully re-capitulated using LP-WGS technology and benchmarked our results against the current field standard (both tNGS and array genotyping). Methods: LP-WGS and tNGS was performed on 96 samples across a range of tumor types (including N=17 breast cancer samples). LP-WGS libraries were prepared using Nextera (Illumina) using 0.4ng DNA input, and sequenced to 0.5-1x coverage. tNGS libraries were prepared using TSO500 (Illumina) using 40-80ng input, and sequenced to >150x unique read coverage. Regions of CNV were estimated using CNVKit v0.9.6, and regions of LOH were estimated using a novel ancestry-aware method. Small variant detection was performed using the TSO500 v2.2.0.12 analysis pipeline. SNP array analysis of 12 tumor samples using Oncoscan (ThermoFisher) was also performed. CNV and LOH estimates derived from LP-WGS, TSO500 and SNP array data were calculated using Jaccard similarity, treating the SNP array data as the “ground truth”. Results: We benchmarked HRD signals derived from LP-WGS compared to the array-based calls and observed near perfect sensitivity for CNV gains across samples (Jaccard index=1.0), as well as for CNV losses between LP-WGS and SNP array (Jaccard index=1.0). We additionally noted that LPS-WGS calls captured both CNV loss and gains that were not detectable via the SNP array. For TAI, LP-WGS re-capitulated 7/10 unique signals also identified via array. We also observed high concordance between regions of the genome called LOH between both platforms (median Jaccard index=0.70, IQR=0.254), but noted an attenuation of sensitivity in samples where estimated tumor heterogeneity was high. We also evaluated LP-WGS CNV calls against the TSO500 assay and noted high sensitivity (96%; 94%) and specificity (89%; 91%) for both CNV gains and losses, respectively. Conclusions: Workflows incorporating LP-WGS can support the detection of HRD genome-wide, paving the way for a more affordable assay that may help to inform clinical decision making in the future treatment of breast cancer. Citation Format: Gillian Belbin, Jie An, Chase Mazur, Joseph Pickrell, Jeremy Li, Daniel Metzger, Shuang Gao, Erik Van Roey, Robert Seager, Sarabjot Pabla, Durga Prasad Dash, Jeffrey M. Conroy. Application of low-pass whole genome sequencing for the detection of Homologous Recombination Deficiency in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-54.

Purpose of Study: Cancer testis antigens (CTA) are highly immunogenic genes with the ability to cause cancer-specific immune responses when expressed. Their tumor cell-specific expression makes them a key target of natural T cell response, cancer vaccines, immune checkpoint blockade (ICB), and cell-based immunotherapies in a wide range of tumor types. In this study, we assess the pan-cancer distribution and ICB survival association of CTA burden (CTAB) in real-world solid tumors. Procedure: Three tumor sample cohorts were studied: 1) a pan-cancer discovery cohort to develop a low- and high-CTAB cutoff (n=5450, 39 tumor types), 2) a TCGA cohort (n=19923, 32 tumor types) used to validate the classifier based on CTAB distribution and serve as a non-ICB-treated population, and 3) an ICB-treated retrospective cohort to validate the classification on overall survival (OS) (n=242, 3 tumor types). The expression levels of 17 CTA were measured using targeted RNA-Seq of FFPE tumor samples and then ranked against a pan-cancer reference population. CTAB was calculated for each sample, cohort and tumor type as the sum of the 17 CTA gene expression ranks. The discovery cohort median CTAB of 171 was used to classify all three cohorts into high- and low-CTAB groups. OS analysis was performed on the TCGA and ICB-treated cohorts using a CoxPH regression model to determine the Hazard Ratio (HR). Results: The three cohorts demonstrated overlapping single-peak, left-skewed CTAB distribution curves centered at CTAB values between 170 (discovery cohort) and 256 (retrospective cohort). When grouping by tumor types and ordering by median CTAB, the CTAB distributions for tumor types within all three cohorts were comparable. CoxPH regression analysis revealed an association between the CTAB threshold classifier and OS in both the ICB-treated retrospective and non-ICB TCGA cohorts. However, the direction of this association differed between the two cohorts, with high-CTAB samples having better survival (HR=0.936, p=0.076) in the ICB-treated retrospective cohort and worse survival (HR: 1.007, p=0.084) in the non-ICB-treated cohort. Conclusion: Our studies show that the CTAB distribution was maintained across the discovery and TCGA cohorts and a wide range of tumor types, supporting that the CTAB classifier is valid and histology agnostic. Additionally, when evaluating the ICB and non-ICB-treated cohorts, CTAB demonstrated the ability to predict OS, pointing to the utility of ICB in supporting CTA-specific natural immune response. However, further studies are necessary to verify these mechanisms of response to ICB as well as cancer vaccines and cell-based immunotherapies. Additional validation is needed to establish the predictive utility of CTAB alone and in combination with other immune oncology biomarkers for resistance or response. Citation Format: R.J. Seager, Erik Van Roey, Shuang Gao, Blake Burgher, Paul DePietro, Mary Nesline, Roger Klein, Shengle Zhang, Jeffrey M. Conroy, Sarabjot Pabla. Cancer testis antigen burden: Pan-cancer distribution and survival implications [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 5137.

Selective cleavage and functionalization of C−C bonds have important applications in organic synthesis and biomass utilization. However, functionalization of C−C bonds by controlled cleavage remains difficult and challenging because they are inert. Herein, we describe an unprecedented efficient protocol for the breaking of successive C−C bonds in alcohols to form esters with one or multiple carbon atoms less using heterogeneous cobalt nanoparticles as catalyst with dioxygen as the oxidant. A wide range of alcohols including inactive long‐chain alkyl aryl alcohols undergo smoothly successive cleavage of adjacent −(C−C)_n− bonds to afford the corresponding esters. The catalyst was used for seven times without any decrease in activity. Characterization and control experiments disclose that cobalt nanoparticles are responsible for the successive cleavage of C−C bonds to achieve excellent catalytic activity, while the presence of Co‐N_x has just the opposite effect. Preliminary mechanistic studies reveal that a tandem sequence reaction is involved in this process.

Selective cleavage and functionalization of C−C bonds have important applications in organic synthesis and biomass utilization. However, functionalization of C−C bonds by controlled cleavage remains difficult and challenging because they are inert. Herein, we describe an unprecedented efficient protocol for the breaking of successive C−C bonds in alcohols to form esters with one or multiple carbon atoms less using heterogeneous cobalt nanoparticles as catalyst with dioxygen as the oxidant. A wide range of alcohols including inactive long‐chain alkyl aryl alcohols undergo smoothly successive cleavage of adjacent −(C−C)_n− bonds to afford the corresponding esters. The catalyst was used for seven times without any decrease in activity. Characterization and control experiments disclose that cobalt nanoparticles are responsible for the successive cleavage of C−C bonds to achieve excellent catalytic activity, while the presence of Co‐N_x has just the opposite effect. Preliminary mechanistic studies reveal that a tandem sequence reaction is involved in this process.

The first example of Wacker-type oxidation catalyzed by a single atom cobalt catalyst under dioxygen using isopropanol as the hydrogen source was established.