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In situ photodeposition of MoO3−x with oxygen vacancies evoked synergistic photo-thermal catalytic CO2 reduction over g-C3N4.

Supplementary Figure Legends, Table Legends

Supplementary Tables - PDF file 753K, Supplementary Tables S1-S15 include transcriptome and exome sequencing results for the FGFR fusion positive index cases, and summaries of sequencing cohorts

Supplementary Figures - PDF file 639K, Supplementary Figures S1-S9 show the phenotypic effects and signaling pathways of FGFR fusions in vitro and in vivo

Supplementary Tables S1 - S6. Supplementary Table S1. Patient clinical characteristics and summary of the observed molecular aberrations in the MTSCC cases studied. Supplementary Table S2. Sequencing quality metrics. Supplementary Table S3. Detailed list of somatic mutation calls in MTSCC cohort. Supplementary Table S4. Twenty three genes commonly regulated by PTPN14 siRNAs in the 3 cell lines identified by analysis of RNAseq data. (Supplementary Fig S4E). Supplementary Table S5. Geneset Enrichment analysis dataset details. Supplementary Table S6. Summary of immunohistochemistry staining results.

Supplementary Figures S1 - S8. Supplementary Figure S1. Intra-tumor mutational heterogeneity in MTSCC. Supplementary Figure S2. Copy number variation and Hippo pathway mutation in the MTSCC validation cohort and the TCGA KIRP outlier samples. Supplementary Figure S3. MTSCC Gene Expression Analyses. Supplementary Figure S4. PTPN14 function and Hippo pathway signature in kidney. Supplementary Figure S5. Gene set enrichment analysis. Supplementary Figure S6. HNF genes expression in normal human tissues, MTSCC and TCGA kidney cancer RNA-seq data. Supplementary Figure S7. Summary of YAP1 immunohistochemistry. Supplementary Figure S8. Gene expression correlation between MTSCC and nephron sections.

Supplementary Table 1: List of the compounds in the epigenetic inhibitor library.

This file includes Supplementary Figures S1-S8. Figure S1: Inhibition of EPZ6438 and ASO-EZH2 sensitizes enzalutamide-resistant LNCaP cells to enzalutamide or ASO-AR. Figure S2: Design and validation of sgRNA targeting EZH2. Figure S3: Growth inhibitory effect of Enzalutamide in EZH2 loss-of-function CRPC cell lines. Figure S4: Knockdown efficiency of ASO-AR and ASO-EZH2 in CRPC cell lines. Figures S5: EZH2 ASOs inhibit proliferation of LNCaP-abl cells. Figure S6: EZH2 ASOs synergize with ASO-AR to inhibit growth of prostate cancer cells in soft-agar colony formation assay and Cell-titer Glo assay. Figure S7: Loss-of-function of EZH2 alters AR cistrome. Figure S8: Tumor characterization of xenografted study.

Representative microphotographs of samples showing different MCPyV RNA in situ hybridization (RNA-ISH) intensity (400X magnification)

ISH product scores.

Supplementary information with additional materials and methods, references, and the legends for all supplementary figures.

Supplemental Figure Legends

Read depth histograms across the Merkel cell polyomavirus (MCPyV) genome for two Merkel cell carcinoma (MCC) tumors.

Advanced prostate cancer initially responds to androgen deprivation therapy (ADT), but the disease inevitably recurs as castration-resistant prostate cancer (CRPC). Although CRPC initially responds to abiraterone and enzalutamide, the disease invariably becomes nonresponsive to these agents. Novel approaches are required to circumvent resistance pathways and to extend survival, but the mechanisms underlying resistance remain poorly defined. Our group previously showed the histone lysine-N-methyltransferase EZH2 to be overexpressed in prostate cancer and quantitatively associated with progression and poor prognosis. In this study, we screened a library of epigenetic inhibitors for their ability to render CRPC cells sensitive to enzalutamide and found that EZH2 inhibitors specifically potentiated enzalutamide-mediated inhibition of proliferation. Moreover, we identified antisense oligonucleotides (ASO) as a novel drug strategy to ablate EZH2 and androgen receptor (AR) expression, which may have advantageous properties in certain settings. RNA-seq, chromatin immunoprecipitation sequencing, and assay for transposase-accessible chromatin using sequencing demonstrated that EZH2 inhibition altered the AR cistrome to significantly upregulate AR signaling, suggesting an enhanced dependence of CRPC cells on this pathway following inhibition of EZH2. Combination treatment with ASO targeting EZH2 and AR transcripts inhibited prostate cancer cell growth in vitro and in vivo better than single agents. In sum, this study identifies EZH2 as a critical epigenetic regulator of ADT resistance and defines ASO-based cotargeting of EZH2 and AR as a promising strategy for the treatment of CRPC.Significance: Simultaneous targeting of lysine methyltransferase EZH2 and the AR with ASO proves a novel and effective therapeutic strategy in patients with CRPC. Cancer Res; 78(20); 5731–40. ©2018 AACR.

Purpose: Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine tumor of the skin. Merkel cell polyomavirus (MCPyV) plays an oncogenic role in the majority of MCCs. Detection of MCPyV in MCCs has diagnostic utility and prognostic potential. We investigated whether RNAscope, an RNA in situ hybridization (ISH) assay for detection of RNA transcripts in tissues, is useful for MCPyV detection.Experimental Design: We applied an RNAscope probe targeting MCPyV T antigen transcripts on tissue microarrays (TMA) and whole-tissue sections encompassing 87 MCCs from 75 patients, 14 carcinomas of other types, and benign tissues. For comparison, qPCR was performed on 57 cases of MCC from 52 patients.Results: RNA-ISH demonstrated the presence of MCPyV in 37 of 75 cases (49.3%). Notably, tumors from younger patients (P = 0.011). Female patients had a higher positive rate of MCPyV than male patients (66.7% vs. 39.6%, P = 0.032). Data from both RNA-ISH and qPCR were available for 57 samples. Considering MCPyV qPCR as the gold standard for determining MCPyV status, RNAscope had 100% sensitivity and 100% specificity. There was a strong correlation between qPCR copy number and RNA-ISH product score (Spearman correlation coefficient R2 = 0.932, P < 0.0001).Conclusions: RNA-ISH is comparably sensitive to qPCR for detection of MCPyV and allows for correlation with tissue morphology. This study also reveals a significant association between age, gender, and MCPyV positivity. Clin Cancer Res; 23(18); 5622–30. ©2017 AACR.

Supplemental Table S7 A. Selected somatic mutation calls and Sanger validation results

Supplemental Table S3. MCPyV detection in MCC tumors by qPCR, immunohistochemistry, and transcriptome sequencing

Supplemental Figure S1. Mutational signatures of Merkel cell polyomavirus-negative Merkel cell carcinomas

Supplemental Figure Legends

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that is classified as Merkel cell polyomavirus (MCPyV)-positive or virus-negative. Epigenetic changes, such as DNA methylation, can alter gene expression and influence cancer progression. However, patterns of DNA methylation and the therapeutic efficacy of hypomethylating agents have not been fully explored in MCC. We characterized genome-wide DNA methylation in 16 MCC cell lines from both molecular subclasses in comparison to other cancer types, and found that the overall profile of MCC is similar to small cell lung carcinoma. Comparison of virus-positive and -negative MCC revealed 2,260 differentially methylated positions. The hypomethylating agent decitabine (DAC) upregulated expression of antigen-presenting machinery in MCC cell lines and stimulated membrane expression of HLA-A in virus-positive and virus-negative MCC xenograft tumors. DAC also induced prominent caspase- and large T antigen-independent cell death in virus-positive MCC, whereas virus-negative MCC cell lines displayed decreased proliferation without increased cell death. In mouse xenografts, decitabine significantly decreased the size of virus-positive tumors, but not virus-negative tumors. Our findings indicate that viral status predicts genomic methylation patterns in MCC, and that DAC may be therapeutically effective against MCC via anti-proliferative effects, cell death, and increased immune recognition.

The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling1 and is altered in over 20% of cancers2,3. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers., PROTAC degrader–induced SWI/SNF inactivation abolishes DNA accessibility at enhancer elements of oncogenes and also tempers supra-physiologic expression of driver transcription factors, resulting in potent inhibition of tumour growth in mouse models.

Background H2O2, as a green and environmentally friendly oxidant, has been widely used in our daily life and industrial production. It is of epoch-making significance to develop highly efficient photocatalysts for producing H2O2. In recent years, g-C3N4 has received much attention due to its high chemical stability, environmental friendliness and suitable energy band structure. However, some shortcomings including the fast recombination of photogenerated electron-hole pairs and small specific surface area in traditional 2D g-C3N4 seriously impede its photocatalytic performance for the production of H2O2. Methods 1D hollow nanostructures possess intriguing physicochemical properties and are adopted to overcome the intrinsic shortcomings of g-C3N4. Herein, g-C3N4 with a hollow hexagonal prism structure (CN HP) is prepared to produce H2O2. It is characterized by XRD, XPS, SEM, HRTEM, ESR and DRS. BET, PL spectra, photocurrent and EIS are used to explain the enhanced photocatalytic performance. Significant findings Compared with traditional 2D g-C3N4, the specific surface area of CN HP increases to 41.513 m2/g, providing more active sites. Meanwhile, its hollow tubular structure can enhance the migration of photogenerated electrons to the catalyst surface, and electrons with a longer lifetime can participate in photocatalytic reactions to achieve high efficiency. The yield of H2O2 production can up to 4.08 μmol over CN HP in 40 min, which is about 7 times higher than that of traditional 2D g-C3N4, and the apparent quantum efficiency (AQE) of H2O2 production at 420 nm is 2.41%. This research provides a valuable reference for the development of green materials for efficient photocatalytic production of H2O2.

Pt is usually used as cocatalyst for g-C

Decreased proliferation and invasion of trophoblast were proven to be involved in the pathogenesis of preeclampsia (PE). However, the regulatory network has not been clarified yet. This study aimed to explore the role of miR-101-3p in the progression of PE.miR-101-3p expression in placentas of pregnant women with or without PE was analyzed by real-time quantitative PCR (RT-qPCR). Trophoblastic HTR-8/SVneo and HPT-8 cell lines were cultured and underwent hypoxia/reoxygenation (H/R) treatment to mimic PE in vitro. Cell proliferation and invasion were analyzed in gain-of and loss-of-function assays. Finally, we undertook in vivo studies to explore effects of miR-101-3p in the PE model.Compared to placentas from patients without PE, miR-101-3p expressed significantly higher in placentas from PE patients, and its level was positively correlated with the severity of patients. In vitro studies found that overexpression of miR-101-3p significantly suppressed cell proliferation and invasion, while knockdown of miR-101-3p reversed the impacts of H/R treatment. Further research showed that the expression of WD repeat domain 5 (WDR5) was significantly lower in placentas from patients with PE, and its level was negatively associated with the severity of patients. In vitro and in vivo studies confirmed that miR-101-3p promoted PE progression through the regulation of WD WDR5 expression.Increased expression of miR-101-3p in placenta contributes to the development of PE by suppressing WDR5-mediated proliferation and invasion of trophoblast.

Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8+ T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+ T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+ monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+ T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity. Liver metastases reduce clinical and preclinical immune-checkpoint inhibitor efficacy through hepatic siphoning of circulating activated CD8+ T cells, but therapeutic benefit can be improved by combining immunotherapy with liver-directed radiotherapy.

Considering the non-ideal performance of g-C3N4 on photocatalytic CO2 reduction, diazanyl and SnO2 bi-activated g-C3N4 (SnO2/HyUCN) was synthesized by changing the surface amino group into diazanyl and in situ depositing SnO2 nanoparticles via two-step redox reactions. The presence of SnO2 and diazanyl was proved by X-ray photoelectron spectroscopy (XPS) and Ag+ oxidation methods, respectively. For comparison, de-diazanyl g-C3N4 (SnO2/UCN) was also prepared. SnO2/HyUCN showed the highest photocatalytic CO2 reduction performance, and its CO generating rate reached 21.5 μmol g−1 h−1, which was 6 and 4.1 times that of pristine g-C3N4 (UCN) and SnO2/UCN, respectively. CO2 adsorption–desorption test and CO2 adsorption energy comparison based on DFT calculations revealed the enhanced CO2 adsorption of SnO2/HyUCN. The time-resolved photoluminescence (PL), surface photovoltage spectrum (SPV) and electrochemical tests revealed the suppressed recombination of photogenerated electron–hole pairs for SnO2/HyUCN. Furthermore, the photocatalytic mechanism was discussed at the molecular level by the in situ Fourier transform infrared (FT-IR) spectroscopy.

To improve the photocatalytic oxidation reaction activity for NO removal, photocatalysts with excellent activity are required to activate molecular oxygen. Solid solution and heterojunction were suggested as effective strategies to enhance the molecular oxygen activation viaexciton and carrier photocatalysis. In this study, a solid solution and heterojunction containing BiOBr0.5I0.5/BiOI catalyst was synthesized, and it showed improved photocatalytic activity for removing NO. The photocatalytic NO removal mechanism indicated that synergistic effects between the solid solution and heterojunction induced the enhanced activity for molecular oxygen activation. The photogenerated holes, superoxide, and singlet oxygen generated by the carrier and exciton photocatalysis supported the high photocatalytic NO removal efficiency. This study provides new ideas for designing efficient Bi-O-X (X = Cl, Br, I) photocatalysts for oxidation reactions.

In this paper, the photocatalytic activity of industrial titanium dioxide (TiO2) based nacreous pigments was researched as functional building materials for photocatalytic NO remove. Three industrial TiO2 based nacreous pigments were selected to estimate the photocatalytic activity for NO remove. This study is a good proof that pearlescent pigments can eliminate NO, and its performance is positively correlated with its titanium dioxide content. And this research will widen the application of nacreous pigments in functional building materials, and provide a new way to eliminate in door nitric oxide pollution.

The effective and highly selective aerobic oxidation of sulfides to sulfoxides under green and mild conditions is still an important but challenging process. Here we present a photocatalytic system for sulfide oxidation to sulfoxides with high yields under blue LED irradiation. The photo-oxidation was carried out in water with oxygen over a bismuth-rich catalyst of Bi4O5Br2. The apparent quantum efficiency of sulfide oxidation reached 57.4%. The developed system provided a simple, robust, green and sustainable promising candidate for the practical application of sulfide oxidation.

Photocatalytic hydrogen evolution is an attractive technology to solve the growing energy crisis. The development of advanced photocatalysts is an attractive but challenging issue. For the first time, we use inorganic ReS2 as a co-catalyst for Zn0.3Cd0.7S using a solvent thermal method, which enables highly efficient and recyclable H2 evolution. The Zn0.3Cd0.7S/ReS2 composite photocatalysts contain 4 wt% ReS2 co-catalysts, and Na2S–Na2SO3 is used as the sacrificial reagent. Compared with bare Zn0.3Cd0.7S, Zn0.3Cd0.7S/ReS2 corresponds to 101 fold enhancement with the highest photocatalytic H2 evolution rates of 92.45 mmol h−1 g−1. Furthermore, it still maintains high hydrogen production after a 30 hours cycle experiment. In this paper, the mechanism of photocatalytic enhancement is expounded by various experimental methods. In situ Fourier Transform Infrared (FT-IR) spectra and online mass spectrometry were used to discover the sources of hydrogen. The experimental results show that ReS2 is a promising joint catalyst for obtaining high-gloss catalytic hydrogen from water under visible light.

Multi-tyrosine kinase inhibitors (MTKIs) have thus far had limited success in the treatment of castration-resistant prostate cancer (CRPC). Here, we report a phase I-cleared orally bioavailable MTKI, ESK981, with a novel autophagy inhibitory property that decreased tumor growth in diverse preclinical models of CRPC. The anti-tumor activity of ESK981 was maximized in immunocompetent tumor environments where it upregulated CXCL10 expression through the interferon gamma pathway and promoted functional T cell infiltration, which resulted in enhanced therapeutic response to immune checkpoint blockade. Mechanistically, we identify the lipid kinase PIKfyve as the direct target of ESK981. PIKfyve-knockdown recapitulated ESK981's anti-tumor activity and enhanced the therapeutic benefit of immune checkpoint blockade. Our study reveals that targeting PIKfyve via ESK981 turns tumors from cold into hot through inhibition of autophagy, which may prime the tumor immune microenvironment in advanced prostate cancer patients and be an effective treatment strategy alone or in combination with immunotherapies.

Significance Renal cell carcinomas (RCCs) are heterogeneous malignancies thought to arise from kidney tubular epithelial cells, and clear cell RCC is the most common entity. This study demonstrates that cell atlases generated from benign kidney and two common RCCs using single-cell RNA sequencing can predict putative cells of origin for more than 10 RCC subtypes. A focused analysis of distinct cell-type compartments reveals the potential role of tumor epithelia in promoting immune infiltration and other molecular attributes of the tumor microenvironment. Finally, an observed association between the lack of immunotherapy response and endothelial cell fraction has important clinical implications. The current study, therefore, significantly contributes toward understanding disease ontogenies and the molecular dynamics of tumor epithelia and the microenvironment., Diverse subtypes of renal cell carcinomas (RCCs) display a wide spectrum of histomorphologies, proteogenomic alterations, immune cell infiltration patterns, and clinical behavior. Delineating the cells of origin for different RCC subtypes will provide mechanistic insights into their diverse pathobiology. Here, we employed single-cell RNA sequencing (scRNA-seq) to develop benign and malignant renal cell atlases. Using a random forest model trained on this cell atlas, we predicted the putative cell of origin for more than 10 RCC subtypes. scRNA-seq also revealed several attributes of the tumor microenvironment in the most common subtype of kidney cancer, clear cell RCC (ccRCC). We elucidated an active role for tumor epithelia in promoting immune cell infiltration, potentially explaining why ccRCC responds to immune checkpoint inhibitors, despite having a low neoantigen burden. In addition, we characterized an association between high endothelial cell types and lack of response to immunotherapy in ccRCC. Taken together, these single-cell analyses of benign kidney and RCC provide insight into the putative cell of origin for RCC subtypes and highlight the important role of the tumor microenvironment in influencing ccRCC biology and response to therapy.

Significance RAS proteins (HRAS, NRAS, and KRAS) integrate extracellular trophic signals to promote cell proliferation. Constitutively active KRAS drives tumor initiation and progression in nonsmall cell lung cancer (NSCLC). As RAS proteins are often refractory to direct pharmacological inhibition, RAS-interacting proteins are under investigation as potential drug targets. We previously found Argonaute 2 (AGO2) to bind RAS and positively regulate RAS-dependent signaling pathways. AGO2 knockdown blunted proliferation in NSCLC cells containing a KRAS-activating mutation. Here, we demonstrate that AGO2 promotes tumor progression in multiple mouse models of KRAS-driven NSCLC. In these animals, Ago2 knockout impairs tumor growth, lowers pathologic grade, and inhibits KRAS signaling. Targeting the AGO2-KRAS interaction may hold future therapeutic promise in NSCLC and other KRAS-driven malignancies., Lung cancer is the deadliest malignancy in the United States. Non–small cell lung cancer (NSCLC) accounts for 85% of cases and is frequently driven by activating mutations in the gene encoding the KRAS GTPase (e.g., KRASG12D). Our previous work demonstrated that Argonaute 2 (AGO2)—a component of the RNA-induced silencing complex (RISC)—physically interacts with RAS and promotes its downstream signaling. We therefore hypothesized that AGO2 could promote KRASG12D-dependent NSCLC in vivo. To test the hypothesis, we evaluated the impact of Ago2 knockout in the KPC (LSL-Kras G12D/+;p53f/f;Cre) mouse model of NSCLC. In KPC mice, intratracheal delivery of adenoviral Cre drives lung-specific expression of a stop-floxed KRASG12D allele and biallelic ablation of p53. Simultaneous biallelic ablation of floxed Ago2 inhibited KPC lung nodule growth while reducing proliferative index and improving pathological grade. We next applied the KPHetC model, in which the Clara cell–specific CCSP-driven Cre activates KRASG12D and ablates a single p53 allele. In these mice, Ago2 ablation also reduced tumor size and grade. In both models, Ago2 knockout inhibited ERK phosphorylation (pERK) in tumor cells, indicating impaired KRAS signaling. RNA sequencing (RNA-seq) of KPC nodules and nodule-derived organoids demonstrated impaired canonical KRAS signaling with Ago2 ablation. Strikingly, accumulation of pERK in KPC organoids depended on physical interaction of AGO2 and KRAS. Taken together, our data demonstrate a pathogenic role for AGO2 in KRAS-dependent NSCLC. Given the prevalence of this malignancy and current difficulties in therapeutically targeting KRAS signaling, our work may have future translational relevance.

Photocatalytic CO2 conversion into solar fuels is an effective means for simultaneously solving both the greenhouse effect and energy crisis. In the past ten years, bismuth-based photocatalysts for environmental remediation have experienced a golden period of development. However, solar photocatalytic CO2 conversion has only been developed over the past five years and, until now, no reviews have been published on bismuth-based photocatalysts for the photocatalytic conversion of CO2 . For the first time, solar photocatalytic CO2 conversion systems are reviewed herein. Synthetic methods and photocatalytic CO2 performances of bismuth-based photocatalysts, including Sillen-structured BiOX (X=Cl, Br, I); Aurivillius-structured Bi2 MO6 (M=Mo, W); and Scheelite-structured BiVO4 , Bi2 S3 , BiYO3 , and BiOIO3 , are summarized. In addition, activity-enhancing strategies for this photocatalyst family, including oxygen vacancies, bismuth-rich strategy, facet control, conventional type II heterojunction, Z-scheme heterojunction, and cocatalyst deposition, are reviewed. Finally, the main mechanistic research methods, such as in situ FTIR spectroscopy and theoretical calculations, are presented. Challenges and research trends reported in studies of bismuth-based photocatalysts for photocatalytic CO2 conversion are discussed and summarized.

Nickel element cannot exist stably on its own, but with an bared of an NiO shell, nickel element can realize desirable stable existence. Herein, Ni2+ was photoreduced to Ni particles and deposited on graphite carbon nitride (g-C3N4) under vacuum. The surface of Ni particles was oxidized to form an NiO shell after the samples were exposed to air, and elemental Ni was protected by the encapsulation of the NiO shell to realize the coexistence of Ni and NiO. The chainmail co-catalyst of NiO shell-encapsulated Ni over g-C3N4 (Ni/NiO/g-C3N4) was prepared and applied in the photocatalytic reduction of CO2 and showed the best photocatalytic activity when the Ni/NiO loading was 3 wt%. After illumination for 2 h, the CO generation rate reached a value of 27.9 μmol g−1 h−1, which was about nine times that of pure g-C3N4. The steady-state surface photovoltage spectrum (SPV), ultrafast spectrum of transient photovoltage (TPV) and time-resolved photoluminescence (PL) spectra as well as electrochemical tests showed that Ni/NiO/g-C3N4 has a low recombination rate of photogenerated electron–hole pairs. In situ Fourier transform infrared spectroscopy (FT-IR) and DFT calculations were used to explain the photocatalytic mechanism at the molecular level.

Photocatalytic conversion of CO2 to solar fuels is considered an alternative approach for simultaneously mitigating the greenhouse effect and solving energy shortage. The efficient light harvesting and the thermochemical conversion have been demanding quests in photocatalysis due to the relatively low solar energy utilization efficiency. In this work, oxygen vacancies are induced in MoO3 for improving photo-thermal CO2 reduction efficiency by capturing near-infrared (NIR) photons. The localized surface plasmon resonance (LSPR) of MoO3−x triggered by oxygen vacancies enables the efficient capture of NIR photons. Additionally, oxygen vacancies can promote the carrier separation, improve CO2 adsorption on the defective surface and lower the barrier of CO2 hydrogenation during the conversion process. As a result, MoO3−x displayed dramatically enhanced photo-thermal synergistic CO2 reduction under simulated sunlight (UV-Vis-IR) irradiation than MoO3. The amount of CO produced by MoO3−x can reach 10.3 μmol g−1 h−1, which is 20 times higher than that of MoO3 (0.52 μmol g−1 h−1). And the CH4 production of MoO3−x can reach 2.08 μmol g−1 h−1, which is 52 times higher than that of MoO3 (0.04 μmol g−1 h−1). In situ FT-IR and theoretical calculations also proved the enhanced activity of MoO3−x. This work highlights the significance of defect engineering for improving the photo-thermal catalytic conversion of CO2.

In mammalian cells, DNA is wrapped around histone octamers (collectively referred to as nucleosomes) which form a physical barrier to all DNA-based processes. The switch/sucrose non-fermentable (SWI/SNF) is a multi-subunit chromatin remodeling complex that uses energy from ATP hydrolysis to reposition or eject nucleosomes at non-coding regulatory elements, thereby enabling access to the underlying DNA for transcriptional activation. Notably, the SWI/SNF complex plays a crucial role in chromatin remodeling and is recurrently altered in over 20% of human cancers, with the revised complex in cancer cells enabling central oncogenic gene programs. Yet, no studies have assessed the therapeutic efficacy of complete SWI/SNF inactivation across human cancers. Here, we developed a proteolysis targeting chimera (PROTAC) degrader of ATPase subunits of the SWI/SNF complex, SMARCA2 and SMARCA4. In a panel with over 90 normal and cancer cell lines from 18 different lineages, we found MYC-driven multiple myeloma and androgen receptor (AR)/forkhead box A1 (FOXA1)-positive prostate and breast cancers to be preferentially sensitive to dual SMARCA2 and SMARCA4 degradation relative to benign prostate as well as other cancer cell lines, including cancer cell lines with inactivating SMARCA4 mutations. We found complete SWI/SNF ATPase degradation to instantaneously compact the cis-regulatory elements that are bound and activated by transcription factors that drive cancer proliferation, namely MYC, IRF4, TCF3, AR, FOXA1, and ERG. This ensued in parallel untethering of these oncogenic drivers from the chromatin, with subsequent chemical decommissioning of their core enhancer circuitry and attenuation of downstream gene programs. Furthermore, using chromatin conformation assays we found SWI/SNF inactivation to disrupt super-enhancer and promoter DNA looping interactions that wire supra-physiologic expression of the MYC, AR, ERG, IRF4, and TCF3 oncogenes themselves, thereby tempering their expression in cancer cells. Treatment with the SMARCA2/4 degrader alone induced potent inhibition of tumor growth in cell line-derived xenograft models of multiple myeloma, as well as prostate cancer, and synergized with AR antagonists, inducing disease remission in several drug-resistant disease models. Notably, no major toxicities were seen in mice upon prolonged treatment with the SMARCA2/4 degrader, including no indications of thrombocytopenia, gastrointestinal goblet cell depletion, or germ cell degeneration—all being major toxicities associated with the BRD4-targeting therapeutics. To our knowledge, this study is the first preclinical proof of concept that targeted obstruction of chromatin accessibility at non-coding regulatory elements can be a potent therapeutic strategy in enhancer-addicted tumors, warranting the safety and efficacy assessments of SWI/SNF inhibitors and degraders in human clinical trials. Citation Format: Abhijit Parolia, Lanbo Xiao, Yuanyuan Qiao, Pushpinder Bawa, Sanjana Eyunni, Eleanor Young, Rahul Mannan, Sandra E. Carson, Yu Chang, Yuping Zhang, James George, Mustapha Jaber, Fengyun Su, Rui Wang, Sanjita Sasmal, Leena Khare, Subhendu Mukerjee, Chandrasekhar AbbinenI, Kiran Aithal, Xuhong Cao, Yuzhuo Wang, Susanta Samajdar, Murali Ramachandra, Arul M. Chinnaiyan. Targeting SWI/SNF ATPases in enhancer-addicted human cancers [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 3592.