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Microbial biostimulants can promote ornamental plant growth during production and improve crop performance under abiotic stresses. Even though biostimulants have shown potential in many agricultural applications, the effectiveness and specificity of many products are not well understood. The objective of this study was to analyze the growth-promoting effects of microbial biostimulants during the greenhouse production of floriculture crops. We evaluated 13 biostimulant products in greenhouse-grown zinnia (Zinnia elegans ‘Magellan Ivory’) and petunia (Petunia ×hybrida ‘Carpet White’) at low fertility (one-third of the optimal fertilizer concentration). Biostimulant products 1 and 2 containing multiple species of beneficial bacteria and fungi, and product 10 containing Bacillus subtilis QST 713, were found to increase various aspects of plant growth, including the growth index, leaf chlorophyll content (SPAD index), and shoot biomass. Both flower biomass and numbers were greater in petunia treated with product 1, and leaf size increased in zinnia treated with products 1, 2, and 10. Plants treated with these effective biostimulants at low fertility had similar or better growth and quality than untreated plants grown under optimal fertility. The concentration of various nutrient elements in leaves was higher in zinnia plants treated with biostimulant products 1, 2, or 10 compared with the negative control. Some putative mechanisms for biostimulant effectiveness, the possible reasons for biostimulant ineffectiveness, and the potential for using biostimulants as a sustainable cultural strategy are discussed. This study provides useful information about microbial biostimulant effectiveness, which is important for the development and utilization of biostimulants in the greenhouse production of floriculture plants.

Ductal-carcinoma-in-situ (DCIS) is the most common early-stage breast cancer and a non-obligate precursor to invasive breast cancer. However our understanding of the spatial microenvironment and the reprogramming of cell types in DCIS remains limited. To address this question, we developed a Spatial Nucleus Barcoding (SNuBar) method that utilizes a single oligonucleotide adaptor to preserve spatial information followed by performing single nucleus RNA sequencing. We validated the accuracy and scalability of SNuBar in cell lines and applied this method to investigate the spatial microenvironment of 4 normal breast tissues, 7 normal adjacent DCIS tissues, and 8 DCIS cancers. The analysis of single cells isolated from 596 macrodissected spatial regions identified 13 major cell types and 43 cell states, that co-localized in different combinations across four main topographic areas. Spatial analysis revealed that vascular and myoepithelial cells were reprogrammed in localized zones near the premalignant cells, while fibroblasts, T-cells and myeloid cells were reprogrammed across broader fields. Our data shows that many diverse cell types are reprogrammed in spatially-defined areas in the DCIS microenvironment, relative to the normal breast tissue regions. Citation Format: Kaile Wang, Zhenna Xiao, Yiyun Lin, Runmin Wei, Jie Ye, Rui Ye, Min Hu, Shanshan Bai, Emi Sei, Aatish Thennavan, Bora Lim, Andrew Futreal, Alastair Thompson, Savitri Krishnamurthy, Nicholas Navin. Reprogramming of the preinvasive breast microenvironment identified by spatial nucleus barcoding [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 76.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks the expression of estrogen receptor (ER), progesterone receptor (PR) and HER2 and therefore have limited hormonal treatment options. Neoadjuvant chemotherapy (NAC) is backbone of treatment for TNBC, and about 50% of patients respond well leading to pathological complete response (pCR). However, the remaining patients develop resistance to NAC and progress to metastatic disease and poor survival in 1-2 years after the initial treatment. Previous studies have performed bulk RNA expression profiling of TNBC patients and identified 5-6 subgroups of patients, however these studies could not resolve expression programs at single cell resolution to distinguish between the tumor cells and different components of the tumor microenvironment (TME). Here we performed scRNA-seq of pre-treatment fresh core biopsy tissue samples from TNBC patients in the ARTEMIS clinical trial and compared these data between pCR and non-pCR patients to identify programs associated with response to NAC. We also compared these data to scRNA-seq data from patients with disease-free breast tissue to understand the basic biology of TNBC and identify cell types that are reprogrammed in malignant disease. Using the single cell tumor cell data, we identified 4 archetypes of TNBC which represent patient-level intertumor expression programs: luminal secretory-like (LS), basal/luminal-like (BL), immunoregulatory (IM), and luminal androgen receptor (LAR). Notably, the archetype BL was associated with non-pCR, while IM was associated with pCR. We further identified 13 metatraits, which are unique intratumoral expression programs that are shared across patients. Across the cancer cells, we identified 13 metatraits such as cell cycling, stress, hypoxia, interferon response, HLA, partial epithelial-mesenchymal transition, and endoplasmic reticulum stress, many of which corresponded to NAC response. In the immune compartment, we found 15 myeloid cell states, 14 T/NK cell states, and 6 B cell states, several of which corresponded to pCR/non-pCR. Similarly, in the stromal compartment, there were 4 fibroblast cell states, 4 pericyte cell states, and 7 endothelial cell subtypes, of which several cell states were associated with NAC response. Overall, these data report the natural biology of TNBC patients and malignant cell states that are reprogrammed in malignant disease, as well as their correspondence to NAC response, providing new data to predict which TNBC patients are likely to respond to chemotherapy. Citation Format: Tapsi Kumar, Yiyun Lin, Yun Yan, Shanshan Bai, Jianzhuo Li, Tuan Tran, Min Hu, Elizabeth Ravenberg, Maia Rauch, Alyson Clayborn, Alastair Thompson, Lei Huo, Stacy Moulder, Clinton Yam, Nicholas Navin. Decoding the natural biology of triple-negative breast cancer and response to chemotherapy by single-cell transcriptomics [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 2147.

Single-cell transcriptomic analysis is widely used to study human tumors. However, it remains challenging to distinguish normal cell types in the tumor microenvironment from malignant cells and to resolve clonal substructure within the tumor. To address these challenges, we developed an integrative Bayesian segmentation approach called copy number karyotyping of aneuploid tumors (CopyKAT) to estimate genomic copy number profiles at an average genomic resolution of 5 Mb from read depth in high-throughput single-cell RNA sequencing (scRNA-seq) data. We applied CopyKAT to analyze 46,501 single cells from 21 tumors, including triple-negative breast cancer, pancreatic ductal adenocarcinoma, anaplastic thyroid cancer, invasive ductal carcinoma and glioblastoma, to accurately (98%) distinguish cancer cells from normal cell types. In three breast tumors, CopyKAT resolved clonal subpopulations that differed in the expression of cancer genes, such as KRAS, and signatures, including epithelial-to-mesenchymal transition, DNA repair, apoptosis and hypoxia. These data show that CopyKAT can aid in the analysis of scRNA-seq data in a variety of solid human tumors. Clonal subpopulations in human tumors are identified from single-cell RNA-seq data.

Graphical abstract, Highlights • Early recognition of chronic pancreatitis (CP) is still lacking. In the setting of CP injury, activated pancreatic stellate cell (PSC) is the central mediator of pancreatic fibrosis. We systematically define highly and uniquely expressed PSC genes and show that these genes are enriched in pancreatic diseases. • Unresolved or recurrent injury causes dysregulation of biological process following AP, which would cause CP. We demonstrated subset genes that may be associated with the progression from AP to CP. Furthermore, SPARC was identified as a candidate marker for the disease progression. • Increased expression of SPARC and canonical PSC genes were verified during AP recovery, especially in recurrent AP mice models., Chronic pancreatitis (CP) is characterized by irreversible fibro-inflammatory changes induced by pancreatic stellate cell (PSC). Unresolved or recurrent injury causes dysregulation of biological process following AP, which would cause CP. Here, we systematically identify genes whose expressions are unique to PSC by comparing transcriptome profiles among total pancreas, pancreatic stellate, acinar, islet and immune cells. We then identified candidate genes and correlated them with the pancreatic disease continuum by performing intersection analysis among total PSC and activated PSC genes, and genes persistently differentially expressed during acute pancreatitis (AP) recovery. Last, we examined the association between candidate genes and AP, and substantiated their potential as biomarkers in experimental AP and recurrent AP (RAP) models. A total of 68 genes were identified as highly and uniquely expressed in PSC. The PSC signatures were highly enriched with extracellular matrix remodeling genes and were significantly enriched in AP pancreas compared to healthy control tissues. Among PSC signature genes that comprised a fibrotic phenotype, 10 were persistently differentially expressed during AP recovery. SPARC was determined as a candidate marker for the pancreatic disease continuum, which was not only persistently differentially expressed even five days after AP injury, but also highly expressed in two clinical datasets of CP. Sparc was also validated as highly elevated in RAP compared to AP mice. This work highlights the unique transcriptional profiles of PSC. These PSC signatures’ expression may help to identify patients with high risk of AP progression to CP.

Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.

Single-cell sequencing (SCS) has impacted many areas of cancer research and improved our understanding of intratumor heterogeneity, the tumor microenvironment, metastasis, and therapeutic resistance. The development and refinement of SCS technologies has led to massive reductions in costs, increased cell throughput, and improved reproducibility, paving the way for clinical applications. However, before translational applications can be realized, there are a number of logistical and technical challenges that must be overcome. This review discusses past cancer research studies, emerging technologies, and future clinical applications that are bound to transform cancer medicine.

Developmental petal senescence is a type of programmed cell death (PCD), during which the production of ethylene is induced, the expression of PCD-related genes is upregulated, and nutrients are recycled. Autophagy is an intracellular mechanism involved in PCD modulation and nutrient cycling. As a central component of the autophagy pathway

Lipid metabolic alterations are associated with cancer progression. Lysine-specific demethylase 1 (LSD1) plays a crucial role in cancer and has become a promising target for cancer therapy. However, the effect of LSD1 on lipid metabolism remains unclear. In the present study, we used a LC-MS/MS-based lipidomics approach to investigate the impact of LSD1 on cancer cell lipid metabolism using ZY0511, a specific LSD1 inhibitor developed by our group as a specific probe. ZY0511 profoundly modified the human colorectal and cervical cancer cell lipid metabolism. A total of 256 differential metabolites were identified in HeLa cells, and 218 differential metabolites were identified in HCT116 cells, respectively. Among these lipid metabolites, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine and sphingomyelin (SM) were downregulated by ZY0511. In contrast, ceramide (Cer) and a small portion of glycerophospholipids such as phosphatidylinositol and phosphatidylethanolamine were upregulated by ZY0511. These results revealed a disturbance in sphingolipids (SPs) and glycerophospholipids, which may be correlated with the progression of cancer. Furthermore, a marked increase in Cer and prominent decrease in SM were consistent with the upregulated expression of key enzymes in the Cer synthesis process including de novo synthesis, hydrolysis of SM and the salvage pathway after ZY0511 exposure. In conclusion, our research reveals a link between LSD1 and lipid metabolism in cancer cells, offering more comprehensive evidence for the application of LSD1 inhibitors for cancer therapy. The underlying mechanisms of how the LSD1 inhibitor regulates lipid metabolism warrant further investigation.

Lysine-specific demethylase1 (LSD1) plays a crucial role in cancer and has become a promising target for cancer therapy. However, the mechanism underlying the role of LSD1 in oncogenesis is poorly understood, and more effective LSD1 inhibitors are needed. Here we report the biological activity of a novel LSD1 inhibitor named ZY0511. ZY0511 specifically inhibited LSD1 activity and the proliferation of various human cancer cells especially the HeLa and HCT116 cells. ZY0511 significantly increased the expression of DDIT4, a known mTORC1 suppressor, which was a direct downstream target of LSD1 confirmed by ChIP-PCR. ZY0511-induced LSD1 inhibition upregulated the expression of DDIT4 by altering histone H3K4 methylation levels at its promoter, thus suppressing mTORC1 activity. Knockdown of DDIT4 attenuated the anticancer effect of ZY0511. Intraperitoneal administration of ZY0511 significantly prevented the growth of HCT116 and HeLa xenografts in mice and showed no detectable toxicity. Moreover, DDIT4 expression was correlated with the sensitivity of human cancer cells to chemotherapy. Taken together, ZY0511 showed therapeutic potential for solid tumors, the induction of DDIT4 may be used as a predictive biomarker of LSD1 inhibitors.

Deficiency of MTAP (MTAPdef) mainly occurs because of homozygous loss of chromosome 9p21, which is the most common copy-number loss in metastatic urothelial cancer (mUC). We characterized the clinical and genomic features of MTAPdef mUC in 193 patients treated at MD Anderson Cancer Center (MDACC) and 298 patients from the phase 2 IMvigor210 trial, which investigated atezolizumab in cisplatin-ineligible and platinum-refractory disease. In the MDACC cohort, visceral metastases were significantly more common for MTAPdef (n = 48) than for MTAP-proficient (MTAPprof; n = 145) patients (75% vs 55.2%; p = 0.02). MTAPdef was associated with poor prognosis (median overall survival [mOS] 12.3 vs 20.2 mo; p = 0.007) with an adjusted hazard ratio of 1.93 (95% confidence interval 1.35-2.98). Similarly, IMvigor210 patients with MTAPlo (n = 29) had a higher incidence of visceral metastases than those with MTAPhi tumors (n = 269; 86.2% vs 72.5%; p = 0.021) and worse prognosis (mOS 8.0 vs 11.3 mo; p = 0.042). Hyperplasia-associated genes were more frequently mutated in MTAPdef tumors (FGFR3: 31% vs 8%; PI3KCA: 31% vs 19%), while alterations in dysplasia-associated genes were less common in MTAPdef tumors (TP53: 41% vs 67%; RB1: 0% vs 16%). Our findings support a distinct biology in MTAPdef mUC that is associated with early visceral disease and worse prognosis. PATIENT SUMMARY: We investigated the outcomes for patients with the most common gene loss (MTAP gene) in metastatic cancer of the urinary tract. We found that this loss correlates with worse prognosis and a higher risk of metastasis in internal organs. There seems to be distinct tumor biology for urinary tract cancer with MTAP gene loss and this could be a potential target for treatment.

The upregulation of endonuclease activities and subsequent decreases in the nucleic acid content of leaves and petals are characteristics of senescence that allow for nutrient remobilization from dying organs. We previously identified a 43-kDa endonuclease activity (PhNUC1) that was upregulated in Petunia × hybrida petals during senescence. PhNUC1 has optimal activity at neutral pH, is enhanced by Co2+, and degrades both DNA and RNA. The peptide sequence of a 43-kDa endonuclease identified from senescing petals by 2-dimensional gel electrophoresis was used to clone the gene (PhENDO1) encoding the senescence-associated protein. PhENDO1 expression was upregulated in petals during the senescence of unpollinated and pollinated flowers and by ethylene treatment. When petunias were grown under nutrient deficient conditions, P-starvation, and to a lesser extent N-starvation, induced expression of PhENDO1. The endogenous expression of PhENDO1 was down regulated using virus induced gene silencing (VIGS), and in-gel endonuclease assays confirmed that the activity of the 43-kDa PhNUC1 was decreased in senescing corollas from PhENDO1-silenced (pTRV2:PhCHS:PhENDO1) plants compared to controls (pTRV2:PhCHS). Down regulating PhENDO1 in petunias did not alter flower longevity. While PhENDO1 may be involved in nucleic acid catabolism during senescence, down regulating this gene using VIGS was not sufficient to delay flower senescence.

Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates cytosolic receptors activating caspase-1 which cleaves pro-IL-18 into mature IL-18, leading to recruitment of interferon (IFN)-γ-secreting T cells and intestinal inflammation. Correspondingly, patients with germline telomere maintenance defects exhibit DNA damage (γH2AX) signaling together with elevated YAP1 and IL-18 expression. In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or pharmacological inhibition of ATM, YAP1, or caspase-1 as well as antibiotic treatment, dramatically reduces IL-18 and intestinal inflammation. Thus, telomere dysfunction-induced activation of the ATM-YAP1-pro-IL-18 pathway in epithelium is a key instigator of tissue inflammation., How telomere dysfunction is directly linked to inflammation in humans is currently unclear. Here the authors reveal that telomere dysfunction drives activation of the YAP1 transcription factor, up-regulating the pro inflammatory factor, pro-IL-18 thus revealing a link between telomere dysfunction and initiation of intestinal inflammation.

Lipids are predominant components of the brain and key regulators for neural structure and function. The neuropsychopharmacological effect of cocaine has been intensively investigated; however, the impact of cocaine on brain lipid profiles is largely unknown. In this study, we used a LC-MS-based lipidomic approach to investigate the impact of cocaine on brain lipidome in two mouse models, cocaine-conditioned place preference (CPP) and hyperlocomotor models and the lipidome was profoundly modified in the nucleus accumbens (NAc) and striatum respectively. We comprehensively analyzed the lipids among 21 subclasses across 7 lipid classes and found that cocaine profoundly modified brain lipidome. Notably, the lipid metabolites significantly modified were sphingolipids and glycerophospholipids in the NAc, showing a decrease in ceramide and an increase in its up/downstream metabolites levels, and decrease lysophosphatidylcholine (LPC) and lysophosphoethanolamine (LPE) and increase phosphatidylcholine (PC) and phosphatidylethanolamines (PE) levels, respectively. Moreover, long and polyunsaturated fatty acid phospholipids were also markedly increased in the NAc. Our results show that cocaine can markedly modify brain lipidomic profiling. These findings reveal a link between the modified lipidome and psychopharmacological effect of cocaine, providing a new insight into the mechanism of cocaine addiction.

Lung metastasis is an important cause for the low 5-year survival rate of colorectal cancer patients. Understanding the metabolic profile of lung metastasis of colorectal cancer is important for developing molecular diagnostic and therapeutic approaches. We carried out the metabonomic profiling of lung tissue samples on a mouse lung metastasis model of colorectal cancer using 1H-nuclear magnetic resonance (1H-NMR). The lung tissues of mice were collected at different intervals after marine colon cancer cell line CT-26 was intravenously injected into BALB/c mice. The distinguishing metabolites of lung tissue were investigated using 1H-NMR-based metabonomic assay, which is a highly sensitive and non-destructive method for biomarker identification. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were applied to analyze 1H-NMR profiling data to seek potential biomarkers. All of the 3 analyses achieved excellent separations between the normal and metastasis groups. A total of 42 metabolites were identified, ~12 of which were closely correlated with the process of metastasis from colon to lung. These altered metabolites indicated the disturbance of metabolism in metastatic tumors including glycolysis, TCA cycle, glutaminolysis, choline metabolism and serine biosynthesis. Our findings firstly identified the distinguishing metabolites in mouse colorectal cancer lung metastasis models, and indicated that the metabolite disturbance may be associated with the progression of lung metastasis from colon cancer. The altered metabolites may be potential biomarkers that provide a promising molecular approach for clinical diagnosis and mechanistic study of colorectal cancer with lung metastasis.

Lipids are predominant components of the brain and key regulators for neural structure and function. The effect of methamphetamine (METH) on behavior, cognition as well as memory has been intensively investigated; however, the impact of METH on brain lipid profiles is largely unknown. Here, we used a global lipidomic approach to investigate brain lipidome of METH-sensitized mice. We found that repeated METH significantly modified the lipidome in the hippocampus, prefrontal cortex (PFC) and striatum. Interestingly, nucleus accumbens showed no obvious alteration in lipidomic profiling. Phospholipid and sphingolipid metabolisms were profoundly modified in the hippocampus of METH-sensitized mice, exhibiting increased phosphatidic acid and ether phosphatidylcholine but decreased lysophosphatidylethanolamine, lactosylceramide and triglycerides. The fatty acyl length of phospholipids and diacylglycerol longer than 40 carbon were clearly decreased in the hippocampus, and that 36 carbon was decreased in the PFC. These results indicate METH can profoundly affect the metabolism of phospholipids, sphingolipids and glycerolipids in the brain. Our findings reveal a link between remodeled brain lipidome and neurobehavior induced by METH.

Pollens from two different types of oil palm, Pisifera and Dura, were used to study the influence of different medium components and temperature on oil palm pollen germination. The results of our study revealed that Murashige and Skoog (MS) and sucrose (0.05% MS + 0.01 g/mL sucrose) played a catalytic role in oil palm pollen germination and pollen tube growth. The catalytic effect could be reversed when the contents of the medium were used at higher concentrations. Besides the nutrients, temperature has also played a vital role in vitro germination of oil palm pollen. The recorded optimum temperature and time for the germination was at 31 °C for 3 h. A fluctuation in time and temperature has inhibited the germination rate, as well as the growth of the pollen tube to a certain level. Thus, we have concluded from this study that a proper combination of culture medium and temperature could enhance the in vitro germination of oil palm pollen. These results will be helpful in preparing pollens for oil palm pollination.

Metabolic interaction between cancer-associated fibroblasts (CAFs) and colorectal cancer (CRC) cells plays a major role in CRC progression. However, little is known about lipid alternations in CAFs and how these metabolic reprogramming affect CRC cells metastasis. Here, we uncover CAFs conditioned medium (CM) promote the migration of CRC cells compared with normal fibroblasts CM. CAFs undergo a lipidomic reprogramming, and accumulate more fatty acids and phospholipids. CAFs CM after protein deprivation still increase the CRC cells migration, which suggests small molecular metabolites in CAFs CM are responsible for CRC cells migration. Then, we confirm that CRC cells take up the lipids metabolites that are secreted from CAFs. Fatty acids synthase (FASN), a crucial enzyme in fatty acids synthesis, is significantly increased in CAFs. CAF-induced CRC cell migration is abolished by knockdown of FASN by siRNA or reducing the uptake of fatty acids by CRC cells by sulfo-N-succinimidyloleate sodium in vitro and CD36 monoclonal antibody in vivo. To conclude, our results provide a new insight into the mechanism of CRC metastasis and suggest FASN of CAFs or CD36 of CRC cells may be potential targets for anti-metastasis treatment in the future.

Petal senescence is a form of developmental programmed cell death (PCD) that is regulated by internal and environmental signals. Autophagy, a metabolic pathway that regulates intercellular nutrient recycling, is thought to play an important role in the regulation of petal senescence-associated PCD. To characterize the function of two central autophagy genes in petal senescence, we down-regulated Autophagy Gene 6 (PhATG6) and Phosphoinositide 3-Kinase (PhPI3K) using Virus-Induced Gene Silencing (VIGS) in Petunia × hybrida. The silencing of PhATG6 and PhPI3K accelerated petal senescence, thereby reducing flower longevity. Both PhATG6- and PhPI3K-silenced petunias had reduced flower numbers, flower biomass, and vegetative shoot biomass. These phenotypes were intensified when plants were grown under low nutrient conditions. Additionally, two important regulators of senescence, an ethylene biosynthesis gene (PhACS) and a type I metacaspase gene (PhMC1), were suppressed in senescing petals of PhATG6- and PhPI3K-silenced plants. In conclusion, our study identified PhATG6 and PhPI3K as negative regulators of flower senescence and demonstrated the influence of nutrient limitation on the function of autophagy during petal senescence. Our study also found that autophagy genes potentially influence the transcriptional regulation of metacaspases and ethylene biosynthetic genes during petal senescence. The results of this project will be fundamental for future studies of petal senescence and will provide genetic information for future crop improvement.

High-throughput single cell transcriptomics analysis is widely used to study human tumors, however a major challenge is distinguishing the stromal cells from the malignant cancer cells, as well as clonal substructure within tumors. To address this challenge, we developed an integrative Bayesian segmentation approach, COPYKAT to estimate genomic copy numbers at 5MB resolution from high-throughput single cell RNA-seq data. We applied COPYKAT to 39,709 single cells from 16 tumors across 4 cancer types, including premalignant and triple-negative breast cancers, pancreatic ductal adenocarcinomas, and anaplastic thyroid cancer. From these data we could accurately (98%) classify tumor cells from stromal cells. In three TNBC tumors COPYKAT resolved multiple clonal subpopulations of genotypes that differed in expression of breast cancer genes and enrichment of cancer hallmarks including EMT and hypoxia. These data show that COPYKAT can accurately resolve clonal copy number substructure in tumors and classify tumor and normal cells in a variety of human cancers. Citation Format: Ruli Gao, Shanshan Bai, Henderson Ying, Yiyun Lin, Tapsi Seth, Min Hu, Emi Sei, Alexander Davis, Fang Wang, Jennifer Rui Wang, Ken Chen, Stacey Moulder, Stephen Lai, Nicholas Navin. Inferring copy number substructure from single-cell transcriptomics in human tumors with CopyKat [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-020.

The DNA mismatch repair (MMR) system plays an important role in the initiation, diagnosis and treatments of colorectal cancer (CRC). Compared to CRC patients deficient in DNA MMR (dMMR), CRC patients proficient in DNA MMR (pMMR) have higher metastasis, short survival and poor response to chemotherapy and immunotherapy. It is well‑known that a high‑fat diet can cause CRC, and lipid metabolism is closely related to the development and metastasis of CRC. However, there have been few studies that address the difference in lipid metabolism between dMMR and pMMR CRC. Liquid chromatography‑tandem mass spectrometry (LC/MS) is an advanced technique that can perform the analysis of lipid metabolites and the roles of lipids present in low abundance in cell signaling and membrane stability. In the present study, we used the LC/MS technique to analyze the difference in the lipid metabolic profiles between dMMR cell lines (HCT116, DLD1, LoVo and HCT15) and pMMR cell lines (SW480, SW620, HT29 and NCM460). The results revealed that, among the 19 classes and 157 intact lipid species identified by the LC/MS analysis, the levels of most phospholipids were lower in dMMR cells than pMMR cells. Higher levels of phosphatidylcholine (PC; 16:0/18:1) and phosphatidic acid (PA; 18:0/18:0) were observed in pMMR cells than in dMMR cells. Furthermore, our results revealed that SCD1 and PLD1, the key enzymes involved in lipid metabolism associated with metastasis, are higher in pMMR cells than dMMR cells. To the best of our knowledge, we are the first to reveal that the levels of metastasis‑associated lipids and key enzymes in lipid metabolism were higher in the CRC patients with pMMR compared with the CRC patients with dMMR. This study identified potential anti‑metastatic targets in the therapy of patients with pMMR, and also personalized therapy for the patients with pMMR.

Background: Functional tricuspid regurgitation (FTR) is frequent in patients with mitral valve disease. Untreated tricuspid regurgitation (TR) may cause poor clinical outcomes. The surgical factors involved in annuloplasty for FTR remain controversial. Our objective was to compare effectiveness of different tricuspid annuloplasty (TVP), and reveal the risk factors of recurrence. Methods: We analyzed the clinical details of 399 consecutive patients who underwent mitral surgery with concomitant TVP, from 2006 to 2011, in two Chinese single-centers. Three methods were used for TVP: De Vega surgery was completed in 242 patients; annuloplasty using a flexible band was completed in 98 patients; and surgery with a rigid ring was performed in 59 patients. Results: The operative mortality rate was 2.3%. After surgery, the TR grade of all patients decreased significantly. At three years postoperatively, 13.7% of patients were diagnosed with recurrent FTR. At the three year time point, severe TR in the De Vega group was 18%, which was higher than those in the flexible (8.4%) and rigid planner ring groups (5.2%). During follow-up, the recurrent rates in the rigid group were significantly lower than in the flexible group. Multivariate analysis revealed that pre-operative atrial fibrillation, severe TR, large left atrial, ejection fraction (EF)

Prosthesis-patient mismatch (PPM) is defined as a too-small effective orifice area (EOA) of an inserted prosthetic relative to body size, resulting in an abnormally high postoperative gradient. It is unclear, however, whether residual stenosis after aortic valve replacement (AVR) has a negative impact on mid- and long-term survivals. We searched electronic databases, including PubMed, Embase, Medline and the Cochrane controlled trials register, through October 2012, to identify published full-text English studies on the association between PPM and mortality rates. A significant PPM was defined as an indexed EOA (iEOA)

Background: Children with infective endocarditis (IE) have to undergo valve replacement instead of valve repair in China due to severe valve damage. The present study is to review our experience on surgical treatment of children with IE in reference to the incidence, pathologic status, diagnosis, surgical strategies and outcomes. Methods: We reviewed 35 patients with a mean age of 13.7±2.2 years who were underwent valve replacement surgery for IE during the period from January 1993 to December 2013. Preoperative transthoracic echocardiographic (TTE) evaluation and transesophageal echocardiography during operation were performed in all patients. All the children underwent chart review and retrospective risk-hazard analysis. Results: Among the patients surveyed congenital cardiac lesions were present in 15 (42.8%), rheumatic heart valve disease in 2 (5.7%) and previous heart surgery in 2 (5.7%). The median stay of intensive care unit was 6 days. Intraoperative findings showed that the endocarditis involved mostly the mitral and aortic valves (88.5%). Triple or quadruple valve involvement was found in one patient each. Ten-year freedom from IE-related death and re-intervention was 94.2% and 91.6%, respectively. Conclusions: Children undergoing surgery for IE frequently have advanced disease with embolic complications. Although valve replacement is not the primary option for pediatric IE, the rate of 5-year survival and freedom from re-operation was optimal prognostically. Pediatric physicians should pay attention to the common clinical features of IE so that the native valve is preserved well.

Background: The aim of this study is to determine the risk factors of delirium after cardiac surgery. Methods: A systematic literature search of MEDLINE, EMBASE, the Cochrane Library, and Science Citation Index limited to 2008 to 2011 and review of studies was conducted. Eligible studies were of randomized controlled trials or cohort studies, using delirium assessment tool, reporting at least one risk factor associated with delirium, and available to full text. Results: The search identified 106 potentially relevant publications; only 25 met selection criteria. Our systematic review revealed 33 risk factors: 17 predisposing and 16 precipitating factors for delirium after elective cardiac surgery. The most established predisposing risk factors were age, depression, and history of stroke, cognitive impairment, diabetes mellitus, and atrial fibrillation. The most established precipitating risk factors were duration of surgery, prolonged intubation, surgery type, red blood cell transfusion, elevation of inflammatory markers and plasma cortisol level, and postoperative complications. Moreover, sedation with dexmedetomidine may significantly predict the absence of postoperative delirium. Conclusions: Postoperative delirium is related to several risk factors following cardiac surgery. Sedation with dexmedetomidine and fast-track weaning protocols may decrease the incidence of delirium in cardiac surgical patients. (J Card Surg 2012;27:481-492)

Aims Currently, myxoma is the most common type of primary cardiac tumor diagnosed. This article describes the experience over the past 16 years with cases of cardiac myxoma in Chinese patients and elucidated the differences between solid and papillary myxomas. Methods The clinical details of 68 patients with cardiac myxomas who underwent surgery between January 1996 and January 2012 at our center were retrospectively analyzed. Results The left atrium was the primary tumor site in 88% of the patients included in this study. The most common implant site was the interatrial septum (69%), especially for patients with solid tumors. Common clinical symptoms included dyspnea and palpitation, whereas embolic events occurred in 12 patients. Myxoma resection involved a midline sternotomy utilizing cardiopulmonary bypass. According to pathological classification, solid myxomas were present in 28 patients (47%), whereas papillary myxomas were detected in 40 patients (53%). In the solid group, arrhythmias and a larger tumor volume were more common. Correspondingly, in 97.4 ± 2.5% of cases, secondary surgery was not needed after 10 years. Overall, the actuarial survival for patients undergoing surgical excision of myxoma was 98.4 ± 1.6% at 5 years and 96.0 ± 2.8% at 10 years. Conclusion Solid myxomas were associated with more arrhythmias, a larger tumor volume, implantation in the interatrial septum, and a need for concomitant surgery compared with papillary myxomas. Further studies should determine whether serum or histological markers could be routinely used in combination with echocardiograms, MRI and computed tomography for the predictions of recurrent myxomas during annual follow-up examinations.

Background Constrictive pericarditis is a rare and disabling disease that can result in chronic fibrous thickening of the pericardium. Prompt treatment of constrictive pericarditis is necessary to limit morbidity and mortality. Methods We analyzed the clinical details of 51 constrictive pericarditis patients who underwent surgery from January 2005 to December 2010 at our center. Results Of the patients, 33 (65%) had tuberculous constrictive pericarditis, 13 (25%) had idiopathic pericarditis, 3 (6%) had previous cardiac surgery, and 1 (2%) had connective tissue disease. All patients underwent total pericardiectomy by midline sternotomy. The in-hospital mortality rate was 3.9% (2 of 51 patients). The cause of death was severe low cardiac output syndrome in 1 patient and acute renal failure in the other patient. There were 2 cases of recurrent constrictive pericarditis after discharge. The actuarial 1-year survival rate was 93.7%. One-year follow-up revealed that an initial higher erythrocyte sedimentation rate, abnormal creatinine value, postoperative low output syndrome, and pleural effusion were all associated with increased mortality. Conclusions Rapid diagnosis and treatment of constrictive pericarditis are crucial to reduce mortality and morbidity. Pericardiectomy should be performed early after diagnosis, in order to prevent chronic illness. After surgery, inotropes, diuretics, salt restriction, and nutrition supply are also critical to improve the prognosis. The inflammation marker erythrocyte sedimentation rate should be evaluated during follow-up.