Imaging-based spatial transcriptomics (ST) is evolving rapidly as a pivotal technology in studying the biology of tumors and their associated microenvironments. However, the strengths of the commercially available ST platforms in studying spatial biology have not been systematically evaluated using rigorously controlled experiments. In this study, we used serial 5-m sections of formalin-fixed, paraffin-embedded surgically resected lung adenocarcinoma and pleural mesothelioma tumor samples in tissue microarrays to compare the performance of the single cell ST platforms CosMx, MERFISH, and Xenium (uni/multi-modal) platforms in reference to bulk RNA sequencing, multiplex immunofluorescence, GeoMx Digital Spatial Profiler, and hematoxylin and eosin staining data for the same samples.
View Article and Find Full Text PDFBackground: Datopotamab deruxtecan (Dato-DXd), is a humanized anti-TROP2 IgG1 monoclonal antibody linked to a potent topoisomerase I inhibitor payload (DXd). Dato-DXd has already shown antitumor activity in breast cancer; however, the determinants of response, including the importance of TROP2 expression, remain unclear. We tested the activity of Dato-DXd in a panel of breast cancer patient-derived xenografts (BCXs) varying in TROP2 expression.
View Article and Find Full Text PDFBackground: Risk of recurrence and progression of ductal carcinoma in situ (DCIS) to invasive cancer remains uncertain, emphasizing the need for developing predictive biomarkers of aggressive DCIS.
Methods: Human cell lines and mouse models of disease progression were analyzed for candidate risk predictive biomarkers identified and validated in two independent DCIS cohorts.
Results: RNA profiling of normal mammary and DCIS tissues (n = 48) revealed that elevated SOX11 expression correlates with MKI67, EZH2, and DCIS recurrence score.
A polarized light microscope (PLM) was utilized to examine the optical textures of mesophase pitch (MP) and MP-derived fibers, which aimed to reveal the arrangement and orientation characteristics of pitch molecules and to clarify the evolution and transformation mechanism of carbonaceous microcrystalline from pitch fibers to graphitized fibers. The results found that there were distinct optical textures in MP, where one side exhibited a transition from a flattening plane to a mountain-like undulating plane. This transition corresponded to the arrangement of pitch molecules, resembling stacked lamellar structures reminiscent of curved paper.
View Article and Find Full Text PDFHematopoietic stem and progenitor cells (HSPCs) maintain blood-forming and immune activity, yet intrinsic regulators of HSPCs remain elusive. STAT3 function in HSPCs has been difficult to dissect as Stat3-deficiency in the hematopoietic compartment induces systemic inflammation, which can impact HSPC activity. Here, we developed mixed bone marrow (BM) chimeric mice with inducible Stat3 deletion in 20% of the hematopoietic compartment to avoid systemic inflammation.
View Article and Find Full Text PDFSensitive and quantitative detection of prostate-specific antigen (PSA) has been determined to be indispensable for clinical diagnostics of prostate cancer, whereas such detection is quite challenging due to the extremely low concentration of biomarkers in human serum samples. In this study, a photoelectrochemical (PEC) sensor was effectively developed for the high-sensitivity analysis of prostate-specific antigen (PSA) using a signal amplification method utilizing sensitized carbon quantum dots (CQDs). In this experiment, cadmium sulfide quantum dots were employed as the substrate materials, and indium copper sulfide quantum dots were loaded on their surfaces.
View Article and Find Full Text PDFIntroduction: NSCLC transformation to SCLC has been best characterized with -mutant NSCLC, with emerging case reports seen in , , and -altered NSCLC. Previous reports revealed transformed SCLC from -mutant NSCLC portends very poor prognosis and lack effective treatment. Genomic analyses revealed and loss of function increase the risk of SCLC transformation.
View Article and Find Full Text PDFSmall cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes.
View Article and Find Full Text PDFEpithelial-mesenchymal transition (EMT) empowers epithelial cells with mesenchymal and stem-like attributes, facilitating metastasis, a leading cause of cancer-related mortality. Hybrid epithelial-mesenchymal (E/M) cells, retaining both epithelial and mesenchymal traits, exhibit heightened metastatic potential and stemness. The mesenchymal intermediate filament, vimentin, is upregulated during EMT, enhancing the resilience and invasiveness of carcinoma cells.
View Article and Find Full Text PDFEmerging evidence suggests that cryptic translation beyond the annotated translatome produces proteins with developmental or physiological functions. However, functions of cryptic non-canonical open reading frames (ORFs) in cancer remain largely unknown. To fill this gap and systematically identify colorectal cancer (CRC) dependency on non-canonical ORFs, we apply an integrative multiomic strategy, combining ribosome profiling and a CRISPR-Cas9 knockout screen with large-scale analysis of molecular and clinical data.
View Article and Find Full Text PDFBackground: Lupus nephritis (LN) constitutes the most severe organ manifestations of systemic lupus erythematosus (SLE), where pathogenic T cells have been identified to play an essential role in 'helping' B cells to make autoantibodies and produce inflammatory cytokines that drive kidney injury in SLE. Regulatory T cells (Tregs), responsible for decreasing inflammation, are defective and decreased in SLE and have been associated with disease progression. We hypothesize that treatment with allogeneic, healthy Tregs derived from umbilical cord blood (UCB) may arrest such an inflammatory process and protect against kidney damage.
View Article and Find Full Text PDFSTAT3 function in hematopoietic stem and progenitor cells (HSPCs) has been difficult to discern as deficiency in the hematopoietic system induces systemic inflammation, which can impact HSPC activity. To address this, we established mixed bone marrow (BM) chimeric mice with CreER-mediated deletion in 20% of the hematopoietic compartment. -deficient HSPCs had impaired hematopoietic activity and failed to undergo expansion in BM in contrast to -sufficient (CreER) controls.
View Article and Find Full Text PDFFor the first time, a PEC immunosensor based on a signal amplification strategy is successfully constructed to quantitatively detect alpha-fetoprotein in serum sample. Three favorable factors explain the ultra-high sensitivity of this method. Firstly, compared with pure BiPO, the BiPO/BiOBr heterojunction has a narrower band gap, which expands the light absorption range and enables the light energy to be fully utilized.
View Article and Find Full Text PDFA photoelectrochemical (PEC) immunosensor based on MIL-101(Cr) and CdTe-QDs composites (M&C) was successfully synthesized to assay the carcinoembryonic antigen (CEA) in human serum and urine samples. This novel method contained three key aspects: 1), the polarity of the photocurrent based on MIL-101(Cr) itself could be altered by applying a different voltage to detect the cathode and anode photocurrent. 2), the introduction of cadmium telluride quantum dots (CdTe-QDs) greatly improved the efficiency of light utilization.
View Article and Find Full Text PDFImmune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (αCTLA-4)-mediated toxicity upon disruption of gut homeostatic immunity.
View Article and Find Full Text PDFLung cancer is a highly aggressive and metastatic disease responsible for approximately 25% of all cancer-related deaths in the United States. Using high-throughput in vitro and in vivo screens, we have previously established Impad1 as a driver of lung cancer invasion and metastasis. Here we elucidate that Impad1 is a direct target of the epithelial microRNAs (miRNAs) miR-200 and miR∼96 and is de-repressed during epithelial-to-mesenchymal transition (EMT); thus, we establish a mode of regulation of the protein.
View Article and Find Full Text PDFPurpose: Intraductal papillary mucinous neoplasms (IPMN) are bona fide precursors to pancreatic ductal adenocarcinoma (PDAC). While genomic alterations during multistep IPMN progression have been well cataloged, the accompanying changes within the tumor immune microenvironment (TIME) have not been comprehensively studied. Herein, we investigated TIME-related alterations during IPMN progression, using multiplex immunofluorescence (mIF) coupled with high-resolution image analyses.
View Article and Find Full Text PDFPurpose: Our understanding of the immunopathology of resectable non-small cell lung cancer (NSCLC) is still limited. Here, we explore immune programs that inform of tumor immunity and response to neoadjuvant chemotherapy and chemoimmunotherapy in localized NSCLC.
Experimental Design: Targeted immune gene sequencing using the HTG Precision Immuno-Oncology panel was performed in localized NSCLCs from three cohorts based on treatment: naïve (n = 190), neoadjuvant chemotherapy (n = 38), and neoadjuvant chemoimmunotherapy (n = 21).
Prostate cancer (PCa) that progresses after androgen deprivation therapy (ADT) remains incurable. The underlying mechanisms that account for the ultimate emergence of resistance to ADT, progressing to castrate-resistant prostate cancer (CRPC), include those that reactivate androgen receptor (AR), or those that are entirely independent or cooperate with androgen signaling to underlie PCa progression. The intricacy of metabolic pathways associated with PCa progression spurred us to develop a metabolism-centric analysis to assess the metabolic shift occurring in PCa that progresses with low AR expression.
View Article and Find Full Text PDFBackground: Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary.
Results: We perform whole exome sequencing (WES), RNA sequencing, methylation microarray, and immunohistochemistry (IHC) on 8 pairs of non-small cell lung cancer (NSCLC) primary tumors and matched distant metastases.
Renal medullary carcinoma (RMC) is a highly lethal malignancy that mainly afflicts young individuals of African descent and is resistant to all targeted agents used to treat other renal cell carcinomas. Comprehensive genomic and transcriptomic profiling of untreated primary RMC tissues was performed to elucidate the molecular landscape of these tumors. We found that RMC was characterized by high replication stress and an abundance of focal copy-number alterations associated with activation of the stimulator of the cyclic GMP-AMP synthase interferon genes (cGAS-STING) innate immune pathway.
View Article and Find Full Text PDFFormalin-fixed paraffin-embedded (FFPE) samples have great potential for biomarker discovery, retrospective studies, and diagnosis or prognosis of diseases. Their application, however, is hindered by the unsatisfactory performance of traditional gene expression profiling techniques on damaged RNAs. NanoString nCounter platform is well suited for profiling of FFPE samples and measures gene expression with high sensitivity, which may greatly facilitate realization of scientific and clinical values of FFPE samples.
View Article and Find Full Text PDFJ Bronchology Interv Pulmonol
January 2020
Background: The behavior of pleural fluid cytokine (PFCs) levels and their association with pleurodesis after indwelling pleural catheter (IPC) placement is unknown.
Objective: A prospective exploratory study was conducted to obtain preliminary data on PFC levels after IPC placement.
Methods: The PFC panel consisted of 4 cytokines [interleukin -8 (IL-8), vascular endothelial growth factor, total (but not activated) transforming growth factor betas, and basic fibroblast growth factor], measured across 5 time points (T0: insertion; T1: 24 to 48 h; T2: 72 to 96 h; T3: 1 wk; and T4: 2 wk).