TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial.

In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684.

SpatialCells: automated profiling of tumor microenvironments with spatially resolved multiplexed single-cell data.

Cancer is a complex cellular ecosystem where malignant cells coexist and interact with immune, stromal and other cells within the tumor microenvironment (TME). Recent technological advancements in spatially resolved multiplexed imaging at single-cell resolution have led to the generation of large-scale and high-dimensional datasets from biological specimens. This underscores the necessity for automated methodologies that can effectively characterize molecular, cellular and spatial properties of TMEs for various malignancies. This study introduces SpatialCells, an open-source software package designed for region-based exploratory analysis and comprehensive characterization of TMEs using multiplexed single-cell data. The source code and tutorials are available at https://semenovlab.github.io/SpatialCells. SpatialCells efficiently streamlines the automated extraction of features from multiplexed single-cell data and can process samples containing millions of cells. Thus, SpatialCells facilitates subsequent association analyses and machine learning predictions, making it an essential tool in advancing our understanding of tumor growth, invasion and metastasis.

Cancer Type and Histology Influence Cutaneous Immunotherapy Toxicities: A Multi-Institutional Cohort Study.

BACKGROUND: Cutaneous immune-related adverse events (cirAEs) are the most common toxicities to occur in the setting of immune checkpoint inhibitor (ICI) therapy. Identifying patients who are at increased risk of developing cirAEs may improve quality of life and outcomes. OBJECTIVE: To investigate the influence of cancer type and histology on the development of cirAEs in the setting of ICI therapy and survival outcomes. METHODS: This retrospective cohort study included patients between December 1, 2011, and October 30, 2020. They received ICIs from 2011-2020 with follow-up of outcomes through October 2021. We identified 3,668 ICI recipients who were seen at Mass General Brigham and Dana-Farber. Of these, 669 developed cirAEs. Records that were incomplete or categories of insufficient sample size were excluded from the study cohort. Multivariate Cox proportional hazards models were utilized to investigate the impact of cancer organ system and histology on cirAE development, after adjusting for demographics, Charlson Comorbidity Index, ICI type, cancer stage at ICI initiation, and year of ICI initiation. Time-varying Cox proportional hazards modeling was utilized to examine the impact of cirAE development on mortality. RESULTS: Compared to other non-epithelial cancers (neuroendocrine, leukemia, lymphoma, myeloma, sarcoma, and central nervous system malignancies), cutaneous squamous cell carcinoma (cSCC) (HR = 3.57, p < 0.001), melanoma (HR = 2.09, p < 0.001), head and neck adenocarcinoma (HR = 2.13, p = 0.009), genitourinary transitional cell carcinoma (HR = 2.15, p < 0.001), and genitourinary adenocarcinoma (HR = 1.53, p = 0.037) were at significantly higher risk of cirAEs in multivariate analyses. The increased risk of cirAEs translated into an adjusted survival benefit for melanoma (HR = 0.37, p < 0.001) and cSCC (HR = 0.51, p = 0.011). CONCLUSIONS: The highest rate of cirAEs and subsequent survival benefits were observed in cutaneous malignancies treated with ICIs. This study improves our understanding of patients who are at highest risk of developing cirAEs and would, therefore, benefit from appropriate counseling and closer monitoring by their oncologists and dermatologists throughout their ICI therapy. Limitations include its retrospective nature and cohort from one geography.

SpatialCells: Automated Profiling of Tumor Microenvironments with Spatially Resolved Multiplexed Single-Cell Data.

Background: Cancer is a complex cellular ecosystem where malignant cells coexist and interact with immune, stromal, and other cells within the tumor microenvironment. Recent technological advancements in spatially resolved multiplexed imaging at single-cell resolution have led to the generation of large-scale and high-dimensional datasets from biological specimens. This underscores the necessity for automated methodologies that can effectively characterize the molecular, cellular, and spatial properties of tumor microenvironments for various malignancies. Results: This study introduces SpatialCells, an open-source software package designed for region-based exploratory analysis and comprehensive characterization of tumor microenvironments using multiplexed single-cell data. Conclusions: SpatialCells efficiently streamlines the automated extraction of features from multiplexed single-cell data and can process samples containing millions of cells. Thus, SpatialCells facilitates subsequent association analyses and machine learning predictions, making it an essential tool in advancing our understanding of tumor growth, invasion, and metastasis.

Green synthesis of novel stable biogenic gold nanoparticles for breast cancer therapeutics via the induction of extrinsic and intrinsic pathways.

Biosynthesis of gold nanoparticles (AuNPs) using algal polysaccharides is a simple, low-cost, and an eco-friendly approach. In the current study, different concentrations of Arthospira platensis exopolysaccharides (EPS) were used to synthetize AuNPs via the reduction of gold ions. The biologically synthesized AuNPs (AuNPs1, AuNPs2, AuNPs3) were prepared in 3 different forms through the utilization of three different ratios of EPS-reducing agents. AuNPs analysis confirmed the spherical shape of the EPS-coated AuNPs. Furthermore, AuNPs prepared by EPS and L-ascorbic acid (AuNPs3) showed more stability than the AuNPs colloidal solution that was prepared using only L-ascorbic acid. Analysis of the antimicrobial effects of AuNPs showed that E. coli was the most sensitive bacterial species for AuNPs3 and AuNPs1 with inhibition percentages of 88.92 and 83.13%, respectively. Also, safety assay results revealed that AuNPs3 was the safest biogenic AuNPs for the tested noncancerous cell line. The anticancer assays of the biogenic AuNPs1, AuNPs2, and AuNPs3 against MCF-7 cell line indicated that this cell line was the most sensitive cell line to all treatments and it showed inhibition percentages of 66.2%, 57.3%, and 70.2% to the three tested AuNPs, respectively. The AuNPs also showed abilities to arrest MCF-7 cells in the S phase (77.34%) and increased the cellular population in the sub G0 phase. Gene expression analysis showed that AuNPs3 down regulated Bcl2, Ikapα, and Survivn genes in MCF-7 treated-cells. Also, transmission electron microscopy (TEM) analysis of MCf-7 cells revealed that AuNPs 3 and AuNPs2 were localized in cell vacuoles, cytoplasm, and perinuclear region.

Intraoperative Factors Associated With Early Recipient Death After Adult-to-Adult Living Donor Liver Transplant.

OBJECTIVES: Living donor liver transplant is the gold standard therapy for patients with terminal hepatic disorders for whom no alternative therapy is available. The primary aim was to assess different intraoperative factors that may predict early death after adult-to-adult living donor liver transplant. The secondary aim was to assess the effect of small-for-size syndrome on mortality. MATERIALS AND METHODS: This retrospective multicenter cohort study was performed on records from 145 adults with cirrhosis who had received a right lobe living donor liver transplant. Patients were divided according to the occurrence of short-term mortality (death within the first month after transplant). The primary intraoperative parameters included graft weight, surgical duration, mean blood pressure, serum lactate and sodium bicarbonate, transfusions, durations of cold and warm ischemia and anhepatic phase, input and output during surgery, and portal venous pressures. RESULTS: There were statistically significant variations between both cohorts for number of units of packed red blood cells, durations of cold and warm ischemia and anhepatic phase, preclamp and postreperfusion portal venous pressures, average urine output, mean serum lactate, mean blood pressure, and surgical duration (P ⟨ .001). Also, there were significant differences in the number of platelets, units of fresh frozen plasma, and mean sodium bicarbonate (P = .025, .003, and .035, respectively). Of the 25 patients who died within the early postoperative period, 20 had developed small-for-size syndrome (P ⟨ .001). CONCLUSIONS: A variety of intraoperative risk factors may affect early posttransplant mortality, which suggests the high complexity of living donor liver transplants and the need for well-trained experienced teams to perform these surgeries.