High potency STING agonists engage unique myeloid pathways to reverse pancreatic cancer immune privilege.

Background: Intratumoral injection of cyclic dinucleotide (CDN) agonists of the stimulator of interferon genes (STING) pathway engages innate immune activation and priming of adaptive immune effectors to foster local and distal tumor clearance. Despite proven therapeutic efficacy in preclinical models, a thorough understanding of how CDNs reprogram suppressive myeloid stroma in mouse and man is lacking.

Methods: Here, we perform deep transcript-level and protein-level profiling of myeloid-derived suppressor cells and M2 macrophages following stimulation with CDNs of ascending potency.

Receptor-Targeted Fluorescence-Guided Surgery With Low Molecular Weight Agents.

Cancer surgery remains the primary treatment option for most solid tumors and can be curative if all malignant cells are removed. Surgeons have historically relied on visual and tactile cues to maximize tumor resection, but clinical data suggest that relapse occurs partially due to incomplete cancer removal. As a result, the introduction of technologies that enhance the ability to visualize tumors in the operating room represents a pressing need.

Non-canonical function of DGCR8 in DNA double-strand break repair signaling and tumor radioresistance.

In response to DNA double-strand breaks (DSBs), repair proteins are recruited to the damaged sites. Ubiquitin signaling plays a critical role in coordinating protein recruitment during the DNA damage response. Here, we find that the microRNA biogenesis factor DGCR8 promotes tumor resistance to X-ray radiation independently of its Drosha-binding ability.

Ether phospholipids govern ferroptosis.

Ferroptosis is a cell death modality triggered by excessive lipid peroxidation. Two recent studies (Zou et al., 2020; Cui et al.

deficiency drives glucose dependency and sensitizes lung cancer cells and tumors to GLUT inhibition.

Metabolic reprogramming in cancer cells can create metabolic liabilities. -mutant lung cancer is refractory to most current therapies. Here we show that deficiency promotes glucose dependency in lung cancer cells, and -mutant/deficient lung cancer cells are more vulnerable to glucose deprivation than their WT counterparts.

Erythrocyte adenosine A2B receptor prevents cognitive and auditory dysfunction by promoting hypoxic and metabolic reprogramming.

Hypoxia drives aging and promotes age-related cognition and hearing functional decline. Despite the role of erythrocytes in oxygen (O2) transport, their role in the onset of aging and age-related cognitive decline and hearing loss (HL) remains undetermined. Recent studies revealed that signaling through the erythrocyte adenosine A2B receptor (ADORA2B) promotes O2 release to counteract hypoxia at high altitude.

mTORC1 and ferroptosis: Regulatory mechanisms and therapeutic potential.

Ferroptosis, a form of regulated cell death triggered by lipid hydroperoxide accumulation, has an important role in a variety of diseases and pathological conditions, such as cancer. Targeting ferroptosis is emerging as a promising means of therapeutic intervention in cancer treatment. Polyunsaturated fatty acids, reactive oxygen species, and labile iron constitute the major underlying triggers for ferroptosis.

A mTORC1-mediated cyst(e)ine sensing mechanism governing GPX4 synthesis and ferroptosis.

Ferroptosis is a cell death mechanism triggered by lipid peroxidation. Our recent study linked cyst(e)ine availability with glutathione peroxidase 4 (GPX4) protein synthesis and ferroptosis mitigation via a Rag-mechanistic target of rapamycin complex 1 (mTORC1) axis, and proposed that co-targeting mTORC1 and ferroptosis is a promising strategy for cancer therapy.

DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer.

Ferroptosis, a form of regulated cell death that is induced by excessive lipid peroxidation, is a key tumour suppression mechanism. Glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) constitute two major ferroptosis defence systems. Here we show that treatment of cancer cells with GPX4 inhibitors results in acute depletion of N-carbamoyl-L-aspartate, a pyrimidine biosynthesis intermediate, with concomitant accumulation of uridine.

Ferroptosis, radiotherapy, and combination therapeutic strategies.

Ferroptosis, an iron-dependent form of regulated cell death driven by peroxidative damages of polyunsaturated-fatty-acid-containing phospholipids in cellular membranes, has recently been revealed to play an important role in radiotherapy-induced cell death and tumor suppression, and to mediate the synergy between radiotherapy and immunotherapy. In this review, we summarize known as well as putative mechanisms underlying the crosstalk between radiotherapy and ferroptosis, discuss the interactions between ferroptosis and other forms of regulated cell death induced by radiotherapy, and explore combination therapeutic strategies targeting ferroptosis in radiotherapy and immunotherapy. This review will provide important frameworks for future investigations of ferroptosis in cancer therapy.

mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation.

Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and plays an essential role in inhibiting ferroptosis. As a selenoprotein, GPX4 protein synthesis is highly inefficient and energetically costly. How cells coordinate GPX4 synthesis with nutrient availability remains unclear.

PAF remodels the DREAM complex to bypass cell quiescence and promote lung tumorigenesis.

The DREAM complex orchestrates cell quiescence and the cell cycle. However, how the DREAM complex is deregulated in cancer remains elusive. Here, we report that PAF (PCLAF/KIAA0101) drives cell quiescence exit to promote lung tumorigenesis by remodeling the DREAM complex.

Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy.

The cystine/glutamate antiporter SLC7A11 (also commonly known as xCT) functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers. Recent studies revealed that SLC7A11 overexpression promotes tumor growth partly through suppressing ferroptosis, a form of regulated cell death induced by excessive lipid peroxidation. However, cancer cells with high expression of SLC7A11 (SLC7A11) also have to endure the significant cost associated with SLC7A11-mediated metabolic reprogramming, leading to glucose- and glutamine-dependency in SLC7A11 cancer cells, which presents potential metabolic vulnerabilities for therapeutic targeting in SLC7A11 cancer.

Aging lowers PEX5 levels in cortical neurons in male and female mouse brains.

Peroxisomes exist in nearly every cell, oxidizing fats, synthesizing lipids and maintaining redox balance. As the brain ages, multiple pathways are negatively affected, but it is currently unknown if peroxisomal proteins are affected by aging in the brain. While recent studies have investigated a PEX5 homolog in aging C.

Sensitivity of IROC phantom performance to radiotherapy treatment planning system beam modeling parameters based on community-driven data.

Purpose: Treatment planning system (TPS) dose calculations have previously been shown to be sensitive to modeling errors, especially when treating with complex strategies like intensity-modulated radiation therapy (IMRT). This work investigates the dosimetric impact of several dosimetric and nondosimetric beam modeling parameters, based on their distribution in the radiotherapy community, in two commercial TPSs in order to understand the realistic potential for dose deviations and their clinical effects.

Methods And Materials: Beam models representing standard 120-leaf Varian Clinac-type machines were developed in Eclipse 13.

Dosimetric performance of a multipoint plastic scintillator dosimeter as a tool for real-time source tracking in high dose rate Ir brachytherapy.

Purpose: This study aims to present the performance of a multipoint plastic scintillation detector (mPSD) as a tool for real-time dose measurements (covering three orders of magnitude in dose rate), source-position triangulation, and dwell time assessment in high dose rate (HDR) brachytherapy.

Methods: A previously characterized and optimized three-point sensor system was used for HDR brachytherapy measurements. The detector was composed of three scintillators: BCF60, BCF12, and BCF10.

H2A Monoubiquitination Links Glucose Availability to Epigenetic Regulation of the Endoplasmic Reticulum Stress Response and Cancer Cell Death.

Epigenetic regulation of gene transcription has been shown to coordinate with nutrient availability, yet the mechanisms underlying this coordination remain incompletely understood. Here, we show that glucose starvation suppresses histone 2A K119 monoubiquitination (H2Aub), a histone modification that correlates with gene repression. Glucose starvation suppressed H2Aub levels independently of energy stress-mediated AMP-activated protein kinase activation and possibly through NADPH depletion and subsequent inhibition of BMI1, an integral component of polycomb-repressive complex 1 (PRC1) that catalyzes H2Aub on chromatin.

Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer.

SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here we show that this comes at a significant cost for cancer cells with high levels of SLC7A11. Actively importing cystine is potentially toxic due to its low solubility, forcing cancer cells with high levels of SLC7A11 (SLC7A11) to constitutively reduce cystine to the more soluble cysteine.

A proton imaging system using a volumetric liquid scintillator: a preliminary study.

With the expansion of proton radiotherapy for cancer treatments, it has become important to explore proton-based imaging technologies to increase the accuracy of proton treatment planning, alignment, and verification. The purpose of this study is to demonstrate the feasibility of using a volumetric liquid scintillator to generate proton radiographs at a clinically relevant energy (180 MeV) using an integrating detector approach. The volumetric scintillator detector is capable of capturing a wide distribution of residual proton beam energies from a single beam irradiation.

Ionization quenching correction for a 3D scintillator detector exposed to scanning proton beams.

The ionization quenching phenomenon in scintillators must be corrected to obtain accurate dosimetry in particle therapy. The purpose of this study was to develop a methodology for correcting camera projection measurements of a 3D scintillator detector exposed to proton pencil beams. Birks' ionization quenching model and the energy deposition by secondary electrons (EDSE) model were used to correct the light captured by a prototype 3D scintillator detector.

TLR9 activation cooperates with T cell checkpoint blockade to regress poorly immunogenic melanoma.

Tumors that lack pre-existing immune infiltration respond poorly to T cell checkpoint blockade immunotherapy. These cancers often surround themselves with high densities of suppressive myeloid stroma while excluding immunostimulatory dendritic cells. Tumor-resident myeloid cells and selected lymphocyte populations retain expression of Toll-like Receptors (TLR) that sense common features of pathogens and activate innate immunity in response.

Reference dataset of users' photon beam modeling parameters for the Eclipse, Pinnacle, and RayStation treatment planning systems.

Purpose: The aim of this work was to provide a novel description of how the radiotherapy community configures treatment planning system (TPS) radiation beam models for clinically used treatment machines. Here we describe the results of a survey of self-reported TPS beam modeling parameter values across different C-arm linear accelerators, beam energies, and multileaf collimator (MLC) configurations.

Acquisition And Validation Methods: Beam modeling data were acquired via electronic survey implemented through the Imaging and Radiation Oncology Core (IROC) Houston Quality Assurance Center's online facility questionnaire.