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At least 1,153 records · Page 64

A comparison of histopathology imaging comprehension algorithms based on multiple instance learning

Whole slide imaging (WSI), also called digital virtual microscopy, is a new imaging modality. It allows for the application of AI and machine learning methods to cancer pathology to help establish a means for the automatic diagnosis of cancer cases. However, designing machine-learning models for WSI is computationally challenging due to its required ultra-high resolution. The current state-of-the-art models use multiple instance learning (MIL). MIL is a weakly-supervised learning method in which the model uses an array of inferences from many smaller instances to make a final classification about the entire set. In the context of WSI, researchers divide the ultra-high-resolution image into many patches. The model then classifies the slide based on an array of inferences from the patches. Among several ways of making the final classification, attention-based mechanisms have resulted in superb accuracy scores. The Transformer, one attention-based algorithm, has reported substantial improvements for WSI comprehension tasks. In this project, we studied and compared several WSI comprehension algorithms. We used the following three datasets: CAMELYON16+17, TCGALung, and TCGA-Kidney. We found that attention-based MIL algorithms performed better than standard MIL algorithms for classifying WSI images, achieving a higher mean accuracy and AUC. However, none of the attention-based algorithms performed significantly better than the others, reporting accuracy scores that varied widely. Presumably, it is due to the limited availability of training samples in the data corpus. Since it is not easy to increase the samples from human subjects, some machine learning techniques like transfer learning could help mitigate this issue.

Saunders, Adam↗

Targeting prostate tumor low–molecular weight tyrosine phosphatase for oxidation-sensitizing therapy

Protein tyrosine phosphatases (PTPs) play major roles in cancer and are emerging as therapeutic targets. Recent reports suggest low–molecular weight PTP (LMPTP)—encoded by the ACP1 gene—is overexpressed in prostate tumors. We found ACP1 up-regulated in human prostate tumors and ACP1 expression inversely correlated with overall survival. Using CRISPR-Cas9–generated LMPTP knockout C4-2B and MyC-CaP cells, we identified LMPTP as a critical promoter of prostate cancer (PCa) growth and bone metastasis. Through metabolomics, we found that LMPTP promotes PCa cell glutathione synthesis by dephosphorylating glutathione synthetase on inhibitory Tyr 270 . PCa cells lacking LMPTP showed reduced glutathione, enhanced activation of eukaryotic initiation factor 2–mediated stress response, and enhanced reactive oxygen species after exposure to taxane drugs. LMPTP inhibition slowed primary and bone metastatic prostate tumor growth in mice. These findings reveal a role for LMPTP as a critical promoter of PCa growth and metastasis and validate LMPTP inhibition as a therapeutic strategy for treating PCa through sensitization to oxidative stress.

60 APPLIED LIFE SCIENCES↗

Discovery of an autoinhibited conformation in mesotrypsin reveals a strategy for selective serine protease inhibition

Selective inhibition of the more than 100 S1 family serine proteases is a long-standing challenge due to their active site similarity. Mesotrypsin, implicated in cancer progression, exemplifies these difficulties; no current inhibitors achieve selectivity over other human trypsins. We found an unexpected autoinhibited conformation of mesotrypsin via x-ray crystallography, revealing a cryptic pocket adjacent to the active site. Using high-throughput virtual screening targeting this cryptic pocket, we identified a conformationally selective small-molecule inhibitor that stabilizes the inactive state of mesotrypsin. This inhibitor demonstrates selectivity for mesotrypsin over other trypsins. Our findings challenge the accepted view of digestive trypsins as constitutively active enzymes lacking potential for allosteric regulation. Furthermore, analyses of other structures suggest that dynamic sampling of closed states with analogous allosteric cryptic pockets appears widespread among S1 serine proteases. These observations point to a potentially generalizable strategy to achieve selective inhibition, offering broad implications for drug development targeting serine proteases in cancer and other diseases.

Coban, Matt↗

Phase IB study of ziv-aflibercept plus pembrolizumab in patients with advanced solid tumors

Background The combination of antiangiogenic agents with immune checkpoint inhibitors could potentially overcome immune suppression driven by tumor angiogenesis. We report results from a phase IB study of ziv-aflibercept plus pembrolizumab in patients with advanced solid tumors. Methods This is a multicenter phase IB dose-escalation study of the combination of ziv-aflibercept (at 2–4 mg/kg) plus pembrolizumab (at 2 mg/kg) administered intravenously every 2 weeks with expansion cohorts in programmed cell death protein 1 (PD-1)/programmed death-ligand 1(PD-L1)-naïve melanoma, renal cell carcinoma (RCC), microsatellite stable colorectal cancer (CRC), and ovarian cancer. The primary objective was to determine maximum tolerated dose (MTD) and recommended dose of the combination. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Exploratory objectives included correlation of clinical efficacy with tumor and peripheral immune population densities. Results Overall, 33 patients were enrolled during dose escalation (n=3) and dose expansion (n=30). No dose-limiting toxicities were reported in the initial dose level. Ziv-aflibercept 4 mg/kg plus pembrolizumab 2 mg/kg every 2 weeks was established as the MTD. Grade ≥3 adverse events occurred in 19/33 patients (58%), the most common being hypertension (36%) and proteinuria (18%). ORR in the dose-expansion cohort was 16.7% (5/30, 90% CI 7% to 32%). Complete responses occurred in melanoma (n=2); partial responses occurred in RCC (n=1), mesothelioma (n=1), and melanoma (n=1). Median OS was as follows: melanoma, not reached (NR); RCC, 15.7 months (90% CI 2.5 to 15.7); CRC, 3.3 months (90% CI 0.6 to 3.4); ovarian, 12.5 months (90% CI 3.8 to 13.6); other solid tumors, NR. Activated tumor-infiltrating CD8 T cells at baseline (CD8+PD1+), high CD40L expression, and increased peripheral memory CD8 T cells correlated with clinical response. Conclusion The combination of ziv-aflibercept and pembrolizumab demonstrated an acceptable safety profile with antitumor activity in solid tumors. The combination is currently being studied in sarcoma and anti-PD-1-resistant melanoma. Trial registration number NCT02298959 .

Rahma, Osama E.↗

Interaction of 25 eV electrons with DNA constituents: XPS analysis of calf thymus DNA, nucleosides, and nucleobases

Abstract Understanding the interactions of secondary electrons generated by ionizing radiation provides a fundamental basis for developing strategies in cancer therapy. In this study, we investigated the interactions of 25 eV low-energy electrons (LEEs) with calf thymus DNA and its constituents, four types of nucleosides and nucleobases, using X-ray photoelectron spectroscopy (XPS). Based on the acquisition and analysis of core-level spectra (O 1s, C 1s, N 1s, and P 2p) in DNA, structural changes induced by 25 eV electrons suggest potential site- and base-specific selectivity. These changes may involve hydroxyl (C–OH) group release from the sugar moiety, cleavage of C–N bonds (likely corresponding to N-glycosidic linkages), and phosphate backbone damage in calf thymus DNA. Among the four nucleosides, thymidine and guanosine showed more evident structural modifications, while cytidine and adenosine were relatively stable. In addition, nucleosides displayed greater susceptibility to LEE-induced structural changes than their corresponding nucleobases. This study reveals the selective damage mechanisms of LEEs on various DNA constituents, which may provide mechanistic insights for future developments in precision cancer therapy based on molecular-level damage. Graphical abstract

Pereira-da-Silva, João (ORCID:0000000220661303)↗

Study on Closely Related Citrus CMMs based on Chemometrics and Prediction of Components-Targets-Diseases Network by Ingenuity Pathway Analysis

As the representatives of closely related Chinese medicinal materials (CMMs) originated from Rutaceae family, Aurantii fructus immaturus (AFI), Aurantii fructus (AF), Citri reticulatae pericarpium viride (CRPV), and Citri reticulatae pericarpium (CRP) have better functions in regulating qi and promoting gastrointestinal motility. However, differences in the quality of closely related Citrus CMMs have not yet been revealed until now. Herein, this study focused on the systematic differentiation and in-depth understanding of closely related Citrus CMMs by a strategy integrating chemometrics and network pharmacology. Determined by ultra performance liquid chromatography, the content of nine flavonoids showed obvious fluctuations in the decoction pieces from different species (Citrus aurantium Linnaeus and Citrus reticulate Blanco) with decreasing levels in the samples of ripe fruits. Decoction pieces from the different species and ripening stages were well distinguished by orthogonal projection to latent structure-discriminate analysis (OPLS-DA) and cluster analysis. As a result, four active components including narirutin, naringenin, hesperidin, and 3,5,6,7,8,3′,4′-heptemthoxyflavone were filtered out by variable importance for the projection (VIP) value (VIP > 1.0), which were regarded as chemotaxonomic markers. Furthermore, a components-targets-diseases network was constructed via ingenuity pathway analysis (IPA), and the correlations were predicted between four chemotaxonomic markers, 223 targets, and three diseases including colitis, breast cancer, and colorectal cancer. The obtained results will be of great significance for identifying closely related Citrus CMMs and conduce to improving the resource utilization of CMMs.

Mu, Qixuan↗

MRI-Based Radiotherapy Planning to Reduce Rectal Dose in Excess of Tolerance

Background and Purpose. Chronic rectal toxicity significantly decreases the quality of life for men who receive radiotherapy for prostate cancer. The most significant predictor of rectal toxicity is rectal dose-volume exceeding tolerance. To minimize the volume of rectum in the high dose field, it is essential to accurately define the prostate-rectum interface. This can be challenging to do by computed tomography (CT) imaging alone. The current study was undertaken to formally demonstrate in a clinical trial setting that image-guided intensity-modulated radiation therapy (IG-IMRT) planning using magnetic resonance imaging (MRI) can reduce the volume of rectum exceeding 70 Gy, a validated metric that predicts the risk of late rectal toxicity. Materials and Methods. This prospective single-arm study enrolled 15 men treated with IG-IMRT for localized prostate cancer. All participants received a dedicated 3 Tesla MRI examination of the prostate in addition to a pelvic CT examination for treatment planning. Two volumetric modulated arc therapy (VMAT) plans with a prescription dose of 79.2 Gy were designed using identical constraints based on CT- and MRI-defined consensus volumes. The volume of rectum exposed to 70 Gy or more was compared using the Wilcoxon paired signed rank test. Results. For CT-based treatment plans, the median volume of rectum receiving 70 Gy or more was 9.3 cubic centimeters (cc) (IQR 7.0 to 10.2) compared with 4.9 cc (IQR 4.1 to 7.8) for MRI-based plans. This resulted in a median volume reduction of 2.1 cc (IQR 0.5 to 5.3, P < .001). Conclusions. Using MRI to plan prostate IG-IMRT to a dose of 79.2 Gy reduces the volume of rectum receiving radiation dose in excess of tolerance (70 Gy or more) and should be considered in men who are at high risk for late rectal toxicity and are not good candidates for other rectal sparing techniques such as hydrogel spacer. This trial is registered with NCT02470910.

Schmidt, Daniel R.↗

Toxicity Values for Chemicals

The toxicity values for chemicals contained in this dataset comprise acute, subchronic, and chronic exposure durations. Cancer slope factors, inhalation unit risk, reference dose, and reference concentrations are available. These values should be used in cancer risk and noncancer hazard assessments for the calculation of preliminary remediation goals (PRGs) and hazard characterization. Users can select toxicity values from 10 combinations of exposure durations and cancer/noncancer toxicity values and select up to 1000 chemicals per query. The dataset supports environmental risk assessments, regulatory decision-making, and environmental planning with tools for benchmarking against risk-based standards. This structured approach ensures a robust evaluation of environmental risks tailored to regulatory needs.

Stewart, Debra [Oak Ridge National Laboratory (ORN↗

Single-Cell Discovery and Multiomic Characterization of Therapeutic Targets in Multiple Myeloma

Multiple myeloma (MM) is a highly refractory hematologic cancer. Targeted immunotherapy has shown promise in MM but remains hindered by the challenge of identifying specific yet broadly representative tumor markers. We analyzed 53 bone marrow (BM) aspirates from 41 MM patients using an unbiased, high-throughput pipeline for therapeutic target discovery via single-cell transcriptomic profiling, yielding 38 MM marker genes encoding cell-surface proteins and 15 encoding intracellular proteins. Of these, 20 candidate genes were highlighted that are not yet under clinical study, 11 of which were previously uncharacterized as therapeutic targets. The findings were cross-validated using bulk RNA sequencing, flow cytometry, and proteomic mass spectrometry of MM cell lines and patient BM, demonstrating high overall concordance across data types. Independent discovery using bulk RNA sequencing reiterated top candidates, further affirming the ability of single-cell transcriptomics to accurately capture marker expression despite limitations in sample size or sequencing depth. Target dynamics and heterogeneity were further examined using both transcriptomic and immuno-imaging methods. In summary, this study presents a robust and broadly applicable strategy for identifying tumor markers to better inform the development of targeted cancer therapy.

60 APPLIED LIFE SCIENCES↗

CD46-Targeted Theranostics for PET and 225 Ac-Radiopharmaceutical Therapy of Multiple Myeloma

Multiple myeloma is a plasma cell malignancy with an unmet clinical need for improved imaging methods and therapeutics. Recently, we identified CD46 as an overexpressed therapeutic target in multiple myeloma and developed the antibody YS5, which targets a cancer-specific epitope on this protein. We further developed the CD46-targeting PET probe [ 89 Zr]Zr-DFO-YS5 for imaging and [ 225 Ac]Ac-DOTA-YS5 for radiopharmaceutical therapy of prostate cancer. These prior studies suggested the feasibility of the CD46 antigen as a theranostic target in multiple myeloma. Herein, we validate [ 89 Zr]Zr-DFO-YS5 for immunoPET imaging and [ 225 Ac]Ac-DOTA-YS5 for radiopharmaceutical therapy of multiple myeloma in murine models. In vitro saturation binding was performed using the CD46 expressing MM.1S multiple myeloma cell line. ImmunoPET imaging using [ 89 Zr]Zr-DFO-YS5 was performed in immunodeficient (NSG) mice bearing subcutaneous and systemic multiple myeloma xenografts. For radioligand therapy, [ 225 Ac]Ac-DOTA-YS5 was prepared, and both dose escalation and fractionated dose treatment studies were performed in mice bearing MM1.S-Luc systemic xenografts. Tumor burden was analyzed using BLI, and body weight and overall survival were recorded to assess antitumor effect and toxicity. [ 89 Zr]Zr-DFO-YS5 demonstrated high affinity for CD46 expressing MM.1S multiple myeloma cells (K d = 16.3 nmol/L). In vitro assays in multiple myeloma cell lines demonstrated high binding, and bioinformatics analysis of human multiple myeloma samples revealed high CD46 expression. [ 89 Zr]Zr-DFO-YS5 PET/CT specifically detected multiple myeloma lesions in a variety of models, with low uptake in controls, including CD46 knockout (KO) mice or multiple myeloma mice using a nontargeted antibody. In the MM.1S systemic model, localization of uptake on PET imaging correlated well with the luciferase expression from tumor cells. A treatment study using [ 225 Ac]Ac-DOTA-YS5 in the MM.1S systemic model demonstrated a clear tumor volume and survival benefit in the treated groups. Our study showed that the CD46-targeted probe [ 89 Zr]Zr-DFO-YS5 can successfully image CD46-expressing multiple myeloma xenografts in murine models, and [ 225 Ac]Ac-DOTA-YS5 can effectively inhibit the growth of multiple myeloma. These results demonstrate that CD46 is a promising theranostic target for multiple myeloma, with the potential for clinical translation.

59 BASIC BIOLOGICAL SCIENCES↗

An African-Specific Variant of TP5 3 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression

TP53 is the most frequently mutated gene in cancer, yet key target genes for p53-mediated tumor suppression remain unidentified. Here, we characterize a rare, African-specific germline variant of TP53 in the DNA-binding domain Tyr107His (Y107H). Nuclear magnetic resonance and crystal structures reveal that Y107H is structurally similar to wild-type p53. Consistent with this, we find that Y107H can suppress tumor colony formation and is impaired for the transactivation of only a small subset of p53 target genes; this includes the epigenetic modifier PADI4, which deiminates arginine to the nonnatural amino acid citrulline. Surprisingly, we show that Y107H mice develop spontaneous cancers and metastases and that Y107H shows impaired tumor suppression in two other models. We show that PADI4 is itself tumor suppressive and that it requires an intact immune system for tumor suppression. We identify a p53–PADI4 gene signature that is predictive of survival and the efficacy of immune-checkpoint inhibitors.

60 APPLIED LIFE SCIENCES↗

Temporal and spatial resolution of magnetosome degradation at the subcellular level in a 3D lung carcinoma model

Magnetic nanoparticles offer many exciting possibilities in biomedicine, from cell imaging to cancer treatment. One of the currently researched nanoparticles are magnetosomes, magnetite nanoparticles of high chemical purity synthesized by magnetotactic bacteria. Despite their therapeutic potential, very little is known about their degradation in human cells, and even less so of their degradation within tumours. In an effort to explore the potential of magnetosomes for cancer treatment, we have explored their degradation process in a 3D human lung carcinoma model at the subcellular level and with nanometre scale resolution. We have used state of the art hard X-ray probes (nano-XANES and nano-XRF), which allow for identification of distinct iron phases in each region of the cell. Our results reveal the progression of magnetite oxidation to maghemite within magnetosomes, and the biosynthesis of magnetite and ferrihydrite by ferritin.

36 MATERIALS SCIENCE↗

Role of immune cells in the removal of deleterious senescent cells

Cellular senescence is an essentially irreversible arrest of cell proliferation coupled to a complex senescence-associated secretory phenotype (SASP). The senescence arrest prevents the development of cancer, and the SASP can promote tissue repair. Recent data suggest that the prolonged presence of senescent cells, and especially the SASP, could be deleterious, and their beneficial effects early in life can become maladaptive such that they drive aging phenotypes and pathologies late in life. It is therefore important to develop strategies to eliminate senescent cells. There are currently under development or approved several immune cell-based therapies for cancer, which could be redesigned to target senescent cells. This review focuses on this possible use of immune cells and discusses how current cell-based therapies could be used for senescent cell removal.

59 BASIC BIOLOGICAL SCIENCES↗

The 20th Gray lecture 2019: Health and heavy ions

Particle radiobiology has contributed new understanding of radiation safety and underlying mechanisms of action to radiation oncology for the treatment of cancer, and to planning of radiation protection for space travel. This manuscript will highlight the significance of precise physical and biologically effective dosimetry to this translational research for the benefit of human health. This review provides a brief snapshot of the evolving scientific basis for, and the complex current global status, and remaining challenges of hadron therapy for the treatment of cancer. The need for particle radiobiology for risk planning in return missions to the Moon, and exploratory deep-space missions to Mars and beyond are also discussed.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Dose optimization of an adjuvanted peptide-based personalized neoantigen melanoma vaccine

The advancements in next-generation sequencing have made it possible to effectively detect somatic mutations, which has led to the development of personalized neoantigen cancer vaccines that are tailored to the unique variants found in a patient’s cancer. These vaccines can provide significant clinical benefit by leveraging the patient’s immune response to eliminate malignant cells. However, determining the optimal vaccine dose for each patient is a challenge due to the heterogeneity of tumors. To address this challenge, we formulate a mathematical dose optimization problem based on a previous mathematical model that encompasses the immune response cascade produced by the vaccine in a patient. We propose an optimization approach to identify the optimal personalized vaccine doses, considering a fixed vaccination schedule, while simultaneously minimizing the overall number of tumor and activated T cells. To validate our approach, we perform in silico experiments on six real-world clinical trial patients with advanced melanoma. We compare the results of applying an optimal vaccine dose to those of a suboptimal dose (the dose used in the clinical trial and its deviations). Our simulations reveal that an optimal vaccine regimen of higher initial doses and lower final doses may lead to a reduction in tumor size for certain patients. Our mathematical dose optimization offers a promising approach to determining an optimal vaccine dose for each patient and improving clinical outcomes.

59 BASIC BIOLOGICAL SCIENCES↗

Production and purification of research scale 161 Tb using cation-exchange semi-preparative HPLC for radiopharmaceutical applications

Terbium-161 ( 161 Tb) is emerging as a promising radionuclide for cancer therapy due to its favorable nuclear properties that are similar to clinically established lutetium-177 ( 177 Lu) along with its therapeutic edge arising from the higher number of Auger and conversion electrons per decay. These low energy electrons result in higher cytotoxicity within a short range of the decaying nuclei to enhance therapeutic efficacy. Despite these promising characteristics, a significant challenge remains in the lack of a domestic 161 Tb supply in the United States, which poses an obstacle to the advancement of 161 Tb-based radiopharmaceutical research and development. Here, this study developed a reliable cation-exchange high-performance liquid chromatography-based method for purification of reactor-produced 161 Tb at quantities suitable to support research and preclinical studies. The purified 161 Tb product showed high radionuclidic purity with excellent radiochemical purity, and the successful labeling studies with the DOTA chelator and DOTA-TATE peptide demonstrated the effective incorporation of the purified 161 Tb into radiopharmaceuticals designed for targeted cancer therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

53BP1 Repair Kinetics for Prediction of In Vivo Radiation Susceptibility in 15 Mouse Strains

We present a novel mathematical formalism to predict the kinetics of DNA damage repair after exposure to both low- and high-LET radiation (X rays; 350 MeV/n 40 Ar; 600 MeV/n 56 Fe). Our method is based on monitoring DNA damage repair protein 53BP1 that forms radiation-induced foci (RIF) at locations of DNA double-strand breaks (DSB) in the nucleus and comparing its expression in primary skin fibroblasts isolated from 15 mice strains. We previously reported strong evidence for clustering of nearby DSB into single repair units as opposed to the classic "contact-first" model where DSB are considered immobile. Here we apply this clustering model to evaluate the number of remaining RIF over time. We also show that the newly introduced kinetic metrics can be used as surrogate biomarkers for in vivo radiation toxicity, with potential applications in radiotherapy and human space exploration. In particular, we observed an association between the characteristic time constant of RIF repair measured in vitro and survival levels of immune cells collected from irradiated mice. Moreover, the speed of DNA damage repair correlated not only with radiation-induced cellular survival in vivo, but also with spontaneous cancer incidence data collected from the Mouse Tumor Biology database, suggesting a relationship between the efficiency of DSB repair after irradiation and cancer risk.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗

A Million Person Study Innovation: Evaluating Cognitive Impairment and other Morbidity Outcomes from Chronic Radiation Exposure Through Linkages with the Centers for Medicaid and Medicare Services Assessment and Claims Data

Here, the study of One Million U.S. Radiation Workers and Veterans, the Million Person Study (MPS), examines the health consequences, both cancer and non-cancer, of exposure to ionizing radiation received gradually over time. Recently the MPS has focused on mortality patterns from neurological and behavioral conditions, e.g., Parkinson's disease, Alzheimer's disease, dementia, and motor neuron disease such as amyotrophic lateral sclerosis. A fuller picture of radiation-related late effects comes from studying both mortality and the occurrence (incidence) of conditions not leading to death. Accordingly, the MPS is identifying neurocognitive diagnoses from fee-for-service insurance claims from the Centers for Medicare and Medicaid Services (CMS), among Medicare beneficiaries beginning in 1999 (the earliest date claims data are available). Linkages to date have identified ∼540,000 workers with available health information. Such linkages provide individual information on important co-factor and confounding variables such as smoking, alcohol consumption, blood pressure, obesity, diabetes and many other health and demographic characteristics. The total person-level set of time-dependent variables, outcomes, organ-specific dose measures, co-factors, and demographics will be massive and much too large to be evaluated with standard software. Thus, development of specialized open-source software designed for large datasets (Colossus) is nearly complete. The wealth of information available from CMS claims data, coupled with individual dose reconstructions, will thus greatly enhance the quality and precision of health evaluations for this new field of low-dose radiation and neurocognitive effects.

Dauer, Lawrence T.↗