IgA transcytosis and antigen recognition govern ovarian cancer immunity.

Most ovarian cancers are infiltrated by prognostically relevant activated T cells1-3, yet exhibit low response rates to immune checkpoint inhibitors4. Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer5,6, but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors.

Early apical release versus En-bloc no touch technique for holmium laser enucleation of the prostate: a high-volume single-surgeon cohort study.

PURPOSE: To determine whether the early apical release (EAR) technique for holmium laser enucleation of the prostate (HOLEP) is associated with improved perioperative outcomes compared to the En-bloc no touch (EBNT) technique. METHODS: Consecutive men treated with HOLEP by a single surgeon from August 2018 to March 2021 were identified. Beginning in June 2021 all procedures were performed using the EAR technique, and these were compared to the preceding cases done with the EBNT technique. Intraoperative outcomes included operative time, need for open conversion, enucleation efficiency (tissue removed per minute of OR time), and enucleation ratio (tissue removed relative to preoperative gland size on imaging). Postoperative outcomes included catheter reinsertion, blood transfusion, and complications classified by the Clavien-Dindo scale. RESULTS: We identified 801 men, including 571 (71%) treated with EBNT and 230 (29%) with EAR. Median preoperative characteristics were similar between groups. The EAR approach was associated with significantly longer mean operating room time, 100.5 min versus 91.9 min, p = 0.003. However, EAR patients had a much lower rate of conversion to open cystotomy (0.43% versus 3.0%). There were no significant differences in rate of catheter reinsertion or perioperative complications between groups (p > 0.05). CONCLUSION: EAR technique by an experienced HoLEP surgeon resulted in longer operative times, potentially reflecting an initial learning curve, but essentially eliminated the need for open cystotomy. Perioperative results including catheter reinsertion rate and bleeding complications were similar between the two cohorts. These data support continued use of the EAR technique for HOLEP to minimize risk of open conversion.

Alternative RNA splicing defects in pediatric cancers: new insights in tumorigenesis and potential therapeutic vulnerabilities.

BACKGROUND: Compared with adult cancers, pediatric cancers are uniquely characterized by a genomically stable landscape and lower tumor mutational burden. Alternative splicing, however, a global cellular process that produces different messenger RNA/protein isoforms from a single messenger RNA transcript, has been increasingly implicated in the development of pediatric cancers. DESIGN: We review the current literature on the role of alternative splicing in adult cancer, cancer predisposition syndromes, and pediatric cancers. We also describe multiple splice variants identified in adult cancers and confirmed through comprehensive genomic profiling in our institutional cohort of rare, refractory, and relapsed pediatric and adolescent young adult cancer patients. Finally, we summarize the contributions of alternative splicing events to neoantigens and chemoresistance and prospects for splicing-based therapies. RESULTS: Published dysregulated splicing events can be categorized as exon inclusion, exon exclusion, splicing factor up-regulation, or splice site alterations. We observe these phenomena in cancer predisposition syndromes (Lynch syndrome, Li-Fraumeni syndrome, CHEK2) and pediatric leukemia (B-cell acute lymphoblastic leukemia), sarcomas (Ewing sarcoma, rhabdomyosarcoma, osteosarcoma), retinoblastoma, Wilms' tumor, and neuroblastoma. Within our institutional cohort, we demonstrate splice variants in key regulatory genes (CHEK2, TP53, PIK3R1, MDM2, KDM6A, NF1) that resulted in exon exclusion or splice site alterations, which were predicted to impact functional protein expression and promote tumorigenesis. Differentially spliced isoforms and splicing proteins also impact neoantigen creation and treatment resistance, such as imatinib or glucocorticoid regimens. Additionally, splice-altering strategies with the potential to change the therapeutic landscape of pediatric cancers include antisense oligonucleotides, adeno-associated virus gene transfers, and small molecule inhibitors. CONCLUSIONS: Alternative splicing plays a critical role in the formation and growth of pediatric cancers, and our institutional cohort confirms and highlights the broad spectrum of affected genes in a variety of cancers. Further studies that elucidate the mechanisms of disease-inducing splicing events will contribute toward the development of novel therapeutics.

Hybrid Automata Library: A flexible platform for hybrid modeling with real-time visualization.

The Hybrid Automata Library (HAL) is a Java Library developed for use in mathematical oncology modeling. It is made of simple, efficient, generic components that can be used to model complex spatial systems. HAL's components can broadly be classified into: on- and off-lattice agent containers, finite difference diffusion fields, a GUI building system, and additional tools and utilities for computation and data collection. These components are designed to operate independently and are standardized to make them easy to interface with one another. As a demonstration of how modeling can be simplified using our approach, we have included a complete example of a hybrid model (a spatial model with interacting agent-based and PDE components). HAL is a useful asset for researchers who wish to build performant 1D, 2D and 3D hybrid models in Java, while not starting entirely from scratch. It is available on GitHub at https://github.com/MathOnco/HAL under the MIT License. HAL requires the Java JDK version 1.8 or later to compile and run the source code.

Low hospital mobility-resurgence of an old epidemic within a new pandemic and future solutions.

Low mobility during hospitalisation poses risks of functional decline and other poor outcomes for older adults. Given the pervasiveness of this problem, low mobility during hospitalisation was first described as 'dangerous' in 1947 and later described as an epidemic. Hospitals have made considerable progress over the last half-century and the last two decades in particular, however, the COVID-19 pandemic presents serious new challenges that threaten to undermine recent efforts and progress towards a culture of mobility. In this special article, we address the question of how to confront an epidemic of immobility within a pandemic. We identify four specific problems for creating and advancing a culture of mobility posed by COVID-19: social distancing and policies restricting patient movement, personnel constraints, personal protective equipment shortages and increased patient hesitancy to ambulate. We also propose four specific solutions to address these problems. These approaches will help support a culture of healthy mobility during and after hospitalisation and help patients to keep moving during the pandemic and beyond.

Improving the assessment and documentation of patient mobility using a quality improvement framework.

OBJECTIVE: To implement a system for assessing and documenting patient mobility in an inpatient geriatric unit using a quality improvement framework. METHODS: Whiteboards incorporating the Johns Hopkins Highest Level of Mobility scale were placed on each door of the unit. Staff were trained to assess and document patient mobility, and documentation compliance was measured. Nurses were surveyed to assess perceived burden of the system. Fall rates were calculated and analyzed for change from baseline. RESULTS: Median daily documentation rates reached 79% by the end of the project. Surveys indicated a low perceived burden of the system. Fall rates did not increase when compared to the previous year baseline (p = 0.80) and the analogous time frames during the previous two years (p = 0.84). CONCLUSION: A quality improvement framework may be used to improve mobility assessment and documentation in a geriatric unit without increasing patient falls or nursing burden.

Histoecology: Applying Ecological Principles and Approaches to Describe and Predict Tumor Ecosystem Dynamics Across Space and Time.

Cancer cells exist within a complex spatially structured ecosystem composed of resources and different cell types. As the selective pressures imposed by this environment determine the fate of cancer cells, an improved understanding of how this ecosystem evolves will better elucidate how tumors grow and respond to therapy. State of the art imaging methods can now provide highly resolved descriptions of the microenvironment, yielding the data required for a thorough study of its role in tumor growth and treatment resistance. The field of landscape ecology has been studying such species-environment relationship for decades, and offers many tools and perspectives that cancer researchers could greatly benefit from. Here, we discuss one such tool, species distribution modeling (SDM), that has the potential to, among other things, identify critical environmental factors that drive tumor evolution and predict response to therapy. SDMs only scratch the surface of how ecological theory and methods can be applied to cancer, and we believe further integration will take cancer research in exciting new and productive directions. Significance: Here we describe how species distribution modeling can be used to quantitatively describe the complex relationship between tumor cells and their microenvironment. Such a description facilitates a deeper understanding of cancers eco-evolutionary dynamics, which in turn sheds light on the factors that drive tumor growth and response to treatment.

EvoFreq: visualization of the Evolutionary Frequencies of sequence and model data.

BACKGROUND: High throughput sequence data has provided in depth means of molecular characterization of populations. When recorded at numerous time steps, such data can reveal the evolutionary dynamics of the population under study by tracking the changes in genotype frequencies over time. This necessitates a simple and flexible means of visualizing an increasingly complex set of data. RESULTS: Here we offer EvoFreq as a comprehensive tool set to visualize the evolutionary and population frequency dynamics of clones at a single point in time or as population frequencies over time using a variety of informative methods. EvoFreq expands substantially on previous means of visualizing the clonal, temporal dynamics and offers users a range of options for displaying their sequence or model data. CONCLUSIONS: EvoFreq, implemented in R with robust user options and few dependencies, offers a high-throughput means of quickly building, and interrogating the temporal dynamics of hereditary information across many systems. EvoFreq is freely available via https://github.com/MathOnco/EvoFreq.

Views of oral antibiotics and advice seeking about acne: a qualitative study of online discussion forums.

BACKGROUND: Acne vulgaris is common and can significantly impair quality of life, yet little is known about patients' understanding of acne and its treatments. Oral antibiotics are widely used for acne despite concerns about antibiotic resistance. People are increasingly turning to online discussion forums for advice, and information on these sites may influence health beliefs and treatment adherence. OBJECTIVES: To explore understandings about the use of oral antibiotics for acne and advice shared among messages posted on online forums. METHODS: We systematically searched for online forums and identified four where acne was frequently discussed. Discussion threads relating to oral antibiotics were analysed thematically. RESULTS: We extracted 136 pages of data comprising 65 discussions among 294 participants. We found a wide range of perceptions around effectiveness of antibiotics for acne and concerns about adverse effects. The delayed onset of action of antibiotics was a source of frustration and compounded dissatisfaction with healthcare providers, who were perceived by people as 'fobbing them off' with prolonged courses of ineffective treatment. Advice ranged from when to ask for or insist on referral to use of costly cleansers. Forum posts related to a wide range of severities, from 'spots' to severe acne, which may make it confusing for users to assess appropriateness of information. CONCLUSIONS: Online forums offer opinions that could confuse patients, or lead to early abandonment of treatments, challenging consultations and patient dissatisfaction. Users expressed frustration about the delayed onset of action of antibiotics for acne, perceptions of only temporary effectiveness and adverse effects.

A murine model of targeted infusion for intracranial tumors.

Historically, intra-arterial (IA) drug administration for malignant brain tumors including glioblastoma multiforme (GBM) was performed as an attempt to improve drug delivery. With the advent of percutaneous neuorovascular techniques and modern microcatheters, intracranial drug delivery is readily feasible; however, the question remains whether IA administration is safe and more effective compared to other delivery modalities such as intravenous (IV) or oral administrations. Preclinical large animal models allow for comparisons between treatment routes and to test novel agents, but can be expensive and difficult to generate large numbers and rapid results. Accordingly, we developed a murine model of IA drug delivery for GBM that is reproducible with clear readouts of tumor response and neurotoxicities. Herein, we describe a novel mouse model of IA drug delivery accessing the internal carotid artery to treat ipsilateral implanted GBM tumors that is consistent and reproducible with minimal experience. The intent of establishing this unique platform is to efficiently interrogate targeted anti-tumor agents that may be designed to take advantage of a directed, regional therapy approach for brain tumors.

Adolescent endogenous sex hormones and breast density in early adulthood.

INTRODUCTION: During adolescence the breasts undergo rapid growth and development under the influence of sex hormones. Although the hormonal etiology of breast cancer is hypothesized, it remains unknown whether adolescent sex hormones are associated with adult breast density, which is a strong risk factor for breast cancer. METHODS: Percentage of dense breast volume (%DBV) was measured in 2006 by magnetic resonance imaging in 177 women aged 25-29 years who had participated in the Dietary Intervention Study in Children from 1988 to 1997. They had sex hormones and sex hormone-binding globulin (SHBG) measured in serum collected on one to five occasions between 8 and 17 years of age. Multivariable linear mixed-effect regression models were used to evaluate the associations of adolescent sex hormones and SHBG with %DBV. RESULTS: Dehydroepiandrosterone sulfate (DHEAS) and SHBG measured in premenarche serum samples were significantly positively associated with %DBV (all P trend ≤0.03) but not when measured in postmenarche samples (all P trend ≥0.42). The multivariable geometric mean of %DBV across quartiles of premenarcheal DHEAS and SHBG increased from 16.7 to 22.1 % and from 14.1 to 24.3 %, respectively. Estrogens, progesterone, androstenedione, and testosterone in pre- or postmenarche serum samples were not associated with %DBV (all P trend ≥0.16). CONCLUSIONS: Our results suggest that higher premenarcheal DHEAS and SHBG levels are associated with higher %DBV in young women. Whether this association translates into an increased risk of breast cancer later in life is currently unknown. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier, NCT00458588 April 9, 2007; NCT00000459 October 27, 1999.

Teriparatide treatment patterns in osteoporosis and subsequent fracture events: a US claims analysis.

UNLABELLED: The objective of this study was to describe the risk of fragility-related fractures in the 2 years following teriparatide initiation. In an administrative claims analysis of over 11,407 patients, approximately one in eight patients had a new or recurrent fragility-related fracture in the 2 years following teriparatide initiation. INTRODUCTION: The objective of this study was to describe the risk of fragility-related fractures in the 2 years following the initiation of teriparatide in a real-world setting. METHODS: This retrospective study used data from the 2002 to 2011 MarketScan® Commercial and Medicare Supplemental Databases to identify patients 50 years and older with a diagnosis of osteoporosis (ICD-9-CM code 733.0x) who were initiating teriparatide. Patients were required to have continuous medical and pharmacy benefit coverage for the 12 months prior to and 24 months following teriparatide initiation (index event). Teriparatide treatment patterns (persistence and adherence) were described, as was the use of antiresorptive therapy. The primary study outcome was the presence of a new or recurring fragility fracture following the initiation of teriparatide. RESULTS: A total of 11,407 patients met the study criteria (mean age = 69.5, standard deviation = 10.6 years; 92.0% female). One in four (25.6%) patients had fragility fracture claims in the year prior to teriparatide initiation, of which 64.0% were on existing antiresorptive therapy. Overall, 13.4% (n = 1527) of patients had a new or recurrent fracture during the 2-year follow-up period. Forty-eight percent of patients on teriparatide treatment were considered persistent; fragility fractures were more common among patients nonpersistent with teriparatide (15.2%) than among those persistent with teriparatide (11.4%). A higher fracture rate (35.7%) was observed in the cohort with previous fragility fracture then those without pre-index fractures (24%). CONCLUSION: More than 13.4% of patients had new or recurrent fragility-related fractures during the 2 years following the initiation of teriparatide; these fractures were more in common in patients with pre-existing fractures and the patients who were nonpersistent with teriparatide.

Infiltration performance of engineered surfaces commonly used for distributed stormwater management.

Engineered porous media are commonly used in low impact development (LID) structures to mitigate excess stormwater in urban environments. Differences in infiltrability of these LID systems arise from the wide variety of materials used to create porous surfaces and subsequent maintenance, debris loading, and physical damage. In this study, the infiltration capacity of six common materials was tested by multiple replicate experiments with automated mini-disk infiltrometers. The tested materials included porous asphalt, porous concrete, porous brick pavers, flexible porous pavement, engineered soils, and native soils. Porous asphalt, large porous brick pavers, and curb cutout rain gardens showed the greatest infiltration rates. Most engineered porous pavements and soils performed better than the native silt loam soils. Infiltration performance was found to be related more to site design and environmental factors than material choice. Sediment trap zones in both pavements and engineered soil rain gardens were found to be beneficial to the whole site performance. Winter chloride application had a large negative impact on poured in place concrete, making it a poor choice for heavily salted areas.

Patterns of treatment among a cohort of older low-income adults starting new medications for osteoporosis.

UNLABELLED: Among 125,954 new users of osteoporosis (OP) medications, 77 % of subjects stopped OP medications, and 23 % of subjects added or started a new OP medication during follow-up, with the first addition or start of a new OP medication occurring in a mean of 739 days after original OP treatment. INTRODUCTION: We described patterns and predictors of OP medication use, focusing on treatment changes over time. METHODS: We analyzed health and pharmacy insurance claims for a large cohort of low-income Medicare beneficiaries with a drug benefit for the years 1998-2008. Study subjects had documented Medicare claims and no receipt of OP medications (i.e., bisphosphonate, raloxifene, calcitonin, teriparatide, or hormonal therapy) during a baseline of 180 days. Subjects were then required to start an OP medication. Baseline patient and prescriber characteristics were assessed in multivariable Cox regression models to identify correlates of adding or starting a new OP medication. Fractures, bone mineral density testing, and visits with endocrinologists or rheumatologists occurring after baseline were also examined as correlates. RESULTS: We included 125,954 new users of OP medications with a mean age of 78 years, 97 % female, and 92 % white. OP medication prescribers included specialists (i.e., endocrinologists or rheumatologists) (6.2 %), orthopedic surgeons (1.0 %), primary care providers (64.9 %), other physicians (3.7 %), and missing (24.1 %). Seventy-seven percent of subjects stopped OP medications, and 23 % of subjects added or started a new OP medication during follow-up, with the first addition or start of a new OP medication occurring in a mean of 739 days after original OP treatment; 4 % added or started a new OP medication more than once. In fully adjusted models, many baseline variables correlated with starting a second OP medication. Post-baseline fractures [hazard ratio (HR) 1.76, 95 % confidence interval (CI) 1.71-1.82] and bone mineral density testing (HR 2.94, 95 % CI 2.86-3.03) were strong predictors. CONCLUSION: Approximately one quarter of patients starting an OP medication added or started a new OP medication during follow-up. Long-term sequential treatment strategy trials would inform optimal medication treatment for OP.

Spatial analysis of recurrent glioblastoma reveals perivascular niche organization.

Tumor evolution is driven by genetic variation; however, it is the tumor microenvironment (TME) that provides the selective pressure contributing to evolution in cancer. Despite high histopathological heterogeneity within glioblastoma (GBM), the most aggressive brain tumor, the interactions between the genetically distinct GBM cells and the surrounding TME are not fully understood. To address this, we analyzed matched primary and recurrent GBM archival tumor tissues with imaging-based techniques aimed to simultaneously evaluate tumor tissues for the presence of hypoxic, angiogenic, and inflammatory niches, extracellular matrix (ECM) organization, TERT promoter mutational status, and several oncogenic amplifications on the same slide and location. We found that the relationships between genetic and TME diversity are different in primary and matched recurrent tumors. Interestingly, the texture of the ECM, identified by label-free reflectance imaging, was predictive of single-cell genetic traits present in the tissue. Moreover, reflectance of ECM revealed structured organization of the perivascular niche in recurrent GBM, enriched in immunosuppressive macrophages. Single-cell spatial transcriptomics further confirmed the presence of the niche-specific macrophage populations and identified interactions between endothelial cells, perivascular fibroblasts, and immunosuppressive macrophages. Our results underscore the importance of GBM tissue organization in tumor evolution and highlight genetic and spatial dependencies.

Inhibition of pyruvate dehydrogenase accelerates anaerobic glycolysis under postmortem simulating conditions.

This research aimed to explore the potential influence of mitochondria on the rate of anaerobic glycolysis. We hypothesized that mitochondria could reduce the rate of anaerobic glycolysis and pH decline by metabolizing a portion of glycolytic pyruvate. We utilized an in vitro model and incorporated CPI-613 and Avidin to inhibit pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC), respectively. Four treatments were tested: 400 µM CPI-613, 1.5 U/ml Avidin, 400 µM CPI-613 + 1.5 U/ml Avidin, or control. Glycolytic metabolites and pH of the in vitro model were evaluated throughout a 1440-min incubation period. CPI-613-containing treatments, with or without Avidin, decreased pH levels and increased glycogen degradation and lactate accumulation compared to the control and Avidin treatments (P < 0.05), indicating increased glycolytic flux. In a different experiment, two treatments, 400 µM CPI-613 or control, were employed to track the fates of pyruvate using [13C6]glucose. CPI-613 reduced the contribution of glucose carbon to tricarboxylic acid cycle intermediates compared to control (P < 0.05). To test whether the acceleration of acidification in reactions containing CPI-613 was due to an increase in the activity of key enzymes of glycogenolysis and glycolysis, we evaluated the activities of glycogen phosphorylase, phosphofructokinase, and pyruvate kinase in the presence or absence of 400 µM CPI-613. The CPI-613 treatment did not elicit an alteration in the activity of these three enzymes. These findings indicate that inhibiting PDH increases the rate of anaerobic glycolysis and pH decline, suggesting that mitochondria are potential regulators of postmortem metabolism.

The ACROBAT 2022 challenge: Automatic registration of breast cancer tissue.

The alignment of tissue between histopathological whole-slide-images (WSI) is crucial for research and clinical applications. Advances in computing, deep learning, and availability of large WSI datasets have revolutionised WSI analysis. Therefore, the current state-of-the-art in WSI registration is unclear. To address this, we conducted the ACROBAT challenge, based on the largest WSI registration dataset to date, including 4,212 WSIs from 1,152 breast cancer patients. The challenge objective was to align WSIs of tissue that was stained with routine diagnostic immunohistochemistry to its H&E-stained counterpart. We compare the performance of eight WSI registration algorithms, including an investigation of the impact of different WSI properties and clinical covariates. We find that conceptually distinct WSI registration methods can lead to highly accurate registration performances and identify covariates that impact performances across methods. These results provide a comparison of the performance of current WSI registration methods and guide researchers in selecting and developing methods.

Promoter polymorphisms in two overlapping 6p25 genes implicate mitochondrial proteins in cognitive deficit in schizophrenia.

In a previous study, we detected a 6p25-p24 region linked to schizophrenia in families with high composite cognitive deficit (CD) scores, a quantitative trait integrating multiple cognitive measures. Association mapping of a 10 Mb interval identified a 260 kb region with a cluster of single-nucleotide polymorphisms (SNPs) significantly associated with CD scores and memory performance. The region contains two colocalising genes, LYRM4 and FARS2, both encoding mitochondrial proteins. The two tagging SNPs with strongest evidence of association were located around the overlapping putative promoters, with rs2224391 predicted to alter a transcription factor binding site (TFBS). Sequencing the promoter region identified 22 SNPs, many predicted to affect TFBSs, in a tight linkage disequilibrium block. Luciferase reporter assays confirmed promoter activity in the predicted promoter region, and demonstrated marked downregulation of expression in the LYRM4 direction under the haplotype comprising the minor alleles of promoter SNPs, which however is not driven by rs2224391. Experimental evidence from LYRM4 expression in lymphoblasts, gel-shift assays and modelling of DNA breathing dynamics pointed to two adjacent promoter SNPs, rs7752203-rs4141761, as the functional variants affecting expression. Their C-G alleles were associated with higher transcriptional activity and preferential binding of nuclear proteins, whereas the G-A combination had opposite effects and was associated with poor memory and high CD scores. LYRM4 is a eukaryote-specific component of the mitochondrial biogenesis of Fe-S clusters, essential cofactors in multiple processes, including oxidative phosphorylation. LYRM4 downregulation may be one of the mechanisms involved in inefficient oxidative phosphorylation and oxidative stress, increasingly recognised as contributors to schizophrenia pathogenesis.