Biology subjects

Aly, M.

Publications and source records attributed to Aly, M..

At least 19 recordsLinked to original sources

bioRxiv2026

What is common to memory retrieval and relational reasoning? Testing neural overlap in anterior lateral prefrontal cortex

Anterior lateral prefrontal cortex (aLPFC) has been consistently implicated in retrieval monitoring and relational reasoning. However, it is unknown whether aLPFC supports a cognitive process that is common to memory retrieval and reasoning tasks. To inform this question, a first step is to ascertain whether there is, within individuals, spatial overlap in aLPFC between tasks. A prior study found overlap in activation of left aLPFC between verbal analogy and source memory retrieval tasks, using tightly matched word stimuli (Westphal et al., 2016). To assess whether this overlap in activation extends to other stimulus types and task designs, and another sensory modality, we collected fMRI data from 35 healthy young adults as they completed an associative memory retrieval task along with four variants of a relational reasoning paradigm that reliably engages left aLPFC. The reasoning tasks followed a 2 (visual/auditory modality) x 2 (spatial/featural relations) x 2 (low/high relational complexity) design. In the associative memory task, participants studied word pairs and decided whether the two words were related. At retrieval, they viewed pairs of previously seen words and judged whether the pair was Intact (words paired together at encoding) or Recombined (previously seen words recombined into new pairs). Response times were slower for Recombined vs. Intact pairs, consistent with heightened retrieval monitoring. As predicted, aLPFC was more active for Recombined than Intact pairs, as well as for the manipulation of relational complexity across the four reasoning tasks. A group-level conjunction analysis demonstrated substantial overlap between memory and reasoning manipulations in left aLPFC (Glasser parcels a47r, p47r, a10p, and p10p). Within individuals, clusters defined from the reasoning task were also sensitive to retrieval monitoring demands. Further, there was within-participant overlap in the pattern of active vertices, as measured via Dice coefficients. Bayes factor testing within each parcel of interest demonstrated greater vertex-level overlap than expected by chance, particularly in p47r. Importantly, degree of overlap varied widely among individuals, and exploratory results showed that both cluster-level activation and vertex overlap in p47r correlated with memory discriminability (d-prime). Thus, we hypothesize that neural overlap in this area reflects engagement in relational thinking during memory retrieval monitoring. Together, these results move beyond general characterizations of aLPFC function by testing whether it meets a precondition -- individual-level neural overlap across varied tasks -- of a unified neurocognitive function in support of reasoning and memory retrieval.

neuroscience↗

bioRxiv2025

The Hippocampus Rapidly Integrates Sequence Representations During Novel Multistep Predictions

Memories for temporally extended sequences can be used adaptively to predict future events on multiple timescales, a function that relies on the hippocampus. For such predictions to be useful, they should be updated when environments change. We investigated how and when new learning shapes hippocampal representations of temporally extended sequences, and how this updating relates to flexible predictions about future events. Human participants learned sequences of environments in immersive virtual reality. They then learned novel environment transitions connecting previously separate sequences. During subsequent fMRI, participants predicted multiple steps into the future in both the newly connected sequence and control sequences that remained separate. The hippocampus integrated representations of the connected sequence, such that activity patterns became more similar across trials for the connected sequence vs. the unconnected sequences. These integrated sequence representations in the hippocampus emerged soon after learning, incorporated representations of the initial sequences as well as new activity patterns not previously present in either sequence, and predicted participants ability to update their predictions in behavior. Together, these results advance our understanding of how structured knowledge dynamically emerges in service of adaptive behavior.

neuroscience↗

bioRxiv2025

Repeated Viewing of a Narrative Movie Changes Event Timescales in The Brain

Many everyday experiences share a recurring structure: routines, familiar routes, rewatched films, and replayed songs. How do repeated encounters with such structure alter the brains representations of events? We hypothesized that, with repeated viewing of a film clip, event representations in the brain may adapt by becoming either finer (more detailed) or coarser (more generalized). To test this hypothesis, we analyzed data from 30 human participants (12 males, 18 females) who underwent functional magnetic resonance imaging (fMRI) while watching three 90-second clips from "The Grand Budapest Hotel" six times each. We used hidden Markov models and pattern similarity analysis applied to searchlights across the brain to quantify the strength of event structure at different timescales for each clip presentation. We then tested how event structure strength changed at both slow and fast timescales with repeated viewings. Most brain regions exhibited stability in the strength of event structure at both slow and fast timescales. Other regions, however, showed flexible event representations that became more or less granular across repeated clip presentations. Notably, several brain regions exhibited consistent changes in the strength of event structure at a slow timescale across different movie clips. Furthermore, in lateral occipital cortex and middle temporal gyrus, slow timescale structure was correlated with subsequent memory for the clips. These results highlight that event dynamics in the brain are not fixed, but can change flexibly with experience. Significance StatementMany day-to-day experiences recur over time, as we retrace the same route to work or listen to our favorite song on repeat. We asked how increasing familiarity with an experience changes the brains representations of it. Individuals repeatedly watched film clips while undergoing fMRI. We examined how the brains temporal representations of events in the clips changed with repeated viewing. As clips became familiar, some brain regions exhibited fine-tuned event representations that divided film clips into smaller events. Other brain regions showed coarser event representations that grouped previously distinct events. The strength of event structure at a coarse timescale was correlated with memory. These results show that the brain flexibly changes how it represents events as they become more familiar.

neuroscience↗

bioRxiv2023

Hippocampal differentiation of competing memories predicts the precision of preparatory coding in visual cortex

Behaving adaptively requires selection of relevant memories and sensations and suppression of competing ones. We hypothesize that these mechanisms are linked, such that hippocampal computations that resolve competition in memory also shape the precision of sensory representations to guide selective attention. We leverage fMRI-based pattern similarity, receptive field modeling, and eye tracking to test this hypothesis in humans performing a memory-dependent visual search task. In the hippocampus, more distinct representations of competing memories are associated with the accuracy of memory-guided eye movements. In visual cortex, preparatory coding of remembered target locations precedes search successes, whereas preparatory coding of competing locations precedes search failures due to interference. These effects are linked: more distinct hippocampal memories are associated with lower competitor activation in visual cortex, yielding more precise preparatory representations. These results demonstrate a role for memory distinctiveness in shaping the precision of sensory representations, highlighting links between mechanisms that overcome competition in memory and perception.

neuroscience↗

bioRxiv2023

The brain hierarchically represents the past and future during multistep anticipation

Memory for temporal structure enables both planning of future events and retrospection of past events. We investigated how the brain flexibly represents extended temporal sequences into the past and future during anticipation. Participants learned sequences of environments in immersive virtual reality. Pairs of sequences had the same environments in a different order, enabling context-specific learning. During fMRI, participants anticipated upcoming environments multiple steps into the future in a given sequence. Temporal structure was represented in the hippocampus and across higher-order visual regions (1) bidirectionally, with graded representations into the past and future and (2) hierarchically, with further events into the past and future represented in successively more anterior brain regions. In hippocampus, these bidirectional representations were context-specific, and suppression of far-away environments predicted response time costs in anticipation. Together, this work sheds light on how we flexibly represent sequential structure to enable planning over multiple timescales.

neuroscience↗

bioRxiv2022

Switching between external and internal attention in hippocampal networks

Everyday experience requires processing external signals from the world around us and internal information retrieved from memory. To do both, the brain must fluctuate between states that are optimized for external vs. internal attention. Here, we focus on the hippocampus as a region that may serve at the interface between these forms of attention, and ask how it switches between prioritizing sensory signals from the external world vs. internal signals related to memories and thoughts. Pharmacological, computational, and animal studies have identified input from the cholinergic basal forebrain as important for biasing the hippocampus towards processing external information, whereas complementary research suggests the dorsal attention network (DAN) may aid in allocating attentional resources towards accessing internal information. We therefore tested the hypothesis that the basal forebrain and DAN drive the hippocampus towards external and internal attention, respectively. We used data from 29 human participants (17 female) who completed 2 attention tasks during fMRI. One task ("memory-guided") required proportionally more internal attention, and proportionally less external attention, than the other ("explicitly instructed"). We discovered that background functional connectivity between the basal forebrain and hippocampus was stronger during the explicitly instructed vs. memory-guided task. In contrast, DAN-hippocampus background connectivity was stronger during the memory-guided vs. explicitly instructed task. Finally, the strength of DAN-hippocampus background connectivity was correlated with performance on the memory-guided but not explicitly instructed task. Together, these results provide evidence that the basal forebrain and DAN may modulate the hippocampus to switch between external and internal attention. Significance StatementHow does the brain balance the need to pay attention to internal thoughts and external sensations? We focused on the human hippocampus, a region that may serve at the interface between internal and external attention, and asked how its functional connectivity varies based on attentional states. The hippocampus was more strongly coupled with the cholinergic basal forebrain when attentional states were guided by the external world rather than retrieved memories. This pattern flipped for functional connectivity between the hippocampus and dorsal attention network, which was higher for attention tasks that were guided by memory rather than external cues. Together, these findings show that distinct networks in the brain may modulate the hippocampus to switch between external and internal attention.

neuroscience↗

bioRxiv2022

Preparation of inactivated whole culture vaccine composed of Pasteurella multocida, Avibacterium paragallinarum, and Ornithobacterium rhinotracheale and evaluation of its protective efficacy in chickens

Poultry, mainly chickens and its white meat represents one of the main, nutritionally valuable, and affordable red meat replacer source of protein throughout the whole world with special reference to developing countries. A long list of microbial agents especially bacterial pathogens threat chickens production cycles. They constitute one of the major problems facing the rapidly expanding poultry industry and are responsible for considerable economic losses.). Fowl Cholera, Infectious Coryza, and Ornithobacterium Rhinotracheale (ORT) diseases were among the serious bacterial infections that affect respiratory tract of chickens with an global adverse effect on poultry production. A formalized whole culture vaccine of composed of P. multocida serotypes A5, A8, A9 and D2, Avibacterium paragallinarum serotype A and C and Ornithobacterium rhinotracheale serotype A was prepared. This polyvalent vaccine proved to be safe producing no adverse side effects when injected in chickens. The immunizing efficacy of this vaccine was evaluated in SPF chickens, which were immunized at 6 weeks of age. The protective efficacy of the vaccine was determined using challenge test. The developed vaccine was effective in protecting chickens against Fowl Cholera, Infectious Coryza and Ornithobacterium Infection (ORT diseases) in chickens against challenge with these pathogens. Vaccinated chickens challenged with virulent Pasteurella Multocida serotypes A5, A8, A9 and D2 showed protection rates of 86.6%, 93.3%, 93.3% and 93.3%, respectively, as compared with 100% mortality in the non-vaccinated control. Vaccinated chickens challenged with Avibacterium paragallinarum serotypes A and C showed protection rates of 86.6% and 93.3%, respectively. Also, the protection rate against challenge with virulent Ornithobacterium rhinotracheale serotype A reached to 96.6%.

immunology↗

bioRxiv2022

Leveraging vision to understand curiosity

Humans are immensely curious and motivated to reduce uncertainty. Inspired by studies of sensory uncertainty, we hypothesized that visual areas provide multivariate representations of uncertainty, which are read out by higher-order areas that encode confidence and, ultimately, translated into curiosity. During fMRI, participants rated their confidence in identifying distorted images of animals and objects and their curiosity to see the clear image. We found that curiosity peaked at low confidence. To link sensory certainty and curiosity, we estimated "OTC Certainty" as the product of absolute and relative evidence for animals vs. object categories in occipitotemporal cortex (OTC) while participants viewed the distorted image. OTC Certainty negatively correlated with curiosity, while univariate activity in two frontal regions - vmPFC and ACC - positively correlated with confidence. The relationship between OTC certainty and curiosity was mediated by the vmPFC but not ACC. The results reveal neural mechanisms that generate curiosity from representations of uncertainty.

neuroscience↗

bioRxiv2021

Age-related change in task-evoked amygdala-prefrontal circuitry: a multiverse approach with an accelerated longitudinal cohort aged 4-22 years

The amygdala and its connections with medial prefrontal cortex (mPFC) play central roles in the development of emotional processes. While several studies have suggested that this circuitry exhibits functional changes across the first two decades of life, findings have been mixed - perhaps resulting from differences in analytic choices across studies. Here we used multiverse analyses to examine the robustness of task-based amygdala-mPFC function findings to analytic choices within the context of an accelerated longitudinal design (4-22 years- old; N=98; 183 scans; 1-3 scans/participant). Participants, recruited from the greater Los Angeles area, completed an event-related emotional face (fear, neutral) task. Parallel analyses varying in preprocessing and modeling choices found that age-related change estimates for amygdala reactivity were more robust than task-evoked amygdala-mPFC functional connectivity to varied analytical choices. Specification curves indicated evidence for age-related decreases in amygdala reactivity to faces, though within-participant changes in amygdala reactivity could not be differentiated from between-participant differences. In contrast, amygdala--mPFC functional connectivity results varied across methods much more, and evidence for age-related change in amygdala-mPFC connectivity was not consistent. Generalized psychophysiological interaction (gPPI) measurements of connectivity were especially sensitive to whether a deconvolution step was applied. Our findings demonstrate the importance of assessing the robustness of findings to analysis choices, although the age-related changes in our current work cannot be overinterpreted given low test-retest reliability. Together, these findings highlight both the challenges in estimating developmental change in longitudinal cohorts and the value of multiverse approaches in developmental neuroimaging for assessing robustness of results. (Preprint: https://www.biorxiv.org/content/10.1101/2021.10.08.463601v1). Key PointsO_LIMultiverse analyses applied to fMRI data are valuable for determining the robustness of findings to varied analytical choices C_LIO_LIIn the current study, age-related change estimates for amygdala reactivity were relatively robust to analytical decisions, though gPPI functional connectivity analyses were much more sensitive, leading some estimates to flip sign C_LIO_LIBoth test-retest reliability and robustness to analytical choices are important considerations for developmental research C_LI

neuroscience↗

bioRxiv2020

Anticipation of temporally structured events in the brain

1Learning about temporal structure is adaptive because it enables the generation of expectations. We examined how the brain uses experience in structured environments to anticipate upcoming events. During fMRI, individuals watched a 90-second movie clip six times. Using a Hidden Markov Model applied to searchlights across the whole brain, we identified temporal shifts between activity patterns evoked by the first vs. repeated viewings of the movie clip. In many regions throughout the cortex, neural activity patterns for repeated viewings shifted to precede those of initial viewing by up to 15 seconds. This anticipation varied hierarchically in a posterior (less anticipation) to anterior (more anticipation) fashion. We also identified specific regions in which the timing of the brains event boundaries were related to those of human-labeled event boundaries, with the timing of this relationship shifting on repeated viewings. With repeated viewing, the brains event boundaries came to precede human-annotated boundaries by 1-4 seconds on average. Together, these results demonstrate a hierarchy of anticipatory signals in the human brain and link them to subjective experiences of events.

neuroscience↗

bioRxiv2020

Cholinergic Modulation of Hippocampally Mediated Attention and Perception

Attention to the relations between visual features modulates hippocampal representations. Moreover, hippocampal damage impairs discrimination of spatial relations. We explore a mechanism by which this might occur: modulation by the acetylcholine system. Acetylcholine enhances afferent input to the hippocampus and suppresses recurrent connections within it. This biases hippocampal processing toward environmental input, and should improve externally-oriented, hippocampally mediated attention and perception. We examined cholinergic modulation on an attention task that recruits the hippocampus. On each trial, participants viewed two images (rooms with paintings). On "similar room" trials, they judged whether the rooms had the same spatial layout from a different perspective. On "similar art" trials, they judged whether the paintings could have been painted by the same artist. On "identical" trials, participants simply had to detect identical paintings or rooms. We hypothesized that cholinergic modulation would improve performance on the similar room task, given past findings that hippocampal representations predicted, and hippocampal damage impaired, behavior on this task. To test this, nicotine cigarette smokers took part in two sessions: one before which they abstained from nicotine for 12 hours, and one before which they ingested nicotine in the past hour. Individual differences in expired breath carbon monoxide levels -- a measure of how recently or how much someone smoked -- predicted performance improvements on the similar room task. This finding provides novel support for computational models that propose that acetylcholine enhances externally oriented attentional states in the hippocampus.

neuroscience↗

bioRxiv2019

Preparation for upcoming attentional states in the hippocampus and medial prefrontal cortex

Goal-directed attention is usually studied by providing individuals with explicit instructions on what they should attend to. But in daily life, we often use past experiences to guide our attentional states. Given the importance of memory for predicting upcoming events, we hypothesized that memory-guided attention is supported by neural preparation for anticipated attentional states. We examined preparatory coding in the human hippocampus and mPFC, two regions that are important for memory-guided behaviors, in two tasks: one where attention was guided by memory and another in which attention was explicitly instructed. Hippocampus and mPFC exhibited higher activity for memory-guided vs. explicitly instructed attention. Furthermore, representations in both regions contained information about upcoming attentional states. In the hippocampus, this preparation was stronger for memory-guided attention, and occurred alongside stronger coupling with visual cortex during attentional guidance. These results highlight the mechanisms by which memories are used to prepare for upcoming attentional goals. Competing InterestsNone.

neuroscience↗

bioRxiv2019

The hippocampus is critical for spatial relational attention

The medial temporal lobe (MTL) is traditionally considered to be a system that is specialized for long-term memory. Recent work has challenged this notion by demonstrating that this region can contribute to many domains of cognition beyond long-term memory, including perception and attention. One potential reason why the MTL (and hippocampus specifically) contributes broadly to cognition is that it contains relational representations -- representations of multidimensional features of experience and their unique relationship to one another -- that are useful in many different cognitive domains. Here, we explore the hypothesis that the hippocampus/MTL plays a critical role in attention and perception via relational representations. We compared human participants with MTL damage to healthy age- and education-matched individuals on attention tasks that varied in relational processing demands. On each trial, participants viewed two images (rooms with paintings). On similar room trials, they judged whether the rooms had the same spatial layout from a different perspective. On similar art trials, they judged whether the paintings could have been painted by the same artist. On identical trials, participants simply had to detect identical paintings or rooms. Patients were significantly and selectively impaired on the similar room task. This work provides further evidence that the hippocampus/MTL plays a ubiquitous role in cognition by virtue of its relational and spatial representations, and highlights its important contributions to rapid perceptual processes that benefit from attention.

neuroscience↗

bioRxiv2019

The effect of sample size on polygenic hazard models for prostate cancer

We aimed to determine the effect of sample size on performance of polygenic hazard score (PHS) models in predicting the age at onset of prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training (34,444 samples) and testing (6,417 samples) sets. Two PHS model-building strategies were investigated. Established-SNP model considered 65 SNPs that had been associated with prostate cancer in the literature. A stepwise SNP selection was used to develop Discovery-SNP models. The performance of each PHS model was calculated for random sizes of the training set (1 to 30 thousand). The performance of a representative Established-SNP model was estimated for random sizes of the testing set (0.5 to 6 thousand). Mean HR98/50 (hazard ratio of top 2% to the average in the test set) of the Established-SNP model increased from 1.73[95%CI: 1.69-1.77] to 2.41[2.40-2.43] when the number of training samples was increased from 1 to 30 thousand. The corresponding HR98/50 of the Discovery-SNP model increased from 1.05[0.93-1.18] to 2.19[2.16-2.23]. HR98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 and 6 thousand observations were 1.78[1.70-1.85] and 1.73[1.71-1.76], respectively. We estimate that a study population of 20 to 30 thousand men is required to develop Discovery-SNP PHS models for prostate cancer. The required sample size could be reduced to 10 thousand samples, if a set of SNPs associated with the disease has already been established.\n\nAuthor summaryPolygenic hazard scores represent a recent advancement in polygenic prediction to model the age of onset of various diseases, such as Alzheimers disease or prostate cancer. These scores accumulate small effect sizes from several tens of genetic variants and can be used to establish an individuals risk of experiencing an event relative to a control population across time. The largest barrier to the development of polygenic hazard scores is the large number of study subjects needed to develop the underlying models. We sought to understand the effect of varying the total number of samples on the performance of a polygenic hazard score in the context of prostate cancer. We found that the performance of the score did not appreciably change beyond 20 to 30 thousand observations when developing the model from scratch. However, when the discovery of the genetic variants can be borrowed from those already identified in the literature to be associated with the disease, the required number of samples is reduced to 10 thousand with no appreciable detriment in performance. We hope that these results can guide the design of future studies of polygenic scores in other diseases and demonstrate the importance of genome-wide association studies.

genetics↗

bioRxiv2019

A genetic hazard score to personalize prostate cancer screening, applied to population data

BackgroundGenetic risk stratification may inform decisions of whether--and when--a man should undergo prostate cancer (PCa) screening. We previously validated a polygenic hazard score (PHS), a weighted sum of 54 single-nucleotide polymorphism genotypes, for accurate prediction of age of onset of aggressive PCa and improved screening performance. We now assess the potential impact of PHS-informed screening.\n\nMethodsUnited Kingdom population data were fit to a continuous model of age-specific PCa incidence. Using hazard ratios estimated from ProtecT trial data, age-specific incidence rates were calculated for percentiles of genetic risk. Incidence of higher-grade PCa (Gleason[≥]7) was estimated from age-specific data from the linked CAP trial. PHS and incidence data were combined to give a risk-equivalent age, when a man with a given PHS percentile will have risk of higher-grade PCa equivalent to that of a typical man at age 50 (50-years standard). Positive predictive value (PPV) of PSA testing was calculated using PHS-adjusted (PCa-risk-equivalent age) groups identified from ProtecT.\n\nResultsExpected age of onset of higher-grade PCa is modulated by 19 years between the 1st and 99th PHS percentiles. A man with PHS in the 99th percentile reaches 50-years-standard risk at age 41; conversely, a man in the 1st percentile reaches this risk at age 60. PPV of PSA was higher for men with higher PHS-adjusted age.\n\nConclusionsPHS informs PCa screening strategies with individualized estimates of risk-equivalent age for higher-grade PCa. Screening initiation could be adjusted according to a mans genetic hazard score, improving PPV of PSA screening.

genetics↗

bioRxiv2018

Focusing on what matters: Modulation of the human hippocampus by relational attention

Hippocampal episodic memory is fundamentally relational, consisting of links between events and the spatial and temporal contexts in which they occurred. Such relations are also important over much shorter time periods, during online visual perception. For example, how do we assess the relative spatial positions of objects, their temporal order, or the relationship between their features? Here, we investigate the role of the hippocampus in such online relational processing by manipulating visual attention to different kinds of relations in a dynamic display. While undergoing high-resolution fMRI, participants viewed two images in rapid succession on each trial and performed one of three relational tasks, judging the images relative: spatial positions, temporal onsets, or sizes. As a control, they sometimes also judged whether one image was tilted, irrespective of the other; this served as a baseline item task with no demands on relational processing. All hippocampal regions of interest (CA1, CA2/3/DG, subiculum) showed reliable deactivation when participants attended to relational vs. item information. Attention to temporal relations was associated with more robust deactivation than the other conditions. One possible interpretation of such deactivation is that it reflects hippocampal disengagement. If true, there should be reduced information content and noisier, less reliable patterns of activity in the hippocampus for the temporal vs. other tasks. Instead, analyses of multivariate activity patterns revealed more stable hippocampal representations in the temporal task. Additional analyses showed that this increased pattern similarity was not simply a reflection of the lower univariate activity. Thus, the hippocampus differentiates between relational and item processing even during online visual perception, and its representations of temporal relations in particular are robust and stable. Together, these findings suggest that the relational computations of the hippocampus, known to be important for memory, extend beyond this purpose, enabling the rapid online extraction of relational information in visual perception.

neuroscience↗

bioRxiv2018

Large-Scale Annotation of Histopathology Images from Social Media

Pathologists are responsible for rapidly providing a diagnosis on critical health issues. Challenging cases benefit from additional opinions of pathologist colleagues. In addition to on-site colleagues, there is an active worldwide community of pathologists on social media for complementary opinions. Such access to pathologists worldwide has the capacity to improve diagnostic accuracy and generate broader consensus on next steps in patient care. From Twitter we curate 13,626 images from 6,351 tweets from 25 pathologists from 13 countries. We supplement the Twitter data with 113,161 images from 1,074,484 PubMed articles. We develop machine learning and deep learning models to (i) accurately identify histopathology stains, (ii) discriminate between tissues, and (iii) differentiate disease states. Area Under Receiver Operating Characteristic is 0.805-0.996 for these tasks. We repurpose the disease classifier to search for similar disease states given an image and clinical covariates. We report precision@k=1 = 0.7618{+/-}0.0018 (chance 0.397{+/-}0.004, mean{+/-}stdev). The classifiers find texture and tissue are important clinico-visual features of disease. Deep features trained only on natural images (e.g. cats and dogs) substantially improved search performance, while pathology-specific deep features and cell nuclei features further improved search to a lesser extent. We implement a social media bot (@pathobot on Twitter) to use the trained classifiers to aid pathologists in obtaining real-time feedback on challenging cases. If a social media post containing pathology text and images mentions the bot, the bot generates quantitative predictions of disease state (normal/artifact/infection/injury/nontumor, pre-neoplastic/benign/ low-grade-malignant-potential, or malignant) and lists similar cases across social media and PubMed. Our project has become a globally distributed expert system that facilitates pathological diagnosis and brings expertise to underserved regions or hospitals with less expertise in a particular disease. This is the first pan-tissue pan-disease (i.e. from infection to malignancy) method for prediction and search on social media, and the first pathology study prospectively tested in public on social media. We will share data through pathobotology.org. We expect our project to cultivate a more connected world of physicians and improve patient care worldwide.

pathology↗

bioRxiv2018

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

BackgroundThere are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited.\n\nMethodsA combination of targeted- and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients.\n\nResultsctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first line mCRPC therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples ([≥]0.1 ctDNA fraction). Sequencing of non-repetitive intronic- and exonic regions of PTEN, RB1 and TP53 detected biallelic inactivation in 47.5%, 20.3% and 44.1% of samples with [≥]0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays.\n\nConclusionsctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenge the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.

genomics↗