Computational modeling of the physical features that influence breast cancer invasion into adipose tissue.

Breast cancer invasion into adipose tissue strongly influences disease progression and metastasis. The degree of cancer cell invasion into adipose tissue depends on both biochemical signaling and the mechanical properties of cancer cells, adipocytes, and other key components of adipose tissue. We model breast cancer invasion into adipose tissue using discrete element method simulations of active, cohesive spherical particles (cancer cells) invading into confluent packings of deformable polyhedra (adipocytes). We quantify the degree of invasion by calculating the interfacial area At between cancer cells and adipocytes. We determine the long-time value of At vs the activity and strength of the cohesion between cancer cells, as well as the mechanical properties of the adipocytes and extracellular matrix in which adipocytes are embedded. We show that the degree of invasion collapses onto a master curve as a function of the dimensionless energy scale Ec , which grows linearly with the cancer cell velocity persistence time and fluctuations, is inversely proportional to the system pressure, and is offset by the cancer cell cohesive energy. When E c > 1 , cancer cells will invade the adipose tissue, whereas for E c < 1 , cancer cells and adipocytes remain de-mixed. We also show that At decreases when the adipocytes are constrained by the ECM by an amount that depends on the spatial heterogeneity of the adipose tissue.

Comparison of treatment response measures in cutaneous sclerosis after allogeneic hematopoietic cell transplantation.

Cutaneous sclerosis, a highly morbid subtype of chronic graft vs. host disease (cGVHD), demonstrates limited treatment response under current NIH Response Measures. We explored novel sclerosis-specific response measures using Chronic GVHD Consortium data. A training cohort included patients with cutaneous sclerosis from a randomized trial of imatinib vs. rituximab, and a Consortium observational study. The validation cohort was a different Consortium observational study. Clinician-reported measures (baseline, and baseline to 6-month change) were examined for association with 6-month clinician-reported response. Patient-reported measures (baseline and baseline to 6-month change) were studied for association with 6-month patient-reported response. A total of 347 subjects were included (training 183, validation 164). While multiple skin and joint measures were associated with clinician-reported response on univariate analysis, PROM total score, PROM total score change, and NIH 0-3 skin change were retained in the final multivariate model (AUC 0.83 training, 0.75 validation). Similarly, many patient-reported measures were associated, but final multivariate analysis retained the HAP AAS, SF36 vitality change, LSS skin, and LSS skin change in the model (AUC 0.86 training, 0.75 validation). We identified which sclerosis measures have greatest association with 6-month clinician- and patient-reported treatment response, a previously unstudied area. However, given the observed performance in the validation cohorts, we conclude that further work is needed. Novel response measures may be needed to optimally assess treatment response in cutaneous sclerosis.

A Positive Psychology Intervention in Allogeneic Hematopoietic Stem Cell Transplantation Survivors (PATH): A Pilot Randomized Clinical Trial.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) survivors experience significant psychological distress and low levels of positive psychological well-being, which can undermine patient-reported outcomes (PROs), such as quality of life (QoL). Hence, we conducted a pilot randomized clinical trial to assess the feasibility and preliminary efficacy of a telephone-delivered positive psychology intervention (Positive Affect for the Transplantation of Hematopoietic stem cells intervention [PATH]) for improving well-being in HSCT survivors. METHODS: HSCT survivors who were 100 days post-HSCT for hematologic malignancy at an academic institution were randomly assigned to either PATH or usual care. PATH, delivered by a behavioral health expert, entailed 9 weekly phone sessions on gratitude, personal strengths, and meaning. We defined feasibility a priori as >60% of eligible participants enrolling in the study and >75% of PATH participants completing ≥6 of 9 sessions. At baseline and 9 and 18 weeks, patients self-reported gratitude, positive affect, life satisfaction, optimism, anxiety, depression, posttraumatic stress disorder (PTSD), QoL, physical function, and fatigue. We used repeated measures regression models and estimates of effect size (Cohen's d) to explore the preliminary effects of PATH on outcomes. RESULTS: We enrolled 68.6% (72/105) of eligible patients (mean age, 57 years; 50% female). Of those randomized to PATH, 91% completed all sessions and reported positive psychology exercises as easy to complete and subjectively useful. Compared with usual care, PATH participants reported greater improvements in gratitude (ß = 1.38; d = 0.32), anxiety (ß = -1.43; d = -0.40), and physical function (ß = 2.15; d = 0.23) at 9 weeks and gratitude (ß = 0.97; d = 0.22), positive affect (ß = 2.02; d = 0.27), life satisfaction (ß = 1.82; d = 0.24), optimism (ß = 2.70; d = 0.49), anxiety (ß = -1.62; d = -0.46), depression (ß = -1.04; d = -0.33), PTSD (ß = -2.50; d = -0.29), QoL (ß = 7.70; d = 0.41), physical function (ß = 5.21; d = 0.56), and fatigue (ß = -2.54; d = -0.33) at 18 weeks. CONCLUSIONS: PATH is feasible, with promising signals for improving psychological well-being, QoL, physical function, and fatigue in HSCT survivors. Future multisite trials that investigate PATH's efficacy are needed to establish its effects on PROs in this population.

Development, feasibility, and acceptability of a process based intervention to decrease internalized ageism.

A lifetime of exposure to ageism may be internalized in older adults, and these ageist beliefs that are directed inwards can have severe consequences. However, research on reducing internalized ageism is scarce. To address this, we designed and implemented a six-week online process-based intervention to reduce internalized ageism and to assess its feasibility. The intervention utilized a process-based therapy approach targeting psychological, behavioral, and physiological pathways through which internalized ageism negatively impacts health, as specified by stereotype embodiment theory. Intervention components included education, acceptance and commitment therapy techniques, and attributional retraining. A total of 81 older adult participants participated in the feasibility study. Most participants rated each session and the overall program as very useful after each session (average program usefulness rating of 4.54/5). Participants also attributed a wide range of novel behaviors to this intervention and stated that they felt it changed their perspectives on ageism and/or internalized ageism. Results from this study provide a promising foundation from which to advance research on interventions that address internalized ageism - a problem that has severe consequences on the health and well-being of growing numbers of older adults globally.

Reimagine Aging: A Process-Based Intervention to Decrease Internalized Ageism.

OBJECTIVES: Exposure to ageism may be internalized in older adults, and this can have severe consequences. However, little research has addressed reducing internalized ageism. Thus, Reimagine Aging, a 6-week process-based intervention to reduce internalized ageism, was designed and implemented, using education, acceptance and commitment therapy, and attributional retraining to target theoretically based mechanisms of change. METHODS: Seventy-two older adults (M = 70.4 years, SD = 6.4 years) participated in Reimagine Aging, consented to participate in this robust single-sample pilot study, and provided valid data. Participants completed questionnaires prior to, immediately following, and 2 months after the intervention. RESULTS: Participants' self-perceptions of aging (ηp2=0.37, p < .001) and perceptions of older adults (ηp2=0.27, p < .001) became significantly more positive, associated with large effect sizes. Furthermore, these positive gains were mediated by increases in psychological flexibility, mindfulness, and perceived control. DISCUSSION: This study provides initial support for this process-based intervention targeting a reduction of internalized ageism. CLINICAL IMPLICATIONS: This program has the potential to reduce the negative impact internalized ageism has on the health of older adults. Furthermore, it provides novel insights into intervention targets and tools that may be useful in achieving this reduction.

Protein folding as a jamming transition.

Proteins fold to a specific functional conformation with a densely packed hydrophobic core that controls their stability. We develop a geometric, yet all-atom model for proteins that explains the universal core packing fraction of ϕc=0.55 found in experimental measurements. We show that as the hydrophobic interactions increase relative to the temperature, a novel jamming transition occurs when the core packing fraction exceeds ϕc. The model also recapitulates the global structure of proteins since it can accurately refold to native-like structures from partially unfolded states.

Identifying the minimal sets of distance restraints for FRET-assisted protein structural modeling.

Proteins naturally occur in crowded cellular environments and interact with other proteins, nucleic acids, and organelles. Since most previous experimental protein structure determination techniques require that proteins occur in idealized, non-physiological environments, the effects of realistic cellular environments on protein structure are largely unexplored. Recently, Förster resonance energy transfer (FRET) has been shown to be an effective experimental method for investigating protein structure in vivo. Inter-residue distances measured in vivo can be incorporated as restraints in molecular dynamics (MD) simulations to model protein structural dynamics in vivo. Since most FRET studies only obtain inter-residue separations for a small number of amino acid pairs, it is important to determine the minimum number of restraints in the MD simulations that are required to achieve a given root-mean-square deviation (RMSD) from the experimental structural ensemble. Further, what is the optimal method for selecting these inter-residue restraints? Here, we implement several methods for selecting the most important FRET pairs and determine the number of pairs Nr that are needed to induce conformational changes in proteins between two experimentally determined structures. We find that enforcing only a small fraction of restraints, Nr/N≲0.08, where N is the number of amino acids, can induce the conformational changes. These results establish the efficacy of FRET-assisted MD simulations for atomic scale structural modeling of proteins in vivo. Significance: Determining protein structure in vivo is essential for understanding protein function. Most protein structures have been studied in non-physiological conditions using x-ray crystallography, NMR spectroscopy, and cryo-electron microscopy. Thus, we do not know whether the cellular environment significantly affects protein structure. We emphasize the benefits of FRET-assisted molecular dynamics simulations in characterizing protein structure in vivo at the atomic scale. We identify the minimum number of FRET pairs that can induce conformational changes in several proteins, including one that has been characterized using in-cell NMR.

A Qualitative Analysis of the Impact of Preoperative Mindfulness-Based Stress Reduction on Total Knee Arthroplasty Surgical Experiences.

We qualitatively explored the impact of preoperative mindfulness-based stress reduction (MBSR) on total knee arthroplasty (TKA) experiences. Participants (n = 10) who received MBSR prior to TKA participated in semi-structured interviews concerning their experiences with MBSR and its perceived impact on surgery. We analyzed interviews according to reflexive thematic analysis, and coded data into three main themes: 1) Impact of MBSR on surgery experiences; 2) Contributors to change; and 3) Motivations for participation. Participants noted they were able to relax, feel more confident, and cope more effectively during the preoperative period, and that others in their lives noticed positive changes following their participation in MBSR. Participants' openness to mindfulness and health-related beliefs and may have contributed to the positive impacts they experienced from MBSR. Participants described being motivated to participate in MBSR to help them prepare for their surgery and to learn new coping strategies. Participants described a strong level of commitment to the intervention. With further research, integration of MBSR into prehabilitation for TKA may be appropriate.

Active infection at the time of CD34+ selected stem cell boost is associated with treatment failure and poor survival.

BACKGROUND: The use of CD34+ selected stem cell boost (SCB) post allogeneic hematopoietic cell transplant (alloHCT) has been increasing. Predictors of treatment failure following SCB, both in the context of poor graft function (PGF) or other settings, are not well-characterized. We report among the largest single center retrospective experiences of the use of SCB and evaluate potential predictors of response and outcomes. METHODS: 58 patients who underwent HCT between 2015 and 2022 and who received SCB were identified. The indication for SCB was predominantly PGF, defined as the presence of 2 or more cytopenias for at least two consecutive weeks beyond day +14 after alloHCT in the presence of ≤ 30% bone marrow cellularity and ≥ 90% donor myeloid chimerism in the absence of morphological disease. RESULTS: The median dose of infused CD34+ selected SCB products was 3.88 x 106 CD34+ cells/kg (range: 0.99-9.92). The median 2-year OS and NRM following SCB was 47% and 38%, respectively. The cumulative incidences of 6-month grade III-IV acute and 2-year moderate-severe chronic GVHD following SCB were 3.4% and 12%, respectively. Overall response (CR + PR) was attained in 36/58 (62%) patients, and in 69% with PGF. On multivariable analysis, an active infection at the time of SCB was the greatest predictor of poor response and survival (p=0.013) following SCB. CONCLUSION: SCB can restore hematopoiesis in the majority of patients, particularly for those with poor graft function in whom there is no active infection at infusion.

Managing emergency department patients with opioid use disorder.

As the United States continues to grapple with the opioid crisis, emergency clinicians are on the front lines of managing patients with opioid use disorder. This issue reviews tools and best practices in emergency department management of patients with opioid overdose and opioid withdrawal, and how substance use history will inform treatment planning and disposition. As growing evidence shows that medications for opioid use disorder (MOUD)- buprenorphine, methadone, and naltrexone-can have lasting impacts on patients' addiction recovery, strategies for assessing patient readiness for MOUD and overcoming barriers to emergency department initiation of these medications are reviewed. Newer approaches to buprenorphine dosing (high-dose, low-dose, home induction, and long-acting injectable dosing) are also reviewed.

The addition of a spatial auditory cue improves spatial updating in a virtual reality navigation task.

Auditory cues are integrated with vision and body-based self-motion cues for motion perception, balance, and gait, though limited research has evaluated their effectiveness for navigation. Here, we tested whether an auditory cue co-localized with a visual target could improve spatial updating in a virtual reality homing task. Participants navigated a triangular homing task with and without an easily localizable spatial audio signal co-located with the home location. The main outcome was unsigned angular error, defined as the absolute value of the difference between the participant's turning response and the correct response towards the home location. Angular error was significantly reduced in the presence of spatial sound compared to a head-fixed identical auditory signal. Participants' angular error was 22.79° in the presence of spatial audio and 30.09° in its absence. Those with the worst performance in the absence of spatial sound demonstrated the greatest improvement with the added sound cue. These results suggest that auditory cues may benefit navigation, particularly for those who demonstrated the highest level of spatial updating error in the absence of spatial sound.

The "Pathology Passport": a redesign of the pathology elective experience to enhance medical student engagement and understanding of pathology as a clinical practice.

Given the trend of condensed preclinical curricula in medical schools nationwide, creating meaningful pathology learning experiences within the clinical and post-clinical curricula is important to both enhance student understanding of how pathology integrates into daily healthcare delivery and spark potential career interest in the field. While pathology electives are a common modality for medical students to explore pathology, they frequently render students passive observers of daily clinical workflows (often in grossing and sign-out rooms of surgical pathology). This can have a negative impact on student engagement with their pathology clinical teams and on their satisfaction with the pathology elective experience. As such, we aim to describe our institutional experience in creating a new pathology elective structure, the "Pathology Passport," which leverages intentional student engagement with existing pathology workflows and introduces a means of criterion-based grading. Data collected from student pre- and post-elective surveys demonstrate the elective's positive impact on students' perceived understanding of pathology and their overall learning experience. We hope that our resources can be leveraged at other institutions and even other non-pathology clerkship/elective rotations to promote active engagement of students in clinical workflows while providing clear expectations for grading.

Unveiling clinical applications of bacterial extracellular vesicles as natural nanomaterials in disease diagnosis and therapeutics.

Bacterial extracellular vesicles (BEVs) are naturally occurring bioactive membrane-bound nanoparticles released by both gram-negative and gram-positive bacterial species, exhibiting a multifaceted role in mediating host-microbe interactions across various physiological conditions. Increasing evidence supports BEVs as essential mediators of cell-to-cell communicaiton, influencing bacterial pathogenicity, disease mechanisms, and modulating the host immune response. However, the extent to which these BEV-mediated actions can be leveraged to predict disease onset, guide treatment strategies, and determine clinical outcomes remains uncertain, particularly in terms of their clinical translation potentials. This review briefly describes BEV biogenesis and their internalisation by recipient cells and summarises methods for isolation and characterization, essential for understanding their composition and cargo. Further, it discusses the potential of biofluid-associated BEVs as biomarkers for various diseases, spanning both cancer and non-cancerous conditions. Following this, we outline the ongoing human clinical trials of using BEVs for vaccine development. In addition to disease diagnostics, this review explores the emerging research of using natural or engineered BEVs as smart nanomaterials for applications in anti-cancer therapy and bone regeneration. This discussion extends to key factors for unlocking the clinical potential of BEVs, such as standardization of BEV isolation and characterisation, as well as other hurdles in translating these findings to the clinical setting. We propose that addressing these hurdles through collaborative research efforts and well-designed clinical trials holds the key to fully harnessing the clinical potential of BEVs. As this field advances, this review suggests that BEV-based nanomedicine has the potential to revolutionize disease management, paving the way for innovative diagnosis, therapeutics, and personalized medicine approaches. STATEMENT OF SIGNIFICANCE: Extracellular vesicles (EVs) from both host cells and bacteria serve as multifunctional biomaterials and are emerging in the fields of biomedicine, bioengineering, and biomaterials. However, the majority of current studies focus on host-derived EVs, leaving a gap in comprehensive research on bacteria-derived EVs (BEVs). Although BEVs offer an attractive option as nanomaterials for drug delivery systems, their unique nanostructure and easy-to-modify functions make them a potential method for disease diagnosis and treatment as well as vaccine development. Our work among the pioneering studies investigating the potential of BEVs as natural nanobiomaterials plays a crucial role in both understanding the development of diseases and therapeutic interventions.

Perceived control moderates the internalized stigma model of seeking mental health services in distressed older adults.

Older adults are especially unlikely to seek mental health services, and internalized stigma is a key reason why. However, little research has investigated which older adults are particularly likely to have stigma influence help-seeking. To address this, we tested whether perceived control (PC) moderates an internalized stigma model in which public stigma is internalized as self-stigma, which negatively predicts help-seeking attitudes and help-seeking intentions. We employed moderated mediation analysis of cross-sectional, secondary data from 348 psychologically distressed Canadian adults aged 65 years and older. Participants completed an online survey that included measures of public stigma of help-seeking, self-stigma of help-seeking, help-seeking attitudes, conditional help-seeking intentions, psychological distress, and PC. PC emerged as a moderator of the internalized stigma model. Those lower in PC were more likely to have public stigma negatively predict help-seeking intentions through the serial mediation of (a) self-stigma and (b) help-seeking attitudes. Further, those lower in PC were more likely to have public stigma internalized as self-stigma and more likely to have negative help-seeking attitudes predict lower help-seeking intentions. Finally, those lower in PC also had lower help-seeking intentions in the face of low levels of self-stigma. These results contribute to a nuanced understanding of which older adults are unlikely to seek help. Identifying PC as a moderator of the internalized stigma model suggests that interventions that enhance PC should protect against public stigma's internalization and improve help-seeking behaviors for older adults who need such help. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Quadriceps Tendon Autograft ACL Reconstruction With Suture Tape Augmentation: Safe Results Based on Minimum 2-Year Follow-up MRI.

Background: The potential intra-articular effects of ≥1 year after anterior cruciate ligament reconstruction (ACLR) with independent suture tape augmentation (STA) are not fully understood. Purpose: To investigate whether incorporating suture tape in an all-soft tissue quadriceps tendon autograft (QTA) ACLR leads to satisfactory patient outcomes while having no intra-articular side effects as determined by magnetic resonance imaging (MRI). Study Design: Case series; Level of evidence, 4. Methods: Included were 25 patients with a mean age of 19.9 years (95% CI, 17.3-22.5 years) who underwent QTA ACLR with STA between 2016 and 2019. All patients underwent MRI at ≥1 year postoperatively and had at least a 2-year follow-up (mean, 28 months [95% CI, 26.5-29.5 months]) that included physical examination with anterior laxity testing with KT-1000 arthrometer, radiographs, and patient-reported outcome measures (PROMs). At the final follow-up, the minimal clinically important difference (MCID) and the Patient Acceptable Symptom State (PASS) for applicable PROMs were applied to each patient. Postoperative graft and joint integrity were assessed using the Howell classification and the MRI Osteoarthritis Knee Score (MOAKS) joint effusion/synovitis grade. The Mann-Whitney U test for continuous variables and the chi-square or the Fisher exact test for categorical variables were used for statistical analyses. Results: The MRI assessment of the grafts demonstrated intact grafts in all patients. Overall, 96% of patients demonstrated grades 0 or 1 MOAKS for joint effusion/synovitis. All patient outcomes significantly improved from preoperatively to the final follow-up (P < .001), except for the Marx score, which decreased significantly (14.2 [95% CI, 12.7-15.8] vs 9.72 [95% CI, 7.3-12.2]; P = .0014). At least 68% of the patients achieved the MCID threshold, and 92% achieved the PASS threshold for all applicable PROMs. Conclusion: QTA ACLR with STA did not demonstrate adverse intra-articular changes on MRI at ≥1 year postoperatively. In addition, STA did not appear to negatively affect PROMs.

Connecting polymer collapse and the onset of jamming.

Previous studies have shown that the interiors of proteins are densely packed, reaching packing fractions that are as large as those found for static packings of individual amino-acid-shaped particles. How can the interiors of proteins take on such high packing fractions given that amino acids are connected by peptide bonds and many amino acids are hydrophobic with attractive interactions? We investigate this question by comparing the structural and mechanical properties of collapsed attractive disk-shaped bead-spring polymers to those of three reference systems: static packings of repulsive disks, of attractive disks, and of repulsive disk-shaped bead-spring polymers. We show that the attractive systems quenched to temperatures below the glass transition T≪T_{g} and static packings of both repulsive disks and bead-spring polymers possess similar interior packing fractions. Previous studies have shown that static packings of repulsive disks are isostatic at jamming onset, i.e., the number of interparticle contacts N_{c} matches the number of degrees of freedom, which strongly influences their mechanical properties. We find that repulsive polymer packings are hypostatic at jamming onset (i.e., with fewer contacts than degrees of freedom) but are effectively isostatic when including stabilizing quartic modes, which give rise to quartic scaling of the potential energy with displacements along these modes. While attractive disk and polymer packings are often considered hyperstatic with excess contacts over the isostatic number, we identify a definition for interparticle contacts for which they can also be considered as effectively isostatic. As a result, we show that the mechanical properties (e.g., scaling of the potential energy with excess contact number and low-frequency contribution to the density of vibrational modes) of weakly attractive disk and polymer packings are similar to those of isostatic repulsive disk and polymer packings. Our results demonstrate that static packings generated via attractive collapse or compression of repulsive particles possess similar structural and mechanical properties.

Pathogenic Gene Variants Identified in Patients Presenting With Perthes or Perthes-like Hip Disorder.

AIMS: Legg-Calve-Perthes disease (LCPD) is a diagnosis of exclusion. Various conditions, such as skeletal dysplasias, can closely mimic LCPD and these must be ruled out to provide appropriate treatment, prognosis, and counseling. Traditionally, genetic testing has not been readily available in pediatric orthopaedic practice. Furthermore, the clinical value of genetic testing patients with LCPD is unclear. With the advance of next-generation sequencing (NGS) technology, genetic testing has become clinically available as a lab test. The purposes of this study were to assess the clinical utility of genetic testing in select patients with LCPD and to determine the patient characteristics of those who tested positive for skeletal dysplasia. METHODS: This is an IRB-approved, retrospective study of 63 consecutive patients who presented with Perthes-like symptoms and/or x-ray findings and who had genetic testing. The reason(s) for genetic testing included bilateral hip disease, family history of LCPD, short stature, suspected skeletal dysplasia, atypical radiographic findings, and/or combinations of these reasons. RESULTS: Of the 63 patients, 19 patients (30%) were found to have a pathogenic gene variant. In 8 of the 19, a variety of skeletal dysplasia was diagnosed. The remaining 11 patients were found to be carriers of autosomal recessive disorders. All 19 patients were referred for genetic counseling. Of the 8 patients found to have skeletal dysplasia, 3 had bilateral disease, 3 were <10 percentile in height, 1 had a family history of "LCPD," and 3 had atypical x-ray findings. In addition to the pathogenic variants, numerous genetic variants of unknown significance were found with 2 gene variants showing exactly the same variant found in 2 unrelated patients. CONCLUSIONS: With 30% of the patients showing pathogenic results, genetic testing of select patients with Perthes-like disease is valuable in detecting an underlying genetic disorder or a carrier status of a genetic disorder.

Computational modeling of the physical features that influence breast cancer invasion into adipose tissue.

Breast cancer invasion into adipose tissue strongly influences disease progression and metastasis. The degree of cancer cell invasion into adipose tissue depends on numerous biochemical and physical properties of cancer cells, adipocytes, and other key components of adipose tissue. We model breast cancer invasion into adipose tissue as a physical process by carrying out simulations of active, cohesive spherical particles (cancer cells) invading into confluent packings of deformable polyhedra (adipocytes). We quantify the degree of invasion by calculating the interfacial area At between cancer cells and adipocytes. We determine the long-time value of At versus the activity and strength of the cohesion between cancer cells, as well as mechanical properties of the adipocytes and extracellular matrix (ECM) in which the adipocytes are embedded. We show that the degree of invasion collapses onto a master curve by plotting it versus a dimensionless energy scale Ec, which grows linearly with mean-square fluctuations and persistence time of the cancer cell velocities, is inversely proportional to the pressure of the system, and has an offset that increases with the cancer cell cohesive energy. The condition, Ec≫1, indicates that cancer cells will invade the adipose tissue, whereas for Ec≪1, the cancer cells and adipocytes remain demixed. We also show that constraints on adipocyte positions by the ECM decrease At relative to that obtained for unconstrained adipocytes. Finally, spatial heterogeneity in structural and mechanical properties of the adipocytes in the presence of ECM impedes invasion relative to adipose tissue with uniform properties.

Allopurinol Disrupts Purine Metabolism to Increase Damage in Experimental Colitis.

Inflammatory bowel disease (IBD) is marked by a state of chronic energy deficiency that limits gut tissue wound healing. This energy shortfall is partially due to microbiota dysbiosis, resulting in the loss of microbiota-derived metabolites, which the epithelium relies on for energy procurement. The role of microbiota-sourced purines, such as hypoxanthine, as substrates salvaged by the colonic epithelium for nucleotide biogenesis and energy balance, has recently been appreciated for homeostasis and wound healing. Allopurinol, a synthetic hypoxanthine isomer commonly prescribed to treat excess uric acid in the blood, inhibits the degradation of hypoxanthine by xanthine oxidase, but also inhibits purine salvage. Although the use of allopurinol is common, studies regarding how allopurinol influences the gastrointestinal tract during colitis are largely nonexistent. In this work, a series of in vitro and in vivo experiments were performed to dissect the relationship between allopurinol, allopurinol metabolites, and colonic epithelial metabolism and function in health and during disease. Of particular significance, the in vivo investigation identified that a therapeutically relevant allopurinol dose shifts adenylate and creatine metabolism, leading to AMPK dysregulation and disrupted proliferation to attenuate wound healing and increased tissue damage in murine experimental colitis. Collectively, these findings underscore the importance of purine salvage on cellular metabolism and gut health in the context of IBD and provide insight regarding the use of allopurinol in patients with IBD.