Clonal Lineage Tracing with Somatic Delivery of Recordable Barcodes Reveals Migration Histories of Metastatic Prostate Cancer.

The patterns by which primary tumors spread to metastatic sites remain poorly understood. Here, we define patterns of metastatic seeding in prostate cancer (PCa) using a novel injection-based mouse model - EvoCaP (Evolution in Cancer of the Prostate), featuring aggressive metastatic cancer to bone, liver, lungs, and lymph nodes. To define migration histories between primary and metastatic sites, we used our EvoTraceR pipeline to track distinct tumor clones containing recordable barcodes. We detected widespread intratumoral heterogeneity from the primary tumor in metastatic seeding, with few clonal populations (CPs) instigating most migration. Metastasis-to-metastasis seeding was uncommon, as most cells remained confined within the tissue. Migration patterns in our model were congruent with human PCa seeding topologies. Our findings support the view of metastatic PCa as a systemic disease driven by waves of aggressive clones expanding their niche, infrequently overcoming constraints that otherwise keep them confined in the primary or metastatic site.

An adapted transdiagnostic sleep and circadian intervention for adults with excess weight and suboptimal sleep health: pilot study results.

Study Objectives: This single-arm, mixed-methods, pilot study examined the feasibility and preliminary efficacy of an adapted version of the transdiagnostic intervention for sleep and circadian dysfunction (TranS-C) on multidimensional sleep health (MDSH) in a sample of adults with excess weight and suboptimal sleep health. Methods: Participants received up to eight, weekly, remotely delivered, tailored TranS-C sessions. At pre- and post-intervention, the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and 7 days of Fitbit data were used to evaluate changes in sleep dimensions (regularity, alertness, timing, satisfaction, duration, and efficiency) and the composite MDSH score. Study feasibility examined recruitment, data collection, and intervention engagement (completion of core TranS-C sessions). Acceptability of the intervention was assessed with semi-structured interviews, which were analyzed using thematic analysis. Results: From 85 referrals, 11 individuals were eligible, and 10 completed the study. All intervention participants completed the measures needed to calculate their composite MDSH score and completed the core intervention sessions. Themes from interviews support the intervention's remote delivery approach, applicability of the information provided, and impact on self-reported health. The intervention resulted in a large improvement in the mean composite MDSH score (Cohen's d = 1.17). Small-to-large effects were also observed for individual sleep health dimensions except for timing. Conclusions: Adapted TranS-C is acceptable for adults with excess weight and suboptimal sleep health and may be effective at improving short-term MDSH. With changes to recruitment methods, a larger study is feasible. Limitations include the small sample size and the lack of a control condition.

A dynamic microRNA profile that tracks a chemotherapy resistance phenotype in osteosarcoma. Implications for novel therapeutics.

Osteosarcoma is a rare primary bone tumor for which no significant therapeutic advancement has been made since the late 1980s despite ongoing efforts. Overall, the five-year survival rate remains about 65%, and is much lower in patients with tumors unresponsive to methotrexate, doxorubicin, and cisplatin therapy. Genetic studies have not revealed actionable drug targets, but our group, and others, have reported that epigenomic biomarkers, including regulatory RNAs, may be useful prognostic tools for osteosarcoma. We tested if microRNA (miRNA) transcriptional patterns mark the transition from a chemotherapy sensitive to resistant tumor phenotype. Small RNA sequencing was performed using 14 patient matched pre-chemotherapy biopsy and post-chemotherapy resection high-grade osteosarcoma frozen tumor samples. Independently, small RNA sequencing was performed using 14 patient matched biopsy and resection samples from untreated tumors. Separately, miRNA specific Illumina DASL arrays were used to assay an independent cohort of 65 pre-chemotherapy biopsy and 26 patient matched post-chemotherapy resection formalin fixed paraffin embedded (FFPE) tumor samples. mRNA specific Illumina DASL arrays were used to profile 37 pre-chemotherapy biopsy and five post-chemotherapy resection FFPE samples, all of which were also used for Illumina DASL miRNA profiling. The National Cancer Institute Therapeutically Applicable Research to Generate Effective Treatments dataset, including PCR based miRNA profiling and RNA-seq data for 86 and 93 pre-chemotherapy tumor samples, respectively, was also used. Paired differential expression testing revealed a profile of 17 miRNAs with significantly different transcriptional levels following chemotherapy. Genes targeted by the miRNAs were differentially expressed following chemotherapy, suggesting the miRNAs may regulate transcriptional networks. Finally, an in vitro pharmacogenomic screen using miRNAs and their target transcripts predicted response to a set of candidate small molecule therapeutics which potentially reverse the chemotherapy resistance phenotype and synergize with chemotherapy in otherwise treatment resistant tumors. Importantly, these novel therapeutic targets are distinct from targets identified by a similar pharmacogenomic analysis of previously published prognostic miRNA profiles from pre chemotherapy biopsy specimens.

Coaching ribosome biogenesis from the nuclear periphery.

Severe invagination of the nuclear envelope is a hallmark of cancers, aging, neurodegeneration, and infections. However, the outcomes of nuclear invagination remain unclear. This work identified a new function of nuclear invagination: regulating ribosome biogenesis. With expansion microscopy, we observed frequent physical contact between nuclear invaginations and nucleoli. Surprisingly, the higher the invagination curvature, the more ribosomal RNA and pre-ribosomes are made in the contacted nucleolus. By growing cells on nanopillars that generate nuclear invaginations with desired curvatures, we can increase and decrease ribosome biogenesis. Based on this causation, we repressed the ribosome levels in breast cancer and progeria cells by growing cells on low-curvature nanopillars, indicating that overactivated ribosome biogenesis can be rescued by reshaping nuclei. Mechanistically, high-curvature nuclear invaginations reduce heterochromatin and enrich nuclear pore complexes, which promote ribosome biogenesis. We anticipate that our findings will serve as a foundation for further studies on nuclear deformation.

Evaluating the Association of the Increase in the WIC Cash Value Benefit on the Diversity of MyPlate Fruits and Vegetables Redeemed and Consumed By Children in Low-Income Households.

Background: Fruits and vegetables (FV) are a critical source of nutrients, yet children in the United States are not meeting the Dietary Guidelines for Americans (DGA). The monthly FV cash value benefit (CVB) included in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC)'s food package to support child FV intake (FVI) received a substantial increase for economic relief during the COVID-19 pandemic. Objectives: To evaluate how an expansion of the monthly WIC CVB to purchase FV for WIC children ages 1-4 y is associated with diversity in FV redeemed, and how changes in redeemed FV are related to FVI. Methods: Caregivers representing 1463 WIC-participating children recruited from Los Angeles County, California, completed surveys during the CVB augmentation (T1: CVB = $9/mo; T2 = $35/mo; T3 = $24/mo). Redeemed price look-up codes (PLUs), corresponding to a food item, were assigned to its corresponding MyPlate FV group. Multivariable generalized estimating equation regression models assessed changes in amount and diversity of FV redemption across MyPlate groups and associations between changes in FV diversity and changes in FVI. Results: Slightly over half of all households were food insecure (55%), half of the children were female (52%), and most were Hispanic (78%). Compared with T1, significant increases in the number of PLUs and dollars redeemed were observed in most MyPlate FV groups. From T1 to T2, significant increases in diversity scores were observed for total fruit (ß: 1.6 pts; 95% confidence interval [CI]: 1.4, 1.7), total vegetable (ß: 3.6 pts; 95%CI: 3.4, 3.9), and total FV (ß:7.8 pts; 95%CI: 7.4, 8.2). Similarly, increases in diversity score were observed at T3 compared with T1. Changes in FV diversity redeemed were not associated with changes in FVI. Conclusions: During the CVB augmentation, WIC participants redeemed a greater amount and variety of FV according to DGA MyPlate recommendations, supporting its permanent increase.

MRI free water mediates the association between water exchange rate across the blood brain barrier and executive function among older adults.

Vascular risk factors contribute to cognitive aging, with one such risk factor being dysfunction of the blood brain barrier (BBB). Studies using non-invasive magnetic resonance imaging (MRI) techniques, such as diffusion prepared arterial spin labeling (DP-ASL), can estimate BBB function by measuring water exchange rate (kw). DP-ASL kw has been associated with cognition, but the directionality and strength of the relationship is still under investigation. An additional variable that measures water in extracellular space and impacts cognition, MRI free water (FW), may help explain prior findings. A total of 94 older adults without dementia (Mean age = 74.17 years, 59.6% female) underwent MRI (DP-ASL, diffusion weighted imaging (DWI)) and cognitive assessment. Mean kw was computed across the whole brain (WB), and mean white matter FW was computed across all white matter. The relationship between kw and three cognitive domains (executive function, processing speed, memory) was tested using multiple linear regression. FW was tested as a mediator of the kw-cognitive relationship using the PROCESS macro. A positive association was found between WB kw and executive function [F(4,85) = 7.81, p < .001, R2= 0.269; ß = .245, p = .014]. Further, this effect was qualified by subsequent results showing that FW was a mediator of the WB kw-executive function relationship (indirect effect results: standardized effect = .060, bootstrap confidence interval = .0006 to .1411). Results suggest that lower water exchange rate (kw) may contribute to greater total white matter (WM) FW which, in turn, may disrupt executive function. Taken together, proper fluid clearance at the BBB contributes to higher-order cognitive abilities.

Procedural and Intermediate-term Results of the Electroanatomical-guided Cardioneuroablation for the Treatment of Supra-Hisian Second- or Advanced-degree Atrioventricular Block: the PIRECNA multicentre registry.

AIMS: Prior case series showed promising results for cardioneuroablation in patients with vagally induced atrioventricular blocks (VAVBs). We aimed to examine the acute procedural characteristics and intermediate-term outcomes of electroanatomical-guided cardioneuroablation (EACNA) in patients with VAVB. METHODS AND RESULTS: This international multicentre retrospective registry included data collected from 20 centres. Patients presenting with symptomatic paroxysmal or persistent VAVB were included in the study. All patients underwent EACNA. Procedural success was defined by the acute reversal of atrioventricular blocks (AVBs) and complete abolition of atropine response. The primary outcome was occurrence of syncope and daytime second- or advanced-degree AVB on serial prolonged electrocardiogram monitoring during follow-up. A total of 130 patients underwent EACNA. Acute procedural success was achieved in 96.2% of the cases. During a median follow-up of 300 days (150, 496), the primary outcome occurred in 17/125 (14%) cases with acute procedural success (recurrence of AVB in 9 and new syncope in 8 cases). Operator experience and use of extracardiac vagal stimulation were similar for patients with and without primary outcomes. A history of atrial fibrillation, hypertension, and coronary artery disease was associated with a higher primary outcome occurrence. Only four patients with primary outcome required pacemaker placement during follow-up. CONCLUSION: This is the largest multicentre study demonstrating the feasibility of EACNA with encouraging intermediate-term outcomes in selected patients with VAVB. Studies investigating the effect on burden of daytime symptoms caused by the AVB are required to confirm these findings.

Hotspots of kidney failure: Analysing Australian metropolitan dialysis demand for service planning.

OBJECTIVE: To locate incident hotspots of dialysis demand in Australian capital cities and measure association with prevalent dialysis demand and socioeconomic disadvantage. METHODS: A retrospective cohort study used Australia and New Zealand Dialysis and Transplant Registry data on people commencing dialysis for kidney failure (KF) resident in an Australian capital city, 1 January 2001 - 31 December 2021. Age-sex-standardised dialysis incidence was estimated by Statistical Area Level 3 (SA3) and dialysis prevalence by SA2. RESULTS: A total of 32,391 people commencing dialysis were referenced to SA3s within city metropolitan areas based on residential postcode. Incident hotspots were located in Western Sydney. The highest average annual change of standardised incidence was 8.3 per million people (false discovery rate-corrected 95% CI 1.0,15.7) in Mount Druitt, reflecting a 263% increase in absolute demand from 2001-3 to 2019-21. Incident dialysis for diabetic kidney disease contributed substantially to total growth. Incident hotspots were co-located with areas where prevalent dialysis demand was associated with socioeconomic deprivation. CONCLUSIONS: Novel spatial analyses of geo-referenced registry data located hotspots of kidney failure and associated socio-demographic and comorbid states. IMPLICATIONS FOR PUBLIC HEALTH: These analyses advance current abilities to plan dialysis capacity at a local level. Hotspots can be targeted for prevention and slowing the progression of kidney disease.

Mobile App-Based Mindfulness Intervention for Addressing Psychological Distress Among Survivors of Hospitalization for COVID-19 Infection.

BACKGROUND: Psychological distress symptoms are present and persistent among many patients who survive a critical illness like COVID-19. RESEARCH QUESTION: Could a self-directed mobile app-delivered mindfulness intervention be feasibly and rapidly implemented within a clinical trials network to reduce distress symptoms? STUDY DESIGN AND METHODS: A randomized clinical trial was conducted between January 2021 and May 2022 at 29 US sites and included survivors of hospitalization due to COVID-19-related illness with elevated symptoms of depression at discharge. Participants were randomized to intervention or usual care control. The intervention consisted of four themed weeks of daily audio, video, and text content. All study procedures were virtual. The primary outcome was depression symptoms assessed with the Patient Health Questionnaire 9 at 3 months. Secondary outcomes included anxiety (Generalized Anxiety Disorder 7-item scale), quality of life (EQ-5D), and adherence. We used general linear models to estimate treatment arm differences in outcomes over time. RESULTS: Among 56 randomized participants (mean age ± SD, 51.0 ± 13.2 years; 38 female [67.9%]; 14 Black participants [25%]), 45 (intervention: n = 23 [79%]; control: n = 22 [81%]) were retained at 6 months. There was no difference in mean improvement between intervention and control participants at 3 months in Patient Health Questionnaire 9 (-0.5 vs 0.1), Generalized Anxiety Disorder 7-item scale (-0.3 vs 0.1), or EQ-5D (-0.03 vs 0.02) scores, respectively; 6-month results were similar. Only 15 participants (51.7%) initiated the intervention, whereas the mean number ± SD of the 56 prescribed intervention activities completed was 12.0 ± 15.2. Regulatory approvals delayed trial initiation by nearly a year. INTERPRETATION: Among survivors of COVID-19 hospitalization with elevated psychological distress symptoms, a self-directed mobile app-based mindfulness intervention had poor adherence. Future psychological distress interventions mobilized at broad scale should focus efforts on patient engagement and regulatory simplification to enhance success. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04581200; URL: www.clinicaltrials.gov.

Cerebrovascular reactivity MRI as a biomarker for cerebral small vessel disease-related cognitive decline: Multi-site validation in the MarkVCID Consortium.

INTRODUCTION: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis. METHODS: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes. RESULTS: CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function. DISCUSSION: The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID. HIGHLIGHTS: This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection.

Scalar and Tensor Charmonium Resonances in Coupled-Channel Scattering from Lattice QCD.

We determine J^{PC}=0^{++} and 2^{++} hadron-hadron scattering amplitudes in the charmonium energy region up to 4100 MeV using lattice QCD, a first-principles approach to QCD. Working at m_{π}≈391 MeV, more than 200 finite-volume energy levels are computed and these are used in extensions of the Lüscher formalism to determine infinite-volume coupled-channel scattering amplitudes. We find that this energy region contains a single χ_{c0} and a single χ_{c2} resonance. Both are found as pole singularities on the closest unphysical Riemann sheet, just below 4000 MeV with widths around 70 MeV. The largest couplings are to kinematically closed D^{*}D[over ¯]^{*} channels in S-wave, and couplings to several decay channels consisting of pairs of open-charm mesons are found to be large and significant in both cases. Above the ground state χ_{c0}, no other scalar bound states or near-DD[over ¯] threshold resonances are found, in contrast to several theoretical and experimental studies.

Ultrasonography of the suspensory ligament branches in yearling and 2-year-old Thoroughbred sales horses: Prevalence, progression of findings and associations with racing performance.

BACKGROUND: Equine suspensory ligament branch (branch) ultrasonography is becoming increasingly commonplace presale. No ultrasonographical branch reference data exists for Thoroughbred sales horses. OBJECTIVES: To define the prevalence of ultrasonographical findings in the forelimb suspensory branches of yearling and 2-year-old sales Thoroughbreds and to analyse associations with racing performance. To track changes in branch findings between 1 and 2 years of age in horses that present for sale at both ages. STUDY DESIGN: Prospective cohort study using an enrolled sample. METHODS: Horses were enrolled from a 2016 yearling sale and five 2017 2-year-old sales with consignor permission. Ultrasonography was performed immediately prior to the sales. Ultrasonographical findings relating to branch size, fibrillar pattern, the presence of hyperechoic foci, periligamentar tissue thickness and the adjacent proximal sesamoid bone surface were examined. Associations with racing performance from 2 to 4 years of age were investigated using multivariate regression analyses. Clinical follow-up was sought to ascertain why horses that did not race never started. RESULTS: A total of 593 sales yearlings and 367 2-year-olds had forelimb branch ultrasonography performed. Grade ≥2 fibrillar branch change was present in 8.9% of yearlings and 14.4% of 2-year-olds. A 0.25 cm increase in branch width was associated with a 49-day delayed start to racing careers (P < 0.001, 95% confidence interval (95% CI): 21-77 days). The presence of grade 2 hyperechoic foci was associated with significantly lower total earnings (P = 0.01, 95% CI: $2000-$16 022) and lower earnings per start (P = 0.003, 95% CI: $349-$1718) in United States Dollars. Grade 3 fibrillar branch change had clinically important reductions in the probability of racing, the calibre of racing performance and earnings. Grade 1 fibrillar pattern was associated with significantly higher earnings per start (P = 0.004, 95% CI: $2641-$5759). MAIN LIMITATIONS: The findings are applicable to horses prepared for public auction and deemed fit to be entered for sale. The results may underestimate the proportion of severe lesions in horses not entered for sale. CONCLUSIONS: Reference values specific to young Thoroughbreds have been established. Grade 1 fibrillar branch change should be regarded as an acceptable appearance in sales yearlings and 2-year-olds. Approximately one-third of grade 2 yearling branches progressed to a grade 3 lesion. Evidence of enlarged branch width and grade 2 hyperechoic foci at 2-year-old sales constitute a risk to racing performance.

Overcoming passivation through improved mass transport in dense ionic fluids.

Deep Eutectic Solvents (DESs) have recently been shown to be part of a dense ionic fluid continuum between ionic liquids and concentrated aqueous brines. Charge transport was shown to be governed by fluidity, with no discontinuity between molar conductivity and fluidity irrespective of cation, charge density or ionic radius. By adjusting the activity of water and chloride ions, mass transport, speciation and reactivity can be altered. It has been shown that while brines provide a high chloride content at a lower viscosity than DESs, unlike DESs, brines are unable to prevent metal passivation due to their high water content. This results in the possibility to impart a level of selectivity towards metal dissolution (or passivation) when processing mixed metal materials. Forced convection can be used to avoid the issue of slow mass transport in viscous media, and the use of jets or targeted ultrasound are effective methods for overcoming this issue. High-powered ultrasound was applied to copper, cobalt, and aluminium electrodes undergoing anodic dissolution, and linear sweep voltammetry showed a linear current-voltage response at potentials anodic of the oxidation potential under sonication, with total charge passed being 5 to 134 times greater than under silent conditions. Application of ultrasound to silver and nickel electrodes displayed an initial linear current-voltage response, but the increased water content of the brines resulted in passivation. Mass transport throughout the bulk solution is governed by the forced convection imparted by the ultrasound and ionic species must only migrate across the electrical double layer. It is shown that the anodic dissolution of a range of metals classically expected to passivate, e.g. aluminium, can be significantly accelerated under insonation conditions.

Iron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer.

Iron accumulation in tumors contributes to disease progression and chemoresistance. While targeting this process can influence various hallmarks of cancer, the immunomodulatory effects of iron chelation in the tumor microenvironment are unknown. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, unleashes innate immune responses that restrain ovarian cancer. Deferiprone reprogrammed ovarian cancer cells towards an immunostimulatory state characterized by production of type I interferon (IFN) and overexpression of molecules that activate natural killer (NK) cells. Mechanistically, these effects were driven by innate sensing of mitochondrial DNA in the cytosol and concomitant activation of nuclear DNA damage responses triggered upon iron chelation. Deferiprone synergized with chemotherapy and prolonged the survival of mice with ovarian cancer by bolstering type I IFN responses that drove NK cell-dependent control of metastatic disease. Hence, iron chelation may represent an alternative immunotherapeutic strategy for malignancies that are refractory to current T cell-centric modalities.

Confinement of excited states in two-dimensional, in-plane, quantum heterostructures.

Two-dimensional (2D) semiconductors are promising candidates for optoelectronic application and quantum information processes due to their inherent out-of-plane 2D confinement. In addition, they offer the possibility of achieving low-dimensional in-plane exciton confinement, similar to zero-dimensional quantum dots, with intriguing optical and electronic properties via strain or composition engineering. However, realizing such laterally confined 2D monolayers and systematically controlling size-dependent optical properties remain significant challenges. Here, we report the observation of lateral confinement of excitons in epitaxially grown in-plane MoSe2 quantum dots (~15-60 nm wide) inside a continuous matrix of WSe2 monolayer film via a sequential epitaxial growth process. Various optical spectroscopy techniques reveal the size-dependent exciton confinement in the MoSe2 monolayer quantum dots with exciton blue shift (12-40 meV) at a low temperature as compared to continuous monolayer MoSe2. Finally, single-photon emission (g2(0) ~ 0.4) was also observed from the smallest dots at 1.6 K. Our study opens the door to compositionally engineered, tunable, in-plane quantum light sources in 2D semiconductors.

Hypoxic Memory Mediates Prolonged Tumor Intrinsic Type I Interferon Suppression to Promote Breast Cancer Progression.

Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis that is associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIFs). Identification of the long-lasting effects of hypoxia beyond the immediate HIF-induced alterations could provide a better understanding of hypoxia-driven metastasis and potential strategies to circumvent it. Here, we uncovered a hypoxia-induced mechanism that exerts a prolonged effect to promote metastasis. In breast cancer patient-derived circulating tumor cell (CTC) lines and common breast cancer cell lines, hypoxia downregulated tumor intrinsic type I interferon (IFN) signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells, via both HIF-dependent and HIF-independent mechanisms. Hypoxia induced durable IFN/AP suppression in certain cell types that was sustained after returning to normoxic conditions, presenting a "hypoxic memory" phenotype. Hypoxic memory of IFN/AP downregulation was established by specific hypoxic priming, and cells with hypoxic memory had an enhanced ability for tumorigenesis and metastasis. Overexpression of IRF3 enhanced IFN signaling and reduced tumor growth in normoxic, but not hypoxic, conditions. The histone deacetylase inhibitor (HDACi) entinostat upregulated IFN targets and erased the hypoxic memory. These results point to a mechanism by which hypoxia facilitates tumor progression through a long-lasting memory that provides advantages for CTCs during the metastatic cascade.