Durable benefit from poly(ADP-ribose) polymerase inhibitors in metastatic prostate cancer in routine practice: biomarker associations and implications for optimal clinical next-generation sequencing testing.

BACKGROUND: Controlled trials have consistently demonstrated the efficacy of poly(ADP-ribose) polymerase inhibitors (PARPis) in patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA1 or BRCA2 alterations (BRCAalt). However, the reported efficacy of PARPi for alterations in other homologous recombination repair (HRR) genes is less consistent. We sought to evaluate the routine practice effectiveness of PARPi between and within these groups. DESIGN: Patient-level data from a deidentified nationwide (USA-based) cancer clinico-genomic database between January 2011 and September 2023 were extracted. Patients with mCRPC and comprehensive genomic profiling by liquid biopsy [circulating tumor DNA (ctDNA)] or tissue (tumor) biopsy and who received single-agent PARPi were included and grouped by BRCAalt, ATMalt, other HRR, or no HRR. We further subcategorized BRCAalt into homozygous loss (BRCAloss) and all other deleterious BRCAalt (otherBRCAalt). RESULTS: A total of 445 patients met inclusion criteria: 214 with tumor and 231 with ctDNA. BRCAalt had more favorable outcomes to PARPi compared with ATM, other HRR, and no HRR groups. Within the BRCAalt subgroup, compared with other BRCAalt, BRCAloss had a more favorable time to next treatment (median 9 versus 19.4 months, P = 0.005), time to treatment discontinuation (median 8 versus 14 months, P = 0.006), and routine practice overall survival (median 14.7 versus 19.4 months, P = 0.016). Tumor BRCAloss prevalence (3.1%) was similar to ctDNA prevalence in liquid biopsy specimens with high tumor fraction (>20%). BRCAloss was not detected in orthogonal germline testing. CONCLUSIONS: PARPi routine practice effectiveness between groups mirrors prospective trials. Within the BRCAalt group, BRCAloss had the best outcomes. Unless the ctDNA tumor fraction is very high, somatic tissue testing (archival or metastatic) should be prioritized to identify patients who may benefit most from PARPi. When tissue testing is not clinically feasible, sufficient ctDNA tumor fraction levels for detection are enriched at clinical timepoints associated with tumor progression.

Kinome state is predictive of cell viability in pancreatic cancer tumor and cancer-associated fibroblast cell lines.

Numerous aspects of cellular signaling are regulated by the kinome-the network of over 500 protein kinases that guides and modulates information transfer throughout the cell. The key role played by both individual kinases and assemblies of kinases organized into functional subnetworks leads to kinome dysregulation driving many diseases, particularly cancer. In the case of pancreatic ductal adenocarcinoma (PDAC), a variety of kinases and associated signaling pathways have been identified for their key role in the establishment of disease as well as its progression. However, the identification of additional relevant therapeutic targets has been slow and is further confounded by interactions between the tumor and the surrounding tumor microenvironment. In this work, we attempt to link the state of the human kinome, or kinotype, with cell viability in treated, patient-derived PDAC tumor and cancer-associated fibroblast cell lines. We applied classification models to independent kinome perturbation and kinase inhibitor cell screen data, and found that the inferred kinotype of a cell has a significant and predictive relationship with cell viability. We further find that models are able to identify a set of kinases whose behavior in response to perturbation drive the majority of viability responses in these cell lines, including the understudied kinases CSNK2A1/3, CAMKK2, and PIP4K2C. We next utilized these models to predict the response of new, clinical kinase inhibitors that were not present in the initial dataset for model devlopment and conducted a validation screen that confirmed the accuracy of the models. These results suggest that characterizing the perturbed state of the human protein kinome provides significant opportunity for better understanding of signaling behavior and downstream cell phenotypes, as well as providing insight into the broader design of potential therapeutic strategies for PDAC.

Rapid synthesis and screening of natively paired antibodies against influenza hemagglutinin stem via oPool+ display.

Antibody discovery is crucial for developing therapeutics and vaccines as well as understanding adaptive immunity. However, the lack of approaches to synthesize antibodies with defined sequences in a high-throughput manner represents a major bottleneck in antibody discovery. Here, we presented oPool+ display, which combines oligo pool synthesis and mRNA display to construct and characterize many natively paired antibodies in parallel. As a proof-of-concept, we applied oPool+ display to rapidly screen the binding activity of >300 natively paired influenza hemagglutinin (HA) antibodies against the conserved HA stem domain. Structural analysis of 16.ND.92, one of the identified HA stem antibodies, revealed a unique binding mode distinct from other known broadly neutralizing HA stem antibodies with convergent sequence features. Yet, despite such differences, 16.ND.92 remained broadly reactive and conferred in vivo protection. Overall, this study not only established an experimental platform that can be applied in both research and therapeutics to accelerate antibody discovery, but also provides molecular insights into antibody responses to the influenza HA stem, which is a major target for universal influenza vaccine development.

Robot-Mediated Nudges for Workplace Health: Not a One-Size-Fits-All Modeling Problem.

Prolonged sedentary behavior in the vast population of office and remote workers leads to increased cardiovascular and musculoskeletal health challenges, and existing solutions for encouraging breaks are either costly health coaches or notification systems that are easily ignored. A socially assistive robot (SAR) for promoting healthy workplace practices could provide the physical presence of a health coach along with the scalability of a notification system. To investigate the impact of such a system, we implemented a SAR as an alternative break-taking support solution and examined its impact on individual users' break-taking habits over relatively long-term deployments. We conducted an initial two-month-long study (N = 7) to begin to understand the robot's influence beyond the point of novelty, and we followed up with a week-long data collection (N = 14) to augment the dataset size. The resulting data was used to inform a robot behavior model and formulate possible methods of personalizing robot behaviors. We found that uninterrupted sitting time tended to decrease with our SAR intervention. During model formulation, we found participant responsiveness to the break-taking prompts could be classified into three archetypes and that archetype-specific adjustments to the general model led to improved system success. These results indicate that break-taking prompts are not a one-size-fits-all problem, and that even a small dataset can support model personalization for improving the success of assistive robotic systems.

The BabySeq Project: A clinical trial of genome sequencing in a diverse cohort of infants.

Efforts to implement and evaluate genome sequencing (GS) as a screening tool for newborns and infants are expanding worldwide. The first iteration of the BabySeq Project (2015-2019), a randomized controlled trial of newborn sequencing, produced novel evidence on medical, behavioral, and economic outcomes. The second iteration of BabySeq, which began participant recruitment in January 2023, examines GS outcomes in a larger, more diverse cohort of more than 500 infants up to one year of age recruited from pediatric clinics at several sites across the United States. The trial aims for families who self-identify as Black/African American or Hispanic/Latino to make up more than 50% of final enrollment, and key aspects of the trial design were co-developed with a community advisory board. All enrolled families receive genetic counseling and a family history report. Half of enrolled infants are randomized to receive GS with comprehensive interpretation of pathogenic and likely pathogenic variants in more than 4,300 genes associated with childhood-onset and actionable adult-onset conditions, as well as larger-scale chromosomal copy number variants classified as pathogenic or likely pathogenic. GS result reports include variants associated with disease (Mendelian disease risks) and carrier status of autosomal-recessive and X-linked disorders. Investigators evaluate the utility and impacts of implementing a GS screening program in a diverse cohort of infants using medical record review and longitudinal parent surveys. In this perspective, we describe the rationale for the second iteration of the BabySeq Project, the outcomes being assessed, and the key decisions collaboratively made by the study team and community advisory board.

Developing non-radioactive, radical methods to screen for radiolytic stability.

Radiolytically generated radicals cause degradation of nutrients in food, materials in satellites and solar cells, and human health. Radiation effects are studied using gamma radiolysis, a low-throughput, high-cost, and low-accessibility method. We developed a higher-throughput, low-cost, non-radioactive, radical assay that produces radicals similar to those generated in gamma radiolysis and examined monoamide degradation. Our radical assay results correspond to those from gamma irradiation in both monoamide stability and decomposition products, establishing this radical assay as a proof-of-concept screening tool for radiolytic stability.

#ForYou? the impact of pro-ana TikTok content on body image dissatisfaction and internalisation of societal beauty standards.

Videos glamourising disordered eating practices and body image concerns readily circulate on TikTok. Minimal empirical research has investigated the impact of TikTok content on body image and eating behaviour. The present study aimed to fill this gap in current research by examining the influence of pro-anorexia TikTok content on young women's body image and degree of internalisation of beauty standards, whilst also exploring the impact of daily time spent on TikTok and the development of disordered eating behaviours. An experimental and cross-sectional design was used to explore body image and internalisation of beauty standards in relation to pro-anorexia TikTok content. Time spent on TikTok was examined in relation to the risk of developing orthorexia nervosa. A sample of 273 female-identifying persons aged 18-28 years were exposed to either pro-anorexia or neutral TikTok content. Pre- and post-test measures of body image and internalisation of beauty standards were obtained. Participants were divided into four groups based on average daily time spent on TikTok. Women exposed to pro-anorexia content displayed the greatest decrease in body image satisfaction and an increase in internalisation of societal beauty standards. Women exposed to neutral content also reported a decrease in body image satisfaction. Participants categorised as high and extreme daily TikTok users reported greater average disordered eating behaviour on the EAT-26 than participants with low and moderate use, however this finding was not statistically significant in relation to orthorexic behaviours. This research has implications for the mental health of young female TikTok users, with exposure to pro-anorexia content having immediate consequences for internalisation and body image dissatisfaction, potentially increasing one's risk of developing disordered eating beliefs and behaviours.

Normative Running Kinematics in Healthy Adolescent Runners: A 2-Dimensional Video Analysis.

Background: The literature on the running kinematics of youth distance runners is limited. Purpose: We sought to describe 2-dimensional (2D) video analysis of running kinematics in healthy adolescent distance runners, which has not been previously described. Methods: We conducted an observational study of healthy, competitive runners between the ages of 14 and 18 years, prospectively recruited through local running clubs and our hospital's outreach between August 2019 and July 2023. Participants ran on a treadmill at a self-selected speed with markers attached to the thorax, pelvis, and lower extremities. A high-definition video camera recorded the runners in the sagittal and frontal planes. Kinematic measurements were completed using Dartfish software and reported as means and standard deviations. Results: Of the 53 participants (51% boys, mean age: 16.0 ± 1.4 years) included in the 2D running analysis, 91% ran with a rearfoot strike pattern, with a mean foot inclination angle of 10.2° ± 6.2°. Knee flexion angle at initial contact was 13.2° ± 3.8°, tibia inclination angle was 8.5° ± 3.2°, and peak knee flexion was 44.5° ± 3.6°. Cadence was 168.7° ± 8.6°. Contralateral pelvic drop was 6.0° ± 2.2° and peak rearfoot eversion was 11.8° ± 3.6°. Conclusions: This study is the first to describe running kinematics as captured by 2D video in healthy adolescent runners and to identify kinematic variables that may differ from those of adult runners. Further research is required to determine if adult recommendations are applicable to adolescent populations.

Single-Task and Dual-Task Gait Performance After Sport-Related Concussion: A Machine Learning Statistical Approach.

BACKGROUND: This study evaluated 2 different dual-task (DT) conditions during tandem gait (TG) to predict sport-related concussion (SRC) diagnosis. HYPOTHESIS: The best (fastest) single-task (ST) gait will differ between groups (controls vs SRC; baseline vs SRC), with auditory pure switching task (APST) response rate being the most important behavioral variable to aid prediction of SRC. STUDY DESIGN: Cohort design. LEVEL OF EVIDENCE: Level 3. METHODS: A total of 409 National Collegiate Athletic Association Division I student-athlete controls and 21 team-physician-diagnosed SRC participated. All data were collected at preseason physicals (baseline) and within 7 days of injury for SRC. Each participant completed 3 conditions of TG in a pseudorandomized order: (1) ST, (2) DT with serial-7s (SS) subtractions, and (3) DT with APST. Outcomes of time-to-complete for TG and behavioral (eg, responses per second) for SS and APST were recorded for each trial. RESULTS: ST Trials 2 (P = 0.03) and 3 (P = 0.01) were significantly different between controls and SRC. ST Trial 3 (P = 0.04) was significantly different between baseline and SRC. Average responses per second for APST were significantly different between- (P < 0.01) and within- (P = 0.01) group. CONCLUSION: The results suggest that ST is significantly slower after SRC. However, DT (both SS and APST) time-to-complete are also important variables when predicting the SRC diagnosis. It is advised that both ST and DT be administered when making clinical decisions regarding postural instability after SRC. CLINICAL RELEVANCE: The best ST TG time to complete gait is an important objective marker of concussion while DT paradigms, specifically SS and APST, are highly variable. DT may be more useful for clinical observable signs of SRC. Both SS and APST have unique usefulness, but APST response rate per second can be relied upon numerically for clinical decisions.

A Case Report of a Mysterious Mycetoma.

Mycetoma, a chronic subcutaneous infection caused by bacterial or fungal species from soil and water, presents a diagnostic challenge due to its rarity and diverse clinical manifestations. Predominantly affecting male workers in endemic regions, mycetoma typically manifests as painless swelling evolving into purulent lesions with draining sinuses in the extremities. Although historically uncommon in regions like North America, rising immigration and international travel have led to an increased prevalence, necessitating heightened clinical suspicion. Early diagnosis is crucial to prevent severe complications such as limb loss and septicemia. This case report details the diagnosis and management of chronic actinomycetoma due to Nocardia spp. in a Guatemalan immigrant landscaper and emphasizes the importance of comprehensive understanding and timely intervention in mycetoma cases.

Introducing 'identification probability' for automated and transferable assessment of metabolite identification confidence in metabolomics and related studies.

Methods for assessing compound identification confidence in metabolomics and related studies have been debated and actively researched for the past two decades. The earliest effort in 2007 focused primarily on mass spectrometry and nuclear magnetic resonance spectroscopy and resulted in four recommended levels of metabolite identification confidence - the Metabolite Standards Initiative (MSI) Levels. In 2014, the original MSI Levels were expanded to five levels (including two sublevels) to facilitate communication of compound identification confidence in high resolution mass spectrometry studies. Further refinement in identification levels have occurred, for example to accommodate use of ion mobility spectrometry in metabolomics workflows, and alternate approaches to communicate compound identification confidence also have been developed based on identification points schema. However, neither qualitative levels of identification confidence nor quantitative scoring systems address the degree of ambiguity in compound identifications in context of the chemical space being considered, are easily automated, or are transferable between analytical platforms. In this perspective, we propose that the metabolomics and related communities consider identification probability as an approach for automated and transferable assessment of compound identification and ambiguity in metabolomics and related studies. Identification probability is defined simply as 1/N, where N is the number of compounds in a reference library or chemical space that match to an experimentally measured molecule within user-defined measurement precision(s), for example mass measurement or retention time accuracy, etc. We demonstrate the utility of identification probability in an in silico analysis of multi-property reference libraries constructed from the Human Metabolome Database and computational property predictions, provide guidance to the community in transparent implementation of the concept, and invite the community to further evaluate this concept in parallel with their current preferred methods for assessing metabolite identification confidence.

Career Length After Surgically Treated ACL Plus Collateral Ligament Injury in Elite Athletes.

BACKGROUND: Limited data are available regarding career length and competition level after combined anterior cruciate ligament (ACL) and medial- or lateral-sided surgeries in elite athletes. PURPOSE: To evaluate career length after surgical treatment of combined ACL plus medial collateral ligament (MCL) and ACL plus posterolateral corner (PLC) injuries in elite athletes and, in a subgroup analysis of male professional soccer players, to compare career length and competition level after combined ACL+MCL or ACL+PLC surgeries with a cohort who underwent isolated ACL reconstruction (ACLR). STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A consecutive cohort of elite athletes undergoing combined ACL+MCL and ACL+PLC surgery was analyzed between February 2001 and October 2019. A subgroup of male elite soccer players from this population was compared with a previously identified cohort having had isolated primary ACLR without other ligament surgery. A minimum 2-year follow-up was required. Outcome measures were career length and competition level. RESULTS: A total of 98 elite athletes met the inclusion criteria, comprising 50 ACL+PLC and 48 ACL+MCL surgeries. The mean career length after surgical treatment of combined ACL+MCL and ACL+PLC injuries was 4.5 years. Return-to-play (RTP) time was significantly longer for ACL+PLC injuries (12.8 months; P = .019) than for ACL+MCL injuries (10.9 months). In the subgroup analysis of soccer players, a significantly lower number of players with combined ACL+PLC surgery were able to RTP (88%; P = .003) compared with 100% for ACL+MCL surgery and 97% for isolated ACLR, as well as requiring an almost 3 months longer RTP timeline (12.9 months; P = .002) when compared with the isolated ACL (10.2 months) and combined ACL+MCL (10.0 months) groups. However, career length and competition level were not significantly different between groups. CONCLUSION: Among elite athletes, the mean career length after surgical treatment of combined ACL+MCL and ACL+PLC injuries was 4.5 years. Professional soccer players with combined ACL+PLC surgery returned at a lower rate and required a longer RTP time when compared with the players with isolated ACL or combined ACL+MCL injuries. However, those who did RTP had the same career longevity and competition level.

Cross-site reproducibility of human cortical organoids reveals consistent cell type composition and architecture.

While guided human cortical organoid (hCO) protocols reproducibly generate cortical cell types at one site, variability in hCO phenotypes across sites using a harmonized protocol has not yet been evaluated. To determine the cross-site reproducibility of hCO differentiation, three independent research groups assayed hCOs in multiple differentiation replicates from one induced pluripotent stem cell (iPSC) line using a harmonized miniaturized spinning bioreactor protocol across 3 months. hCOs were mostly cortical progenitor and neuronal cell types in reproducible proportions that were consistently organized in cortical wall-like buds. Cross-site differences were detected in hCO size and expression of metabolism and cellular stress genes. Variability in hCO phenotypes correlated with stem cell gene expression prior to differentiation and technical factors associated with seeding, suggesting iPSC quality and treatment are important for differentiation outcomes. Cross-site reproducibility of hCO cell type proportions and organization encourages future prospective meta-analytic studies modeling neurodevelopmental disorders in hCOs.

Religious Involvement and Cognitive Function Among White, Black, and Hispanic Older Adults.

We examined whether religious involvement was associated with cognitive function among older adults in the 2006-2020 waves of the Health and Retirement Study. Using growth curve analysis, we found the association between religious involvement and cognition varied by facet of religious involvement and race and Hispanic ethnicity. Attending religious services with friends was associated with higher initial levels of cognitive function (b = 0.22, p < .05). For Hispanic older adults, frequent attendance at religious services was associated with a slower rate of cognitive decline (b = 0.16, p < .01). Stratified models by race and Hispanic ethnicity demonstrated that religious salience was associated with lower initial levels of cognitive function among non-Hispanic White adults (b = -0.19, p < .01). We found no association between religious involvement and cognitive function among non-Hispanic Black respondents. In sum, elements of religious involvement are positively or negatively related to cognitive function in later life and vary by race and ethnicity.

Primary Care Providers' Experiences With an Active Elective Genetic Testing Program.

Elective genetic testing (EGT) programs that provide pharmacogenomic information to guide medication management and screen for medically actionable disease predispositions are emerging in a number of health systems. Primary care providers (PCPs) are at the forefront of test initiation, patient education, and management of EGT results. However, little research has examined the experiences of PCPs in health systems offering clinical EGT. We conducted semi-structured interviews, a sub-study of the larger mixed-methods Imagenetics Initiative, with 16 PCPs at a health system in the Midwest with a clinical EGT program supported by provider education, automated clinical decision support, and enhanced access to genetic specialists. The purpose of these interviews was to understand perceptions about the benefits and barriers of implementing EGT in clinical practice. Thematic analysis indicated that EGT is conceptualized similar to traditional diagnostic services. PCPs were generally favorable toward EGT; however, targeted education did not dispel misconceptions about the goals, results, and limitations of EGT. Most PCPs endorsed the potential utility of EGT. Pharmacogenomic profiling was seen as having more immediate impact for patients than screening for monogenic disease risks. PCPs reported that they weighed discussions about EGT against time limitations and the need to prioritize patients' existing health concerns. Regardless of their education levels and familiarity with genetics, PCPs desired additional educational resources and greater access to genetic specialists. Our study provides unique insight into PCPs' experiences with clinical EGT in health systems that have adopted EGT and highlights the practical challenges and potential opportunities of EGT integration.

Liposuction as a Treatment for Lipedema: A Scoping Review.

Background: Lipedema is the progressive symmetrical deposition of subcutaneous fat and fluid in the lower body, ordinarily sparing the trunk, upper limbs, face, and neck. It may follow an autosomal dominant inheritance pattern. The gold standard treatment for lipedema is complete decongestive therapy, consisting of manual lymphatic drainage and compression garments. This scoping review assessed the existing literature on the effectiveness of liposuction as an alternative treatment for lipedema. Methods: A scoping review of electronically available literature within PubMed, Scopus, and Cochrane focused on liposuction as a treatment for lipedema considering the following inclusion criteria: human studies, case series of 10 or more, controlled trials, randomized controlled trials, patient-reported outcome measurement studies, survey analyses, descriptive studies, retrospective analyses, recurrence included, follow-up of 6 months or more, age 18 years or older, and treatment modality being liposuction. Results: Thirteen studies were selected. Nine studies reported decreased compression therapy use among patients following liposuction. No studies reported a long-term increase in compression therapy following liposuction. Studies found self-reported improvements in pain, mobility, bruising, and overall quality of life for patients following liposuction, many of whom had previously been on compressive therapy. Studies reported low rates of serious adverse events following liposuction, including deep vein thrombosis, pulmonary embolism, and infection. Conclusions: These results suggest that liposuction can be a viable treatment alternative to compression therapy for lipedema in patients whose compression therapy has not been helpful. However, there is not enough evidence to say whether liposuction is as effective as compression for patients first presenting with lipedema.

The fate of the abstract: presentation and publication characteristics of abstracts presented at the Society of Gynecologic Surgeons Annual Scientific Meetings 2013-2020.

OBJECTIVE: To evaluate what proportion of abstracts presented at the Society of Gynecologic Surgeons (SGS) Annual Scientific Meetings went on to be published in publicly available journals. DESIGN: Retrospective observational study SETTING: Single organization PARTICIPANTS: Abstracts (oral presentations, oral posters, video presentations, non-oral posters) presented at the SGS Annual Scientific Meeting from 2013-2020 INTERVENTIONS: Variables were collected pertaining to abstract authors, study type, timing of the session presented, and journal factors. To identify possible publication, abstracts were cross-referenced in PubMed and Google Scholar. MEASUREMENTS AND MAIN RESULTS: A total of 912 abstracts were reviewed: 155 oral presentations, 184 oral posters, 79 video presentations, and 490 non-oral posters. 45.8% of abstracts went on to publication in a peer-reviewed journal. Most abstracts (75.0%) were published from institutions with a fellowship presence and at a university-based program (71.5%). The five most represented institutions presented 27.5% of all abstracts during an SGS session. Oral presentations were more likely than oral posters to be structured as randomized controlled trials (20% vs 9%, p=.028), and to be published in a journal with a higher impact factor (6.36 ± 11.74 vs. 3.88 ± 2.72, p=.031). Type of presentation and fellowship presence significantly affected the likelihood of abstract publication (oral presentation OR 0.73, 95% CI [0.466, 1.141], p=0.167; video OR 0.14, 95% CI [0.075, 0.261; non-oral poster OR 0.30, 95% CI [0.204, 0.439]; p<.001; fellowship OR 1.62, 95% CI [1.167, 2.237], p=.004). CONCLUSION: Over eight years of the SGS Annual Scientific Meeting, the rate of abstract publication was 45.8%. Abstract origination from an academic institution with a fellowship program significantly affected the likelihood of publication. Abstract presentation at a society meeting is a prestigious opportunity, and prioritization of resources and elimination of barriers should be encouraged to further promote progression of these projects to publication.

Assessing the impact of extracellular matrix fiber orientation on breast cancer cellular metabolism.

The extracellular matrix (ECM) is a dynamic and complex microenvironment that modulates cell behavior and cell fate. Changes in ECM composition and architecture have been correlated with development, differentiation, and disease progression in various pathologies, including breast cancer [1]. Studies have shown that aligned fibers drive a pro-metastatic microenvironment, promoting the transformation of mammary epithelial cells into invasive ductal carcinoma via the epithelial-to-mesenchymal transition (EMT) [2]. The impact of ECM orientation on breast cancer metabolism, however, is largely unknown. Here, we employ two non-invasive imaging techniques, fluorescence-lifetime imaging microscopy (FLIM) and intensity-based multiphoton microscopy, to assess the metabolic states of cancer cells cultured on ECM-mimicking nanofibers in a random and aligned orientation. By tracking the changes in the intrinsic fluorescence of nicotinamide adenine dinucleotide and flavin adenine dinucleotide, as well as expression levels of metastatic markers, we reveal how ECM fiber orientation alters cancer metabolism and EMT progression. Our study indicates that aligned cellular microenvironments play a key role in promoting metastatic phenotypes of breast cancer as evidenced by a more glycolytic metabolic signature on nanofiber scaffolds of aligned orientation compared to scaffolds of random orientation. This finding is particularly relevant for subsets of breast cancer marked by high levels of collagen remodeling (e.g. pregnancy associated breast cancer), and may serve as a platform for predicting clinical outcomes within these subsets [3-6].

Metaplastic neuromodulation via transcranial direct current stimulation has no effect on corticospinal excitability and neuromuscular fatigue.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation tool with potential for managing neuromuscular fatigue, possibly due to alterations in corticospinal excitability. However, inconsistencies in intra- and inter- individual variability responsiveness to tDCS limit its clinical use. Emerging evidence suggests harnessing homeostatic metaplasticity induced via tDCS may reduce variability and boost its outcomes, yet little is known regarding its influence on neuromuscular fatigue in healthy adults. We explored whether cathodal tDCS (ctDCS) prior to exercise combined with anodal tDCS (atDCS) could augment corticospinal excitability and attenuate neuromuscular fatigue. 15 young healthy adults (6 males, 22 ± 4 years) participated in four pseudo-randomised neuromodulation sessions: sham stimulation prior and during exercise, sham stimulation prior and atDCS during exercise, ctDCS prior and atDCS during exercise, ctDCS prior and sham stimulation during exercise. The exercise constituted an intermittent maximal voluntary contraction (MVC) of the right first dorsal interosseous (FDI) for 10 min. Neuromuscular fatigue was quantified as an attenuation in MVC force, while motor evoked potential (MEP) amplitude provided an assessment of corticospinal excitability. MEP amplitude increased during the fatiguing exercise, whilst across time, force decreased. There were no differences in MEP amplitudes or force between neuromodulation sessions. These outcomes highlight the ambiguity of harnessing metaplasticity to ameliorate neuromuscular fatigue in young healthy individuals.

The DNA Methyltransferase Inhibitor 5-Aza-4'-thio-2'-Deoxycytidine Induces C>G Transversions and Acute Lymphoid Leukemia Development.

DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that decrease 5'-cytosine methylation. DNMTi are used clinically based on the hypothesis that cytosine demethylation will lead to re-expression of tumor suppressor genes. 5-Aza-4'-thio-2'-deoxycytidine (Aza-TdCyd or ATC) is a recently described thiol-substituted DNMTi that has been shown to have anti-tumor activity in solid tumor models. In this study, we investigated the therapeutic potential of ATC in a murine transplantation model of myelodysplastic syndrome. ATC treatment led to the transformation of transplanted wild-type bone marrow nucleated cells into lymphoid leukemia, and healthy mice treated with ATC also developed lymphoid leukemia. Whole-exome sequencing revealed 1,000 acquired mutations, almost all of which were C>G transversions in a specific 5'-NCG-3' context. These mutations involved dozens of genes involved in human lymphoid leukemia, such as Notch1, Pten, Pax5, Trp53, and Nf1. Human cells treated in vitro with ATC showed 1,000 acquired C>G transversions in a similar context. Deletion of Dck, the rate-limiting enzyme for the cytidine salvage pathway, eliminated C>G transversions. Taken together, these findings demonstrate a highly penetrant mutagenic and leukemogenic phenotype associated with ATC. Significance: Treatment with a DNA methyltransferase inhibitor generates a distinct mutation signature and triggers leukemic transformation, which has important implications for the research and clinical applications of these inhibitors.