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Sheri J Hartman1, Shira I Dunsiger1, Paul B Jacobsen21Centers for Behavioral and Preventive Medicine, The Miriam Hospital and W Alpert Medical School of Brown University, Providence, RI; 2Department of Health Outcomes and Behavior, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USAAbstract: This study examined the relationship of psychosocial factors to health-promoting behaviors in sisters of breast cancer patients. One hundred and twenty sisters of breast cancer patients completed questionnaires assessing response efficacy of mammography screenings, physical activity, and fruit and vegetable consumption on decreasing breast cancer risk, breast cancer worry, involvement in their sister’s cancer care, mammography screenings, physical activity, and fruit and vegetable consumption. Results indicate that greater perceived effectiveness for mammograms was associated with a 67% increase in odds of yearly mammograms. Greater involvement in the patient’s care was associated with a 7% decrease in odds of yearly mammograms. Greater perceived effectiveness for physical activity was significantly related to greater physical activity. There was a trend for greater perceived effectiveness for fruits and vegetables to be associated with consuming more fruits and vegetables. Breast cancer worry was not significantly associated with the outcomes. While perceived effectiveness for a specific health behavior in reducing breast cancer risk was consistently related to engaging in that health behavior, women reported significantly lower perceived effectiveness for physical activity and fruits and vegetables than for mammograms. Making women aware of the health benefits of these behaviors may be important in promoting changes.Keywords: breast cancer risk, mammograms, physical activity, diet, perceived effectiveness

Background: Nicotine dependence (ND) is a key construct that organizes physiological and behavioral symptoms associated with persistent nicotine intake. Measurement of ND has focused primarily on cigarette smokers. Thus, validation of brief instruments that apply to a broad spectrum of tobacco product users is needed. Methods: We examined multiple domains of ND in a longitudinal national study of the United States population, the United States National Epidemiological Survey of Alcohol and Related Conditions (NESARC). We used methods based in item response theory to identify and validate increasingly brief measures of ND that included symptoms to assess ND similarly among cigarette, cigar, smokeless, and poly tobacco users. Results: Confirmatory factor analytic models supported a single, primary dimension underlying symptoms of ND across tobacco use groups. Differential Item Functioning (DIF) analysis generated little support for systematic differences in response to symptoms of ND across tobacco use groups. We established significant concurrent and predictive validity of brief 3- and 5-symptom indices for measuring ND. Conclusions: Measuring ND across tobacco use groups with a common set of symptoms facilitates evaluation of tobacco use in an evolving marketplace of tobacco and nicotine products.

As mentioned in part I of our research, the shortage of nurses in the United States remains a persistent problem. Faced with this reality, nursing programs in colleges and universities continue to struggle to expand enrollment levels to meet the spiraling demand. In this part II of our research, we used another familiar tool in strategic management, stakeholder analysis, as one of the steps to discover ways to capitalize on stakeholder relations in a way that draws more students to the profession of nursing. As was the case in part I of our 2-part research, in a 2-round modified Delphi survey, chief administrators of schools of nursing identify those groups who are most influenced by schools of nursing and those groups who have the most influence over schools of nursing. [ABSTRACT FROM AUTHOR]

The shortage of nurses in the United States remains a persistent problem. Faced with this reality, nursing programs in colleges and universities continue to struggle to expand enrollment levels to meet the spiraling demand. This research uses familiar tools in strategic management: the strengths, weaknesses, opportunities, and threats (SWOT) analysis and stakeholder analysis as initial steps to draw more students to the profession of nursing. In a 2-round modified Delphi survey, chief administrators of schools of nursing identify the main SWOT of schools of nursing and the important internal and external stakeholders that influence nursing school success. The authors of the research suggest ways to use that knowledge to increase the enrollment level of nursing students. Part I of this research focuses on the SWOT analyses. [ABSTRACT FROM AUTHOR]

Vocational choice theory asserts that an individual's career choice will be based on that person's anticipated satisfaction from working in a particular field and that the person's personality will determine which field will be most satisfying. This study measured personalities and job satisfaction among public health workers to determine if public health work is satisfying to individuals with particular personality types. The study was performed on 47 public health workers in the Southeastern region of Louisiana. These workers were given a questionnaire consisting of the Big 5 personality profile, the Job Descriptive Index, several open-ended questions, and a demographic survey. The findings indicate that emotional stability is a personality characteristic associated with satisfaction from public health work. Possible reasons for this finding and its implications are discussed. [ABSTRACT FROM AUTHOR]

Problems with attracting and retaining nurses during a tight labor market are compounded by some fundamental issues related to attrition from the field. It is important to recognize that, of the students who graduate from nursing schools each year and enter the field of nursing, significant attrition occurs during the first 5 years in the profession [www.aacn.nche.edu/media/backgrounders/shortagefacts.htm (2002)]. This article uses data from the National Science Foundation's National Survey of College Graduates to examine various scenarios and possible reasons for why some nurses abandon their careers [www.nsf.gov/sbe/srs/snscg/start.htm (2003)]. In doing so, we consider entry into, and attrition from, the nursing profession at various stages. Using data from the National Survey of College Graduates, the initial evaluation suggests that, at points during the career, the individual confronts potential problems and issues which can lead to career attrition. [ABSTRACT FROM AUTHOR]

Healthcare organizations, like all organizations, are increasingly more concerned about workplace violence. This paper discusses the collision of a cultural context that encourages macho posturing and moral panic related to highly publicized violence in schools and workplaces. At issue is the need for healthcare organizations to react to evidence of potential workplace violence but not to overreact. [ABSTRACT FROM AUTHOR]

This case study reports on an organizational decline situation involving a historically well-known and respected professional organization outside the health care field, with the intention of pointing to several implications for health care. We begin by discussing the results of a survey that involved both members of the organization and 'outsiders.' Our primary finding, both in the survey and in presenting the results to the membership, was that while those outside the organization perceived the organization as increasingly irrelevant and in decline, those inside it reacted with defensiveness to 'meddling by outsiders.' We then reviewed the literature on decline, with emphasis upon important findings by Guy, to further understand our results and to make recommendations. We then turn to the situation in health care organizations and point out why some organizations may be at risk and conclude with a series of recommendations with emphasis on health care. [ABSTRACT FROM AUTHOR]

Globally, severe acute malnutrition (SAM), defined as a weight-for-length z -score more than three SDs below a reference mean (WLZ < -3), affects 14 million children under 5 years of age. Complete anthropometric recovery after standard, short-term interventions is rare, with children often left with moderate acute malnutrition (MAM; WLZ -2 to -3). We conducted a randomized controlled trial (RCT) involving 12- to 18-month-old Bangladeshi children from urban and rural sites, who, after initial hospital-based treatment for SAM, received a 3-month intervention with a microbiome-directed complementary food (MDCF-2) or a calorically more dense, standard ready-to-use supplementary food (RUSF). The rate of WLZ improvement was significantly greater in MDCF-2-treated children ( P = 8.73 × 10 -3 ), similar to our previous RCT of Bangladeshi children with MAM without antecedent SAM ( P = 0.032). A correlated meta-analysis of plasma levels of 4520 proteins in both RCTs revealed 215 positively associated with WLZ (largely representing musculoskeletal and central nervous system development) and 44 negatively associated (primarily related to immune activation). Moreover, the positively associated proteins were significantly enriched by MDCF-2 ( q = 1.1 × 10 -6 ). Characterizing the abundances of 754 bacterial metagenome-assembled genomes in serially collected fecal samples disclosed the effects of acute rehabilitation for SAM on the microbiome and how, during treatment for MAM, specific strains of Prevotella copri function at the intersection between MDCF-2 glycan metabolism and anthropometric recovery. These results provide a rationale for further testing the generalizability of MDCF efficacy and for identifying biomarkers to define treatment responses.

Cancer-related cognitive impairment (CRCI) is a broad term encompassing subtle cognitive problems to more severe impairment. CRCI severity is influenced by host, disease, and treatment factors and affects patients prior to, during, and following cancer treatment. The National Cancer Institute (NCI) Symptom Management and Health-Related Quality of Life Steering Committee (SxQoL SC) convened a Clinical Trial Planning Meeting (CTPM) to review the state of the science on CRCI and to develop both Phase II/III intervention trials aimed at improving cognitive function in cancer survivors with non-central nervous system (CNS) disease and longitudinal studies to understand the trajectory of cognitive impairment and contributing factors. Participants included experts in the field of CRCI, members of the SxQOL SC, patient advocates, representatives from all seven NCI Community Oncology Research Program (NCORP) Research Bases, and the NCI. Presentations focused on the following topics: measurement, lessons learned from pediatric and geriatric oncology, biomarker and mechanism endpoints, longitudinal study designs, and pharmacologic and behavioral intervention trials. Panel discussions provided guidance on priority cognitive assessments, considerations for remote assessments, inclusion of relevant biomarkers, and strategies for ensuring broad inclusion criteria. Three CTPM working groups (longitudinal studies and pharmacologic and behavioral intervention trials) convened for one year to discuss and report on top priorities and to design studies. The CTPM experts concluded sufficient data exist to advance Phase II/Phase III trials utilizing selected pharmacologic and behavioral interventions for the treatment of CRCI in the non-CNS setting with recommendations included herein., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: In this single-institution phase II investigator-initiated study, we assessed the ability of MAPK and VEGF pathway blockade to overcome resistance to immunotherapy in microsatellite-stable metastatic colorectal cancer (MSS mCRC)., Patients and Methods: Patients with MSS, BRAF wild-type mCRC who progressed on ≥2 prior lines of therapy received pembrolizumab, binimetinib, and bevacizumab until disease progression or unacceptable toxicity. After a safety run-in, patients were randomized to a 7-day run-in of binimetinib or simultaneous initiation of all study drugs, to explore whether MEK inhibition may increase tumor immunogenicity. The primary endpoint was objective response rate (ORR) in all patients combined (by Response Evaluation Criteria in Solid Tumors v1.1)., Results: Fifty patients received study drug treatment; 54% were male with a median age of 55 years (range, 31-79). The primary endpoint, ORR, was 12.0% [95% confidence interval (CI) 4.5%-24.3%], which was not statistically different than the historical control data of 5% (P = 0.038, exceeding prespecified threshold of 0.025). The disease control rate was 70.0% (95% CI, 55.4%-82.1%), the median progression-free survival 5.9 months (95% CI, 4.2-8.7 months), and the median overall survival 9.3 months (95% CI, 6.7-12.2 months). No difference in efficacy was observed between the randomized cohorts. Grade 3 and 4 adverse events were observed in 56% and 8% of patients, respectively; the most common were rash (12%) and increased aspartate aminotransferase (12%)., Conclusions: Pembrolizumab, binimetinib, and bevacizumab failed to meet its primary endpoint of higher ORR compared with historical control data, demonstrated a high disease control rate, and demonstrated acceptable tolerability in refractory MSS mCRC., (©2024 The Authors; Published by the American Association for Cancer Research.)

We examined the relationship between subjective and objective sleep outcomes and loneliness in older women at risk for Alzheimer's disease (AD). Our sample consisted of 39 participants (aged 65+) with mild cognitive deficits who completed the UCLA Loneliness Scale, the Pittsburgh Sleep Quality Index (PSQI), and an at home sleep test, to determine presence of obstructive sleep apnea. Based on sleep quality scores, individuals categorized as "poor sleepers" had significantly higher loneliness scores than "good sleepers." However, total loneliness scores did not significantly differ between groups with or without sleep apnea. We found that higher loneliness was significantly associated to lower habitual sleep efficiency and sleep duration and was also influenced by use of sleep medication. Our findings suggest that increased loneliness relates to worse subjective sleep quality, but not to sleep apnea. These findings suggest that combined interventions targeting loneliness and sleep quality may be important for older women., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Latinas face an increased risk for chronic diseases associated with insufficient physical activity (PA). The researchers previously showed that a website-based intervention could increase PA among insufficiently active Latinas, yet rates of meeting national PA guidelines were low. The original intervention was enhanced by adding additional features, content, and points of contact, including via text messaging. This study tests the efficacy of the enhanced intervention compared with the original, aimed at maximizing and sustaining PA gains across 24 months. It also examines if increases in PA differed by baseline PA., Study Design: The researchers conducted a superiority randomized controlled trial (data collected 2018-2022, analyzed 2023)., Setting/participants: Participants were 195 Spanish-speaking Latinas ages 18-65 in the Providence, RI area., Intervention: The original intervention is an empirically supported Spanish-language, individually-tailored, website-delivered PA intervention. The enhanced intervention includes text messaging and additional data-driven content and interactive features., Main Outcome Measures: Total weekly minutes of moderate to vigorous PA (MVPA) was measured via accelerometry and self-report at 6, 12, 18, and 24 months., Results: Participants in both groups increased their MVPA over 24 months. There were no significant between-group differences at 6 or 12 months; at 18 months the enhanced intervention group had higher levels of self-reported (mean (sd): 90.35 (43.55) vs 70.18 [9.99]) and accelerometer-measured (66.21 [18.26] vs 60.27 [16.00]) MVPA compared to the original intervention group. They also had higher levels of self-reported (111.17 [23.35] vs 81.44 [1.82]) and accelerometer-measured (63.76 [15.12] vs 54.86 [14.59]) MVPA at 24 months. Baseline PA moderated the intervention effect., Conclusions: This study demonstrates the potential to enhance the efficacy of website-based PA interventions by utilizing text messaging, and adding more interactive features, content, and phone support. These enhancements may be particularly beneficial in supporting long-term PA maintenance., Trial Registration: This study is registered at www., Clinicaltrial: gov (NCT03491592)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Despite advancements in treating cutaneous melanoma, patients with acral and mucosal (A/M) melanomas still have limited therapeutic options and poor prognoses. We analyzed 156 melanomas (101 cutaneous, 28 acral, and 27 mucosal) using the Foundation One cancer-gene specific clinical testing platform and identified new, potentially targetable genomic alterations (GAs) in specific anatomic sites of A/M melanomas. Using novel pre-clinical models of A/M melanoma, we demonstrate that several GAs and corresponding oncogenic pathways associated with cutaneous melanomas are similarly targetable in A/M melanomas. Other alterations, including MYC and CRKL amplifications, were unique to A/M melanomas and susceptible to indirect targeting using the BRD4 inhibitor JQ1 or Src/ABL inhibitor dasatinib, respectively. We further identified new, actionable A/M-specific alterations, including an inactivating NF2 fusion in a mucosal melanoma responsive to dasatinib in vivo. Our study highlights new molecular differences between cutaneous and A/M melanomas, and across different anatomic sites within A/M, which may change clinical testing and treatment paradigms for these rare melanomas., (© 2024 UICC.)

Background: More than half (55%) of Latina women do not meet aerobic physical activity (PA) guidelines, and frequently cite time, childcare, and transportation as barriers to PA. In addition to linguistic adaptations for this population, successful PA interventions for Latina women addressed these barriers through remote intervention delivery approaches (eg, mail, phone, or web delivery)., Objective: We aimed to evaluate 6-month outcomes of a randomized trial comparing a Spanish-language, individually tailored, web-delivered PA intervention (original) to an enhanced version with text messages and additional features (enhanced). Further, we evaluated if increases in PA at 6 months were moderated by baseline activity status., Methods: In total, 195 Latina women aged 18-65 years participated in a trial comparing the efficacy of the enhanced versus original interventions at initiating PA behavior change. We examined minutes per week of accelerometer-measured PA in the enhanced versus original arms, and the proportion of each arm meeting aerobic PA guidelines (150 min/wk at 6 mo). For moderator analyses, participants were classified as inactive (0 min/wk) or low active (1-90 min/wk) at baseline, measured via the 7 Day Physical Activity Recall interview., Results: PA increased from 19.7 (SD 47.9) minutes per week at baseline to 46.9 (SD 66.2) minutes per week at 6 months in the enhanced arm versus 20.6 (SD 42.7) minutes per week to 42.9 (SD 78.2) minutes per week in the original arm (P=.78). Overall, 30% (31/103) of the enhanced group met aerobic PA guidelines at 6 months, compared to 21% (19/92) of the original group (odds ratio [OR] 1.75, 95% CI 0.87-3.55). Baseline PA (inactive vs low active) moderated treatment effects on PA. For inactive participants, there were no group differences at 6 months (b=7.1; SE 22.8; P=.75), while low-active participants increased more in enhanced than original (b=72.5; SE 27.9; P=.01). For low-active participants, 45% (46/103) of the enhanced group met PA guidelines at 6 months, versus 20% (18/92) of the original arm (OR 3.29, 95% CI 1.05-11.31). For inactive participants, there were no group differences (25/103, 24% vs n=19/92, 21% for enhanced vs original, respectively; OR 1.28, 95% CI 0.54-3.06)., Conclusions: Intervention effects were conditional on baseline PA. For low-active Latina women, the enhanced intervention was more effective at increasing PA. Additional tailored intervention enhancements may be necessary to increase PA for inactive Latina women., Trial Registration: ClinicalTrials.gov NCT03491592; https://www.clinicaltrials.gov/study/NCT03491592., International Registered Report Identifier (irrid): RR2-10.1186/s13063-022-06575-4., (©Lauren Connell Bohlen, Shira I Dunsiger, Tayla von Ash, Britta A Larsen, Dori Pekmezi, Becky Marquez, Tanya J Benitez, Andrea Mendoza-Vasconez, Sheri J Hartman, David M Williams, Bess H Marcus. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 06.06.2024.)

Background: Globally, stunting affects ∼150 million children under five, while wasting affects nearly 50 million. Current interventions have had limited effectiveness in ameliorating long-term sequelae of undernutrition including stunting, cognitive deficits and immune dysfunction. Disrupted development of the gut microbiota has been linked to the pathogenesis of undernutrition, providing potentially new treatment approaches., Methods: 124 Bangladeshi children with moderate acute malnutrition (MAM) enrolled (at 12-18 months) in a previously reported 3-month RCT of a microbiota-directed complementary food (MDCF-2) were followed for two years. Weight and length were monitored by anthropometry, the abundances of bacterial strains were assessed by quantifying metagenome-assembled genomes (MAGs) in serially collected fecal samples and levels of growth-associated proteins were measured in plasma., Findings: Children who had received MDCF-2 were significantly less stunted during follow-up than those who received a standard ready-to-use supplementary food (RUSF) [linear mixed-effects model, β treatment group x study week (95% CI) = 0.002 (0.001, 0.003); P = 0.004]. They also had elevated fecal abundances of Agathobacter faecis, Blautia massiliensis, Lachnospira and Dialister, plus increased levels of a group of 37 plasma proteins (linear model; FDR-adjusted P < 0.1), including IGF-1, neurotrophin receptor NTRK2 and multiple proteins linked to musculoskeletal and CNS development, that persisted for 6-months post-intervention., Interpretation: MDCF-2 treatment of Bangladeshi children with MAM, which produced significant improvements in wasting during intervention, also reduced stunting during follow-up. These results suggest that the effectiveness of supplementary foods for undernutrition may be improved by including ingredients that sponsor healthy microbiota-host co-development., Funding: This work was supported by the BMGF (Grants OPP1134649/INV-000247)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Sedentary behavior (SB) is a recognized risk factor for many chronic diseases. ActiGraph and activPAL are two commonly used wearable accelerometers in SB research. The former measures body movement and the latter measures body posture. The goal of the current study is to quantify the pattern and variation of movement (by ActiGraph activity counts) during activPAL-identified sitting events, and examine associations between patterns and health-related outcomes, such as systolic and diastolic blood pressure (SBP and DBP)., Methods: The current study included 314 overweight postmenopausal women, who were instructed to wear an activPAL (at thigh) and ActiGraph (at waist) simultaneously for 24 hours a day for a week under free-living conditions. ActiGraph and activPAL data were processed to obtain minute-level time-series outputs. Multilevel functional principal component analysis (MFPCA) was applied to minute-level ActiGraph activity counts within activPAL-identified sitting bouts to investigate variation in movement while sitting across subjects and days. The multilevel approach accounted for the nesting of days within subjects., Results: At least 90% of the overall variation of activity counts was explained by two subject-level principal components (PC) and six day-level PCs, hence dramatically reducing the dimensions from the original minute-level scale. The first subject-level PC captured patterns of fluctuation in movement during sitting, whereas the second subject-level PC delineated variation in movement during different lengths of sitting bouts: shorter (< 30 minutes), medium (30 -39 minutes) or longer (> 39 minute). The first subject-level PC scores showed positive association with DBP (standardized β ^ : 2.041, standard error: 0.607, adjusted p = 0.007), which implied that lower activity counts (during sitting) were associated with higher DBP., Conclusion: In this work we implemented MFPCA to identify variation in movement patterns during sitting bouts, and showed that these patterns were associated with cardiovascular health. Unlike existing methods, MFPCA does not require pre-specified cut-points to define activity intensity, and thus offers a novel powerful statistical tool to elucidate variation in SB patterns and health., Trial Registration: ClinicalTrials.gov NCT03473145; Registered 22 March 2018; https://clinicaltrials.gov/ct2/show/NCT03473145 ; International Registered Report Identifier (IRRID): DERR1-10.2196/28684., (© 2024. The Author(s).)

Pancreatic ductal adenocarcinoma (PDAC) presents at advanced stages and is refractory to most treatment modalities. Wnt signaling activation plays a critical role in proliferation and chemotherapeutic resistance. Minimal media conditions, growth factor dependency, and Wnt dependency were determined via Wnt inhibition for seven patient derived organoids (PDOs) derived from pancreatic tumor organoid libraries (PTOL). Organoids demonstrating response in vitro were assessed in vivo using patient-derived xenografts. Wnt (in)dependent gene signatures were identified for each organoid. Panc269 demonstrated a trend of reduced organoid growth when treated with ETC-159 in combination with paclitaxel or gemcitabine as compared with chemotherapy or ETC-159 alone. Panc320 demonstrated a more pronounced anti-proliferative effect in the combination of ETC-159 and paclitaxel but not with gemcitabine. Panc269 and Panc320 were implanted into nude mice and treated with ETC-159, paclitaxel, and gemcitabine as single agents and in combination. The combination of ETC-159 and paclitaxel demonstrated an anti-tumor effect greater than ETC-159 alone. Extent of combinatory treatment effect were observed to a lesser extent in the Panc320 xenograft. Wnt (in)dependent gene signatures of Panc269 and 320 were consistent with the phenotypes displayed. Gene expression of several key Wnt genes assessed via RT-PCR demonstrated notable fold change following treatment in vivo. Each pancreatic organoid demonstrated varied niche factor dependencies, providing an avenue for targeted therapy, supported through growth analysis following combinatory treatment of Wnt inhibitor and standard chemotherapy in vitro. The clinical utilization of this combinatory treatment modality in pancreatic cancer PDOs has thus far been supported in our patient-derived xenograft models treated with Wnt inhibitor plus paclitaxel or gemcitabine. Gene expression analysis suggests there are key Wnt genes that contribute to the Wnt (in)dependent phenotypes of pancreatic tumors, providing plausible mechanistic explanation for Wnt (in)dependency and susceptibility or resistance to treatment on the genotypic level., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hawkins et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: With Alzheimer's disease and related dementias (ADRD) representing an enormous public health challenge, there is a need to support individuals in learning about and addressing their modifiable risk factors (e.g., diet, sleep, and physical activity) to prevent or delay dementia onset. However, there is limited availability for evidence-informed tools that deliver both quality education and support for positive behavior change such as by increasing self-efficacy and personalizing goal setting. Tools that address the needs of Latino/a, at higher risk for ADRD, are even more scarce., Methods: We established a multidisciplinary team to develop the Healthy Actions and Lifestyles to Avoid Dementia or Hispanos y el ALTo a la Demencia (HALT-AD) program, a bilingual online personalized platform to educate and motivate participants to modify their risk factors for dementia. Grounded in social cognitive theory and following a cultural adaptation framework with guidance from a community advisory board, we developed HALT-AD iteratively through several cycles of rapid prototype development, user-centered evaluation through pilot testing and community feedback, and refinement., Results: Using this iterative approach allowed for more than 100 improvements in the content, features, and design of HALT-AD to improve the program's usability and alignment with the interests and educational/behavior change support needs of its target audience. Illustrative examples of how pilot data and community feedback informed improvements are provided., Discussion: Developing HALT-AD iteratively required learning through trial and error and flexibility in workflows, contrary to traditional program development methods that rely on rigid, pre-set requirements. In addition to efficacy trials, studies are needed to identify mechanisms for effective behavior change, which might be culturally specific. Flexible and personalized educational offerings are likely to be important in modifying risk trajectories in ADRD., Competing Interests: Derek Lomas is Chief Executive Officer of Playpower Labs Inc. Howard Feldman reports grant funding from Annovis (QR Pharma), Vivoryon (Probiodrug), Biohaven Pharmaceuticals, AC Immune, and LuMind; service agreements for consulting activities with LuMind, Genentech (DSMB), Roche/Banner (DMC), Tau Consortium (SAB), Biosplice Therapeutics, Axon Neuroscience, Janssen Research & Development LLC, and Arrowhead Pharmaceuticals and a philanthropic donation for the Epstein Family Alzheimer's Research Collaboration with no personal funds received and all payments to UCSD. Sarah Banks is a member of the Alzheimer's & Dementia: Translational Research & Clinical Intervention (TRCI) editorial board. All other co‐authors have no conflicts of interest to declare. Author disclosures are available in the supporting information., (© 2024 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Little is known about the impact of environmental exposure change on metabolic biomarkers associated with cancer risk. Furthermore, this limited epidemiological evidence on metabolic biomarkers focused on residential exposure, without considering the activity space which can be done by modelling dynamic exposures. In this longitudinal study, we aimed to investigate the impact of environmental exposures change on metabolic biomarkers using GPS-GIS based measurements., Methods: Among two weight loss interventions, the Reach for Health and the MENU studies, which included ∼460 women at risk of breast cancer or breast cancer survivors residing in Southern California, three metabolic biomarkers (insulin resistance, fasting glucose, and C-reactive protein) were assessed. Dynamic GPS-GIS based exposure to green spaces, recreation, walkability, NO 2 , and PM2.5 were calculated at baseline and 6 months follow-up using time-weighted spatial averaging. Generalized estimating equations models were used to examine the relationship between changes in environmental exposures and biomarker levels over time., Results: Overall, six-month environmental exposure change was not associated with metabolic biomarkers change. Stratified analyses by level of environmental exposures at baseline revealed that reduced NO2 and PM2.5 exposure was associated with reduced fasting glucose concentration among women living in a healthier environment at baseline (β -0.010, 95%CI -0.025, 0.005; β -0.019, 95%CI -0.034, -0.003, respectively). Women living in poor environmental conditions at baseline and exposed to greener environments had decreased C-reactive protein concentrations (β -1.001, 95%CI -1.888, -0.131)., Conclusions: The impact of environmental exposure changes on metabolic biomarkers over time may be modified by baseline exposure conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Colorectal cancer is one of the most common malignancies worldwide. Approximately half of the patients diagnosed will develop colorectal liver metastases (CRLM). Liver resection has a 50% 5-year survival; however, only a fourth of cases are resectable. Unresectable CRLM has poor prognosis despite improved systemic and local ablative treatments. Liver transplantation (LT) has demonstrated a survival benefit in initial prospective clinical trials. Current use of LT for CRLM is limited to several randomized trials and high-performing centers. Improving patient selection criteria and perioperative management, LT will likely become an important part of the multidisciplinary approach to managing the metastatic disease., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Cancer related cognitive decline is a common long-term side effect of cancer and its treatments among breast cancer survivors. Physical activity is a modifiable risk factor related to cognitive decline. However, existing research lacks consensus regarding the relationship between cognition and exercise as well as the impact of cancer treatments on this relationship. Baseline data from an ongoing randomized clinical trial was utilized to examine the relationship between self-reported and objectively measured cognition with physical activity. Exploratory analyses examined cancer treatments as potential moderators., Methods: Breast cancer survivors ( N = 253) completed a battery of neurocognitive tests, the PROMIS Cognitive abilities questionnaire, medical charts abstracted for treatment information, and wore an ActiGraph accelerometer at the waist for 7 days. Data were analyzed using multiple linear regression models., Results: Participants were on average 58.5 (SD = 8.88) years old, diagnosed 3 years prior to enrollment (SD = 1.27) with 57% treated with chemotherapy and 80% receiving hormone therapy at baseline. Better self-reported cognitive ability was significantly associated with greater min of moderate to vigorous physical activity (MVPA; β = 0.070, se = 0.028, p = 0.012). There were no significant associations with any objectively measured cognitive domains. Time since diagnosis (years) was a significant moderator of MVPA and Processing Speed (β = -0.103, se = 0.043, p = 0.017). Treatment with chemotherapy and/or hormones did not significantly moderate the relationship between MVPA and any of the cognitive measures or domains., Conclusion: Findings suggest that physical activity is related to self-reported cognition but not objectively measured cognition. Greater physical activity was associated with faster processing speed in participants closer in time to their cancer diagnosis. These results emphasize the need for more research to understand when cancer survivors may benefit from physical activity and what aspects of cognition may be improved., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Sedentary behavior among breast cancer survivors is associated with increased risk of poor physical function and worse quality of life. While moderate to vigorous physical activity can improve outcomes for cancer survivors, many are unable to engage in that intensity of physical activity. Decreasing sitting time may be a more feasible behavioral target to potentially mitigate the impact of cancer and its treatments., Objective: The purpose of this study was to investigate the feasibility and preliminary impact of an intervention to reduce sitting time on changes to physical function and quality of life in breast cancer survivors, from baseline to a 3-month follow-up., Methods: Female breast cancer survivors with self-reported difficulties with physical function received one-on-one, in-person personalized health coaching sessions aimed at reducing sitting time. At baseline and follow-up, participants wore the activPAL (thigh-worn accelerometer; PAL Technologies) for 3 months and completed physical function tests (4-Meter Walk Test, Timed Up and Go, and 30-Second Chair Stand) and Patient-Reported Outcomes Measurement Information System (PROMIS) self-reported outcomes. Changes in physical function and sedentary behavior outcomes were assessed by linear mixed models., Results: On average, participants (n=20) were aged 64.5 (SD 9.4) years; had a BMI of 30.4 (SD 4.5) kg/m 2 ; and identified as Black or African American (n=3, 15%), Hispanic or Latina (n=4, 20%), and non-Hispanic White (n=14, 55%). Average time since diagnosis was 5.8 (SD 2.2) years with participants receiving chemotherapy (n=8, 40%), radiotherapy (n=18, 90%), or endocrine therapy (n=17, 85%). The intervention led to significant reductions in sitting time: activPAL average daily sitting time decreased from 645.7 (SD 72.4) to 532.7 (SD 142.1; β=-112.9; P=.001) minutes and average daily long sitting bouts (bout length ≥20 min) decreased from 468.3 (SD 94.9) to 366.9 (SD 150.4; β=-101.4; P=.002) minutes. All physical function tests had significant improvements: on average, 4-Meter Walk Test performance decreased from 4.23 (SD 0.95) to 3.61 (SD 2.53; β=-.63; P=.002) seconds, Timed Up and Go performance decreased from 10.30 (SD 3.32) to 8.84 (SD 1.58; β=-1.46; P=.003) seconds, and 30-Second Chair Stand performance increased from 9.75 (SD 2.81) to 13.20 completions (SD 2.53; β=3.45; P<.001). PROMIS self-reported physical function score improved from 44.59 (SD 4.40) to 47.12 (SD 5.68; β=2.53; P=.05) and average fatigue decreased from 52.51 (SD 10.38) to 47.73 (SD 8.43; β=-4.78; P=.02)., Conclusions: This 3-month pilot study suggests that decreasing time spent sitting may be helpful for breast cancer survivors experiencing difficulties with physical function and fatigue. Reducing sitting time is a novel and potentially more feasible approach to improving health and quality of life in cancer survivors., (©Rowena M Tam, Rong W Zablocki, Chenyu Liu, Hari K Narayan, Loki Natarajan, Andrea Z LaCroix, Lindsay Dillon, Eleanna Sakoulas, Sheri J Hartman. Originally published in JMIR Cancer (https://cancer.jmir.org), 19.12.2023.)

Physical activity (PA) is significantly associated with many health outcomes. The wide usage of wearable accelerometer-based activity trackers in recent years has provided a unique opportunity for in-depth research on PA and its relations with health outcomes and interventions. Past analysis of activity tracker data relies heavily on aggregating minute-level PA records into day-level summary statistics in which important information of PA temporal/diurnal patterns is lost. In this paper we propose a novel functional data analysis approach based on Riemann manifolds for modeling PA and its longitudinal changes. We model smoothed minute-level PA of a day as one-dimensional Riemann manifolds and longitudinal changes in PA in different visits as deformations between manifolds. The variability in changes of PA among a cohort of subjects is characterized via variability in the deformation. Functional principal component analysis is further adopted to model the deformations, and PC scores are used as a proxy in modeling the relation between changes in PA and health outcomes and/or interventions. We conduct comprehensive analyses on data from two clinical trials: Reach for Health (RfH) and Metabolism, Exercise and Nutrition at UCSD (MENU), focusing on the effect of interventions on longitudinal changes in PA patterns and how different modes of changes in PA influence weight loss, respectively. The proposed approach reveals unique modes of changes, including overall enhanced PA, boosted morning PA, and shifts of active hours specific to each study cohort. The results bring new insights into the study of longitudinal changes in PA and health and have the potential to facilitate designing of effective health interventions and guidelines.

Purpose: Pregnancy intentions are associated with preconception health behaviors but are understudied among female adolescent and young adult (AYA) cancer survivors. Preconception health is critical for survivors because they face unique risks to fertility and pregnancy from late effects of cancer treatments. This study prospectively assessed the effect of pregnancy intention on physical activity (PA) and smoking behaviors among female AYA survivors., Methods: A cohort of 1049 female AYA survivors were recruited between 2013 and 2017. Participants were 18-39 years and had completed primary cancer treatment. Longitudinal mixed effects analysis was conducted on participants who completed at least 2 of 4 questionnaires over 1.5 years. Two measures were used to capture multiple dimensions of pregnancy intention. The pregnancy intention score (PIS) captured wanting and planning dimensions and represented a scaled response of low to high intention. The trying dimension captured urgent intention and ranged from not trying, ambivalent (neither attempting nor avoiding pregnancy), and trying now. Intention change was assessed between each consecutive time points. Final analysis was conducted with multiple imputations., Results: Survivors with increased intention measured by trying was associated with increased PA over time (adjusted B [95%CI]: 0.3 [0.01, 0.5]) compared to survivors with no changes or decreased trying intention. PIS was not significantly associated with preconception behaviors. No measure of intention was associated with smoking behavior., Conclusions: Increasingly urgent pregnancy intention (trying dimension) was associated with higher preconception PA., Implications for Cancer Survivors: Screening for immediate intentions can identify AYA survivors in need of early preconception health promotion., (© 2022. The Author(s).)

Importance: Fertility is important to many survivors of adolescent and young adult (AYA) cancer, yet data on this population's fertility perceptions and their alignment with objective infertility risk are scant., Objective: To assess whether estimated treatment gonadotoxicity and posttreatment menstrual pattern are associated with higher infertility risk perception., Design, Setting, and Participants: This retrospective cohort study included female young adult survivors of cancer diagnosed between ages 15 and 39 years were recruited between March 25, 2015, and September 24, 2018, from 2 state cancer registries, social media, and clinician referrals to participate in a study of posttreatment ovarian function. Data analysis occurred between March 1 and September 1, 2022., Exposures: Participants reported their menstrual pattern. Estimated treatment gonadotoxicity was ascertained through medical record review., Main Outcomes and Measures: Participants reported infertility risk perception and were categorized as increased risk (feeling less fertile or unable to become pregnant) or no increased risk (feeling more or as fertile) compared with female individuals their age. Objective infertility risk was determined by estimated gonadotoxicity, menstrual pattern, and ovarian reserve testing of self-collected dried blood spots. Multivariable logistic regression identified factors associated with perceived infertility and underestimation or overestimation of infertility risk., Results: This study included 785 female participants with a mean (SD) age of 33.2 (4.8) years at enrollment and 25.9 (5.7) years at diagnosis. Most participants self-identified their race and ethnicity as White (585 [74.5%]) and non-Hispanic (628 [78.7%]). Most participants (483 [61.5%]) perceived a higher risk of infertility compared with female participants their age. Prior exposure to moderate- or high-gonadotoxicity treatments was associated with higher odds of perceiving increased infertility risk compared with exposure to low-gonadotoxicity treatments (adjusted odds ratio [AOR], 2.73 [95% CI, 1.87-3.97] and 15.39 [95% CI, 5.52-42.96], respectively). Amenorrhea and irregular cycles were associated with higher odds of perceiving increased infertility risk (AOR, 3.98 [95% CI, 2.13-7.41] and 1.69 [95% CI, 1.19-2.40], respectively). Perceived infertility risk had minimal agreement with objective risk (κ = 0.19). Multiparity (AOR, 4.17 [95% CI, 2.61-6.64]) was associated with increased odds of underestimation, while older age (AOR, 0.94 [95% CI, 0.89-0.98]), endocrine comorbidity (AOR, 0.35 [95% CI, 0.18-0.69]), and prior infertility (AOR, 0.16 [95% CI, 0.07-0.38]) were associated with lower odds of underestimation. Multiparity (AOR, 0.48 [95% CI, 0.27-0.86]), breast cancer (AOR, 0.38 [95% CI, 0.20-0.73]), and skin cancer (AOR, 0.24 [95% CI, 0.11-0.51]) were associated with lower odds of overestimation., Conclusions and Relevance: In this cohort study, survivors of AYA cancer had high rates of perceiving increased infertility risk but frequently overestimated or underestimated their risk. These findings suggest that counseling on infertility risk throughout survivorship may reduce misalignment between perceptions and actual risk, decrease fertility-related psychological distress, and inform family planning decisions.

Latinas report low levels of physical activity (PA) and disproportionate risk of lifestyle-related diseases. Enhancements to evidence-based PA interventions may increase efficacy; however, uptake of interventions will likely depend on costs. To describe costs and examine the cost-effectiveness of two interventions for helping Latinas reach national aerobic PA guidelines. Adult Latinas (N = 199) were randomly assigned to an Original theory-based mail-delivered intervention or an Enhanced version with texting and additional calls and materials. Meeting PA guidelines was measured by the 7-Day PA Recall interview at baseline, 6 and 12 months. Intervention costs were estimated from a payer perspective. Incremental cost-effectiveness ratios (ICERs) were calculated as the additional cost per participant meeting guidelines in the Enhanced versus Original intervention. At baseline, no participants met guidelines. After 6 months, 57% and 44% in the Enhanced and Original arms met guidelines, respectively; at 12 months, rates fell to 46% and 36%. Cost per person of the Enhanced and Original interventions were $184 and $173 at 6 months, respectively, and $234 and $203 at 12 months. The primary additional expense in the Enhanced arm was staff time. ICERs were $87 per additional person meeting guidelines at 6 months (per sensitivity analysis, $26 if delivered by volunteers and $114 by medical assistants), and $317 at 12 months (sensitivity analysis: $57 and $434). Incremental costs per person meeting guidelines in the Enhanced arm were modest and could be warranted given the potential health benefits of meeting PA guidelines., (© Society of Behavioral Medicine 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Biliary atresia (BA) is a life-threatening cholangiopathy occurring in infancy, the most common indication for pediatric liver transplantation. The etiology of BA remains unknown; however, a viral etiology has been proposed as multiple viruses have been detected in explants of infants afflicted with BA. In the murine model of BA, Rhesus rotavirus (RRV) infection of newborn BALB/c pups results in a cholangiopathy that mirrors human BA. Infected BALB/c pups experience 100% symptomatology and mortality, while C57BL/6 mice are asymptomatic. Interferon-λ (IFN-λ) is an epithelial cytokine that provides protection against viral infection. We demonstrated that IFN-λ is highly expressed in C57BL/6, leading to reduced RRV replication. RRV-infection of C57BL/6 IFN-λ receptor knockout (C57BL/6 IFN-λR KO) pups resulted in 90% developing obstructive symptoms and 45% mortality with a higher viral titer in bile ducts and profound periportal inflammation compared to C57BL/6. Histology revealed complete biliary obstruction in symptomatic C57BL/6 IFN-λR KO pups, while C57BL/6 ducts were patent. These findings suggest that IFN-λ is critical in preventing RRV replication. Deficiency in IFN-λ permits RRV infection, which triggers the inflammatory cascade causing biliary obstruction. Further IFN-λ study is warranted as it may play an important role in infant susceptibility to BA.

Colorectal cancer with liver metastases is a condition with significant morbidity and mortality that affects many people around the world. Many treatments exist to target liver metastases, including surgical resection, chemotherapy, nonsurgical liver-directed therapies, and liver transplantation. The field of transplant oncology is emerging as a promising alternative to palliative chemotherapy alone in appropriately selected patients. Though few clinical trials have been completed to evaluate safety of liver transplant for colorectal cancer metastases, there are several ongoing trials to hopefully make transplant a viable option for more patients with limited options., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Younger breast cancer survivors (YBCS) consistently report poorer quality of life (QOL) than older survivors. Increasing physical activity (PA) may improve QOL, but this has been understudied in YBCS. This single arm pilot study evaluated the feasibility and acceptability of a 3-month, peer-delivered, remote intervention to increase PA and improve QOL in YBCS. Data were collected from October 2019 - July 2020. Participants (n = 34, 43.1 ± 5.5 years old, 46 ± 34.4 months post-diagnosis, BMI = 30.2 ± 7.4 kg/m 2 ) completed six video sessions with a trained peer mentor; self-monitored PA with a Fitbit activity tracker; and interacted with a private Fitbit Community for social support. At baseline, 3-and 6-months, participants completed QOL questionnaires and PA was measured through accelerometer (moderate-to-vigorous PA [MVPA]) and self-report (strength and flexibility). A parallel mixed-methods approach (qualitative interviews and quantitative satisfaction survey at 3-months) explored intervention feasibility and acceptability. One-way repeated-measures ANOVAs examined impacts on PA and QOL at 3-and 6-months. The intervention was feasible as evidenced by efficient recruitment, high retention, and adherence to intervention components. Remote delivery, working with a peer mentor, and using Fitbit tools were highly acceptable. From baseline to 3-months, participants increased time spent in objectively measured MVPA, strength, and flexibility exercises, and reported meaningful improvements to body image, fatigue, anxiety, and emotional support. A fully remote, peer-to-peer intervention is an acceptable and promising strategy to increase PA and improve QOL in YBCS. Refinements to the intervention and its delivery should be further assessed in future studies, toward the goal of disseminating an evidence-based, scalable intervention to the growing number of YBCS.Trial registration Prospectively registered as NCT04064892., (© 2022. The Author(s).)

Colorectal cancer with unresectable liver metastases has significant mortality when treated with chemotherapy alone. In appropriately selected patients, liver transplant is emerging as a treatment alternative for this population. Some key clinical trials, including SECA-I and SECA-II, have shown promising survival results: more trials are being conducted to evaluate safety of this practice., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Glypican-3 (GPC3) is a cell-surface glycoprotein that is frequently overexpressed in hepatocellular carcinoma (HCC). GPC3 undergoes extensive posttranslational modification (PTM) including cleavage and glycosylation. This review focuses on the structure and function of GPC3 in liver cancer, highlighting the PTM of the tertiary and quaternary structures of GPC3 as a potential oncogenic regulatory mechanism. We propose that the function of GPC3 in normal development can vary with extensive PTM and that dysregulation of these processes leads to disease. Defining the regulatory impact of these modifications can provide a deeper understanding of the role of GPC3 in oncogenesis, epithelial-mesenchymal transition, and drug development. Through review of current literature, this article provides a unique perspective on the role of GPC3 in liver cancer, focusing on potential regulatory mechanisms of PTM on GPC3 function at the molecular, cellular, and disease level., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Extensive research suggests that physical activity (PA) is important for brain and cognitive health and may help to delay or prevent Alzheimer's disease and related dementias. Most PA interventions designed to improve brain health in older adults have been conducted in laboratory, gym, or group settings that require extensive resources and travel to the study site or group sessions. Research is needed to develop novel interventions that leverage mobile health (mHealth) technologies to help older adults increase their engagement in PA in free-living environments, reducing participant burden and increasing generalizability of research findings. Moreover, promoting engagement in moderate-to-vigorous PA (MVPA) may be most beneficial to brain health; thus, using mHealth to help older adults increase time spent in MVPA in free-living environments may help to offset the burden of Alzheimer's disease and related dementias and improve quality of life in older age., Objective: We developed a novel PA intervention that leverages mHealth to help older adults achieve more minutes of MVPA independently. This pilot study was a 12-week randomized controlled trial to investigate the feasibility of providing just-in-time (JIT) feedback about PA intensity during free-living exercise sessions to help older adults meet current PA recommendations (150 minutes per week of MVPA)., Methods: Participants were eligible if they were cognitively healthy English speakers aged between 65 and 80 years without major cardiovascular, neurologic, or mental health conditions; could ambulate independently; and undergo magnetic resonance imaging. Enrollment occurred from October 2017 to March 2020. Participants randomized to the PA condition received an individualized exercise prescription and an mHealth device that provided heart rate-based JIT feedback on PA intensity, allowing them to adjust their behavior in real time to maintain MVPA during exercise sessions. Participants assigned to the healthy aging education condition received a reading prescription consisting of healthy aging topics and completed weekly quizzes based on the materials., Results: In total, 44 participants were randomized to the intervention. A follow-up manuscript will describe the results of the intervention as well as discuss screening, recruitment, adverse events, and participants' opinions regarding their participation in the intervention., Conclusions: The long-term goal of this intervention is to better understand how MVPA affects brain and cognitive health in the real world and extend laboratory findings to everyday life. This pilot randomized controlled trial was conducted to determine the feasibility of using JIT heart rate zone feedback to help older adults independently increase time spent in MVPA while collecting data on the plausible mechanisms of change (frontal and medial temporal cerebral blood flow and cardiorespiratory fitness) that may affect cognition (memory and executive function) to help refine a planned stage 2 behavioral trial., Trial Registration: ClinicalTrials.gov NCT03058146; https://clinicaltrials.gov/ct2/show/NCT03058146., International Registered Report Identifier (irrid): DERR1-10.2196/42980., (©Chelsea C Hays Weeks, Alison A Moore, Matthew Allison, Kevin Patrick, Mark W Bondi, Camille Nebeker, Thomas T Liu, David Wing, Michael Higgins, Sheri J Hartman, Robert A Rissman, Zvinka Z Zlatar. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 13.02.2023.)

Background: Obesity is a major health concern for breast cancer survivors, being associated with high recurrence and reduced efficacy during cancer treatment. Metformin treatment is associated with reduced breast cancer incidence, recurrence and mortality. To better understand the underlying mechanisms through which metformin may reduce recurrence, we aimed to conduct metabolic profiling of overweight/obese breast cancer survivors before and after metformin treatment., Methods: Fasting plasma samples from 373 overweight or obese breast cancer survivors randomly assigned to metformin (n = 194) or placebo (n = 179) administration were collected at baseline, after 6 months (Reach For Health trial), and after 12 months (MetBreCS trial). Archival samples were concurrently analyzed using three complementary methods: untargeted LC-QTOF-MS metabolomics, targeted LC-MS metabolomics (AbsoluteIDQ p180, Biocrates), and gas chromatography phospholipid fatty acid assay. Multivariable linear regression models and family-wise error correction were used to identify metabolites that significantly changed after metformin treatment., Results: Participants (n = 352) with both baseline and study end point samples available were included in the analysis. After adjusting for confounders such as study center, age, body mass index and false discovery rate, we found that metformin treatment was significantly associated with decreased levels of citrulline, arginine, tyrosine, caffeine, paraxanthine, and theophylline, and increased levels of leucine, isoleucine, proline, 3-methyl-2-oxovalerate, 4-methyl-2-oxovalerate, alanine and indoxyl-sulphate. Long-chain unsaturated phosphatidylcholines (PC ae C36:4, PC ae C38:5, PC ae C36:5 and PC ae C38:6) were significantly decreased with the metformin treatment, as were phospholipid-derived long-chain n-6 fatty acids. The metabolomic profiles of metformin treatment suggest change in specific biochemical pathways known to impair cancer cell growth including activation of CYP1A2, alterations in fatty acid desaturase activity, and altered metabolism of specific amino acids, including impaired branched chain amino acid catabolism., Conclusions: Our results in overweight breast cancer survivors identify new metabolic effects of metformin treatment that may mechanistically contribute to reduced risk of recurrence in this population and reduced obesity-related cancer risk reported in observational studies., Trial Registration: ClinicalTrials.gov identifier: NCT01302379 and EudraCT Protocol #: 2015-001001-14., (© 2022. The Author(s).)

Immune checkpoint inhibitors have been found to be effective in metastatic MSI-high colorectal cancers (CRC), however, have no efficacy in microsatellite stable (MSS) cancers, which comprise the majority of mCRC cases. Cabozantinib is a small molecule multi-tyrosine kinase inhibitor that is FDA approved in advanced renal cell, medullary thyroid, and hepatocellular carcinoma. Using Human Immune System (HIS) mice, we tested the ability of cabozantinib to prime MSS-CRC tumors to enhance the potency of immune checkpoint inhibitor nivolumab. In four independent experiments, we implanted distinct MSS-CRC patient-derived xenografts (PDXs) into the flanks of humanized BALB/c-Rag2 null Il2rγ null Sirpα NOD (BRGS) mice that had been engrafted with human hematopoietic stem cells at birth. For each PDX, HIS-mice cohorts were treated with vehicle, nivolumab, cabozantinib, or the combination. In three out of the four models, the combination had a lower tumor growth rate compared to vehicle or nivolumab-treated groups. Furthermore, interrogation of the HIS in immune organs and tumors by flow cytometry revealed increased Granzyme B+, TNFα+ and IFNγ+ CD4+ T cells among the human tumor infiltrating leukocytes (TIL) that correlated with reduced tumor growth in the combination-treated HIS-mice. Notably, slower growth correlated with increased expression of the CD4+ T cell ligand, HLA-DR, on the tumor cells themselves. Finally, the cabozantinib/nivolumab combination was tested in comparison to cobimetinib/atezolizumab. Although both combinations showed tumor growth inhibition, cabozantinib/nivolumab had enhanced cytotoxic IFNγ and TNFα+ T cells. This pre-clinical in vivo data warrants testing the combination in clinical trials for patients with MSS-CRC., Competing Interests: Exelixis supplied cabozantinib and funded this study, with TP as Principal Investigator, but had no role in study design, data collection, data analysis, data interpretation, or writing of the report. WM is the principal investigator of a phase II clinical trial of cabozantinib in patients with refractory metastatic colorectal cancer that is sponsored by Exelixis NCT03542877. AL is the principal investigator of a phase II clinical trial of cabozantinib in combination with nivolumab in metastatic colorectal cancer which is co-sponsored by Bristol Myers Squibb and Exelixis NCT04963283. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lang, Leal, Marín-Jiménez, Hartman, Shulman, Navarro, Lewis, Capasso, Bagby, Yacob, MacBeth, Freed, Eckhardt, Jordan, Blatchford, Pelanda, Lieu, Messersmith and Pitts.)

Background: AZD0156 is an oral inhibitor of ATM, a serine threonine kinase that plays a key role in DNA damage response (DDR) associated with double-strand breaks. Topoisomerase-I inhibitor irinotecan is used clinically to treat colorectal cancer (CRC), often in combination with 5-fluorouracil (5FU). AZD0156 in combination with irinotecan and 5FU was evaluated in preclinical models of CRC to determine whether low doses of AZD0156 enhance the cytotoxicity of irinotecan in chemotherapy regimens used in the clinic., Methods: Anti-proliferative effects of single-agent AZD0156, the active metabolite of irinotecan (SN38), and combination therapy were evaluated in 12 CRC cell lines. Additional assessment with clonogenic assay, cell cycle analysis, and immunoblotting were performed in 4 selected cell lines. Four colorectal cancer patient derived xenograft (PDX) models were treated with AZD0156, irinotecan, or 5FU alone and in combination for assessment of tumor growth inhibition (TGI). Immunofluorescence was performed on tumor tissues. The DDR mutation profile was compared across in vitro and in vivo models., Results: Enhanced effects on cellular proliferation and regrowth were observed with the combination of AZD0156 and SN38 in select models. In cell cycle analysis of these models, increased G2/M arrest was observed with combination treatment over either single agent. Immunoblotting results suggest an increase in DDR associated with irinotecan therapy, with a reduced effect noted when combined with AZD0156, which is more pronounced in some models. Increased TGI was observed with the combination of AZD0156 and irinotecan as compared to single-agent therapy in some PDX models. The DDR mutation profile was variable across models., Conclusions: AZD0156 and irinotecan provide a rational and active combination in preclinical colorectal cancer models. Variability across in vivo and in vitro results may be related to the variable DDR mutation profiles of the models evaluated. Further understanding of the implications of individual DDR mutation profiles may help better identify patients more likely to benefit from treatment with the combination of AZD0156 and irinotecan in the clinical setting., (© 2022. The Author(s).)

Background: Latinas are at increased risk for many lifestyle-related chronic diseases and are one of the least physically active populations in the US Innovative strategies are needed to help Latinas achieve the health benefits associated with physical activity (PA). This manuscript describes the study protocol of the Pasos Hacia La Salud II Study, which builds upon our previous research to test an enhanced individually-tailored, text-message and website-delivered, Spanish-language intervention (enhanced intervention), in comparison to the original web-based Pasos Hacia La Salud Intervention (original intervention)., Methods: Sedentary Latinas between the ages of 18-65 will be recruited and will complete an orientation and baseline assessments. Participants will be subsequently randomized to the original intervention, or the Enhanced Intervention, which has greater targeting of theoretical constructs such as self-efficacy, enjoyment, and social support, and which uses text messages and more dynamic and refined website features to encourage increased website use. Using a linear mixed effects regression model, we will simultaneously estimate the intervention effects on mean accelerometer-measured hours/week of moderate-to-vigorous PA (MVPA) at 6, 12, 18, and 24 months, with a subject-specific intercept (intent-to-treat sample). Change in self-reported MVPA, measured via the 7-day Physical Activity Recall, will be assessed as a secondary outcome using a similar model. We will investigate potential mediators of the intervention effect using a multiple mediation approach, and potential moderators by evaluating potential interactions. As an exploratory outcome, we will study the differences (among both study arms) in cost, in US dollars, per minute increases in weekly mean MVPA., Discussion: The original Pasos PA intervention showed efficacy in helping Latinas increase PA; we expect the Enhanced Intervention to help a larger proportion of participants to increase and maintain their PA long term. This web- and text-based enhanced intervention could have great reach and dissemination potential, which could be capitalized on in the future to help to advance health equity. Adaptations made in response to the COVID-19 pandemic are also described in this manuscript., Trial Registration: Clinical Trial Number: NCT03491592 . First posted April 9, 2018., (© 2022. The Author(s).)

Background: Ceramides are bioactive lipid species that mediate numerous cell-signaling events. Elevated plasma ceramides concentration constitutes a risk factor for several pathologies. Multiple studies have affirmed the plasma concentrations of 4 specific ceramides (Cer16:0, Cer18:0, Cer24:0, and Cer24:1) can predict cardiovascular disease risk. Furthermore, these ceramides can be altered by many lipid-lowering therapies. Understanding the biological variability within an individual, and within a population, will further inform the clinical use of plasma ceramides as a biomarker. In this study, we aimed to define the intra- and interbiological variability of ceramides in a healthy reference population in a weekly and monthly manner., Methods: Fasting plasma from 24 healthy adults was collected daily (5 days), weekly (4 weeks), and monthly (7 months). Ceramide concentrations were measured with liquid chromatography-mass spectrometry (LC-MS). For analysis, we used random-effects regression models to estimate variance components., Results: The analytical variability was smaller compared to the biological variability overall. The greatest variation reported was between-subject variation for all ceramide species. The critical difference-reference change value (RCV) for within-subject variations monthly were 0.07 mcmol/L (Cer16:0), 0.04 mcmol/L (Cer18:0), 1.09 mcmol/L (Cer24:0), and 0.27 mcmol/L (Cer24:1). The index of individuality (IOI) of ceramides were 0.82 (Cer16:0), 0.96 (Cer18:0), 1.06 (Cer24:0), and 0.89 (Cer24:1). The most consistent ceramide species was Cer18:0 with the lowest within- and between-subject critical differences in weekly and monthly measurements., Conclusions: Overall, this study demonstrates that the variability of ceramide concentrations at different time points is minimal within individuals, allowing a single draw to be sufficient at least in a yearly time frame., (© American Association for Clinical Chemistry 2022. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: There has been a rapid increase in the use of commercially available activity trackers, such as Fitbit, in physical activity intervention research. However, little is known about the long-term sustained use of trackers and behavior change after short-term interventions., Objective: This study aims to use minute-level data collected from a Fitbit tracker for up to 2 years after the end of a randomized controlled trial to examine patterns of Fitbit use and activity over time., Methods: Participants in this secondary data analysis were 75 female breast cancer survivors who had been enrolled in a 12-week physical activity randomized controlled trial. Participants randomized to the exercise intervention (full intervention arm) received a Fitbit One, which was worn daily throughout the 12-week intervention, and then were followed for 2 years after the intervention. Participants randomized to the waitlist arm, after completing the randomized controlled trial, received a Fitbit One and a minimal version of the exercise intervention (light intervention arm), and then were followed for 2 years after the intervention. Average and daily adherence and MVPA were compared between the 2 groups in the interventional and postinterventional periods using both linear and generalized additive mixed effects models., Results: Adherence to wearing the Fitbit during the 12-week intervention period was significantly higher in the full intervention arm than in the light intervention arm (85% vs 60%; P<.001). Average adherence was significantly lower for both study arms during the follow-up period than in the intervention period; however, there were statistically different patterns of adherence during the follow-up period, with the light intervention arm having steeper declines than the full intervention arm over time (P<.001). Similar to the adherence results, mean minutes of Fitbit-measured MVPA was higher for the full intervention arm than for the light intervention arm during the 12-week intervention period (mean MVPA 27.89 minutes/day, SD 16.38 minutes/day vs 18.35 minutes/day, SD 12.64 minutes/day; P<.001). During the follow-up period, average MVPA was significantly lower than the 12-week intervention period for both the full intervention arm (21.74 minutes/day, SD 24.65 minutes/day; P=.002) and the light intervention arm (15.03 minutes/day, SD 13.27 minutes/day; P=.004). Although the mean MVPA in each arm was similar across the follow-up period (P=.33), the pattern of daily MVPA was significantly different between the 2 groups (P<.001)., Conclusions: While adherence to wearing activity trackers and maintaining physical activities declined after completion of a 12-week exercise intervention, a more active interventional strategy resulted in greater wear time and activity levels during the intervention and more stable patterns of adherence and activity in the long term. An improved understanding of long-term maintenance patterns may inform improved exercise interventions that result in sustained increases in physical activity., Trial Registration: ClinicalTrials.gov NCT02332876; https://clinicaltrials.gov/ct2/show/NCT02332876., (©Sheri J Hartman, Ruohui Chen, Rowena M Tam, Hari K Narayan, Loki Natarajan, Lin Liu. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 30.06.2022.)

The overall 5-year relative survival rate for all cancers combined is now 68%, and there are over 16.9 million survivors in the United States. Evidence from laboratory and observational studies suggests that factors such as diet, physical activity, and obesity may affect risk for recurrence and overall survival after a cancer diagnosis. The purpose of this American Cancer Society guideline is to provide evidence-based, cancer-specific recommendations for anthropometric parameters, physical activity, diet, and alcohol intake for reducing recurrence and cancer-specific and overall mortality. The audiences for this guideline are health care providers caring for cancer survivors as well as cancer survivors and their families. The guideline is intended to serve as a resource for informing American Cancer Society programs, health policy, and the media. Sources of evidence that form the basis of this guideline are systematic literature reviews, meta-analyses, pooled analyses of cohort studies, and large randomized clinical trials published since 2012. Recommendations for nutrition and physical activity during cancer treatment, informed by current practice, large cancer care organizations, and reviews of other expert bodies, are also presented. To provide additional context for the guidelines, the authors also include information on the relationship between health-related behaviors and comorbidities, long-term sequelae and patient-reported outcomes, and health disparities, with attention to enabling survivors' ability to adhere to recommendations. Approaches to meet survivors' needs are addressed as well as clinical care coordination and resources for nutrition and physical activity counseling after a cancer diagnosis., (© 2022 The Authors. CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Histone deacetylases (HDACs) play critical roles in epigenomic regulation, and histone acetylation is dysregulated in many human cancers. Although HDAC inhibitors are active in T-cell lymphomas, poor isoform selectivity, narrow therapeutic indices, and a deficiency of reliable biomarkers may contribute to the lack of efficacy in solid tumors. In this article, we report the discovery and preclinical development of the novel, orally bioavailable, class-I-selective HDAC inhibitor, OKI-179. OKI-179 and its cell active predecessor OKI-005 are thioester prodrugs of the active metabolite OKI-006, a unique congener of the natural product HDAC inhibitor largazole. OKI-006, OKI-005, and subsequently OKI-179, were developed through a lead candidate optimization program designed to enhance physiochemical properties without eroding potency and selectivity relative to largazole. OKI-005 displays antiproliferative activity in vitro with induction of apoptosis and increased histone acetylation, consistent with target engagement. OKI-179 showed antitumor activity in preclinical cancer models with a favorable pharmacokinetic profile and on-target pharmacodynamic effects. Based on its potency, desirable class I HDAC inhibition profile, oral bioavailability, and efficacy against a broad range of solid tumors, OKI-179 is currently being evaluated in a first-in-human phase I clinical trial with plans for continued clinical development in solid tumor and hematologic malignancies., (©2021 American Association for Cancer Research.)

Background: Female adolescent and young adult (AYA) cancer survivors face higher infertility and pregnancy risks than peers with no cancer history. Preconception health behaviors such as physical activity (PA), tobacco smoking, and alcohol intake influence reproductive outcomes. In general populations, pregnancy intention is positively associated with healthy preconception behaviors, but it has not been studied among AYA survivors. The authors hypothesized that higher pregnancy intention would be associated with healthier behaviors, especially among AYA survivors with perceived infertility risk., Methods: A cross-sectional analysis was conducted with data collected between 2013 and 2017 from 1071 female AYA survivors aged 18 to 39 years who had completed their primary cancer treatment and enrolled in an ovarian function study. Self-reported intention dimensions were measured as a pregnancy intention score (PIS) and trying now to become pregnant. Multivariable linear (PA), binary (smoking), and ordinal (alcohol use) logistic regressions were used to estimate associations between intentions and preconception behaviors, with adjustments made for demographic and cancer characteristics. Effect modification by perceived infertility risk was assessed., Results: The mean PIS was 1.1 (SD, 0.77) on a 0 to 2 scale (2 = high intention), and 8.9% were attempting pregnancy now. A higher PIS was associated with increased PA (β, 0.08; 95% CI, 0.11-1.04), whereas ambivalence in pregnancy intention was associated with lower alcohol consumption (odds ratio, 0.72; 95% CI, 0.55-0.95). Pregnancy intentions were not associated with smoking. Perceived infertility risk strengthened the relationship between PIS and PA (P < .05)., Conclusions: Pregnancy intentions were associated with some healthier preconception behaviors in AYA survivors. Medical professionals caring for AYA survivors may consider pregnancy intention screening to guide conversations on preconception health., (© 2021 American Cancer Society.)